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17th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma Meeting in a Box.

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Presentation on theme: "17th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma Meeting in a Box."— Presentation transcript:

1 17th Annual International Congress on Hematologic Malignancies®: Focus on Leukemias, Lymphomas, and Myeloma Meeting in a Box

2 Multiple myeloma

3 What Can We Learn From Multiple Myeloma Genomic Analysis?
Nikhil Munshi, MD Dr Nikhil Munshi presented a lecture discussing what we can learn from multiple myeloma genomic analysis.

4 Genomic Analysis Takeaways
Methods of genomic analysis Established techniques: cytogenetics, FISH Emerging techniques: RNA- and DNA-based arrays, transcript- processing arrays, genomic sequencing, and proteomics Current goals of genomic analysis in myeloma Understand the biology of myeloma Identify risk categories to improve prognostication Identify and validate novel targets Develop biologic agents that target the myeloma cell Ultimately, develop personalized therapy Currently, gene expression profiling has prognostic value, predicting survival of patients with different genomic signatures, but it cannot yet predict response to therapy. Although genomic analysis is on the cutting edge of science, multiple myeloma genetics has been routinely assessed for many years, using the established techniques of both cytogenetics and FISH (fluorescence in situ hybridization). However, a wide array of novel genomic techniques are also emerging. Examples include RNA-based arrays – such as gene expression profiling , DNA-based arrays – such as SNP arrays, transcript-processing arrays, genome and exome sequencing, as well as proteomics. In myeloma, genomic analysis has a number of broad goals, such as understanding its biology, improving our prognostic abilities by identifying categories of risk, identifying and validating novel targets, and developing biologic agents based on these targets. The ultimate goal of genomic analysis is to develop personalized therapy to treat multiple myeloma. Most genomic analysis techniques are still under development, but gene expression profiling has already been shown to have prognostic value, predicting survival of patients with different genomic signatures. Investigations continue regarding the use of genomic analysis to improve the care of myeloma patients.

5 High-Risk Smoldering Myeloma – Should We Intervene Early?
Ola Landgren, MD, PhD Next, Dr Ola Landgren discussed high-risk smoldering myeloma and whether or not we should intervene early in the disease course.

6 Smoldering Myeloma Definition of smoldering myeloma1
Serum monoclonal IgG or IgA ≥ 3 g/dL and/or clonal bone marrow plasma cells ≥ 10% AND Absence of end-organ damage (ie, hypercalcemia, renal insufficiency, anemia, or bone lesions attributed to plasma cell proliferative disorder) Overall risk of progression2 10% per year in years 0-5 3% per year in years 6-10 1% per year in years 11-20 Risk stratification Mayo Clinic analysis3 stratifies patients according to their 5-yr risk of progression into 3 groups: 25% risk, 51% risk, and 76% risk PETHEMA Study Group analysis4 stratifies patients according to their 5-yr risk of progression into 3 groups: 4% risk, 46% risk, and 72% risk e To fit the definition of smoldering myeloma, a patient must have either serum monoclonal protein at least 3 g/dL and/or at least 10% clonal plasma cells in the bone marrow. In addition, the patient cannot have any end-organ damage, such as renal insufficiency or plasma cell-related bone lesions. A large, retrospective study from 2007 demonstrated how the overall risk of progression from smoldering myeloma to symptomatic multiple myeloma changes over time. In the first 5 years, patients with smoldering myeloma have a 10% risk per year of progression. This drops to a 3% risk per year for the next 5 years. During years 11-20, patients have only a 1% per year risk of progression, which is the same risk as those patients with MGUS. Taken together, these data suggest that the population of smoldering myeloma patients are likely made up of patients with MGUS and patients with early myeloma. Multiple, small, single-center, retrospective studies, such as those conducted by the Mayo Clinic and the PETHEMA Study Group, have been conducted to stratify patients based on risk. However, according to a Mayo Clinic analysis, only 26% of patients have concordant risk assignments using these 2 different risk stratification systems (eg, a patient is categorized as high risk by both systems), showing that current risk stratification lacks accuracy. 1Kyle RA, et al. Leukemia. 2010;24: 2Kyle RA, et al. N Engl J Med. 2007;356: 3Dispenzieri A, et al. Blood. 2008;111:785-9. 4Perez-Persona E, et al. Blood. 2007;110:

7 First Randomized Phase III Trial for Smoldering Myeloma
Randomization of high-risk smoldering MM patients: Median time to symptomatic progression Len/dex: not yet reached Observation: 21 months 4-year overall survival Len/dex: 94% Observation: 85% Lenalidomide 25 mg/day, D1-21 Dexamethasone 20 mg D1-D4 and D12-D15 Therapeutic abstention Induction: Nine 28-day cycles Lenalidomide 10 mg/day, D1-21 every 2 months Therapeutic abstention Maintenance: Until progression Primary endpoint: time to progression to symptomatic MM Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability This is the first randomized phase III trial in smoldering myeloma, and it compares lenalidomide + low-dose dexamethasone with observation in 119 patients with high-risk smoldering myeloma. Patients receiving active treatment received 9 cycles of lenalidomide 25 mg/day for 3 of 4 weeks and dexamethasone 20 mg/day on days 1-4 and days Following this, lenalidomide maintenance was given 10 mg/day for 3 weeks every 2 months until progression. Patients were found to have a 5.67-fold increase in the risk of progression with observation vs active therapy, which was statistically significant. In addition, the 4-year absolute overall survival increased from 85% with observation to 94% with lenalidomide/dexamethasone, for a hazard ratio of 3.5 and a P value of <.01. Toxicities with lenalidomide/dexamethasone are primarily hematologic in nature. HR = 5.67; P < .0001 HR = 3.5; P < .01 Mateos MV, et al. ASH Abstract 991.

8 Smoldering Myeloma Takeaways
Current clinical recommendation for smoldering myeloma: no treatment unless part of a clinical trial1 Better understanding of pathogenesis from MGUS to myeloma needed: To develop better biological markers To predict a patient’s risk of progression To develop early intervention strategies The latest clinical recommendation for smoldering myeloma, which was published in 2010, is to avoid active treatment unless it is part of a clinical trial. However, results from the ongoing phase III lenalidomide/dexamethasone study, showing both a decline in the risk of progression and an increase in survival with active therapy, may lead to a change in this recommendation in the future. A better understanding of the pathogenesis of disease, from MGUS to symptomatic myeloma, is necessary in order to develop better biological markers, predict a patient’s risk of progression, and develop early intervention strategies. 1Kyle R, et al. Int’l Myeloma Working Group. Leukemia 2010.

9 Current Trends: Treatment Strategies for Newly Diagnosed Elderly Patients With Myeloma
James Berenson, MD Dr James Berenson then presented information on current treatment strategies for newly diagnosed patients with myeloma, particularly the elderly.

10 Dexamethasone ± Lenalidomide SWOG S0232
Len + Dex (n = 97) Len: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, 17-20 Three 35-day cycles Dexamethasone (n = 95) Placebo: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, 17-20 Three 35-day cycles Responding/stable disease Disease progression Len + Dex Len: 25 mg/day, D1-21 Dex: 40 mg/day, D1-4 and 15-18 28-day cycles until progression Dexamethasone Placebo: 25 mg/day, D1-21 Dex: 40 mg/day, D1-21 28-day cycles until progression Unblinded Treatment Len: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, 17-20 Three 35-day cycles Because the number of first-line treatment choices for myeloma is expanding rapidly, choosing the optimal treatment paradigm for these patients is becoming increasingly difficult and requires careful examination of the current clinical study results. A SWOG study by Zonder and colleagues reports on the use of lenalidomide and high-dose dexamethasone in newly diagnosed patients compared with dexamethasone alone. Unblinded Len + Dex Len: 25 mg/day, D1-21 Dex: 40 mg/day, D1-4 and 15-18 Objective: to determine the efficacy and safety of Len + Dex as induction therapy in NDMM patients Primary endpoint: PFS Zonder JA, et al. Blood. 2010;116:

11 Dexamethasone ± Lenalidomide SWOG S0232
1-yr PFS was significantly improved with the addition of lenalidomide (78% vs 53%; P = .002) ORR = 78% ORR, P < .0001 VGPR, P < .001 ORR = 48% Not surprisingly, the overall response rate of the combination therapy was significantly greater than dexamethasone alone – 78% vs 48%. In addition, PFS was significantly prolonged in the combination arm, with a 1-year PFS rate of 78% compared with 53%. Zonder JA, et al. Blood. 2010;116:

12 Transplant-eligible patients can proceed to SCT Continue therapy until
Lenalidomide + High-Dose Dex vs Lenalidomide + Low-Dose Dex: ECOG E4A03 Lenalidomide + High-Dose Dexamethasone (RD)a Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1-4, 9-12, 17-20 (n = 223) Transplant-eligible patients can proceed to SCT Four 28-day cycles Lenalidomide + Low-Dose Dexamethasone (Rd) Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1, 8, 15, 22 (n = 222) Continue therapy until disease progression Objective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacy Primary endpoint: ORR after first 4 cycles This ECOG trial is well recognized for determining that dexamethasone dosing of 40 mg/day on a 4-days-on, 4-days-off schedule is too high. This randomized trial of lenalidomide and dexamethasone compared the then-standard dosing of dexamethasone to a once-weekly dosage of 40 mg and found that survival was significantly improved in the low-dose dexamethasone arm -- 1-year OS was