Hematologic Malignancies CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *CCO is an independent medical education.

Hematologic Malignancies CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting*
May 29 - June 2, 2015 *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from AstraZeneca, Bayer, Celgene Corporation, Genentech, Incyte, and Novartis.

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Faculty Sagar Lonial, MD Professor and Executive Vice Chair Department of Hematology and Medical Oncology Chief Medical Officer Winship Cancer Institute of Emory University Atlanta, Georgia Farhad Ravandi, MD Professor of Medicine Department of Leukemia University of Texas M. D. Anderson Cancer Center Houston, Texas Jeff P. Sharman, MD Medical Director Hematology Research US Oncology Research Eugene, Oregon Julie M. Vose, MD, MBA Chief, Division of Oncology and Hematology Neumann M. and Mildred E. Harris Professor Department of Internal Medicine University of Nebraska Medical Center Omaha, Nebraska This slide lists the faculty who were involved in the production of these slides.

Faculty Disclosures Sagar Lonial, MD, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Celgene, Janssen, Millennium, Novartis, Onyx, and sanofi-aventis. Farhad Ravandi, MD, has disclosed that he has received consulting fees from Amgen, Pfizer, Seattle Genetics, and Sunesis and has received funds for research from Amgen, Bristol-Myers Squibb, Cellerant, MedImmune, Merck, Seattle Genetics, and Sunesis. Jeff P. Sharman, MD, has disclosed that he has received consulting fees from Celgene, Genentech, Gilead Sciences, Pharmacyclics, Seattle Genetics, and TG Therapeutics and funds for research support from Acerta, Celgene, Genentech, Gilead Sciences, Pharmacyclics, Seattle Genetics, and TG Therapeutics and fees for non-CME services from Gilead. Julie M. Vose, MD, MBA, has disclosed that she has received funds for research from Bristol-Myers Squibb, Celgene, Genentech, GlaxoSmithKline, Incyte, Janssen Biotech, Pharmacyclics, and Spectrum.

Outline Chronic Lymphocytic Leukemia Non-Hodgkin’s Lymphoma
HELIOS: Longer PFS With Addition of Ibrutinib to Bendamustine/Rituximab in Previously Treated CLL/SLL Ibrutinib in CLL: Effect of Dose Adherence and Baseline Exposure on PFS Improved PFS With Addition of Idelalisib to Ofatumumab in Previously Treated CLL Connect CLL Registry Study: Prognostic Testing Patterns in CLL Patients Non-Hodgkin’s Lymphoma GADOLIN: Obinutuzumab + Bendamustine and Maintenance Obinutuzumab in Rituximab-Refractory Indolent NHL CD19 CAR-T Cells Induce Durable Responses in Relapsed/Refractory CD19-Positive Lymphomas Poorer Outcomes With Rituximab + Chemo in Heavier Patients, Older Men With Follicular Lymphoma CR Rate at 30 Mos Is a Feasible Surrogate Endpoint for PFS in First-line Follicular Lymphoma Trials CAR, chimeric antigen receptor; CLL, chronic lymphocytic leukemia; CR, complete response; NHL, non-Hodgkin’s lymphoma; PFS, progression-free survival; SLL, small lymphocytic lymphoma.

Outline Multiple Myeloma
ENDEAVOR: Kd Superior to Vd in Relapsed Multiple Myeloma Phase III ASPIRE: Lenalidomide/Dexamethasone ± Carfilzomib in R/R MM Phase III PANORAMA 1: Bortezomib/Dexamethasone ± Panobinostat in R/R Myeloma ELOQUENT-2: Addition of Elotuzumab to Len/Dex Extends PFS in R/R Myeloma Phase II SIRIUS: Daratumumab Active, Safe in Highly Refractory Multiple Myeloma Phase I/II Study: Panobinostat/Carfilzomib Active in R/R Myeloma Extended Carfilzomib, Lenalidomide, Dexamethasone + ASCT Effective in Newly Diagnosed MM ASCT, autologous stem cell transplantation; Kd, carfilzomib/dexamethasone; Len/Dex, lenalidomide/dexamethasone; MM, multiple myeloma; PFS, progression-free survival; R/R, relapsed/refractory; Vd, bortezomib/dexamethasone.

Outline Acute Leukemia Myelodysplastic Syndrome
Leukemia Stem Cell Phenotypes Correlate With Cytogenetic Risk Factors and Outcomes FLT3/Axl Inhibitor Gilteritinib (ASP2215) Safe and Active in Relapsed/Refractory AML 19-28ζ CAR T Cells Induce High CR Rate in Relapsed/Refractory Adult ALL Myelodysplastic Syndrome PERSIST-1: Pacritinib Improved Spleen Volume Reductions in Myelofibrosis vs Best Available Therapy RESPONSE: Ruxolitinib in polycythemia vera KIR Genes Associated With MDS Risk ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; CAR, chimeric antigen receptor; CR, complete response; MDS, myelodysplastic syndromes.

Please review the slide notes for a discussion of each study by the expert faculty
At the 2015 American Society of Clinical Oncology (ASCO) annual meeting, investigators presented data from studies evaluating prevention and treatment of chronic lymphocytic leukemia (CLL) and non-Hodgkin’s lymphoma (NHL), acute leukemias, myelodysplastic syndromes (MDS), and multiple myeloma. In this slideset, Julie M. Vose, MD, MBA, and I discuss the clinical relevance of key findings in CLL and NHL presented at the meeting. In addition, Sagar Lonial, MD, discusses current multiple myeloma clinical trial findings and Farhad Ravandi, MD, reviews results in acute leukemias and MDS.

Chronic Lymphocytic Leukemia

HELIOS: Study Design Primary endpoint: PFS (independent review)
Stratified by refractory to purine analogue regimen (failure to respond or relapse within 12 mos); 1 vs > 1 prior therapy Ibrutinib 420 mg orally QD (starting Day 2, cycle 1) + BR (n = 289) Treat to PD or unacceptable toxicity Crossover to ibrutinib arm permitted after confirmed progression Pts with previously treated R/R CLL/SLL, ECOG PS 0-1, measurable LN, no del(17p) (N = 578) Placebo orally QD (starting Day 2, cycle 1) + BR (n = 289) BR, bendamustine/rituximab; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; ECOG, Eastern Cooperative Oncology Group; LN, lymph node; MRD, minimum residual disease; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PS, performance status; QD, once daily; R/R, relapsed/refractory. Jeff P. Sharman, MD: Dr. Vose and I begin our analysis with the phase III HELIOS study of a novel BTK inhibitor, ibrutinib, in patients with previously treated, relapsed/refractory CLL or small lymphocytic lymphoma (SLL).[1] Ibrutinib is currently approved for the treatment of CLL, mantle cell lymphoma, and Waldenström’s macroglobulinemia. In addition to these 3 labeled indications at this point, there are further data to support the use of ibrutinib in relapsed/refractory CLL. In the HELIOS study, 578 patients were randomized to receive bendamustine/rituximab with or without ibrutinib. This study was started prior to the original approval of ibrutinib; whether the study results change practice patterns will remain to be seen, as the data raise some provocative questions. Although HELIOS enrolled patients with high-risk CLL/SLL, it excluded patients with the 17p deletion as the efficacy of bendamustine/rituximab in this group is quite poor, with a median PFS of less than 1 year.[2] These patients would not be appropriate for the control arm. The study stratified patients based on the number of previous therapies received and whether or not they were refractory to their most recent purine analogue regimen. Julie M. Vose, MD, MBA: Clinicians should keep in mind that the more previous therapies a patient has received, the less effective ibrutinib will be; therefore, keeping the arms balanced was important in this study. The primary endpoint was PFS with secondary endpoints of overall response rate (ORR), overall survival (OS), responses in minimal residual disease (MRD)–negative patients, as well as safety. Of importance, in this study, patients were allowed to cross over to ibrutinib after a confirmed progression. The treatment arms were well balanced regarding baseline characteristics, including the fraction of patients who were refractory to purine analogues and the median number of previous therapies received. Few patients had received prior bendamustine, which is expected for a study in this population. References: 1. Chanan-Khan AAA, Cramer P, Demirkan F, et al. Ibrutinib combined with bendamustine and rituximab (BR) in previously treated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): first results from a randomized, double-blind, placebo-controlled, phase III study. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract LBA7005. 2. Zaja F, Mian M, Volpetti S, et al. Bendamustine in chronic lymphocytic leukemia: outcome according to different clinical and biological prognostic factors in the everyday clinical practice. Am J Hematol. 2013;88: Primary endpoint: PFS (independent review) Secondary endpoints: ORR (independent review), OS, MRD-negative response rate, safety Chanan-Khan AA, et al. ASCO Abstract LBA7005.

HELIOS: Survival Outcomes (ITT)
PFS OS 100 100 Ibrutinib + BR Ibrutinib + BR (mPFS: NR) 80 80 Placebo + BR 60 60 PFS (%) OS (%) 40 40 Placebo + BR (mPFS: 13.3 mos) 20 20 BR, bendamustine/rituximab; IgVH, immunoglobulin variable region heavy chain; ITT, intent to treat; NR, not reached; OS, overall survival; PD, progressive disease; mPFS, median progression-free survival. Jeff P. Sharman, MD: Results showed that the PFS curves remained relatively stable through the end of bendamustine/rituximab therapy and then a very rapid split happens at approximately 6-8 months. While bendamustine/rituximab was being administered, patients could be kept under control, but as soon as it was stopped, patients who received a placebo quickly progressed. The median PFS in the bendamustine/rituximab plus placebo arm was 13.3 months. This is an important statistic because this study used a well‑measured control arm with a commonly used regimen. Many medical oncologists might assume that bendamustine/rituximab would produce longer PFS than this in the relapsed/refractory setting, but this is consistent with previous studies that showed good response rates which were not durable. By contrast, the addition of ibrutinib generated a strikingly different PFS curve, with an HR of 0.20 (ie, an 80% improvement in the rate of progression). What is not known is how patients with relapsed/refractory CLL might do on ibrutinib alone, and we are unsure how much benefit is conferred by bendamustine/rituximab. I suspect the PFS curve for ibrutinib alone in this population would look much like the ibrutinib curve in this study. Two ongoing phase III studies with ibrutinib-only arms should shed light on this question. The RESONATE trial comparing ibrutinib with ofatumumab has published results and trials are still ongoing.[1,2] Another phase III trial is evaluating ibrutinib vs rituximab in relapsed/refractory CLL.[3] It has become clear that after 2-3 years, rates of progression on ibrutinib significantly increase, likely due to the acquisition of resistance mutations (eg, mutations in BTK, PLCG2).[4] As a result, rates of ibrutinib discontinuation rise. In one study of 232 patients, 31 had discontinued (median follow-up: 20 months) due to progression to Richter’s transformation or progressive CLL.[4] Hypothetically, bendamustine/rituximab could limit the size of the pool of susceptible cells that could potentially acquire drug resistance, which suggests that it could take up to 3 years to determine whether bendamustine/rituximab is a beneficial addition to ibrutinib. But at least at this early follow‑up, it is not clear if the addition of bendamustine/rituximab increased the efficacy of ibrutinib. Therefore, whether or not these data change practice patterns remains to be seen. Of importance, there was less separation between the OS curves, with an HR of 0.628, indicating an approximately 37% reduction in the rate of death. Julie M. Vose, MD, MBA: The take-home lesson from this study is that the PFS was much better with the combination of bendamustine/rituximab plus ibrutinib vs bendamustine/rituximab alone. However, the OS difference was not quite statistically significant, which may be due in part to the cross over of 90 patients; one third of the patients was able to cross over. My suspicion is that, with additional follow‑up, we will see the OS benefit become statistically significant. Of note, the PFS benefit was present in all groups, including patients with del(11q) and multiple previous therapies. The addition of ibrutinib to bendamustine/rituximab seemed to overcome some of these core, negative prognostic characteristics. This information might be used to identify high‑risk patients who might benefit from this combination. Lower‑risk patients could receive bendamustine/rituximab alone, or maybe ibrutinib alone, which of course was not addressed by this particular trial. References: 1. Byrd JC, Brown JR, O’Brien S, et al. Ibrutinib vs ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371: 2. ClinicalTrials.gov. A randomized, multicenter, open-label, phase 3 study of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) versus ofatumumab in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Available at: Accessed August 3, 2015. 3. ClinicalTrials.gov. A randomized, multicenter, open-label, phase 3 study of the Bruton's tyrosine kinase (BTK) inhibitor PCI (ibrutinib) versus rituximab in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Available at: Accessed August 3, 2015. 4. Maddocks KJ, Ruppert AS, Lozanski G, et al. Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncol. 2015;1:80-87. HR: (95% CI: ; P < .0001) HR: (95% CI: ; P = .0598) 4 8 12 16 20 24 28 32 4 8 12 16 20 24 28 32 Mos Mos PFS benefit in all subgroups analyzed, including bulky disease, IgVH mutation status, number of prior therapies, presence of del(11q) OS results confounded by crossover of 90 (31%) pts in placebo arm to ibrutinib arm after PD Chanan-Khan AA, et al. ASCO Abstract LBA7005. Reprinted with permission.

Investigator Assessment
HELIOS: Responses IRC Assessment ORR: 82.7% vs 67.8% (P < .0001) Investigator Assessment ORR: 86.2% vs 68.9% (P < .0001) 100 100 80 80 10.4 21.4 2.8 5.9 60 60 % % 40 72.3 65.1 40 64.4 61.9 23.9 22.5 20 20 8.7 BR, bendamustine/rituximab; CR, complete response; CRi, complete response with incomplete bone marrow recovery; IRC, independent review committee; L, lymphocytosis; MRD, minimum residual disease; nPR, near partial response; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease. Jeff P. Sharman, MD: As is often seen, the investigators scored patients more favorably than the independent review committee. Nevertheless, very few complete responses (CRs) were seen with bendamustine/rituximab alone, and this was only slightly increased with the addition of ibrutinib. However, the rate of negative MRD was 3 times higher in the experimental arm. Although these are relatively low rates of MRD negativity, they represent a clinically meaningful difference between arms in the relapsed/refractory setting. The partial response (PR) rates were similar between arms, at 62% to 64% by investigator assessment. The most significant difference between arms, in my opinion, is the rates of stable disease; far fewer patients achieved stable disease with ibrutinib. 7.6 0.7 2.1 2.4 0.3 0.3 1.0 CR Cri PR CR Cri PR CR CRi nPR PR CR Cri nPR PR PR+L SD PD PR+L SD PD PR+L SD PD PR+L SD PD Ibrutinib + BR (n = 289) Placebo + BR (n = 289) Ibrutinib + BR (n = 289) Placebo + BR (n = 289) MRD negative response rate was higher with ibrutinib + BR than with placebo + BR (12.8% vs 4.8%, P = .0011) Chanan-Khan AA, et al. ASCO Abstract LBA7005. Reprinted with permission.

HELIOS: Safety Outcome, % Ibrutinib + BR (n = 289)
Placebo + BR (n = 289) Treatment discontinuation Progression or relapse AE 29.1 4.8 14.2 64.7 45.0 11.8 Grade 3/4 treatment-emergent AE ≥ 5% of pts Neutropenia Thrombocytopenia Anemia (n = 287) 53.7 15.0 3.5 50.5 8.0 Any grade bleeding Major hemorrhage 31.0 3.8 14.6 1.7 Atrial fibrillation Grade 3/4 7.3 2.8 0.7 AE, adverse events; BR, bendamustine/rituximab. Jeff P. Sharman, MD: One of the most significant differences between the two arms was the rates of progression or relapse: 4.8% in the ibrutinib arm vs 45.0% with bendamustine/rituximab alone. Julie M. Vose, MD, MBA: The rates of neutropenia and thrombocytopenia are similar, suggesting that ibrutinib is not significantly associated with neutropenia. The rate of anemia is actually better on the experimental arm (3.5% vs 8.0%), which may be due to better clearance of the marrow and is a clinically meaningful difference. Similar to every previous ibrutinib trial, any‑grade bleeding was approximately 30% in the ibrutinib arm, about a 2-fold increase over bendamustine/rituximab alone. In fact, many ibrutinib studies have excluded patients on concurrent anticoagulant therapy simply because of this concern. As Dr. Vose pointed out, another concern with ibrutinib is bleeding and the risk of a major hemorrhage; the rate tends to be fairly low, but these are typically grade 3/4 hemorrhages, so clinically very significant. In this trial, approximately 4% of patients receiving ibrutinib had a major hemorrhage. Finally, in multiple studies, the rate of atrial fibrillation has been approximately 5.0% with ibrutinib, which is consistent with the 7.0% rate seen in this study (vs 2.8% on the control arm). The mechanism of atrial fibrillation caused by ibrutinib is not yet understood. Chanan-Khan AA, et al. ASCO Abstract LBA7005.

HELIOS: Conclusions Ibrutinib plus BR is superior to BR alone in previously treated CLL/SLL Ibrutinib significantly extended PFS and time to progression compared with placebo PFS benefit seen across all subgroups, including high risk Risk of progression or death reduced by 80% Significantly improved ORR Risk of death reduced by 37% with ibrutinib despite crossover of 31% of pts on placebo arm No unexpected toxicities reported with the combination of ibrutinib plus BR BR, bendamustine/rituximab; CLL/SLL, chronic lymphocytic leukemia/small lymphocytic lymphoma; ORR, overall response rate; PFS, progression-free survival. Jeff P. Sharman, MD: In conclusion, in the phase III HELIOS study, ibrutinib plus bendamustine/rituximab was definitely superior to bendamustine/rituximab alone in patients with previously treated CLL/SLL. Ibrutinib is not yet approved for this indication, but I expect that the US Food and Drug Administration (FDA) will do so in late 2015 or early 2016. In my practice, if a patient is appropriate for bendamustine/rituximab in the relapsed setting with CLL, the addition of ibrutinib would be appropriate. I think the more challenging question is who is appropriate for bendamustine/rituximab in the relapsed/refractory setting; many clinicians are already using single-agent ibrutinib in that setting. Julie M. Vose, MD, MBA: The PFS benefit with ibrutinib was seen across all subgroups with an approximately 80% reduction in the rates of progression. Ibrutinib was also associated with an improved overall response rate and decreased mortality rate, although the latter point was not statistically significant. Toxicities were consistent with what has been seen in prior publications of ibrutinib studies. For more information on this study go to: Coverage/Clin Onc June 2015/Hematologic Malignancies/LBA7005.aspx Chanan-Khan AA, et al. ASCO Abstract LBA7005.

Pt Characteristics (N = 195)
Ibrutinib in CLL: Effect of Dose Adherence and Baseline Exposure on PFS Analysis of ibrutinib on PFS in pts with previously treated CLL from phase III RESONATE study of ibrutinib vs ofatumumab All pts began with ibrutinib mg QD Mean dose intensity: 95% at median of 8.6 mos of treatment At time of interim analysis, ibrutinib significantly lengthened PFS (HR: 0.22) and OS (HR: 0.43) vs ofatumumab Pt Characteristics (N = 195) Male, % 66 Median age, yrs (range) 67 (30-86) Prior therapies, median n 1 2 ≥3 18 29 53 Cytogenetic risk del(11q) del(17p) TP53 32 50 CIRS score (range) 5.3 (0-16) Median weight, kg (range) Male Female 82.0 ( ) 67.9 ( ) CIRS, cumulative illness rating scale; CLL, chronic lymphocytic leukemia OS, overall survival; PFS, progression-free survival; QD, once daily. Julie M. Vose, MD, MBA: With certain oral medications, adverse events (AEs) can affect adherence, and clinicians need to understand how that changes patient outcomes. To that end, Barr and colleagues[1] conducted an analysis of ibrutinib-treated patients with previously treated CLL from a phase III study of ibrutinib vs ofatumumab in which they looked at the median dose intensity, intervals vs ofatumumab, and different risk stratifications to see which were factors affecting adherence and baseline exposure with resulting effects on PFS. Jeff P. Sharman, MD: This is one of the most important studies presented at the 2015 ASCO annual meeting. Recently, data presented at the 2015 American Association for Cancer Research annual meeting demonstrated how effectively different ibrutinib doses inhibited the BTK pathway.[2] The take-home point was that dose reductions lead to incomplete pathway inhibition. The development of mutations and the subsequent acquisition of resistance may very well be a consequence of inadequate dosing. References: 1. Barr PM, Brown JR, Hillmen P, et al. Dose adherence and baseline exposure analysis of the ibrutinib 420 mg dose administered to patients with previously treated chronic lymphocytic leukemia (CLL). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7012. 2. Coutre S. Long-term treatment with single-agent ibrutinib 420 mg leads to durable responses including complete responses in CLL. Program and abstracts of the Annual American Association for Cancer Research; April 18 – 22, 2015; Philadelphia, PA. Abstract CT132. Barr PM, et al. ASCO Abstract 7012.

Ibrutinib in CLL: PFS by Dose Intensity
Favorable toxicity profile of ibrutinib allowed for overall high dose intensity in RESONATE clinical trial Higher ibrutinib dose intensity associated with improved PFS, independent of del(17p) or P53 mutations 100 80 60 40 20 No correlation between baseline weight or age and estimated steady-state AUC, or Cmax PFS (%) AUC, area under the curve; CLL, chronic lymphocytic leukemia; Cmax, maximum concentration; DI, dose intensity; NR, not reached; PFS, progression-free survival. Julie M. Vose, MD, MBA: The favorable toxicity profile of ibrutinib did allow for high-intensity dosing, and patients were largely adherent. Ibrutinib dosing above the mean dose intensity was associated with improvement in PFS, independent of del(17p). There was no correlation between baseline weight or age and ibrutinib concentrations, which shows that if patients do take their medication and have a consistently high blood level, outcomes are improved. Jeff P. Sharman, MD: Many physicians routinely do dose reductions for patients on virtually any medication that they are not tolerating, and in fact, that is even recommended on the label for ibrutinib.[1] In my opinion, the consequences of reducing the dose are underappreciated, and every effort should be made to keep patients on the highest dose intensity that they will permit, consistent with the label. References: 1. Imbruvica [package insert]. Sunnyvale, CA: Pharmacyclics; 2013. ≥ % Mean DI NR < % Mean DI 6.9 P Value .0127 ≥ % mean DI < % mean DI Median PFS, mos 3 6 9 12 15 Mos Barr PM, et al. ASCO Abstract 7012.

Ibrutinib in CLL: Missing Treatment = More Progression
PFS shorter in pts missing ≥ 8 consecutive days of ibrutinib vs missing < 8 days Results demonstrate importance of sustained adherence to continuous ibrutinib 420 mg QD in pts with previously treated CLL 100 80 60 40 20 Missed < 8 consecutive days Missed ≥ 8 consecutive days PFS (%) Missed Dose < 8 Consecutive Days NR Missed Dose ≥ 8 Consecutive Days 10.9 CLL, chronic lymphocytic leukemia; PFS, progression-free survival; QD, once daily. Jeff P. Sharman, MD: This figure shows the impact of dose interruptions—a dose interruption longer than 7 days nearly triples the rates of progression events. This is really important because it suggests patients who interrupt ibrutinib might not be getting the most benefit from the drug. Presumably, the longer the dose is held, the more likely resistance will develop. Although guidelines recommend holding drugs before surgery, I think that if surgeries are elective, it is probably better to wait until the patients have cleared out most of their CLL, so that fewer malignant cells are potentially able to acquire resistance. For more information on this study go to: Median PFS, mos 3 6 9 12 15 18 Mos Barr PM, et al. ASCO Abstract 7012.

Idelalisib + Ofatumumab in CLL: Study Design
Open-label, randomized, phase III study Primary endpoints: PFS Secondary endpoints: PFS in pts with del(17p)/TP53 mutation, OS, ORR, LNR rate, CR rate Stratified by del(17p) or TP53 mutation (either vs neither), IgVH mutation (mutated vs unmutated), recurrent disease status (refractory vs relapsed) IDELA 150 mg BID continuously + OFA 300 mg Wk 1, then 1000 mg q1w x 7 then q4w x 4 for 12 doses (n = 174) Fit or unfit pts with B-cell CLL that progressed < 24 mos from completion of last therapy and KPS ≥ 60 (N = 261) Until disease progression or death from any cause OFA 300 mg Wk 1, then 2000 mg q1w x 7 then q4w x 4 for 12 doses (n = 87) BID, twice daily; CLL, chronic lymphocytic leukemia; CR, complete response; IgVH, immunoglobulin variable region heavy chain; KPS, Karnofsky performance score; LNR, lymph node response; OFA, ofatumumab; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; q1w, every 1 weeks; q4w, every 4 weeks. Jeff P. Sharman, MD: Idelalisib is a PI3K inhibitor, whereas ibrutinib is a BTK inhibitor. Idelalisib is already approved, in combination with rituximab, for patients with CLL in whom rituximab alone would be considered appropriate therapy. These patients typically have secondary comorbidities and chronic illness. Ofatumumab is a fully human anti-CD20 antibody approved for previously treated CLL refractory to fludarabine and alemtuzumab. Julie M. Vose, MD, MBA: Jones and colleagues[1] conducted an open‑label randomized phase III study (N = 261) of ofatumumab with or without idelalisib in patients with progressive CLL. Patients with del(17p) and mutated TP53 were allowed, as in previous studies the presence of del(17p) did not seem to influence outcomes with idelalisib. By contrast, these are important variables regarding ibrutinib. Patients in this study had progressed less than 24 months from completion of their last therapy and had adequate performance status. Ofatumumab was dosed differently in each arm of this study due to its use as monotherapy vs combination therapy. Patients were randomized 2:1 to idelalisib plus ofatumumab or ofatumumab alone. In the combination arm, following the conclusion of ofatumumab, patients remained on idelalisib until progression or death from any cause. The primary endpoint was PFS and secondary endpoints included OS, ORR, the lymph node response rate, and the CR rate. It may be surprising to many clinicians that rates of del(17p) and/or TP53 mutation is as high as 40% in the relapsed CLL setting. If most doctors were asked how many of their patients are 17p deleted, they might say, “Well, only a few.” That may be true in the frontline setting, but relapse enriches high‑risk features; many doctors do not realize that del(17p) and/or TP53 mutations are very common in the relapsed setting. However, TP53 mutation testing is uncommon in routine practice. Similar to previous studies, in this trial, approximately four fifths of patients had the less favorable unmutated IGHV. References: 1. Jones J, Wach M, Robak T, et al. Results of a phase III randomized, controlled study evaluating the efficacy and safety of idelalisib (IDELA) in combination with ofatumumab (OFA) for previously treated chronic lymphocytic leukemia (CLL). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7023. Jones J, et al. ASCO Abstract 7023.

Idelalisib + Ofatumumab in CLL: PFS
IDELA + OFA (n = 174) OFA (n = 87) Events, n (%) 76 (44) 54 (62) Median PFS, mos (95% CI)* 16.3 ( ) 8.0 ( ) Adjusted HR (95% CI)* 0.27 ( ) P value† < .0001 Median observation, mos 11.1 5.3 All Pts 100 80 60 Progression Free (%) 40 20 *Based on Cox proportional hazards with stratification factors. †Based on stratified log-rank test. IDELA + OFA OFA CLL, chronic lymphocytic leukemia; IDELA, idelalisib; LNR, lymph node response; OFA, ofatumumab; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Julie M. Vose, MD, MBA: In patients with del(17p), there was an improvement in median PFS with the combination—13.7 months—which more than doubled from 5.8 months with ofatumumab alone. This means that clinicians can be reassured that adding idelalisib to ofatumumab is likely to benefit all patient subgroups. Jeff P. Sharman, MD: Even though this study used a 2:1 randomization, fewer events were seen with idelalisib plus ofatumumab than with ofatumumab alone (44% vs 62%, respectively). It is interesting that the median PFS on the experimental arm here is approximately 16 months, which is very close to results from a recent study of rituximab plus idelalisib[1]; final results have not been published but the median PFS was approximately 19 months. So, with both anti-CD20 agents, median PFS is approximately 1.5 years in combination with idelalisib. The median observation time was twice as long for the experimental arm due to lower rates of progression. This raises concern of an ascertainment bias, as rates of AEs are often higher in the experimental arm simply because they are observed longer. References: 1. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370: 5 10 15 20 25 Mos In del(17p)/TP53 subgroup, the median PFS for the IDELA + OFA group was vs 5.8 mos for OFA alone (HR: 0.32; 95% CI: ; P < .0001) Jones J, et al. ASCO Abstract Reprinted with permission.

Idelalisib + Ofatumumab in CLL: OS, Response, and PFS by Subgroup
Efficacy Outcome IDELA + OFA (n = 174) OFA (n = 87) HR/OR* (95% CI) P Value Median OS, mos 20.9 19.4 0.74 ( ) .27 ORR, % 75 18 15.94 ( ) < .0001 LNR rate, % ( ) PFS by Subgroup Favors IDELA + OFA Favors OFA Overall 0.27 ( ) Disease Relapsed Refractory 0.42 ( ) 0.20 ( ) IgVH Mutated Unmutated 0.37 ( ) 0.25 ( ) del(17p)/TP53 Either Neither 0.32 ( ) 0.29 ( ) del(17p) Yes No 0.21 ( ) 0.29 ( ) Sex Male Female 0.30 ( ) 0.28 ( ) Age < 65 years ≥ 65 years 0.29 ( ) 0.30 ( ) Race White Non-white 0.31 ( ) 0.28 ( ) 0.5 1.0 1.5 CLL, chronic lymphocytic leukemia; IDELA, idelalisib; IgVH, immunoglobulin variable region heavy chain; LNR, lymph node response; OFA, ofatumumab; OR, odds ratio; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Julie M. Vose, MD, MBA: The ORR was dramatically higher in the experimental arm, with an HR of nearly 16. Even more significant was the lymph node response rate, which had an HR of 487. These are almost unheard of HRs in a highly positive study, although similar findings were reported from the study of rituximab plus idelalisib. Moreover, across risk characteristic subgroups—relapsed, refractory, mutated, unmutated, del(17p), sex, age, and race—all results favored the experimental arm. *HR for OS; OR for ORR and LNR rate. PFS HR (95% CI) Jones J, et al. ASCO Abstract Reprinted with permission

Idelalisib + Ofatumumab in CLL: Overall Safety
Safety Outcome, % IDELA + OFA (n = 173) OFA (n = 86) AEs Grade ≥ 3 AEs 99 88 56 AEs related to IDELA 90 67 -- AEs related to OFA 79 47 78 34 Serious AEs Related to IDELA Related to OFA 70 42 23 20 AE, adverse event; CLL, chronic lymphocytic leukemia; IDELA, idelalisib; OFA, ofatumumab. Jeff P. Sharman, MD: The AEs with idelalisib were as expected, including serious treatment-related events in 42% of patients. Of importance, 31% of patients receiving idelalisib in combination with ofatumumab discontinued treatment due to an AE. I would not be surprised to see these rates increase over time because patients now have additional options in the relapsed/refractory setting, which means there is an increased likelihood that a patient will discontinue this therapy in favor of another. The rates of treatment‑related death were very similar between arms (7% to 10%). Overall, these data suggest that idelalisib does contribute clinically meaningful AEs. 31% of pts receiving IDELA + OFA discontinued treatment due to an AE Treatment-related AEs leading to death in 10% pts receiving IDELA + OFA and 7% pts receiving OFA Jones J, et al. ASCO Abstract 7023.

Idelalisib + Ofatumumab in CLL: Common Treatment-Related AEs
AE (≥ 18% IDELA + OFA), % IDELA + OFA (n = 173) OFA (n = 86) All Grades Grade ≥ 3 Diarrhea and/or colitis 49 20 23 1 Neutropenia 35 34 16 15 Pyrexia 32 7 2 Fatigue 3 28 5 Cough 30 < 1 21 Nausea 27 Rash 4 11 Constipation Anemia 12 10 6 Headache 19 Upper respiratory infection 18 AE; adverse event; CLL, chronic lymphocytic leukemia; IDELA, idelalisib; OFA, ofatumumab. Jeff P. Sharman, MD: The most obvious AE of idelalisib is the high rate of diarrhea and/or colitis. Although these also occurred in the control arm (diarrhea in 23%, almost all grade 1/2), nearly one half of patients on the experimental arm were affected, and 20% were grade 3/4. This is fairly consistent with results from other studies of idelalisib. There are 2 types of diarrhea related to idelalisib: an early diarrhea, but which is not necessarily inflammatory, and a later diarrhea, which is more inflammatory and for which antimotility agents generally are not useful. Instead, drugs like budesonide or steroids tend to be more useful. Other rates of treatment-related AEs were relatively similar between arms. Jones J, et al. ASCO Abstract 7023.

Idelalisib + Ofatumumab in CLL: Investigator Conclusions
IDELA + OFA significantly improved PFS, ORR, and LNR rate vs OFA alone in previously treated CLL pts with varying fitness Benefits observed across all subgroups, including pts with del(17p)/TP53m CLL OS not significantly improved with IDELA + OFA Results could be confounded by subsequent therapy in OFA monotherapy arm Toxicity increased with addition of IDELA to OFA but toxicity profile manageable Similar benefit-to-risk ratio as in previous studies of CLL pts CLL, chronic lymphocytic leukemia; IDELA, idelalisib; LNR, lymph node response; OFA, ofatumumab; ORR, objective response rate; OS, overall survival; PFS, progression-free survival. Jeff P. Sharman, MD: In conclusion, the benefits of adding idelalisib to ofatumumab in patients with relapsed/refractory CLL were observed across all subgroups, including patients with del(17p) and/or mutated TP53. These included PFS, ORR, and the lymph node response rate. However, OS was not significantly improved, which was probably confounded by subsequent therapy in the ofatumumab arm where, presumably, many patients may have gone on to receive ibrutinib. Although toxicity did increase with the addition of idelalisib, this was consistent with prior studies. For more information on this study, go to: Coverage/Clin Onc June 2015/Hematologic Malignancies/7023.aspx Jones J, et al. ASCO Abstract 7023.

Connect CLL Registry Study: Prognostic Testing Patterns in CLL Pts
Clinical, genetic, molecular markers inform prognosis and treatment selection in CLL Genetic abnormalities particularly relevant to individualizing treatment strategies involving immunochemotherapies, TKIs, SCT, and trials Evolution of CLL clone over time suggests retesting important when choosing subsequent lines of therapy Connect CLL: large, prospective, observational registry designed to identify patterns of CLL management regardless of treatment (N = 1494) First line: n = 889 (60%) Second line: n = 260 (17%) Third line: n = 345 (23%) CLL, chronic lymphocytic leukemia; PRO, patient-reported outcome; SCT, stem cell transplantation; TKI, tyrosine kinase inhibitor. Julie M. Vose, MD, MBA: In the Connect CLL registry study, Mato and colleagues[1] looked at a large number of patients and prognostic patterns, taking into account genetics, molecular markers, and clinical data. The investigators assessed patterns in first-line, second-line, and third-line treatment in approximately 1500 patients. References: 1. Mato A, Flowers C, Farber CM, et al. Prognostic testing patterns in CLL pts treated in U.S. practices from the Connect CLL registry. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7013. Follow-up: baseline then quarterly for up to 60 mos Treatment, clinical data, PROs Mato A, et al. ASCO Abstract 7013.

Connect CLL Registry Study: FISH and/or Cytogenetic Testing
Overall, only 58% of pts assessed for genetic alterations Although CLL clones can acquire new genetic abnormalities, 60% not retested before receiving next line of therapy Testing at Enrollment, % First Line (n = 889) Second Line (n = 260) ≥ Third Line (n = 345) All (N = 1494) FISH and/or cytogenetic 65 50 45 58 FISH 40 34 49 Cytogenetic 39 31 33 36 FISH and cytogenetic 32 22 28 FISH/cytogenetic retesting with next line of therapy 41 48 CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization. Julie M. Vose, MD, MBA: Regarding genetic abnormalities, only approximately 58% of patients were tested for genetic alterations after the first line of treatment, and increasingly fewer patients were retested in subsequent lines, even though it is known that CLL patients can acquire new genetic abnormalities. Typically, I retest patients if they have had a change in their clinical characteristics, aggressive increase in their white blood cell count, or very aggressive growth of lymphadenopathy. Jeff P. Sharman, MD: The rate of fluorescence in situ hybridization (FISH) testing decreases with additional lines of treatment, which I think is a very dangerous and concerning finding. Only one third of patients receiving third-line or greater treatment are tested for genetic alterations. We now have drugs that are approved in specific FISH subgroups, and the list is likely to increase after the approval of venetoclax, a Bcl-2 inhibitor developed for patients with CLL and del(17p). Essentially, high-risk cytogenetics are often not identified, which is unfortunate as there are therapies that are appropriate in those settings. On the other hand, giving all patients with CLL ibrutinib is foolish as well because patients with low-risk CLL who require therapy can often survive for 8-14 years with cytotoxic therapy; 6 months of chemotherapy may be better for such an individual than ibrutinib. The second concerning finding here is that people underappreciate that FISH test results change over time. CLL often becomes resistant, and high-risk variables enrich over time. For example, del(17p) is seen in only approximately 5% of previously untreated patients, but in the relapsed/refractory setting, it can be present in up to 50% of patients. In this subgroup, the number of previous therapies received greatly influences responses to ibrutinib, so the earlier ibrutinib is used in such a patient, the better. Mato A, et al. ASCO Abstract 7013.

Connect CLL Registry Study: Predictors of FISH or Cytogenetic Testing
Univariate Analysis Variable P Value OR (95% CI) Enrollment: first vs ≥ second line of therapy < .0001 2.1 ( ) Rai stage: ≥ 2 vs 0-1 1.7 ( ) Age: ≤ 75 vs > 75 yrs .0002 1.5 ( ) Insurance: private vs other .0024 1.4 ( ) Site: academic vs community/government .0045 1.7 ( ) Multivariate Analysis Variable (First Line) OR (95% CI) Academic vs community/government site 1.76 ( ) White vs other race 1.90 ( ) Private vs other insurance 1.44 ( ) CLL, chronic lymphocytic leukemia; FISH, fluorescence in situ hybridization; OR, odds ratio. Julie M. Vose, MD, MBA: Predictors of genetic testing using FISH and/or cytogenetic tests included first vs second or greater lines of therapy, age (younger than 75 years were more likely to be tested), private insurance vs other insurance, and academic institution vs other locations. These are some variables that might predict who is more likely to be tested. Most important, if clinicians are made aware that we are not testing enough, that is a good start toward improving this situation. For more information on this study, go to: Mato A, et al. ASCO Abstract 7013.

Non-Hodgkin’s Lymphoma

Obinutuzumab maintenance 1000 mg IV q2m
GADOLIN: Study Design Randomized, open-label, international phase III trial Primary endpoint: PFS assessed independently Secondary endpoints: investigator-assessed PFS, OS, responses, safety, PK, PROs Stratified by NHL subtype (FL vs other), prior therapies (≤ 2 vs > 2), refractory type, and geographic region Up to 6 28-day cycles For 2 yrs or until PD Bendamustine 90 mg/m2/day IV Days 1, 2 + Obinutuzumab 1000 mg IV Days 1, 8, 15 cycle 1; Day 1 cycles 2-6 Obinutuzumab maintenance 1000 mg IV q2m CR/PR/SD Rituximab-refractory CD20-positive indolent NHL (N = 413) CR, complete response; FL, follicular lymphoma; IV, intravenous; NHL, non-Hodgkin’s lymphoma; PFS, progression-free survival; q2m, every 2 months; PD, progressive disease; PK, pharmacokinetics; PR, partial response; PROs, patient-reported outcomes; SD, stable disease. Jeff P. Sharman, MD: We will now discuss a phase III study of obinutuzumab, which may potentially lead to changes in the FDA prescribing information. Obinutuzumab is a next-generation anti-CD20 antibody that differs in a number of significant ways from rituximab.[1] Obinutuzumab is a type II antibody, as opposed to type I, and has been glycoengineered to enhance antigen-dependent cell-mediated cytotoxicity (ADCC) activity and direct cell killing. Sehn and colleagues[2] previously presented phase II data showing a higher ORR with obinutuzumab in patients with indolent NHL compared with rituximab when given for short durations (every 2 months for 2 years). So there is at least some signal that there might be higher efficacy with obinutuzumab than rituximab. Obinutuzumab is hoped to be effective in the setting of rituximab-refractory NHL as well. Therefore, Sehn and colleagues[3] sought to evaluate the efficacy of obinutuzumab and bendamustine in this fairly common clinical situation. The randomized phase III GADOLIN clinical trial enrolled rituximab-refractory patients with indolent NHL (N = 413).[3] Patients received bendamustine with or without obinutuzumab for up to 6 cycles. This study is important because, in practice, it is unclear whether one should continue anti-CD20 therapy in that setting; it is not certain that the antibody is adding anything. In the bendamustine-only arm, patients received a very high dose of 120 mg/m2/day, which is consistent with the FDA label. Of importance, those patients who are considered double refractory, that is, to both rituximab and alkylators, are the same population tested in studies that led to the approval of idelalisib.[4] This allows some degree of comparison across studies because of the similarities of the patients. In the GADOLIN study, the patients with NHL had advanced, fairly refractory disease: a median time since diagnosis of 4 years, and a median number of 2 previous therapies. Julie M. Vose, MD, MBA: That is a higher dose of bendamustine than most of us use and does lead to some early discontinuations. The dose in the experimental combination arm was lower—90 mg/m2/day. In this particular study, after patients received induction therapy, those patients who were randomly allocated to obinutuzumab continued it as maintenance therapy for up to 2 years or until progression. No maintenance therapy was given to patients in the control arm. The primary endpoint was PFS. References: 1. Herting F, Friess T, Bader S, et al. Enhanced anti-tumor activity of the glycoengineered type II CD20 antibody obinutuzumab (GA101) in combination with chemotherapy in xenograft models of human lymphoma. Leuk Lymphoma. 2014;55: 2. Sehn LH, Goy A, Offner FC, et al. Randomized phase II trial comparing GA101 (obinutuzumab) with rituximab in patients with relapsed CD20+ indolent B-cell non Hodgkin lymphoma: preliminary analysis of the GAUSS study. Program and abstracts of the 53rd American Society of Hematology Annual Meeting and Exposition; December 10-13, 2011; San Diego, California. Abstract 269. 3. Sehn LH, Chua NS, Mayer J, et al. GADOLIN: primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract LBA8502. 4. Keating GM. Idelalisib: a review of its use in chronic lymphocytic leukaemia and indolent non-Hodgkin's lymphoma. Target Oncol. 2015;10: Bendamustine 120 mg/m2/day IV Days 1, 2 Sehn LH, et al. ASCO Abstract LBA8502.

GADOLIN: IRF-Assessed PFS
IRF-Assessed PFS Events, n (%) Median PFS, mos (95% CI) Stratified HR (95% CI) Log-rank P value O + B (n = 194) 71 (37) NR (22.5-NR) B (n = 202) 104 (51) 14.9 ( ) 0.2 0.4 0.6 0.8 1.0 0.55 ( ) .0001 Probability of PFS Median follow-up: 21 mos O + B B Censored 14.9 B, bendamustine; IRF, independent radiology facility; NR, not reached; O, obinutuzumab; OS, overall survival; PFS, progression-free survival. Jeff P. Sharman, MD: The PFS results from GADOLIN show that patients who received 6 months of high-dose bendamustine vs bendamustine/obinutuzumab do relatively similar for the first 6 months, but then the curves begin to separate. The median PFS is approximately 15 months in the bendamustine arm, which is similar to idelalisib. By contrast, the median PFS when obinutuzumab is added had not been reached at the time of presentation. I think that it is likely to be demonstrated with additional follow-up because the Kaplan‑Meier curve is just barely above the median mark, and so any additional progressions will likely define the median PFS. One question that arises from interpretation of this study is what happens if bendamustine/rituximab were used? Although we do not know that answer, we have to infer that obinutuzumab would benefit rituximab-refractory patients when combined with bendamustine/rituximab. So, how much this changes practice patterns is likely going to depend on how the FDA chooses to update the prescribing information for obinutuzumab. In my opinion, for a patient who is refractory to rituximab and appropriate for cytotoxic chemotherapy, the addition of obinutuzumab is likely to be useful, as demonstrated here. Of note, at this interim analysis there was no significant OS difference, but this may change with additional follow-up. Julie M. Vose, MD, MBA: Caveats include that more patients discontinued in the bendamustine-alone arm because of toxicity. I note that the curves start to separate at approximately the time maintenance therapy started in the combination arm. It is possible that much of the benefit is due to this maintenance treatment. 6 12 18 24 30 36 42 48 54 Mos Investigator-assessed median PFS O + B vs B: 29.2 vs 14.0 mos, respectively; HR: (95% CI: ; P < .0001) No significant OS difference observed in interim analysis Sehn LH, et al. ASCO Abstract LBA8502. Reprinted with permission.

GADOLIN: Grade 3/4 AEs Grade 3/4 AEs, % O + B (n = 194) B (n = 202)
Hematologic Neutropenia Thrombocytopenia Anemia Febrile neutropenia Leukopenia 33.0 10.8 7.7 4.6 1.0 26.3 16.2 10.1 3.5 1.5 Nonhematologic Infusion-related reactions Vomiting Decreased appetite Fatigue Nausea Diarrhea Pyrexia Headache 2.1 0.5 5.6 2.5 3.0 AE, adverse event; B, bendamustine; O, obinutuzumab. Jeff P. Sharman, MD: Likewise, rates of AEs were quite similar between arms, with perhaps a slight increase in AEs in the combination arm leading to dose modification and/or grade 3/4 events. Julie M. Vose, MD, MBA: I want to call attention to the rates of grade 3/4 infusion-related reactions, which in CLL studies tends to be quite high with obinutuzumab but was fairly low in this trial, at 10%. Now, 10% with a grade 3/4 AE is certainly not trivial, and it is peculiar to see an even lower rate with bendamustine alone—5.5%. It appears that obinutuzumab-related infusion reactions are not nearly as bad in follicular lymphoma (FL) as in CLL. Sehn LH, et al. ASCO Abstract LBA8502.

GADOLIN: Conclusion Obinutuzumab + bendamustine followed by obinutuzumab maintenance therapy associated with statistically significant improvement in PFS vs bendamustine alone Benefit of combination observed across most subgroups Response rates similar between regimens despite higher bendamustine dose in monotherapy arm No unanticipated adverse events reported Investigators concluded obinutuzumab + bendamustine and obinutuzumab maintenance therapy is effective for rituximab-refractory pts with indolent NHL NHL, non-Hodgkin’s lymphoma; PFS, progression-free survival. Jeff P. Sharman, MD: The authors conclude that obinutuzumab plus bendamustine followed by obinutuzumab maintenance in patients with rituximab-refractory NHL is associated with a statistically significant improvement in PFS vs bendamustine alone. This was true in most of the subgroups analyzed. ORRs were similar, despite the higher bendamustine dose in the monotherapy arm, and AEs were largely as expected for the combination therapy. For more information on this study, go to: Coverage/Clin Onc June 2015/Hematologic Malignancies/LBA8502.aspx Sehn LH, et al. ASCO Abstract LBA8502.

CTL019 in B-Cell Lymphomas: Study Design
Apheresis Pts with CD19+ B-cell lymphoma with no curative options (N = 30) Restaging, lymphodepleting chemotherapy Monitoring, response assessments CTL019 infusion ORR, overall response rate; OS, overall survival; PFS, progression-free survival. Jeff P. Sharman, MD: Numerous different technology platforms and treatment centers are developing what is called cytotoxic T‑lymphocyte therapy, or engineered T‑cells, as treatment for B-cell lymphomas. This approach has shown to be effective in acute lymphocytic leukemia (ALL) and CLL.[1-3] CTL019 comprises autologous T cells engineered to express a chimeric antigen receptor (CAR) including a fragment of a monoclonal antibody that targets CD19 plus signaling domains responsible for activation, proliferation, survival, and cytokine production by T cells.[4] These CAR T cells (ie, CTL019) are then reinfused into the patient where they expand and target CD19-expressing malignant B cells, which they attach to and cause cell death. Julie M. Vose, MD, MBA: CTL019 was evaluated in a single-arm study of 30 patients with CD19-positive B-cell lymphoma.[4] The primary endpoint was ORR at 3 months, and response by histology was assessed. Secondary endpoints included safety, survival, and CTL019 characterization in vivo. The preponderance of patients had relapsed/refractory diffuse large B-cell lymphoma (DLBCL), whereas much fewer had FL or mantle cell lymphoma. The median number of previous therapies received was very high, at Approximately 25% to 40% had received previous stem cell transplantations, and up to three quarters had elevated lactate dehydrogenase. In short, these were quite heavily pretreated patients coming into the study. References: 1. Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371: 2. Grupp SA, Kalos M, Barrett D, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368: 3. Porter D, Levine B, Kalos M, Bagg A, June C. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2014;365: 4. Schuster S, Svoboda J, Nasta S, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8516. Primary endpoints: ORR at 3 mos; response by histology Secondary endpoints: CTL019 manufacturing feasibility; safety, tolerability, PFS, OS, characteristics of CTL019 cells in vivo Schuster S, et al. ASCO Abstract 8516.

CTL019 in B-Cell Lymphomas: Efficacy
High ORR, durable responses observed in DLBCL FL Response improvements (PR  CR) observed in DLBCL, FL Some losses of PR observed; all CRs maintained Response DLBCL (n = 12) FL (n = 7) MCL (n = 2) Best response ORR, % CR, n PR, n PD, n 50 5 1 6 100 Not yet evaluable; 1 pt with clinical response > 50 days, 1 pt with PD at 70 days Median PFS, days 90 Not reached (> 290) 41 Median response duration (> 274) Not reported Not evaluable CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MCL, mantle cell lymphoma; ORR, overall response rate; PD, progressive disease; PR, partial response. Julie M. Vose, MD, MBA: The ORR in patients with DLBCL was 50%, vs 100% in FL. It appears that achieving a CR is important for this therapy, and PRs are not as durable. Schuster S, et al. ASCO Abstract 8516.

CTL019 in B-Cell Lymphomas: PFS in DLBCL
DLBCL: PFS (Days) DLBCL: PFS 1.00 N = 13 Median PFS: 90 days 0.75 0.50 0.25 DLBCL, diffuse large B-cell lymphoma; PFS, progression-free survival. Julie M. Vose, MD, MBA: For those patients who do achieve a response, it can be very durable. Of 13 patients with DLBCL, the median PFS was 90 days. Although that may seem fairly short, some patients maintained freedom from progression for a fairly long period of time—more than 1 year—and others are approaching that landmark. Normally, patients with relapsed DLBCL with approximately 4 previous therapies would likely have died from the disease; these results suggest both that CTL019 is effective, and responses are potentially durable. 100 200 300 400 100 200 300 400 Days Ongoing clinical responses Days to progressive disease Schuster S, et al. ASCO Abstract Reprinted with permission.

CTL019 in B-Cell Lymphomas: AEs Potentially Related to Treatment
No deaths from cytokine release syndrome; 1 death from encephalopathy Grade ≥ 3 AE Grade 3 Grade 4 Grade 5 Acute kidney injury 2 Cytokine release syndrome 1 Hypotension Encephalopathy Acidosis Delirium Fever Hypertension Infection AE, adverse event. Julie M. Vose, MD, MBA: Toxicity data showed few grade ≥ 3 AEs, but it is worth paying attention to the low rate of cytokine release syndrome in NHL, which appears to be quite a bit less than seen in either ALL or CLL. People have speculated that this might be due to factors such as the bulk of disease, whether it is in the marrow or in the nodes. I also want to draw attention to the presence of encephalopathy. This is probably a cytokine-mediated symptom, and the clinical presentation can be mistaken for a stroke. Patients with encephalopathy can have focal neurologic deficits, which last for a period of time. The fact that 1 patient died of encephalopathy is illustrative that this can be a very serious AE, although not necessarily frequent. It has been associated with multiple B‑cell cytotoxic therapies, including blinatumomab and other bispecific antibodies, as well as the full range of engineered T cells. Other mild organ toxicities included renal injury, hypotension, central nervous system toxicity, and delirium, which accompany the encephalopathy, as well as fevers and hypertension. By learning to predict and deal with these toxicities, clinicians may be able to manage them in patients as early as possible. Schuster S, et al. ASCO Abstract 8516.

CTL019 in B-Cell Lymphomas: Conclusion
CTL019: CAR T-cells directed against CD19 Associated with durable responses in relapsed/refractory CD19-positive DLBCL, FL[1] All pts achieving CR remained in CR as of most recent follow-up Therapy had manageable toxicity profile with no deaths from cytokine release syndrome Study is currently ongoing[2] CAR, chimeric antigen receptor, CR, complete response; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma. Jeff P. Sharman, MD: In conclusion, CTL019 was associated with durable responses in relapsed/refractory CD19-positive DLBCL and FL, and all patients achieving CR remained in CR as of the most recent follow-up, which highlights the importance of achieving a CR. The toxicity was very manageable, and no patients died from cytokine release syndrome, which has been a hallmark of this therapy. Multiple other studies of CAR T cells are ongoing, and it is very likely that this approach will be developed in a full range of B‑cell malignancies.[1] Julie M. Vose, MD, MBA: Yes, many multicenter studies of CAR T cells are going to be initiated over the next year or so in multiple settings, which will provide much more data on the optimal way to administer this therapy and how to prevent or minimize toxicities.[2] For more information on this study, go to: References: Schuster S, Svoboda J, Nasta S, et al. Phase IIa trial of chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8516. ClinicalTrials.gov. Phase IIa Study of Redirected Autologous T Cells Engineered to Contain Anti-CD19 Attached to TCRz and 4-Signaling Domains in Patients With Chemotherapy Relapsed or Refractory CD19+ Lymphomas. Available at: Accessed August 10, 2015. 1. Schuster S, et al. ASCO Abstract ClinicalTrials.gov. NCT

Rituximab in NHL: Study Design
Pts receiving rituximab-containing initial therapy for indolent NHL from 1997 to 2014 N = 303; 3 cohorts Rituximab only (n = 119) Rituximab + chemotherapy (n = 120) R-chemo followed by R maintenance (n = 64) Cohorts assessed based on FL (n = 184) or non-FL (n = 199) histology EFS: treatment Day 1 until relapse, progression, histologic transformation, loss of follow-up, start of second-line therapy, or death EFS, event free survival; FL, follicular lymphoma; NHL, non-Hodgkin’s lymphoma; R, rituximab. Julie M. Vose, MD, MBA: Multiple factors affect rituximab pharmacokinetics in patients with NHL.[1,2] For example, several studies have looked at sex as a possible predictor for outcome with rituximab in NHL, and almost always found that female patients did better than male patients.[1,3,4] However, determining which characteristics are predictive of outcome and affect rituximab pharmacokinetics requires a large number of patients. So, Sawalha and colleagues[5] conducted a retrospective analysis of patients treated at the Cleveland clinic. This analysis (N = 303) included patients with indolent NHL who received rituximab only, rituximab in combination with chemotherapy, or rituximab plus chemotherapy followed by rituximab maintenance. Cohorts were stratified by follicular lymphoma vs other indolent NHLs. The investigators assessed progression, relapse, transformation, and other characteristics. Jeff P. Sharman, MD: This study continues a theme of papers that have looked at the differential impact of rituximab in different subgroups of patients with NHL. Rituximab, when it was clinically developed, never went through an appropriate phase I dose-escalation study to determine the optimal dose. The standard dose of 375 mg/m2 was chosen as the “effective” dose purely empirically, without much sound scientific rationale. In short, it is not clear that this is the right dose. References: 1. Müller C, Murawski N, Wiesen MH, et al. The role of sex and weight on rituximab clearance and serum elimination half-life in elderly patients with DLBCL. Blood. 2012;119: 2. Pfreundschuh M, Muller C, Zeynalova S, et al. Suboptimal dosing of rituximab in male and female patients with DLBCL. Blood. 2014; 123: 3. Gisselbrecht C, Schmitz N, Mounier N, et al. Rituximab maintenance therapy after autologous stem-cell transplantation in patients with relapsed CD20(+) diffuse large B-cell lymphoma: final analysis of the collaborative trial in relapsed aggressive lymphoma. J Clin Oncol. 2012;30: 4. Carella AM, de Souza CA, Luminari S, et al. Prognostic role of gender in diffuse large B-cell lymphoma treated with rituximab containing regimens: a Fondazione Italiana Linfomi/Grupo de Estudos em Moléstias Onco-Hematológicas retrospective study. Leuk Lymphoma. 2013;54:53-57. 5. Sawalha Y, Rouphail B, Jia X, et al. Is rituximab sub-optimally dosed in indolent B cell lymphoma? Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8567. Sawalha Y, et al. ASCO Abstract 8567.

Rituximab in NHL: R-Chemo Cohort EFS
1.00 R-Chemo 1.00 FL in the R-Chemo Cohort Elderly females Young females Elderly males Young males Elderly females Young females Elderly males Young males 0.75 0.75 EFS 0.50 EFS 0.50 0.25 0.25 Yr 3 6 9 Yr 3 6 9 1.00 R-Chemo 1.00 FL in the R-Chemo Cohort EFS, event-free survival; FL, follicular lymphoma; NHL, non-Hodgkin’s lymphoma; R, rituximab. Julie M. Vose, MD, MBA: Results showed that rituximab‑containing regimens produced better event-free survival (EFS) in older female patients vs younger female patients, older males, or younger males. In addition, patients that had a higher body mass index, or higher weight, appeared to do more poorly than patients that had a lower weight. Jeff P. Sharman, MD: Each analysis of clinical variables has shown that different subgroups have different responses to rituximab. Some of the improved efficacy seen with obinutuzumab or ofatumumab could be due in part to higher dosing or to patient characteristics, including, age, sex, and body size. Weight ≤ 81.8 kg Weight > 81.8 kg Weight ≤ 81.8 kg Weight > 81.8 kg 0.75 0.75 0.50 0.50 EFS EFS 0.25 0.25 Yr 3 6 9 Yr 3 6 9 Sawalha Y, et al. ASCO Abstract Reprinted with permission.

Rituximab in NHL: R-Chemo Cohort Outcomes
In univariate analysis, heavier pts had worse outcomes, older females had better outcomes among R-chemo–treated pts with FL Effect not observed in R-only or R-chemo  R cohorts HR for EFS in Pts Receiving R-Chemo (95% CI; P Value) Characteristic All Pts (n = 120) FL (n = 81) Non-FL (n = 39) Weight ≥ 81.8 kg 1.81 ( ; .02) 2.40 ( ; .005) 1.05 ( ; NS) BSA ≥ 2 m2 1.44 ( ; 1.90 ( ; .037) 0.84 ( ; Females aged 65 yrs or older 0.34 ( ; .035) 0.21 ( ; .033) 0.71 ( ; BSA, body surface area; EFS, event-free survival; FL, follicular lymphoma; NHL, non-Hodgkin’s lymphoma; NS, not significant; R, rituximab. Julie M. Vose, MD, MBA: This slide discusses the univariate analysis, and again the characteristics that they found were weight over 81.8 kg; high body surface area, > 2 m2; and females who were older than 65 years of age had differences in their outcomes in FL and in non-FL patients. Sawalha Y, et al. ASCO Abstract 8567.

Rituximab in NHL: Combined Cohort Outcomes
In univariate analysis, weight, BSA, sex, associated with outcomes in combined cohorts In multivariate analysis of all pts, weight significantly associated outcome (HR: 1.55; P = .031) HR for EFS for All Cohorts (95% CI; P Value) Characteristic All Pts (N = 303) FL (n = 184) Non-FL (n = 119) Weight ≥ 81.8 kg 1.52 ( ; .01) 1.65 ( ; .019) 1.31 ( ; NS) BSA ≥ 2 m2 1.39 ( ; .041) 1.45 ( ; 1.24 ( ; Female 0.73 ( ; 0.88 ( ; 0.59 ( ; .048) BSA, body surface area; EFS, event-free survival; FL, follicular lymphoma; NHL, non-Hodgkin’s lymphoma; NS, not significant. Jeff P. Sharman, MD: In multivariate analysis, weight was significantly associated with outcome, with a fairly significant HR of It is clear that age, sex, and size do affect outcomes and may be related to rates of rituximab clearance. These data further call into question whether the empiric dose of 375 mg/m2 is optimal in NHL. Sawalha Y, et al. ASCO Abstract 8567.

Rituximab in NHL: Conclusions
In pts with indolent lymphoma (particularly FL), outcomes among pts receiving R-chemo worse in heavier pts, better in older females vs older males Same effect not observed in R alone or R-chemo  R cohorts Investigator conclusions Pt weight shown to negatively affect outcomes in pts treated with R- chemo Likely due to faster rituximab clearance Hypothesis: higher rituximab levels (weekly and/or maintenance) exceed therapeutic threshold, counteract negative impact of pt weight Subsets of pts with FL may receive suboptimal doses of rituximab FL, follicular lymphoma; NHL, non-Hodgkin’s lymphoma; R, rituximab. Julie M. Vose, MD, MBA: In this study, patients with indolent lymphoma, particularly FL, who received rituximab plus chemotherapy had a much worse outcome if they were heavier, older, and male. The same effect was not observed in the rituximab alone arm or in patients who received rituximab plus chemotherapy followed by maintenance rituximab. It is likely that some of these differences are related to pharmacokinetics; future studies may try to modify the dose based on patient characteristics and follow their pharmacokinetics more closely. For more information on this study, go to: Sawalha Y, et al. ASCO Abstract 8567.

CR30 for PFS in FL: Study Design
Prospective meta-analysis of surrogacy evaluation Previously untreated FL pts in randomized, multicenter studies published after 1990 FLASH (Follicular Lymphoma Analysis of Surrogate Hypotheses): collaboration of clinicians and statisticians created to analyze data Prespecified principal surrogacy candidate: CR at 30 mos after enrollment CRu not included; PET not used Primary evaluation: trial-level surrogacy analysis with R2 linear regression models to determine if CR at 30 mos predicts PFS Additional surrogacy analysis at individual pt level CR, complete response; CRu, complete response unconfirmed; FL, follicular lymphoma; PET, positron emission tomography; PFS, progression-free survival. Julie M. Vose, MD, MBA: It is challenging to use PFS as an endpoint in FL studies because many patients can survive longer than 15 years. So, Sargent and colleagues[1] assessed an alternative outcome, the CR rate at 30 months (CR30), as a potential surrogate endpoint for PFS in patients with FL receiving first‑line treatment. Jeff P. Sharman, MD: Practicing clinicians should be aware that this endpoint of CR30 is likely to be reported in future studies of indolent lymphoma. This was the FLASH study, a meta-analysis of randomized studies. Of note, CR was determined by computed tomography (CT) scanning without positron emission tomography (PET). This is because PET was not standardized whereas CT was simple and available across multiple studies. In addition to determining whether CR30 is a suitable surrogate endpoint for PFS in the setting of FL, the investigators also evaluated the clinical value of this measure for individual patients. The more than 3800 patients in this analysis were drawn from 13 studies with 26 treatment arms, including induction and maintenance therapy. A total of 9 studies included rituximab in at least 1 treatment arm, 8 used induction therapy, and 5 had maintenance therapy. References: 1. Sargent DJ, Shi Q, De Bedout S, et al. Evaluation of complete response rate at 30 months (CR30) as a surrogate for progression-free survival (PFS) in first-line follicular lymphoma (FL) studies: Results from the prospectively specified Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) analysis with individual patient data (IPD) of 3,837 patients (pts). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8504. Sargent DJ, et al. ASCO Abstract 8504.

CR30 for PFS in FL: Results
Log(HRPFS) = – x log(ORCR30) CR30 rate met prespecified surrogacy qualification criteria for PFS R2WLS: 0.88 (95% CI: ) R2Copula: 0.86 (95% CI: ) Correlation similar for induction vs maintenance trials and R vs non-R trials Surrogate threshold suggests that observed OR ≥ 1.56 in an ongoing trial will predict nonzero PFS treatment effect At individual pt level, overall global OR shows CR30 associated with greatly reduced odds of progression 0.5 0.0 Log (HR) on PFS -0.5 -1.0 CR30, complete response at 30 months; CR, complete response; FL, follicular lymphoma; OR, odds ratio; PFS, progression-free survival; R, rituximab. Jeff P. Sharman, MD: In the FLASH study, it was shown that the CR30 rate was indeed a good surrogate endpoint for PFS, in both induction vs maintenance studies and trials of rituximab vs other agents. The odds ratio of for individual surrogacy further highlights that achieving CR30 substantially reduces risk of progression. -1.5 -0.5 0.0 0.5 1.0 1.5 2.0 Log (OR) on CR30 Object size is proportional to sample size Sargent DJ, et al. ASCO Abstract Reprinted with permission.

CR30 for PFS in FL: Individual Level Surrogacy
Global odds ratio: PFS in pts with CR30 vs those without CR30 Group Number of Trials Global OR (95% CI) Overall 13 11.84 ( ) Rituximab trials 9 11.08 ( ) Non-rituximab trials 4 14.40 ( ) Induction trials 8 10.34 ( ) Maintenance trials 5 14.14 ( ) CR30, complete response at 30 months; FL, follicular lymphoma; OR, odds ratio; PFS, progression-free survival. Jeff P. Sharman, MD: Achieving CR30 clearly predicts an improvement of at least 10% in PFS with longer follow-up. I think that we will see CR30 embedded in future studies as a marker of surrogate efficacy. Sargent DJ, et al. ASCO Abstract Reprinted with permission.

CR30 for PFS in FL: Conclusions
CR at 30 mos met criteria as surrogate endpoint for PFS Surrogacy conclusions limited to pt population evaluated (untreated FL pts receiving rituximab or non-rituximab therapy) Surrogacy threshold effect: OR of 1.56 or improvement in CR at mos rate from a control rate of 50% to experimental rate of 61% would predict a nonzero treatment effect on PFS in clinical trials CR at 30 mos may be appropriate primary endpoint in future studies of first-line FL treatment FLASH database offers rich resource for future FL studies CR, complete response; FL, follicular lymphoma; FLASH, Follicular Lymphoma Analysis of Surrogate Hypotheses; OR, odds ratio; PFS, progression-free survival. Julie M. Vose, MD, MBA: In conclusion, yes, CR30 is a surrogate endpoint for PFS, based on statistical analysis. The odds ratio of 1.56 meant an experimental rate of 61% vs a control rate of 50%. So, in future trials, this may be a very appropriate endpoint in trying to predict outcomes for patients with FL where OS and PFS would take too many years to assess. For more information on this study, go to: Sargent DJ, et al. ASCO Abstract 8504.

Multiple Myeloma Sagar Lonial, MD:
I will discuss key clinical trial data in multiple myeloma presented at the 2015 ASCO annual meeting.

ENDEAVOR: Comparing Kd vs Vd in Relapsed MM
Randomized, open-label, multicenter phase III trial Primary endpoint: PFS Secondary endpoints: OS, ORR, DoR, grade ≥ 2 peripheral neuropathy, safety Stratified by prior PI therapy, prior lines of treatment, ISS stage, and route of V administration (IV vs SC) Carfilzomib + Dexamethasone (Kd) (n = 464) Relapsed MM with 1-3 previous lines of therapy; prior V or K if response occurred with no discontinuation due to toxicity (N = 929) Until PD or unacceptable toxicity Bortezomib + Dexamethasone (Vd) (n = 465) DoR, duration of response; ISS, International Staging System; IV, intravenous; K, carfilzomib; Kd, carfilzomib/dexamethasone; MM, multiple myeloma; PD, progressive disease; PI, proteasome inhibitor; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; SC, subcutaneous; V, bortezomib; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: Let us begin with the phase III ENDEAVOR study, from Dimopoulos and colleagues,[1] comparing the 2 proteasome inhibitors carfilzomib and bortezomib head to head. These data follow early-phase results showing the feasibility of carfilzomib plus dexamethasone.[2] Carfilzomib is a second-generation epoxyketone proteasome inhibitor, which is approved as a single-agent for the treatment of relapsed/refractory myeloma.[3] Bortezomib combinations are a standard of care in this setting. In this large study (N = 929), carfilzomib was given at a dose of 20 mg/m2 in cycle 1 and 56 mg/m2 thereafter compared with bortezomib at the standard dose and schedule (intravenous or subcutaneous). Of note, the standard dose of carfilzomib with dexamethasone is 20/27 mg/m2, so it was essentially doubled in this study. The primary endpoint was PFS, with secondary endpoints including OS, ORR, duration of response (DoR), and peripheral neuropathy of grade 2 or higher. References: 1. Dimopoulos MA, Moreau P, Palumbo A, et al. Carfilzomib and dexamethasone (Kd) vs bortezomib and dexamethasone (Vd) in patients (pts) with relapsed multiple myeloma (RMM): results from the phase III study ENDEAVOR. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8509. 2. Papadopoulos KP, Siegel DS, Vesole D, et al. Phase I study of 30-minute infusion of carfilzomib as single agent or in combination with low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma. J Clin Oncol. 2014;33: 3. Kyprolis [package insert]. Thousand Oaks, CA: Onyx Pharmaceuticals; 2012. Dimopoulos MA, et al. ASCO Abstract 8509.

ENDEAVOR: Kd Results in 2-Fold Increase in Median PFS vs Vd in Relapsed MM
Significant PFS benefit with Kd vs Vd observed across most subgroups, including age (including ≥ 75 yrs), renal function, risk, prior treatment (including prior bortezomib) OS data not mature (HR: 0.79; P = .066) Parameter Kd (n = 464) Vd (n = 465) P Value Median PFS, mos 18.7 9.4 < .0001 (1 sided) HR (95% CI) 0.53 ( ) ORR, % ≥ CR (sCR + CR) ≥ VGPR 77 13 54 63 6 29 Median DoR, mos 21.3 10.4 CR, complete response; DoR, duration of response; Kd, carfilzomib/dexamethasone; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Vd, bortezomib/dexamethasone; sCR, stringent complete response; VGPR, very good partial response. Sagar Lonial, MD: The median PFS in this trial was 18.7 months with carfilzomib/dexamethasone vs 9.4 months in the bortezomib/dexamethasone arm (P < .0001). The ORR was also significantly higher with carfilzomib, as was the CR rate, the rate of very good PR (VGPR) or better, and the DoR. The OS data remain immature, but certainly the ORR and PFS results support the higher dose of carfilzomib. Dimopoulos MA, et al. ASCO Abstract 8509.

ENDEAVOR: Safety Parameter Kd (n = 464) Vd (n = 465)
Median treatment duration, wks (range) 40 (1-108) 27 (1-106) Dose reduction due to AE, % 23 48 Treatment discontinuation due to AE, % 14 16 Deaths due to AE, % 4 3 Any AE/grade ≥ 3 AE/serious AE, % 98/73/48 98/67/36 Grade ≥ 3 hematologic AE, % Anemia Thrombocytopenia Neutropenia Febrile neutropenia 15.0 8.0 2.2 0.6 10.0 9.0 1.3 Most common grade ≥ 3 infections, % Pneumonia Upper respiratory tract infection Sepsis Herpes zoster 7.0 1.9 0.7 0.4 AE, adverse event; Kd, carfilzomib/dexamethasone; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: The safety profiles associated with each treatment were relatively similar, including grade 3 or higher infections such as Herpes zoster, sepsis, and upper respiratory tract infections. There was a little bit more grade 3 or worse anemia in the carfilzomib group (15% vs 10% with bortezomib), but this was not sufficient to interrupt treatment. Regarding nonhematologic toxicity, the incidence of grade 3 or greater hypertension was 3 times higher with carfilzomib/dexamethasone, rates of fatigue were similar, and cardiac failure and dyspnea were slightly more frequent with carfilzomib. However, these were relatively uncommon events for the trial in aggregate. Dimopoulos MA, et al. ASCO Abstract 8509.

ENDEAVOR: Conclusion Phase III ENDEAVOR trial showed significant PFS improvement and higher response rates with Kd vs Vd in relapsed MM PFS benefit with Kd vs Vd seen across important subgroups, including older pts and those with prior bortezomib exposure Kd associated with higher rates of grade ≥ 3 hypertension, dyspnea, cardiac failure but significantly lower rates of grade ≥ 2 PN and comparable rate of discontinuation due to AEs despite longer time on treatment in Kd arm (40 vs 27 wks) OS data not yet mature Investigators suggested Kd is new standard of care in relapsed MM AE, adverse event; Kd, carfilzomib/dexamethasone; MM, multiple myeloma; OS, overall survival; PFS, progression-free survival; PN, peripheral neuropathy; Vd, bortezomib/dexamethasone. Sagar Lonial, MD: In conclusion, the ENDEAVOR results support high-dose carfilzomib/dexamethasone being superior to bortezomib/dexamethasone in terms of PFS and ORR. For some patients, that did come with more toxicity, such as occasional shortness of breath or dyspnea, hypertension, and a slightly higher incidence of cardiac failure, although whether this was statistically significant is not clear. The OS difference is not yet clear, but the median PFS time was twice as high in the carfilzomib arm as in the bortezomib arm, which strongly supports the use of carfilzomib/dexamethasone at the higher dose in the relapsed and refractory setting. For more information on this study, go to: Dimopoulos MA, et al. ASCO Abstract 8509.

ASPIRE: Lenalidomide/Dexamethasone ± Carfilzomib in R/R MM
Randomized, open-label, multicenter phase III trial previously published results[1]; current study is a secondary analysis[2] Stratified by β2-microglobulin, prior bortezomib, and prior lenalidomide KRd Carfilzomib* 27 mg/m2 IV Days 1, 2, 8, 9, 15, 16 (20 mg/m2 Days 1, 2, cycle 1 only) + Lenalidomide 25 mg Days Dexamethasone 40 mg Days 1, 8, 15, 22 (n = 396) Pts with symptomatic R/R MM after 1-3 prior treatments with ≥ PR to ≥ 1 prior regimen (N = 792) KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma, PR, partial response; Rd, lenalidomide, dexamethasone; R/R, relapsed/refractory. Sagar Lonial, MD: The next trial we will review is an update to the randomized phase III ASPIRE trial evaluating lenalidomide and dexamethasone with or without carfilzomib in patients with relapsed or refractory myeloma (N = 792). Interim findings from ASPIRE were reported at the 2015 American Society of Hematology annual meeting by Stewart and colleagues[1] and published in The New England Journal of Medicine.[2] At ASCO 2015, Dimopoulos and colleagues[3] presented subset analyses from ASPIRE. On July 24, 2015, the FDA approved carfilzomib in combination with lenalidomide and dexamethasone for the treatment of patients with relapsed multiple myeloma who have received 1-3 previous lines of therapy. References: 1. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients (pts) with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Program and abstracts of the 56th American Society for Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 79. 2. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372: 3. Dimopoulos MA, Stewart AK, Rajkumar SV, et al. Effect of carfilzomib, lenalidomide, and dexamethasone (KRd) vs lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma (RMM) by line of therapy: secondary analysis from an interim analysis of the phase III study ASPIRE (NCT ). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8525. Rd Lenalidomide 25 mg Days Dexamethasone 40 mg Days 1, 8, 15, 22 (n = 396) *After cycle 12, carfilzomib given on Days 1, 2, 15, 16. After cycle 18, carfilzomib discontinued. 1. Stewart AK, et al. N Engl J Med. 2015; 372: Dimopoulos MA, et al. ASCO Abstract 8525.

ASPIRE: Progression-Free Survival
1.0 KRd Rd (n = 396) (n = 396) Median PFS, mos HR (KRd/Rd) (95% CI) ( ) P value (one sided) < .0001 0.8 0.6 Proportion Surviving Without Progression 0.4 0.2 KRd Rd KRd, carfilzomib/lenalidomide/low-dose dexamethasone; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone; R/R, relapsed/refractory. Sagar Lonial, MD: The published PFS curve favors the use of carfilzomib with lenalidomide/dexamethasone over lenalidomide/dexamethasone alone (median PFS of 26 months vs 17 months, respectively). Looking at PFS by previous lines of therapy, those with only 1 previous line of therapy had a median PFS of 30 months with carfilzomib/lenalidomide/dexamethasone vs 18 months with lenalidomide/dexamethasone. Those with 2 previous lines had median PFS times of 26 months vs 17 months. Taken together, these data show that in the early relapse setting, the benefit of the triplet seems quite striking and was statistically significant. The ORR data also show that the triplet was superior to the doublet in patients with 1 line of therapy and in those with at least 2 lines. Moreover, CR rates were much higher with the triplet. 6 12 18 24 30 36 42 48 Mos Since Randomization Prior Lines of Therapy Median PFS, Mos KRd Rd HR P Value 1 29.6 17.6 0.694 .0083 2 25.8 16.7 0.688 .0017 Stewart AK, et al. N Engl J Med. 2015;372: Dimopoulos MA, et al. ASCO Abstract 8525.

ASPIRE: Grade ≥ 3 Adverse Events
8/6/2018 ASPIRE: Grade ≥ 3 Adverse Events Grade ≥ 3 Adverse Event, % 1 Prior Line of Therapy 2 Prior Lines of Therapy KRd (n = 182) Rd (n = 154) KRd (n = 210) Rd (n = 235) Neutropenia 26.4 22.1 32.4 29.4 Anemia 17.0 19.5 18.6 15.7 Thrombocytopenia 15.4 11.7 17.6 12.8 Pneumonia 12.1 10.4 12.9 10.6 Hypophosphatemia 9.9 5.2 7.1 4.3 Hypokalemia 7.7 11.0 3.4 Fatigue 6.5 8.1 6.4 Hyperglycemia 6.0 Cataract 5.5 2.6 1.9 2.1 Pulmonary embolism 4.4 Respiratory tract infection 3.8 Asthenia 3.2 3.3 1.3 Hypertension 0.6 4.8 Hypocalcemia 2.9 Insomnia 3.0 KRd, carfilzomib/lenalidomide/low-dose dexamethasone; Rd, lenalidomide/low-dose dexamethasone. Sagar Lonial, MD: AE rates were lower across the board for patients with 1 vs 2 previous lines of therapy, in both the triplet and doublet arms. The toxicity profiles were not appreciably different between the two arms. Dimopoulos MA, et al. ASCO Abstract 8525. Confidential. Not for Distribution.

ASPIRE: Conclusions Results from this post hoc analysis confirm previously published interim analysis data showing clinical benefit to KRd vs Rd in relapsed myeloma The use of KRd after first relapse associated with median PFS improvement of ~ 12 mos vs Rd in pts with 1 prior line of therapy ORRs significantly higher with KRd vs Rd regardless of whether pts had received 1 or ≥ 2 lines of prior therapy CR rates 5-fold higher with KRd in pts with 1 prior line, and 3-fold higher with ≥ 2 lines Grade ≥ 3 AEs similar between KRd and Rd Favorable risk–benefit profile with 1 and ≥ 2 prior lines of therapy AE, adverse event; CR, complete response; KRd, carfilzomib/lenalidomide/low-dose dexamethasone; ORR, overall response rate; PFS, progression-free survival; Rd, lenalidomide/low-dose dexamethasone. Sagar Lonial, MD: In conclusion, results of the ASPIRE study post hoc analysis demonstrated significant benefit of the triplet combination of carfilzomib/lenalidomide/dexamethasone over the doublet of lenalidomide/dexamethasone in patients with relapsed myeloma. The magnitude of benefit was even greater among people with only 1 previous line of therapy. Likewise, ORRs were higher in the triplet arm, in both prior therapy groups. For more information on this study, go to: Dimopoulos MA, et al. ASCO Abstract 8525.

Phase III PANORAMA 1: Bort/Dex ± Panobinostat in R/R Myeloma
Randomized, double-blind trial Stratified by prior lines of therapy and prior bortezomib Treatment Phase I: Eight 21-day cycles (24 wks) Treatment Phase II: Four 42-day cycles (24 wks) Panobinostat 20 mg 3 x/wk + Bort 1.3 mg/m2 IV Days 1, 4, 8, 11 + Dex 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12 (n = 387) Panobinostat 20 mg 3 x/wk + Bort* 1.3 mg/m2 IV + Dex* 20 mg Pts with symptomatic R/R MM after 1-3 prior treatments (bort- refractory excluded) (N = 768) Bort, bortezomib; Dex; dexamethasone; IV, intravenous; MM, multiple myeloma; R/R, relapsed/refractory; SD, stable disease; tx, treatment. Sagar Lonial, MD: PANORAMA 1 was a randomized phase III trial evaluating the benefit of adding panobinostat to bortezomib/dexamethasone in patients with myeloma refractory to 1-3 previous treatments (other than bortezomib).[1] Patients (N = 768) received treatment starting with an induction phase of eight 21-day cycles followed by a maintenance phase where the drugs were given at an attenuated dose and schedule to try and reduce long-term toxicity. References: 1. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma who received prior bortezomib and IMiDs: A predefined subgroup analysis of PANORAMA 1. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8526. Placebo 3 x/wk + Bort 1.3 mg/m2 IV Days 1, 4, 8, 11 + Dex 20 mg Days 1, 2, 4, 5, 8, 9, 11, 12 (n = 381) Placebo 3 x/wk + Bort* 1.3 mg/m2 IV + Dex* 20 mg Pts with ≥ SD in tx phase I can proceed to tx phase II San-Miguel JF, et al. ASCO Abstract 8526. *Reduced frequency.

PANORAMA 1: PFS by Prior Therapy
Median PFS by Prior Treatment, Mos Panobinostat/Bortezomib/ Dexamethasone Bortezomib/Dexamethasone IMiD 12.3 7.4 IMiD + bortezomib 10.6 5.8 IMiD + bortezomib with ≥ 2 prior lines 12.5 4.7 100 PFS With IMiD, bortezomib, and ≥ 2 prior lines 80 IMiD, immunomodulatory drug; PFS, progression-free survival. Sagar Lonial, MD: Previously, it was demonstrated that the triplet arm was clearly superior to the doublet arm in terms of PFS, but this varied based on previous therapy: Patients who had only received an IMiD had a median PFS of 12 months with the triplet vs 7 months with the doublet, whereas for those who had received both an IMiD and bortezomib, median PFS times were 10 months vs 5 months.[1] Patients who had received an IMiD and bortezomib as part of at least 2 previous lines of therapy had median PFS times of 12.5 months vs only 4.7 months, again, speaking to the potential ability of panobinostat to overcome drug resistance in this setting. References: 1. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 2014;15: 60 Pano-Bort-Dex Bort-Dex PFS Probability (%) 40 20 28 24 20 16 12 8 4 2 6 10 14 18 22 26 Mos San-Miguel JF, et al. ASCO Abstract 8526.

PANORAMA 1: Grade 3/4 AEs by Prior Treatment
Select Grade 3/4 AEs (≥ 20% Incidence), % Prior IMiD Prior IMiD + Bort Prior IMID, Bort With ≥ 2 Lines Pan/Bort/Dex Bort/Dex Pan/Bort/ Dex Hematologic Thrombocytopenia 67.2 35.7 68.5 48.0 68.1 44.4 Leukopenia 23.7 10.0 19.6 12.1 20.8 11.0 Lymphopenia 53.9 40.6 50.0 46.5 48.6 49.3 Neutropenia 36.9 12.6 35.9 17.2 40.3 16.4 Anemia 17.0 21.3 18.5 19.2 20.5 Nonhematologic Diarrhea 26.1 7.9 30.4 13.1 33.3 15.1 Fatigue/asthenia 25.3 11.7 25.0 26.4 13.7 PN 14.2 15.2 9.1 16.7 6.8 Nausea 5.8 0.8 8.7 1.0 11.1 1.4 Peripheral edema 1.7 2.2 2.8 AE, adverse event; Bort, bortezomib; Dex, dexamethasone; IMiD, immunomodulatory drug; Pan, panobinostat; PN, peripheral neuropathy. Sagar Lonial, MD: Across the board, AEs were relatively similar for patients who received the triplet, regardless of previous treatment. But for those who received bortezomib and dexamethasone only, the AEs were worse with more previous treatment. This is important point because much of the benefit attributed to panobinostat may simply be the effect of panobinostat in combination with bortezomib in a very heavily treated, relapsed and refractory patient population. San-Miguel JF, et al. ASCO Abstract 8526.

PANORAMA 1: Conclusions
Subgroup analyses confirmed PFS benefit with addition of panobinostat to bortezomib/dexamethasone maintained among pts with varying prior treatment Prior IMiDs, prior IMiDs plus bortezomib, prior IMiDs plus bortezomib and ≥ 2 prior lines of therapy Magnitude of PFS benefit between arms in subgroups was clinically meaningful (difference in median PFS) Prior IMiD: 4.9 mos Prior IMiD plus bortezomib: 4.8 mos Prior IMiD plus bortezomib and ≥ 2 prior lines of therapy: 7.8 mos Safety profiles of subgroups similar to overall population IMiD, immunomodulatory drug; PFS, progression-free survival. Sagar Lonial, MD: The conclusion for the PANORAMA 1 study was that the addition of panobinostat to bortezomib and dexamethasone provides a significant PFS benefit, particularly among patients who have had at least 2 previous lines of therapy including IMiDs and bortezomib: Median PFS was 12.5 months in that subset vs less than 5 months for the other 2 subsets. In addition, the safety profile seemed relatively similar across all 3 patient subgroups. Going forward, examination of alternative doses and schedules of panobinostat will help determine how to best use this drug in the treatment of patients with relapsed and refractory myeloma. San-Miguel JF, et al. ASCO Abstract 8526.

ELOQUENT-2: Elotuzumab With Lenalidomide/Dexamethasone R/R MM
Randomized, open-label, multicenter international phase III trial Primary endpoints: PFS, ORR Secondary endpoints: OS (data not mature), DoR, QoL, safety Elotuzumab* 10 mg/kg IV QW in cycles 1, 2; q2w thereafter + Lenalidomide 25 mg PO Days Dexamethasone 40 mg/wk equiv 28-day cycles (n = 321) R/R MM with 1-3 prior lines of therapy (prior lenalidomide exposure allowed in 10%) (N = 646) Assessed q4w until PD; followed q12w thereafter for survival Lenalidomide 25 mg PO Days Dexamethasone 40 mg PO Days 1, 8, 15, 22; 28-day cycles (n = 325) DoR, duration of response; equiv, equivalent; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; QW, once weekly; q2w, every 2 weeks; q4w, every 4 weeks; q12w, every 12 weeks; QoL, quality of life; R/R, relapsed/refractory. Sagar Lonial, MD: We will now discuss the ELOQUENT-2 trial, a phase III study of elotuzumab,[1] a humanized IgG1 monoclonal antibody directed against SLAMF7. Elotuzumab eliminates myeloma cells by an indirect mechanism involving activation of natural killer (NK) cells.[2-4] However, it has limited single-agent activity. Phase II data showed a very high ORR and a strong PFS benefit when elotuzumab was combined with lenalidomide/dexamethasone in patients with relapsed/refractory myeloma.[5] In this combination, elotuzumab does appear to activate NK cells and to target myeloma cells for ADCC. The subsequent ELOQUENT-2 trial evaluated lenalidomide/dexamethasone with or without elotuzumab.[6] In this randomized phase III trial, patients (N = 646) received standard doses of lenalidomide and dexamethasone in both arms, with the experimental arm also receiving elotuzumab 10 mg/kg. Primary endpoints were PFS and ORR, with secondary endpoints including OS, DoR, and safety. Approximately one third of patients in this trial had high-risk disease evidenced by the 17p deletion, one third met the International Myeloma Working Group criteria for high-risk disease, and one third were refractory to their most recent therapy. So although this was an early subset of patients, they were quite refractory. This factor may speak to some of the differences between the control arm of this trial and the control arm in the ASPIRE trial.[7] References: 1. Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): MMY2002 (SIRIUS). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract LBA8512. 2. Hsi ED, Steinle R, Balasa B, et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin Cancer Res. 2008;14: 3. Collins SM, Bakan CE, Swartzel GD, et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol Immunother. 2013;62: 4. Guo H, Cruz-Munoz ME, Wu N, et al. Immune cell inhibition by SLAMF7 is mediated by a mechanism requiring Src kinases, CD45, and SHIP-1 that is defective in multiple myeloma cells. Mol Cell Biol. 2015;35:41-51. 5. Richardson PG, Jagannath S, Moreau P, et al. Final results for the 1703 phase 1b/2 study of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma. Program and abstracts of the 56th American Society for Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 302. 6. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone vs lenalidomide and dexamethasone in patients (pts) with relapsed multiple myeloma: interim results from ASPIRE, a randomized, open-label, multicenter phase 3 study. Program and abstracts of the 56th American Society for Hematology Annual Meeting and Exposition; December 6-9, 2014; San Francisco, California. Abstract 79. 7. Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med. 2015;372: *Premedication administered before elotuzumab. Lonial S, et al. ASCO Abstract 8508.

Probability Progression Free Combined Response (sCR + CR + VGPR)
ELOQUENT-2: PFS and OS 1-yr PFS 2-yr PFS 1.0 Elo-Rd Rd 0.8 HR: 0.70 (95% CI: ) P = .0004 Median PFS, mos (95% CI) ( ) ( ) 68% Probability Progression Free 0.6 42% 0.4 57% Elo-Rd Rd 0.2 27% 4 8 12 16 20 24 28 32 36 Mos P = .0002 100 CR, complete response; Elo, elotuzumab; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; Rd, lenalidomide, dexamethasone; sCR, stringent complete response; VGPR, very good partial response. Sagar Lonial, MD: Results showed that the addition of elotuzumab to lenalidomide/dexamethasone conferred a significant improvement in PFS: Median PFS was 19.4 months vs 14.9 months, with 41% of elotuzumab-treated patients without progression at 2 years. OS data are not yet available. The ORR favored the elotuzumab arm over the control arm as well, at 79% vs 66%, respectively. Of importance, the shape of the PFS curves speaks to the power of immune-based treatment in that, to date, the curves do not appear to be coming back together. This is an important benefit of using monoclonal antibody–based therapy in the context of relapsed and refractory myeloma. We also found consistent benefit across subgroups. For example, patients with del(17p) had a similar benefit as those without del(17p). This suggests that elotuzumab may be able to overcome the poor risk associated with this abnormality. Elo-Rd Rd 79 80 66 60 Response Rate (%) 46 38 40 33 28 28 21 20 7 4 ORR* Combined Response (sCR + CR + VGPR) CR (sCR + CR )† VGPR PR Lonial S, et al. ASCO Abstract 8508.

ELOQUENT-2: Safety Elotuzumab well tolerated, had no negative effect on QoL Infusion reactions reported in 10% of pts (9% grade 1/2; 1% grade 3); 70% occurred with initial dose 2 discontinuations (1%) due to infusion reaction Selected Grade 3/4 AEs, % Elotuzumab-Rd (n = 318) Rd (n = 317) Lymphopenia 77 49 Neutropenia 34 44 Infection 28* 24* Nonhematologic Fatigue Pyrexia Diarrhea 9 3 5 8 4 AE, adverse event; Rd, lenalidomide/dexamethasone; QoL, quality of life. Sagar Lonial, MD: In terms of AEs, elotuzumab was well tolerated. There was no impact on quality of life. Infusion reactions were only seen in 10% of patients, and most were grade 1/2. Approximately 70% occurred with just the first dose of elotuzumab, and only 2 patients had to discontinue because of an infusion reaction. *Incidence similar after controlling for duration of therapy. Lonial S, et al. ASCO Abstract 8508.

ELOQUENT-2: Conclusions
Addition of elotuzumab to lenalidomide/dexamethasone associated with statistically and clinically significant increase in PFS, ORR in pts with R/R MM PFS benefit with elotuzumab maintained across important subgroups, including high-risk and elderly pts Adding elotuzumab did not increase the incidence of AEs and without a negative effect on QoL OS data not yet mature Investigators noted elotuzumab is first monoclonal antibody to show PFS benefit when added to lenalidomide/dexamethasone in randomized, phase III trial in R/R MM AE, adverse event; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; QoL, quality of life; R/R, relapsed/refractory. Sagar Lonial, MD: In summary, elotuzumab is the first antibody to demonstrate PFS improvements in combination with lenalidomide/dexamethasone in a phase III trial in relapsed/refractory myeloma. There may be a tail on the PFS curve, suggesting a long-term benefit of immune-based therapy that targets not only myeloma cells but also the effectors of ADCC and other immune parameters. This study is very powerful and very important, although longer follow-up is needed to understand the OS benefit. Most important, this combination appears to overcome high-risk characteristics and appears to prolong the depth of response vs lenalidomide/dexamethasone alone for patients who have achieved at least a PR. For more information on this study, go to: Lonial S, et al. ASCO Abstract 8508.

Stage 1 Response assessment
SIRIUS: Study Design Stage 1 Response assessment Open-label, international, multicenter, 2-stage study Primary objective: ORR Secondary objectives: PFS, OS, duration of response, time to response, clinical benefit rate Stage 2 Enrollment of additional pts at 16 mg/kg dose (outcomes reported for all pts at 16 mg/mg dose) Daratumumab 8 mg/kg q4w (n = 18) Pts with MM who had received ≥ 3 prior lines of therapy or were refractory to a PI and an IMiD (N = 53) Daratumumab 16 mg/kg QW x 8 then q2w x 16, then q4w thereafter (n = 16) Daratumumab 16 mg/kg QW x 8 then q2w x 16, then q4w thereafter (n = 90) IMiD, immunomodulatory drug; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PI, proteasome inhibitor; q2w, every 2 weeks; q4w, every 4 weeks; QW, once weekly. Sagar Lonial, MD: This is the phase II SIRIUS trial, which was a large phase II study evaluating daratumumab in an unmet medical need population in myeloma: in patients who had previously received ≥ 3 lines of therapy or were refractory to a proteasome inhibitors and an immunomodulatory drug (IMID).[1] Daratumumab is a human monoclonal antibody that targets CD38, which is a protein found on the surface of nearly all myeloma cells and has lower expression levels on lymphoid and myeloid cells as well.[2,3] An early phase I first-in-man study, GEN501, suggested some activity of daratumumab as a single agent in relapsed myeloma.[4] The goal of the SIRIUS trial was to evaluate the efficacy of daratumumab in a much larger patient population of heavily pretreated patients with myeloma to hopefully meet requirements for accelerated approval. The first stage of the SIRIUS study was designed to determine the optimal dose and schedule of daratumumab in patients with multiple myeloma and at least 3 previous lines of therapy or who were refractory to both a proteasome inhibitor and an IMiD. After approximately 30 patients were evaluated, it was very clear that the 16 mg/kg dose given every week for 2 months, then every 2 weeks for 4 months, and then every month after was the optimal dose. In the second stage of the study, an additional 90 patients were given daratumumab on the chosen dose and schedule. The primary objective of this trial was ORR. Secondary objectives include safety, DoR, and clinical benefit rate. The population in this study had a median time since diagnosis of almost 5 years and median of 5 previous therapies. Both pomalidomide and carfilzomib were approved for the treatment of myeloma based on studies with similarly heavily pretreated patients. All patients had received IMiDs, including pomalidomide, and proteasome inhibitors, including approximately 50% who had received carfilzomib. Patients were highly refractory, including 48% who were refractory to carfilzomib and 88% who were refractory to lenalidomide. More than 30% were refractory to bortezomib, lenalidomide, carfilzomib, and pomalidomide. References: Lonial S, Weiss BM, Usmani SZ, et al. Phase II study of daratumumab (DARA) monotherapy in patients with ≥ 3 lines of prior therapy or double refractory multiple myeloma (MM): MMY2002 (SIRIUS). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract LBA8512. 2. Lin P, Owens R, Tricot G, et al. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121: 3. Laubach JP, Tai YT, Richardson PG, et al. Daratumumab granted breakthrough drug status. Expert Opin Investig Drugs. 2014;23: 4. Lokhorst HM, Laubach J, Nahi H, et al. Dose-dependent efficacy of daratumumab (DARA) as monotherapy in patients with relapsed or refractory multiple myeloma (RR MM). Program and abstracts of the 50th annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2014; Chicago, Illinois. Abstract 8513. Lonial S, et al. ASCO Abstract LBA8512.

Change in Paraprotein From Baseline Maximum Change From Baseline (%)
SIRIUS: Efficacy Responses observed across subgroups Deepening of responses with continued treatment Median time to response: 1 mo Median DoR: 7.4 mos (95% CI: 5.5-NE) Median PFS: 3.7 mos (95% CI: ) 1-yr OS: 65% (95% CI: 51.2% to 75.5%) 100 Change in Paraprotein From Baseline 75 50 DoR, duration of response; NE, not estimable; OS, overall survival; PFS, progression-free survival. Sagar Lonial, MD: A significant fraction of patients had at least some response to single-agent daratumumab and, in fact, many of those responses did continue to deepen over time. The median PFS was 3.7 months, and the 1-year OS rate was 65%. 25 Maximum Change From Baseline (%) -25 -50 -75 -90 -100 Lonial S, et al. ASCO Abstract LBA8512. Reprinted with permission.

SIRIUS: ORR ORR by Subgroup 35 40 30 ORR = 29% sCR n = 3 (3%) 30 20 25
33 33 30 30 30 29 ORR = 29% sCR n = 3 (3%) 28 28 26 30 21 21 ORR (%) 20 20 25 10 VGPR n = 10 (9%) 20 ORR (%) 15 Aged ≥ 75 yrs 10 PR n = 18 (17%) CrCl ≥ 60 mL/min > 3 Lines of Therapy 5 CrCl, creatinine clearance; IMiD, immunomodulatory drug; ORR, overall response rate; OS, overall survival; PI, proteasome inhibitor; PR, partial response; sCR, stringent complete response; VGPR, very good partial response. Sagar Lonial, MD: The ORR in this study was approximately 29%, including 3 patients who achieved a stringent CR and 10 who achieved a VGPR. We have not seen such strong depth-of-response data from a new drug or a new target since the phase II SUMMIT trial of bortezomib.[1] The achievement of not just responses but CRs in patients with a median of 5 previous lines of therapy is quite impressive. Of note, the response and depth of response were independent of prior exposure, lines of therapy, extramedullary disease, genetics, or other factors defining subgroups. References: 1. Jagannath S, Richardson PG, Barlogie B, et al. Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica. 2006;91: Extramedullary Disease High-Risk Cytogenetics Pls and IMiDs Carfilzomib Pomalidomide Carfilzomib + Pomalidomide Bortezomib + Lenalidomide Bortezomib + Lenalidomide + Carfilzomib + Pomalidomide 16 mg/kg Refractory to Lonial S, et al. ASCO Abstract LBA8512. Reprinted with permission.

SIRIUS: Safety Most common grade 3/4 AEs: thrombocytopenia (25%), anemia (24%), neutropenia (14%) Grade 3/4 anemia, thrombocytopenia more frequent in nonresponders Note that trial allowed pts with hemoglobin > 7.5 g/dL, platelet count ≥ 50 x 109/L at baseline Infusion-related reactions: 43% Primarily grade 1/2, > 90% occurred during first infusion 7% of pts had another infusion reaction beyond first dose No discontinuations due to treatment-related AEs, including infusion reactions AE, adverse event. Sagar Lonial, MD: Most of the common hematologic toxicities in SIRIUS occurred in nonresponders and were not considered a consequence of therapy. However, one aspect of daratumumab that is common to all monoclonal antibodies is infusion-related reactions, which occurred in 43% of patients. Most were grade 1 and grade 2, and 90% occurred with the first infusion. Only 7% of patients had a subsequent infusion-related reaction. No patients discontinued treatment because of infusion reactions. Lonial S, et al. ASCO Abstract LBA8512.

SIRIUS: Conclusion Daratumumab associated with single-agent activity in heavily pretreated MM; ORR 29%[1] Responses were rapid, appeared durable, and improved over time (appearance of sCRs, VGPR) Daratumumab was well tolerated, with no discontinuations due to AEs Infusion reactions mild to moderate, manageable Investigators concluded daratumumab is a potential new standard of care in this population Study is currently ongoing[2] AE, adverse event; MM, multiple myeloma; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response. Sagar Lonial, MD: In conclusion, daratumumab had an impressive ORR of 29% in patients with a median of 5 previous lines of therapy. Responses, including CRs, were seen in this heavily pretreated population. Infusion reactions were relatively mild. Given the activity of data and the fact that many of these patients had no additional treatment options, daratumumab likely does represent a new potential standard of care in this population of patient. Several phase III trials are ongoing to further confirm the benefit of daratumumab.[1-3] For more information on this study, go to: to References: 1. ClinicalTrials.gov. Addition of daratumumab to combination of bortezomib and dexamethasone in participants with relapsed or refractory multiple myeloma. Available at: Accessed August 3, 2015 2. ClinicalTrials.gov. A study comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. Available at: Accessed August 3, 2015 3. ClinicalTrials.gov. Study Comparing daratumumab, lenalidomide, and dexamethasone with lenalidomide and dexamethasone in participants with previously untreated multiple myeloma. Available at: Accessed August 3, 2015. 1. Lonial S, et al. ASCO Abstract LBA ClinicalTrials.gov. NCT

Panobinostat/Carfilzomib in R/R MM: Study Design
Pts with MM and PD during/after 1 prior therapy; ECOG PS 0-2 (N = 36) Panobinostat PO on Days 1, 3, 5, 15, 17, 19 30 mg (dose level 5) or 20 mg (dose level 6) + Carfilzomib 20/56 mg/m2 IV on Days 1, 2, 8, 9, 15, 16 Response evaluated every 4 wks Pts with SD or better continued treatment until progression or intolerable toxicity ECOG, Eastern Cooperative Oncology Group; IV, intravenous; MM, multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PO, orally; PS, performance status; R/R, relapsed/refractory; SD, stable disease; TTP, time to progression. Sagar Lonial, MD: The HDAC inhibitor panobinostat clearly has activity when combined with other agents. However, trying to find the ideal partner has been an issue, given that there was so much overlapping toxicity when combined with bortezomib. As a result, Berdeja and colleagues[1,2] sought to determine whether the proteasome inhibitor carfilzomib might be effective and associated with less toxicity when combined with panobinostat. In this study of panobinostat in patients with relapsed/refractory myeloma (N = 36), panobinostat was dosed differently from other studies: 30 mg on Days 1, 3, and 5 of the first week and then Days 15, 17, and 19 in the third week. This is basically a week on, a week off, another week on, and a week off in conjunction with standard dose-escalated carfilzomib up to 56 mg/m2. The primary endpoints were safety, tolerability, and ORR, with secondary objectives including time to progression, PFS, and OS. References: 1. Berdeja JG, Hart L, Mace J, et al. Phase I/II study of the combination of panobinostat and carfilzomib in patients with relapsed/refractory multiple myeloma. Haematologica. 2015;100: 2. Berdeja JG, Gregory TK, Matous J, et al. A phase I/II study of the combination of panobinostat (PAN) and carfilzomib (CFZ) in patients (pts) with relapsed or relapsed/refractory multiple myeloma (MM). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8513. Primary objective: safety, tolerability, ORR Secondary objectives: TTP, PFS, OS Berdeja JG, et al. ASCO Abstract Used with permission.

Panobinostat/Carfilzomib in R/R MM: Efficacy
With a median follow-up of 7.9 mos, the median TTP, PFS, and OS has not been reached Parameter All Pts (N = 35) Pts at Dose Level 6* (n = 32) ORR, % CR VGPR PR MR SD 77 3 29 45 11 75 28 44 13 Median time to best response, wks (range) 4.1 (0-27.3) 4.4 (0-23) CR, complete response; MM, multiple myeloma; MR, minimal response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; R/R, relapsed/refractory; SD, stable disease; TTP time to progression; VGPR, very good partial response. Sagar Lonial, MD: In this study, the ORR was 77% and included both VGPRs and a few CRs. The median time to best response was 4 weeks, and at a median follow-up of 7.9 months, the median time to progression, EFS, and OS have not yet been reached. *Starting doses: panobinostat 20 mg (avg: 17.9 mg), carfilzomib 20/56 mg/m2 (avg: 52.2 mg/m2). Berdeja JG, et al. ASCO Abstract Reprinted with permission.

Panobinostat/Carfilzomib in R/R MM: Safety
GI toxicities most common; primarily grade 1/2 Cardiac AEs primarily grade 1/2 Grade 3/4 Treatment-Related AEs, % (Observed in > 5% of Pts) Grade 3 Grade 4 Hematologic Thrombocytopenia Neutropenia Anemia 31 8 3 17 Nonhematologic Fatigue Diarrhea Confusion Increased creatinine 11 6 AE, adverse event; GI, gastrointestinal; MM, multiple myeloma; R/R, relapsed/refractory. Sagar Lonial, MD: In addition to clearly being an active combination in a very heavily pretreated patient population, this combination appears tolerable. Most gastrointestinal toxicity was grade 1/2. There was some grade 3 hematologic toxicity, including thrombocytopenia in 31% (grade 4 in 17%). But in general, this dose and schedule was tolerated quite well, which suggests that the week on, week off schedule for panobinostat makes a big difference. Berdeja JG, et al. ASCO Abstract Reprinted with permission.

Panobinostat/Carfilzomib in R/R MM: Conclusion
Panobinostat 20 mg 3 x every other wk + carfilzomib 20/56 mg/m2 twice weekly was active in pts with R/R MM[1] ORR: 77% Regimen was well tolerated; GI toxicity primarily grade 1/2 90% of planned doses administered for both drugs Investigators concluded further studies warranted of this dose/schedule of panobinostat/carfilzomib and are currently ongoing[2] GI, gastrointestinal; MM, multiple myeloma; ORR, overall response rate; R/R, relapsed/refractory. Sagar Lonial, MD: In conclusion, escalated carfilzomib 56 mg/m2 twice weekly, plus panobinostat 20 mg used on a 1 week on, 1 week off, 1 week on schedule produced a very high ORR of 77%. Most gastrointestinal toxicity was limited. Additional phase II and phase III studies of this dose and schedule are planned and under way. For more information on this study, go to: 1. Berdeja JG, et al. ASCO Abstract ClinicalTrials.gov. NCT

KRd With ASCT in Newly Diagnosed MM: Study Design
Open-label, multicenter phase II clinical trial N = 62 ASCT-eligible pts with MM requiring treatment Primary endpoint: sCR rate after 8 cycles of KRd Secondary endpoints: ORR, ≥ nCR, DoR, TTP, PFS, OS, safety Induction (Cycles 1-4) Consolidation (Cycles 5-8) Maintenance (Cycles 9-18) Carfilzomib 20/36 mg/m2 IV Days 1, 2, 8, 9, 15, 16 + Lenalidomide 25 mg Days Dexamethasone 40 mg/wk every 28 days ASCT Carfilzomib LTD Days 1, 2, 8, 9, 15, 16 + Lenalidomide 15 mg (cycle 5) up to LTD (cycles 6-8) Days Dexamethasone 20 mg or LTD weekly, every 28 days Carfilzomib LTD Days 1, 2, 15, 16 + Lenalidomide LTD Days Dexamethasone LTD weekly ASCT, autologous stem cell transplantation; DoR, duration of response; IV, intravenous; KRd, carfilzomib/lenalidomide/dexamethasone; LTD, last tolerated dose; MM, multiple myeloma; nCR, near complete response; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; sCR, stringent complete response; TTP, time to progression. Sagar Lonial, MD: The combination of carfilzomib/lenalidomide/dexamethasone (KRd) as frontline therapy has been shown at some small centers to delay the need for transplantation because of the high response rate and efficacy.[1] It was hypothesized that continuation of KRd after transplantation could further improve outcomes.[2] Zimmerman and colleagues[2] conducted an open-label phase II trial of extended KRd in patients with transplantation-eligible myeloma (N = 62). Patients received 4 cycles of KRd at the standard dose and schedule,[1] followed by autologous stem cell transplantation. Patients then received 3 cycles of KRd as consolidation therapy, 9 cycles as maintenance therapy, and continual lenalidomide maintenance until progression. The primary endpoint was stringent CR after 8 cycles. Secondary endpoints included ORR, DoR, time to progression, and PFS. The majority (~ 60%) of patients were International Staging System stage II/III; approximately 40% had high-risk cytogenetics and more than one third had a β2-microglobulin level > 3.5 mg/L. References: 1. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase I/II study of the combination of panobinostat (PAN) and carfilzomib (CFZ) in patients (pts) with relapsed or relapsed/refractory multiple myeloma (MM). Blood. 2012;120: 2. Zimmerman TM, Griffith KA, Jasielec J, et al. Phase II MMRC trial of extended treatment with carfilzomib (CFZ), lenalidomide (LEN, and dexamethasone (DEX) plus autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (NDMM). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 8510. Indefinite Maintenance Lenalidomide LTD Days 1-21 (off protocol) Zimmerman TM, et al. ASCO Abstract Used with permission.

KRd With ASCT in Newly Diagnosed MM: Responses Over Treatment Course
≥ VGPR ≥ nCR ≥ CR sCR 100 100 100 100 97 85 87 87 87 80 75 71 60 Response (%) 40 32 21 24 22 ASCT, autologous stem cell transplantation; CR, complete response; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; nCR, near complete response; sCR, stringent complete response; VGPR, very good partial response. Sagar Lonial, MD: Looking at the response rate over different points in treatment shows important changes. For example, the rate of VGPR or better after induction was 85%, which improved to 97% after autologous stem cell transplantation, with 32% of patients in near CR or better. After consolidation and prolonged maintenance, at cycle 18, all patients had achieved at least a near CR, with at least stringent CR or CR in 87%. These results demonstrate the power of continuing therapy. 20 12 8 Induction (n = 48) ASCT (n = 37) Consolidation (n = 24) End of KRd (n = 8) Zimmerman TM, et al. ASCO Abstract Reprinted with permission.

KRd With ASCT in Newly Diagnosed MM: Efficacy and MRD Evaluation
Proportion of pts with MRD- negative disease increased over time 85% after consolidation; 100% after KRd maintenance Outcomes after median follow-up of 11 mos 61/62 pts progression free All pts alive sCR MRD negative 100 100 85 87 80 71 60 60 Response (%) 40 22 20 ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MRD, minimal residual disease; sCR, stringent complete response. Sagar Lonial, MD: One of the challenges in evaluating this study is that the number of evaluable patients declined to only 8 beyond the consolidation phase, and the median follow-up of 11 months is very short. Nevertheless, even with such a small group, 87% achieving stringent CR speaks to the feasibility of long-term triplet therapy as consolidation and maintenance. The MRD results showed that 60% were MRD negative after the transplantation, which rose to 85% after consolidation, and 100% after maintenance, again with the caveat of an n of 8. ASCT (n = 37) (n = 21*) Consolidation (n = 24) (n = 17*) End of KRd (n = 8) (n = 8*) *MRD by 10-color flow cytometry from indicated number of pts available for MRD evaluation. Zimmerman TM, et al. ASCO Abstract Reprinted with permission.

KRd With ASCT in Newly Diagnosed MM: Safety
AEs Reported in ≥ 25% of Pts, % Any Grade (n = 62) Grade ≥ 3 Hematologic Thrombocytopenia Leukopenia Lymphopenia Anemia 58.1 37.1 35.5 32.3 11.3 9.7 25.8 6.5 Nonhematologic Fatigue Hyperglycemia Rash Pyrexia Dyspnea Peripheral neuropathy 48.4 38.7 29.0 27.4 1.6 3.2 AE, adverse event; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma. Sagar Lonial, MD: In this study, many AEs were reported and associated with a transplantation, although few were grade 3 or higher, other than lymphopenia in 26% and thrombocytopenia in 11%. Most toxicities were hematologic and not unexpected. Grade 3 or worse nonhematologic events included hyperglycemia, rash, and fever. But overall, KRd was relatively tolerable. Zimmerman TM, et al. ASCO Abstract Reprinted with permission.

KRd With ASCT in Newly Diagnosed MM: Conclusion
KRd induction and consolidation with ASCT after cycle 4 was associated with sCR rate of 71% after 8 cycles Higher than historical control without ASCT (30% after 8 cycles) Responses deepened with continued therapy 8 of 8 evaluable pts attained MRD negativity after KRd consolidation and maintenance Toxicity profile similar to previous studies Investigators concluded the addition of ASCT after KRd appears to improve outcomes ASCT, autologous stem cell transplantation; KRd, carfilzomib/lenalidomide/dexamethasone; MM, multiple myeloma; MRD, minimal residual disease; sCR, stringent complete response. Sagar Lonial, MD: In conclusion, KRd is feasible with this dose and schedule. It produced a very high stringent CR of 71% after 8 cycles of therapy, and responses deepened over time. The toxicity profile was not prohibitive. These results suggest that KRd might be of benefit as an induction regimen for patients with newly diagnosed myeloma, followed by consolidation and maintenance in the posttransplantation period. For more information on this study, go to: Zimmerman TM, et al. ASCO Abstract 8510.

Acute Leukemia Farhad Ravandi, MD:
I will discuss key clinical trial data in acute leukemia and myelodysplasias presented at the 2015 ASCO annual meeting. We will begin with some key aspects of treating patients with acute myeloid leukemia (AML).

Poor Prognostic Phenotype: CD34+CD38- ALDHint
ALDH identifies CD34+CD38- stem cells in AML Cells with CD34+CD38- ALDHint phenotype are 96% leukemic by FISH Resistant to induction therapy Total leukemic burden decreased by 1.0 log10 cells vs 2.5 logs for bulk leukemic cells Pts with persistent CD34+CD38- ALDHint cells relapse 6/7 in pt sample with persistent CD34+CD38- ALDHint ultimately relapsed despite no overt relapse at follow-up In same sample, 9/9 without ALDHint cells remained in remission with follow-up of 688 days ALDH, aldehyde dehydrogenase; AML, acute myeloid leukemia; int, intermediate; FISH, fluorescence in situ hybridization. Farhad Ravandi, MD: In this setting of relapsed AML, better prognostic and predictive markers are needed. Clinical features, as well as cytogenetic and molecular data have been used. However, it can take a long time to obtain results of cytogenetics or molecular testing, so other potential markers would be very helpful. Gerber and colleagues[1,2] have been studying utility of leukemic stem cells to fill this need. This group has been trying to identify leukemia stem cells with prognostic or predictive value, as well as other biomarkers. The testing is done by flow cytometry. Traditionally, the CD4+CD38- population of cells is thought to be enriched among the population of stem cells. In a previous report, this group showed that the CD34+CD38-ALDHInt phenotype was enriched among leukemic stem cells, and then this was verified by testing for these cytogenetic abnormalities in the specific population.[2] In addition, this population of cells also appears useful as a marker of minimal residual disease. In the current study,[1] 3 subtypes of potential leukemic stem cell-rich populations were evaluated: CD34-,[3,4] CD34+CD38-ALDHint, and CD34+CD38-ALDHhigh. These phenotypes were correlated with pretreatment characteristics, as well as response to chemotherapy and long-term outcomes. References: 1. Gerber JM, Zeidner JF, Morse S, et al. Correlation of acute myeloid leukemia (AML) stem cell phenotype with cytogenetic/molecular features and prognosis. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7000. 2. Gerber JM, Smith BD, Ngwang B, et al. A clinically relevant population of leukemic CD34(+)CD38(-) cells in acute myeloid leukemia. Blood. 2012;119: 3. van der Pol MA, Feller N, Roseboom M, et al. Assessment of the normal or leukemic nature of CD34+ cells in acute myeloid leukemia with low percentages of CD34 cells. Hematologica. 2003;88: 4. Taussig DC, Vargaftig J, Miraki-Moud F, et al. Leukemia-initiating cells from some acute myeloid leukemia patients with mutated nucleophosmin reside in the CD34(-) fraction. Blood. 2010;115: Gerber JM, et al. ASCO Abstract Gerber JM, et al. Blood. 2012;119:

Leukemia Stem Cell Phenotypes: Study Design
Multicenter, randomized phase II trial[1,2] to determine correlation of stem cell phenotype with response to chemotherapy Primary endpoint: CR 2:1 randomization; stratified by < or ≥ 50 yrs of age, secondary AML, WBC < or ≥ 50,000/mm³ Flavopiridol 50 mg/m2 IV Days 1-3 + Cytarabine 2 g/m2 IV over 72 hrs, Days 6-8 + Mitoxantrone 40 mg/m² IV Day 9 Pts with AML (N = 165) AML, acute myeloid leukemia; Ara-c, cytarabine; CR, complete response; IV, intravenous; WBC, white blood cell. Farhad Ravandi, MD: The patients (N = 165) in this randomized phase II trial were randomized to receive either cytarabine plus daunorubicin or cytarabine plus mitoxantrone and flavopiridol. The primary endpoint was the CR rate. Of note, this study was less about determining responses to 2 different regimens and more about correlation of responses to stem cell phenotypes. This is because, after many years of AML therapy, we know that responses to most of initial induction regimens are approximately the same. In this population, approximately 40% had adverse cytogenetics, and about 10% had the FLT3-ITD mutation, which is fewer than expected. Approximately 22% had NPM1 mutations. Most (70%) patients were randomized to receive the investigational regimen of flavopiridol, cytarabine, and mitoxantrone. Cytarabine 100 mg/m2 IV Days 1-7 + Daunorubicin* 90 mg/m² IV Days 1-3† *Idarubicin 12 mg/m2 if daunorubicin not available. †Followed by cytarabine 100 mg/m2 IV Days daunorubicin* 45 mg/m² IV Days 1-2 if residual leukemia after 14 days. 1. Gerber JM, et al. ASCO Abstract ClinicalTrials.gov. NCT

Phenotypes and Risk Factors
AML Stem Cell Phenotype Correlates With Cytogenetic and Molecular Risk Factors All correlations highly significant, P < .001 (Fisher’s exact and Mantel-Haenszel tests were used to analyze differences) Phenotypes and Risk Factors Characteristic, n (%) CD34- (n = 22) CD34+CD38-ALDHint (n = 43) CD34+CD38-ALDHhigh (n = 33) NPM1 mutations 14 (64)* 6 (14) 2 (6)† Poor cytogenetic risk factors and/or FLT3-ITD 4 (18)‡ 15 (35) 28 (85)§ ALDH, aldehyde dehydrogenase; AML, acute myeloid leukemia; ELN, European LeukemiaNet; int, intermediate. Farhad Ravandi, MD: The investigators reported that CD34- stem cells were enriched in the NPM1 mutation–positive population (64%), while they were much less common (18%) in patients with poor-risk cytogenetics or who were FLT3-ITD positive. On the other hand, more adverse cytogenetics were associated with the CD34+CD38-ALDHhigh stem cell phenotype: 85% vs only 6% in patients with NPM1 mutations. There does seem to be a correlation between the type of stem cell and the cytogenetic risk group. This makes sense because these groups may represent different diseases and, therefore, respond to therapy differently. The more-favorable risk patients tend to have the NPM1 mutation with no FLT3-ITD, whereas less favorable patients tend to have the poor risk cytogenetics or FLT3-ITD mutations. Of note, such testing is readily available, depending on the expertise of the flow cytometry laboratory that analyzes the samples. *Sole abnormality, n = 11. †+FLT3-ITD or complex karyotype. ‡9% with ELN poor phenotype; 11q23, n = 2. §73% with ELN poor phenotype; 55% with earlier myelodysplastic syndrome or myeloproliferative neoplasm. Gerber JM, et al. ASCO Abstract 7000.

Stem Cell Phenotype Correlates With Clinical Outcomes
All correlations highly significant Phenotypes and Outcomes Outcome CD34- (n = 22) CD34+CD38-ALDHint (n = 43) CD34+CD38-ALDHhigh (n = 33) CR, % 86* 67* 45* EFS, mos EFS at 2 yrs, % HR (95% CI) 13 46 0.58 ( )* 11.3 26 Ref* 2.2 2.15 ( )* OS, mos OS at 2 yrs, % HR (95% CI)† Not reached 76 0.53 18.7 38 Ref ( )† 9.4 34 1.3 ( ) † ALDH, aldehyde dehydrogenase; CR, complete response; EFS, event-free survival; int, intermediate; OS, overall survival. Farhad Ravandi, MD: In addition, the stem cell phenotype correlated with patient outcomes. Patients who have the CD34- phenotype tended to have a superior EFS and OS vs those with the CD34+CD38- phenotype; 2-year OS rates were 76% vs 34% to 38%, respectively. Likewise, the CR rate was 86% in patients with the CD34- phenotype vs 45% for CD34+CD38-ALDHhigh. *P < .01 †P = .02 Gerber JM, et al. ASCO Abstract 7000.

Leukemia Stem Cell Phenotypes: Conclusions
In AML, 3 distinct leukemia stem cell phenotypes correlate with cytogenetic or molecular abnormalities and outcomes CD34-: most favorable Particularly in those with NPM1 CD34+CD38-ALDHint: intermediate (most common) CD34+CD38-ALDHhigh: poorest outcome High percentage refractory cases No leukemia-free survival at 2 yrs without allogeneic BMT ALDH, aldehyde dehydrogenase; AML, acute myeloid leukemia; BMT, bone marrow transplant; int, intermediate. Farhad Ravandi, MD: The investigators concluded that these 3 distinct leukemia stem cell phenotypes are predictive for outcomes with chemotherapy in patients with AML. Of importance, patients with the CD34- phenotype had the best outcomes, whereas those with CD34+CD38-ALDHhigh had the worst outcomes. This finding needs to be confirmed in a larger study. For more information on this study, go to: Gerber JM, et al. ASCO Abstract 7000.

Gilteritinib in Relapsed/Refractory AML: Background
FLT3-ITD mutations associated with poor survival Activating FLT-ITD3 mutations seen in ~ 30% of AML pts Secondary FLT3-TKD mutations associated with TKI failure FLT3 inhibitors clinically active in AML Gilteritinib (ASP2215): potent FLT3, Axl inhibitor Active against FLT3-ITD, FLT3-TKD, D835, gatekeeper mutations Phase I/II trial to identify tolerable dose that inhibits FLT3 in relapsed/refractory AML with any FLT3 mutation status AML, acute myeloid leukemia; TKI, tyrosine kinase inhibitor. Farhad Ravandi, MD: Gilteritinib is a novel FLT3 kinase inhibitor which is also active against AXL and other mutations. FLT3-ITD mutations are associated with poor survival in AML and other FLT3 inhibitors have shown promise in this setting.[1] Levis and colleagues[2] conducted a phase I/II study of gilteritinib in patients with relapsed/refractory AML, with either mutated or unmutated FLT3. References: 1. Sudhindra A, Smith CC. FLT3 inhibitors in AML: are we there yet? Curr Hematol Malig Rep. 2014;9: 2. Levis MJ, Perl AE, Altman JK, et al. Results of a first-in-human, phase I/II trial of ASP2215, a selective, potent inhibitor of FLT3/Axl in patients with relapsed or refractory (R/R) acute myeloid leukemia (AML). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7003. Levis MJ, et al. ASCO Abstract 7003.

Gilteritinib in Relapsed/Refractory AML: Study Design
450 mg (n = 2) 300 mg (n = 3) No DLT CR/CRp/CRi obs, expanded to n = 14-17 200 mg (n = 3) No DLT CR/CRp/CRi obs, expanded to n = 14-17 Dose Escalation 120 mg (n = 3) No DLT CR/CRp/CRi obs, expanded to n = 14-17 80 mg (n = 3) No DLT CR/CRp/CRi obs, expanded to n = 14-17 AML, acute myeloid leukemia; CR, complete response; CRi, complete response with incomplete hematologic recovery; CRp, complete response with incomplete platelet recovery; DLT, dose-limiting toxicity; mut, mutation; obs, observation. Farhad Ravandi, MD: This phase I/II trial enrolled cohorts of 3 patients at escalating gilteritinib dose levels. Following demonstration of efficacy with no dose-limiting toxicity, the cohorts were expanded to patients each. This study enrolled 194 patients with a median age of 62 years (range: 21-90), that is, very old patients as well as very young patients. All were pretreated, and approximately one third each had 1, 2, or more than 3 previous therapies for AML, mostly chemotherapy. Although patients with wild-type FLT3 were allowed, approximately two thirds of patients were FLT3 mutation positive. Expanded with FLT3 mut+ subjects (n = 40) 40 mg (n = 3) No DLT CR/CRp/CRi obs, expanded to n = 14-17 20 mg (n = 3) No DLT CR/CRp/CRi obs, expanded to n = 14-17 Levis MJ, et al. ASCO Abstract 7003.

Gilteritinib in Relapsed/Refractory AML: Outcomes
20 mg (n = 13) 40 mg (n = 8) 80 mg (n = 12) 120 mg (n = 40) 200 mg (n = 45) 300 mg (n = 7) 450 mg (n = 2) CRc,* n (%) 2 (15) 5 (42) 20 (50) 23 (51) 2 (28) PR, n (%) 3 (38) 3 (25) 3 (8) 3 (7) 2 (29) Median OS, days 128.0 105.5 201.0 199.0 161.0 -- *CR/CRp/CRi. ORR FLT3 mutation, all doses: 52% FLT3 mutation, ≥ 80 mg: 58% Wild-type FLT3, all doses: 9% AML, acute myeloid leukemia; CR, complete response; CRc, composite complete response; CRi, complete response with incomplete hematologic recovery; CRp, complete response with incomplete platelet recovery; ORR, overall response rate; OS, overall survival; PR, partial response. Farhad Ravandi, MD: Responses were achieved even at the lower doses; at the lowest dose of 20 mg, 2 patients achieved a composite CR, at the higher doses much more significant responses were seen. For example, at the 200-mg dose, 51% achieved composite CR and 7% had a PR. Overall, any dose higher than 80 mg/day was associated with an approximately 58% response rate, which is very reasonable. It is not dramatically higher than responses with prior FLT3 inhibitors, but it is still a very good response rate. Levis MJ, et al. ASCO Abstract 7003.

Gilteritinib in Relapsed/Refractory AML: Safety
Maximum tolerated dose: 300 mg Common treatment-related AEs Diarrhea (13%), fatigue (12%), elevated AST (11%), elevated ALT (9%), decreased platelet count (8%), anemia (7%), peripheral edema (7%), constipation (7%), nausea (7%), dizziness (6%), vomiting (6%) Serious AEs Febrile neutropenia (27%), sepsis (12%), disease progression (10%), pneumonia (9%), hypotension (6%), respiratory failure (6%) AE, adverse event; ALT, alanine aminotransferase; AML, acute myeloid leukemia; AST, aspartate aminotransferase. Farhad Ravandi, MD: Overall, gilteritinib was very well tolerated. The maximum tolerated dose was 300 mg, with main toxicities including diarrhea (13%), fatigue (12%), and elevated aspartate aminotransferase (11%). Of importance, there was no QT prolongation as seen with quizartinib, another small molecule receptor tyrosine kinase inhibitor in clinical trials, or any rashes or other problems which can be severe with some other FLT3 kinase inhibitors. Levis MJ, et al. ASCO Abstract 7003.

Gilteritinib in Relapsed/Refractory AML: Conclusions
Gilteritinib clinically active in relapsed/refractory AML with sustained FLT3 inhibition CRc rate (CR/CRp/CRi) in pts with FLT3 mutation: 47% with dose ≥ 80 mg Median duration of response: 18 wks Median OS: ~ 27 wks in FLT3 mutation–positive pts Well tolerated up to 300 mg/day with manageable toxicity Randomized phase III trials planned at 120 mg/day AML, acute myeloid leukemia; CR, complete response; CRc, composite complete response; CRi, complete response with incomplete hematologic recovery; CRp, complete response with incomplete platelet recovery; OS, overall survival. Farhad Ravandi, MD: In conclusion, gilteritinib is clinically active with sustained FLT3 inhibition. The composite CR rate in patients with mutated FLT3 was 47% with doses above 80 mg/day, and the median OS was approximately 27 weeks in this population. The investigators selected a dose of 120 mg/day for future randomized trials of this agent. For more information on this study, go to: Levis MJ, et al. ASCO Abstract 7003.

19-28ζ CAR T Cells in Adult ALL: Background
Adult ALL associated with poor prognosis 5-yr OS among pts who experience first relapse: 7% to 8%[1,2] CR rates from conventional regimens 18% to 45% in R/R ALL[3-5] CAR technology modifies host T cells to induce antitumor activity[6] Autologous T cells isolated, genetically modified to express CD19- targeted CAR, expanded, and reintroduced into pt 19-28z CAR: combination of CD19 antigen-specific antibody with CD28 costimulatory receptor and the CD3ζ chain of T cell receptor[7] Phase I study undertaken to evaluate CD19-targeted CAR T-cell therapy in adults with R/R CD19-positive B-cell ALL[6] ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CR, complete response; OS, overall survival; R/R, relapsed/refractory. Farhad Ravandi, MD: CAR technology is a novel approach to cancer treatment that involves leukapheresis to isolate T cells, followed by ex vivo modification of the autologous T cells (using retrovirus-related constructs), which are then reinfused into the patient and target malignant cells. There have been many reports of CAR T cells, particularly in ALL, and these have generated significant interest in the scientific community. 1. Fielding AK, et al. Blood. 2007;109: Tavernier E, et al. Blood. 2007;21: O’Brien S, et al. Cancer. 2008;113: Oriol A, et al. Haematologica. 2010;95: Tavernier E, et al. Leukemia. 2007;21: Park JH, et al. ASCO Abstract Stefanski J, et al. Mol Ther. 2006;13(suppl 1). Abstract 268.

19-28ζ CAR T Cells in Adult ALL: Study Design
Eligibility criteria Adult pts with R/R CD19-positive B-cell ALL Relapse following allogeneic HSCT permitted No active CNS disease, GVHD requiring immunosuppression, or significant heart disease Pts underwent leukapheresis to isolate T cells for modification During T-cell production, salvage chemotherapy allowed Repeat bone marrow biopsy performed prior to CAR T-cell infusion Conditioning regimen (cyclophosphamide) administered 2 days prior to infusion of 1-3 x ζ CAR T cells/kg Bone marrow biopsy performed at Day 28 or at cell count recovery ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CNS, central nervous system; HSCT, hematopoietic stem cell transplantation; GVHD, graft-vs-host disease; R/R, relapsed/refractory. Farhad Ravandi, MD: In this phase I study by Park and colleagues,[1] the T cells were engineered to express 19-28ζ CAR, which allows them to target CD19-positive ALL B cells. Expression of CD19- and CD3-specific antigens is crucial for the activation of the CAR T cells and for activity against leukemic cells. This study enrolled 39 adult patients with CD19-positive relapsed B-cell ALL with no central nervous system disease or graft-vs-host disease. Patients who had relapsed after allogeneic transplantation were eligible for participation as well. The patients received salvage chemotherapy while waiting for production of the CAR T-cell product because when ALL relapses, it can be fairly indolent but also can be very proliferative. So, chemotherapy was allowed but with the understanding that it was very unlikely to produce responses by itself. Then, prior to administering the CAR T cells, patients received a conditioning regimen of cyclophosphamide. This was a heavily pretreated population. Approximately one half had morphologic disease, and approximately one half had only MRD-positive disease with less than 5% blasts in the bone marrow. I assume this is the result of the previous chemotherapy they received. Approximately one quarter of patients had received 4 or more previous lines of therapy. Approximately one third had previous transplantations. This study included patients with Philadelphia chromosome–positive ALL, including 11% with the T315I mutation. References: 1. Park JH, Riviere I, Wang X, et al. Efficacy and safety of CD19-targeted 19-28z CAR modified T cells in adult patients with relapsed or refractory B-ALL. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7010. Park JH, et al. ASCO Abstract 7010.

19-28ζ CAR T Cells in Adult ALL: Responses
High CR rate in relapsed/refractory ALL Subgroup analysis found no significant differences in overall CR or MRD-negative CR pts based on disease burden, prior allogeneic HSCT, Ph-positive status, age, or prior lines of therapy Parameter Evaluable Pts CR rate, % (n/N) 87 (33/38) MRD-negative CR rate, % (n/N) 81 (26/32) Median time to CR, days (range) 23.0 (8-46) ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CR, complete response; HSCT, hematopoietic stem cell transplantation; MRD, minimal residual disease; Ph, Philadelphia chromosome. Farhad Ravandi, MD: Results showed an 87% CR rate which, if proven in subsequent studies, is completely remarkable in relapsed and refractory ALL. One caveat about this study is that the investigators defined a population where 46% of patients had fewer than 5% blasts as “relapsed and refractory.” Many other studies would not have considered these patients to be relapsed and refractory. Another important point is that the majority of patients—81%—became MRD negative. In addition, responses occurred quickly, within a median of 23 days. There was no difference in terms of response based on disease burden, prior therapy, or other factors. Park JH, et al. ASCO Abstract 7010.

19-28ζ CAR T Cells in Adult ALL: Survival
Outcome Evaluable Pts Median duration of response or RFS, mos (95% CI) 5.3 (3-9) Disease free at last follow-up, n Without HSCT With > 1-yr follow-up 14 10 6 Proceeded to posttherapy allogeneic HSCT, n 11 Relapse during follow-up, n Post-HSCT 3* Median OS All pts (N = 38), mos 6-mo OS rate, % (95% CI) MRD-negative CR pts (n = 26), mos 8.5 59 (39-74) 10.8 75 (50-89) ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CR, complete response; HSCT, hematopoietic stem cell transplantation; MRD, minimum residual disease; OS, overall survival; RFS, relapse-free survival. Farhad Ravandi, MD: Unfortunately, the median DoR remains only approximately 5 months. About 10% of patients became disease free without a subsequent stem cell transplantation, although some did eventually receive one. Median OS was 8.5 months, with nearly 60% remaining alive at 6 months. OS outcomes were slightly better in patients who had a MRD-negative CR. *2 pts had CD19-negative blasts. Park JH, et al. ASCO Abstract 7010.

19-28ζ CAR T Cells in Adult ALL: Safety
Severe cytokine release syndrome: 23% Fever, hypotension, respiratory insufficiency Severity correlated with disease burden Only in those with morphologic disease pre–T-cell transfer Managed with IL-6 receptor inhibitor and/or steroids Grade 3/4 neurotoxicity: 28% Rate higher in pts with morphologic disease pretransfer Symptoms reversible; can occur independent of CRS 3 deaths: ventricular arrhythmia (DNR); seizure; sepsis ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CRS, cytokine release syndrome; DNR, do not resuscitate; IL, interleukin. Farhad Ravandi, MD: The toxicity profiles seen in many studies of immunotherapies and other new agents are notably different from chemotherapy. One concern with CAR T cells is cytokine release syndrome, which can be quite severe and require intensive care management. It generally can be managed with steroids and, in some patients, with an anti–IL-6 antibody. Nearly 30% of patients experienced grade 3/4 neurotoxicity, but this was reversible. Park JH, et al. ASCO Abstract 7010.

19-28ζ CAR T Cells in Adult ALL: Conclusions
In adults with relapsed/refractory ALL, 19-28ζ CAR T-cell therapy associated with high CR rate (87%) Similar CR rates observed among all subgroups, including disease status, age, Ph positive, or previous allogeneic HSCT Longer survival in pts with MRD-negative CR vs MRD-positive CR after CAR T-cell transfer Durable responses observed, including in some pts without allogeneic HSCT Adverse events included severe CRS, neurologic toxicity Both correlate with response and disease burden ALL, acute lymphoblastic leukemia; CAR, chimeric antigen receptor; CR, complete response; CRS, cytokine release syndrome; HSCT, hematopoietic stem cell transplantation; MRD, minimum residual disease; Ph, Philadelphia chromosome. Farhad Ravandi, MD: In conclusion, CAR T cells are generating a lot of excitement in the setting of ALL, especially with 87% CR rate in this study. This study was particularly important because of the strong suggestion of significant activity of CAR T cells in ALL. Of note, MRD negativity appeared to confer longer survival in these patients. For more information on this study, go to: Park JH, et al. ASCO Abstract 7010.

Myelodysplastic Syndrome
Farhad Ravandi, MD: I will now discuss key data in the setting of MDS, a relatively rare hematologic malignancy. Patients with MDS have ineffective hematopoiesis and dysplastic cytologic features and are at risk of secondary AML.

Myelofibrosis and JAK Inhibition
Myelofibrosis: rare hematologic malignancy that is associated with poor prognosis and pt quality of life[1,2] Disease-related thrombocytopenia, anemia, and red blood cell transfusion increase within 1 yr of diagnosis[2] Thrombocytopenia is a negative prognostic factor for OS[3] Associated with risk of leukemic transformation Medical need to develop therapies that can simultaneously alleviate symptoms, splenomegaly, and cytopenias in pts with myelofibrosis Pacritinib, a selective JAK2/FLT3 inhibitor, showed positive efficacy in phase II trial and favorable safety profile in phase I studies[4,5] Current phase III study evaluated pacritinib vs BAT in pts with PMF, PPV-MF, or PET-MF[6] BAT, best available therapy; OS, overall survival; PMF, primary myelofibrosis; PPV-MF, postpolycythemia vera myelofibrosis; PET-MF, postessential thrombocythemia-myelofibrosis. Farhad Ravandi, MD: Myelofibrosis is a rare bone marrow disorder that disrupts normal hematopoiesis; thrombocytopenia, anemia, and the need for red blood cell transfusions increase within a year.[1-4] Pacritinib is a selective JAK2/FLT3 inhibitor and has shown promise in phase I and phase II trials.[5,6] (By contrast, ruxolitinib is an approved JAK1 and 2 inhibitor.) Mesa and colleagues[7] conducted a phase III randomized study of pacritinib vs best available therapy in patients with primary myelofibrosis, postpolycythemia vera myelofibrosis, or postessential thrombocythemia myelofibrosis. References: 1. Tefferi A, Cervantes F, Mesa R, et al. Revised response criteria for myelofibrosis: International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and European LeukemiaNet (ELN) consensus report. Blood. 2013;122: 2. Mesa RA, Niblack J, Wadleigh M, et al. The burden of fatigue and quality of life in myeloproliferative disorders (MPDs): an international Internet-based survey of 1179 MPD patients. Cancer. 2007;109:68-76. 3. Geyer HL, Mesa RA. Therapy for myeloproliferative neoplasms: when, which agent, and how? Hematology Am Soc Hematol Educ Prog. 2014; 4. Tefferi A, Lasho TL, Jimma, et al. One thousand patients with primary myelofibrosis: the mayo clinic experience. Mayo Clin Proc. 2012;87:25-33. 5. Komrokji RS, Wadleigh M, Seymour JF, et al. Results of a phase 2 study of pacritinib (SB1518), a novel oral JAK2 inhibitor, in patients with primary, post-polycythemia vera, and post-essential thrombocythemia myelofibrosis. Blood (ASH Annual Meeting Abstracts) 2011;118(21):282. 6. Komrokji RS, Seymour JF, Roberts AW, et al. Results of a phase 2 study of pacritinib (SB1518), a JAK2/JAK2(V617F) inhibitor, in patients with myelofibrosis. Blood. 2015;125: 7. Mesa RA, Egyed M, Szoke A, et al. Results of the PERSIST-1 phase III study of pacritinib (PAC) versus best available therapy (BAT) in primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF), or post-essential thrombocythemia-myelofibrosis (PET-MF). Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract LBA7006. 1. Tefferi A, et al. Blood. 2013;122: Tefferi A, et al. Mayo Clin Proc. 2012;87: Gangat N, et al. J Clin Oncol. 2010;29: Seymour F, et al. ASH Abstract Komrokji RS, et al. Blood. 2015;125: Mesa RA, et al. ASCO Abstract LBA7006.

PERSIST-1: Study Design
Randomized phase III study Primary endpoint: proportion of pts achieving a ≥ 35% reduction in spleen volume (by MRI/CT) from baseline to Wk 24 Stratified by platelet count (< 100,000/µL vs < 50,000/µL), risk category, region Wk 24 Pacritinib 400 mg/day (n = 220) Pts with intermediate- or high-risk myelofibrosis, palpable spleen ≥ 5 cm, and no previous treatment with JAK2 inhibitors (N = 327) Best Available Therapy* (n = 107) CT, computed tomography; MRI, magnetic resonance imaging. Farhad Ravandi, MD: In the PERSIST-1 study, patients (N = 327) with intermediate-risk or high-risk myelofibrosis were randomized 2:1 to receive either pacritinib at 400 mg/day or best available therapy. Of note, the best available therapy did not include the current standard of care, ruxolitinib. The patients were stratified based on their platelet counts, as well as International Prognostic Scoring System (IPSS) risk category and region of treatment. The primary endpoint was very similar to the endpoint used in the pivotal study of ruxolitinib: proportion of patients achieving a greater than 35% reduction in spleen volume measured by imaging from baseline to Week 24. Shrinking the spleen improves the quality of life of the patient. *Ruxolitinib excluded. Best available therapies included hydroxyurea, glucocorticoids, erythropoiesis-stimulating agents, immunomodulatory agents, mercaptopurine, danazol, interferons, cytarabine, melphalan. Mesa RA, et al. ASCO Abstract LBA7006.

PERSIST-1: Reduction of Spleen Volume ≥ 35% at Wk 24
Significantly greater percentage of pts in the pacritinib arm reached the primary endpoint 60 Pacritinib (n = 168) Best available therapy (n = 85) 50 40 30 20 10 -10 Change From Baseline (%) -20 BAT, best available therapy; CT, computed tomography; MRI, magnetic resonance imaging; PAC, pacritinib. Farhad Ravandi, MD: The primary endpoint of spleen volume reduction of at least 35% at 24 weeks of therapy was met by a significantly higher proportion of patients receiving pacritinib vs best available therapy. In fact, on the pacritinib arm, although only approximately one quarter of patients met the primary endpoint, the vast majority of patients had some degree of spleen reduction, whereas in the best available therapy arm, approximately one half of patients had progressive splenomegaly. Very few (~ 5%) patients receiving best available therapy met the primary endpoint. PERSIST-1 is yet another study that shows JAK2 inhibition is important and useful in myelofibrosis. -30 35% decrease -40 -50 Pts Reaching Primary Endpoint, % Population PAC BAT P Value ITT 19.1 4.7 .0003 Evaluable* 25.0 5.9 .0001 -60 -70 -80 -90 -100 Pts Mesa RA, et al. ASCO Abstract LBA7006. Reprinted with permission. *Baseline + Wk 24 spleen assessment by MRI or CT..

PERSIST-1: Primary Endpoint Subanalyses
Correlation of Spleen Volume Reduction With OS Spleen Volume Reduction HR† (95% CI) P Value PAC 10% to < 20% ≥ 20% 0.15 ( ) 0.26 ( ) .071 .014 BAT 2.31 ( ) NA .0287 P =. 0370 35 33.3 PAC BAT P = .0072 30 P = .0451 23.5 25 22.9 P = .0086 20 16.7 Pts (%) 15 10 5 BAT, best available therapy; CT, computed tomography; ITT, intent to treat; MRI, magnetic resonance imaging; NA, not applicable; OS, overall survival; PAC, pacritinib. Farhad Ravandi, MD: One AE that occurs with ruxolitinib is cytopenias, including thrombocytopenia. In this study, patients were allowed to enroll even with baseline thrombocytopenia. And a significant proportion of patients with a low platelet count achieved the primary endpoint of spleen volume reduction at 24 weeks: 33% of evaluable patients. So thrombocytopenia was not a substantial issue with pacritinib. Of note, essentially no patients receiving the best available therapy achieved the primary endpoint. One of the early criticisms of ruxolitinib was that it was not clear whether it affects survival, but subsequent follow-up studies did show an improvement.[1] Likewise, this study of pacritinib also showed that a 20% or greater spleen volume reduction at Week 24 was significantly associated with an OS improvement. In short, JAK2 inhibition is not just cosmetic; it does affect survival. Similar to the ruxolitinib trials, pacritinib demonstrated a significant reduction in the total symptom score; significant improvements in favor of the pacritinib arm were seen all platelet subgroups. References: 1. Vannucchi AM, Kantarjian HM, Kiladjian JJ, et al. A pooled analysis of overall survival in COMFORT-I and COMFORT-II, 2 randomized phase 3 trials of ruxolitinib for the treatment of myelofibrosis. Haematologica. 2015;[Epub ahead of print]. ITT Evaluable* ITT Evaluable* Significant percentage of pts in the pacritinib arm reached the primary endpoint regardless of baseline thrombocytopenia Spleen volume reduction ≥ 20% at Wk 24 significantly associated with OS *Baseline + Wk 24 spleen assessment by MRI or CT. †Reference: < 10% spleen volume reduction. Mesa RA, et al. ASCO Abstract LBA7006. Reprinted with permission.

PERSIST-1: Adverse Events
Most common AEs: diarrhea, nausea, vomiting Grade 3/4 GI events higher in PAC arm than BAT Clinical benefit of pacritinib preserved regardless of any GI AE More frequent in pts aged older than 65 yrs and in pts with platelets < 100,000/μL Diarrhea resulted in discontinuation or dose interruption in 3 and 13 pts, respectively Blood and lymphatic system disorders similar between arms GI AE, n (%) All Grades Grade 3 Grade 4 PAC (n = 220) BAT (n = 106) Diarrhea 117 (53.2) 13 (12.3) 11 (5.0) Nausea 59 (26.8) 7 (6.6) 2 (0.9) Vomiting 35 (15.9) 6 (5.7) AE, adverse event; BAT, best available therapy; GI, gastrointestinal; PAC, pacritinib. Farhad Ravandi, MD: Overall, pacritinib was well tolerated. The main AEs were gastrointestinal and mostly grade 1/2 (eg, diarrhea in more than one half of patients and nausea in one quarter of patients). Mesa RA, et al. ASCO Abstract LBA7006.

PERSIST-1: Conclusions
Pacritinib associated with Significantly more pts reaching primary endpoint (≥ 35% reduction of spleen volume), regardless of baseline platelet count (P = .0003) At Wk 24 demonstrated significant improvement of HR of survival for pts with ≥ 20% SVR (HR: 0.26; 95% CI: ; P = .014) Significant treatment effect in pts with baseline platelets < 50,000/μL (highest risk subset; P < .05) In this subset, 35% achieved mean increase in platelet counts by Wk 24 Significant reduction in total symptom score (P < .0001) Significantly higher proportion of pts developed RBC transfusion independence Based on preliminary data, additional studies of pacritinib in combination with other potentially disease-modifying agents are warranted in pts with myelofibrosis SVR, spleen volume reduction; RBC, red blood cell. Farhad Ravandi, MD: In conclusion, pacritinib showed substantial benefit in the setting of intermediate-risk or high-risk myelofibrosis. Compared with best available therapy, significantly more patients reached the primary endpoint of spleen reduction, regardless of baseline platelet count. In addition, significantly more patients receiving pacritinib became red cell transfusion independent. PERSIST-1 is another important study confirming the role of JAK2 inhibitors in myelofibrosis. Going forward, future studies will evaluate these agents in combinations with other classes of agents. For more information on this study, go to: Mesa RA, et al. ASCO Abstract LBA7006.

RESPONSE: Trial Design
Randomized, open-label phase III study; current study is the second preplanned analysis 80 wks after the last pt’s first treatment Primary endpoint: percentage of pts achieving a primary response at Wk 32 (having achieved hematocrit control and spleen volume reduction or ≥ 35% reduction from baseline in spleen volume at Wk 32) Ruxolitinib 10 mg BID (n = 91) Pts with polycythemia vera who had an inadequate response to or unacceptable AEs from hydroxyurea Best Available Therapy* (n = 93) AE, adverse event; BID, twice daily; IFN, interferon; pegIFN, peginterferon. Farhad Ravandi, MD: The phase III RESPONSE study compared ruxolitinib with best available therapy in patients with polycythemia vera (N = 184) who had either an inadequate response or unacceptable toxicity from hydroxyurea.[1] The primary endpoint was achievement of hematocrit control and spleen volume reduction by Week 32. At ASCO 2015, Verstovsek and colleagues[1] presented results from a preplanned analysis at 80 weeks. References: 1. Verstovsek S, Vannucchi AM, Griesshammer M, et al. Ruxolitinib in polycythemia vera: Follow-up from the RESPONSE trial. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7087. *Includes hydroxyurea, IFN/pegIFN, pipobroman, anagrelide, lenalidomide, pomalidomide, observation only. Verstovsek S, et al. ASCO Abstract 7087.

RESPONSE: Results 21% of pts receiving ruxolitinib who achieved a primary response at Wk 32, only 1 lost response 60% of pts who received ruxolitinib and who achieved hematocrit control at Wk 32 Probability of maintaining this response for 80 wks from time of initial response was 89% Of the 98 pts on ruxolitinib at Wk 32, 90% did not have control without phlebotomy from Wk 32 to 80 A ≥ 35% spleen volume reduction at Wk 32 was achieved in 38% of ruxolitinib pts; all maintained their response CHR at Wk 32 was achieved in 24% of pts on ruxolitinib The probability of maintaining CHR for 80 wks was 69% CHR, complete hematologic response. Farhad Ravandi, MD: Results from RESPONSE confirmed previous reports showing durable benefit from ruxolitinib. Of patients who received ruxolitinib in the initial report and achieved a response (21% at Week 32), only 1 lost their response. Maintenance of hematocrit control continued in 89% of patients. These durable responses with continued therapy are encouraging. Verstovsek S, et al. ASCO Abstract 7087.

RESPONSE: Adverse Events and Conclusions
The most common nonhematologic AEs for ruxolitinib were headache, diarrhea, pruritus, and fatigue; most were grade 1/2 Grade 3/4 anemia and thrombocytopenia occurred in 1.8% and 5.5% of pts, respectively Rate of treatment discontinuation in ruxolitinib arm due to AEs remained low (4.5%) Ruxolitinib responses were durable and treatment remained generally well tolerated 83% still receiving ruxolitinib at a median exposure of wks AE, adverse event. Farhad Ravandi, MD: As has been shown with other ruxolitinib studies, nonhematologic AEs were typically grade 1/2. A small percentage of patients developed grade 3/4 anemia and thrombocytopenia, which is expected from a JAK1/2 inhibitor. However, responses were durable, and continued therapy does not result in new AEs, which is important because these drugs can be used for extended periods of time. Verstovsek S, et al. ASCO Abstract 7087.

Natural Killer Cells in MDS
Cytotoxic blood lymphocytes important in tumor surveillance and infectious disease control[1] 5% to 15% of peripheral blood lymphocytes Do not require previous antigen sensitization Phenotype: CD3- CD56+ Large array of activating and inhibitory killer cell immunoglobulin-like receptors[2] KIR gene complex Chromosome 19q13.4[3] Haplotype A: only 1 activating KIR gene Haplotype B: ≥ 1 of 6 activating KIR genes Pts with higher number of activating KIR genes associated with significant risk reduction in developing childhood ALL[4] ALL, acute lymphocytic leukemia; MDS, myelodysplastic syndromes Farhad Ravandi, MD: NK cells are a normal component of a healthy person and are key components of tumor surveillance and control of infections.[1] They account for up to 15% of peripheral blood lymphocytes and are an active component of immunity against infections, and, potentially, cancer. NK cells have a CD3-CD56+ phenotype, with inhibitory receptors as well as activating receptors (eg, KIRs).[2] KIR genes can be both activating and suppressing; patients with more activating KIR genes are less likely to develop childhood ALL.[3,4] Daher and colleagues[5] conducted a study to determine any correlation between the number of activating KIR genes on NK cells and risk of MDS. In addition, these KIR genes can make patients susceptible to leukemias and other cancers. References: 1. Terszowski G, Passweg JR, Stern M. Natural killer cell immunity after transplantation. Swiss Med Wkly. 2012;142:w13668. 2. Kaur G, Trowsdale J, Fugger L. Natural killer cells and their receptors in multiple sclerosis. Brain. 2013;136: 3. Moussa P, Marton J, Vidal SM, et al. Genetic dissection of NK cell responses. Front Immunol. 2013;3:425. 4. Almalte Z, Samarani S, Iannello A, et al. Novel associations between activating killer-cell immunoglobulin-like receptor genes and childhood leukemia. Blood. 2011;8: 5. Daher M, Sobieski C, Marin D, et al. Association between KIR genes and risk of MDS. Program and abstracts of the 51st annual meeting of the American Society of Clinical Oncology; May 29 - June 2, 2015; Chicago, Illinois. Abstract 7001. 1. Terszowski G, et al. Swiss Med Wkly. 2012;142:w Kaur G, et al. Brain. 2013;136: Moussa P, et al. Front Immunol. 2013;18: Almalte Z, et al. Blood. 2011;8:

KIR Gene Study in MDS: Study Design and Pt Characteristics
Current study sought to determine if association exists between number of activating KIR genes and risk of MDS MDS pts (n = 180) compared with healthy controls (n = 117) MDS pts both high risk (n = 60) and low risk (n = 120) by IPSS Analysis of KIR genes by PCR Samples correlated for phenotypic, genotypic, and outcome data Logistic regression model used to study relationship of number of activating KIR genes and MDS risk category MDS Pt Characteristics Characteristic, % Low-Risk MDS (n = 120) High-Risk MDS (n = 60) Male sex 72 70 Age older than 60 yrs 88 87 AML transformation 12 22 Previously treated 29 34 AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; PCR, polymerase chain reaction. Farhad Ravandi, MD: This is a novel study, the first of its kind, with few prior data to support any association. The study enrolled 180 patients with MDS and compared them with 117 healthy controls. Of the patients with MDS, 120 were low risk by IPSS and 60 had high-risk disease. The KIR genes were analyzed by polymerase chain reaction, and again, they correlated them with MDS characteristics of the patients. Daher M, et al. ASCO Abstract 7001.

Number of Activating KIRs
KIR Gene Study: Number of Activating KIR Genes Associated With Risk of MDS Each additional activating KIR gene conferred protective effect against development of high-risk MDS No independent survival benefit seen with higher number of activating KIR genes No association shown between number of activating KIR genes and AML transformation P = P = .009 P = .04 60 50 Number of Activating KIRs 0 or 1 2 or 3 4 or more 40 Frequencies (%) 30 AML, acute myeloid leukemia; IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome. Farhad Ravandi, MD: Results showed that a higher number of activating KIR genes was associated with a lower IPSS score, and a lower number of activating KIR genes was associated with a higher IPSS score. However, there was no association between the number of activating KIR genes and AML transformation. The effect of the number of activating genes was cumulative, so every additional activating gene led to more protection against development of high-risk MDS. Also, there was no independent survival benefit associated with the number of activating KIR genes. 20 10 High IPSS Low IPSS Healthy Control Daher M, et al. ASCO Abstract 7001.

KIR Gene Study: Conclusions
Inheritance of a lower number of activating KIR genes associated with increased risk of developing MDS Low number of activating KIR genes associated with a high- risk score (IPSS) in MDS pts Each additional activating KIR gene in pts appears to lower risk of high-risk MDS Future directions: development of immunotherapies for MDS using NK cells IPSS, International Prognostic Scoring System; MDS, myelodysplastic syndrome; NK, natural killer. Farhad Ravandi, MD: These are really early data, and more work is needed to understand the role of KIR genes in MDS. We need to clarify why low numbers of activating KIR genes may be associated with high-risk MDS, whereas more activating genes may be associated with a lower risk of high-risk MDS. For more information on this study, go to: Coverage/Clin Onc June 2015/Hematologic Malignancies/7001.aspx Daher M, et al. ASCO Abstract 7001.

Go Online for More CCO Coverage of ASCO 2015!
Short slidesets of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in: Gastrointestinal cancers Genitourinary cancer Hematologic malignancies Immunotherapy Lung cancer For more information on this study, go to: clinicaloptions.com/oncology

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Hematologic Malignancies CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *CCO is an independent medical education.

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Presentation on theme: "Hematologic Malignancies CCO Independent Conference Highlights of the 2015 ASCO Annual Meeting* May 29 - June 2, 2015 *CCO is an independent medical education."— Presentation transcript:

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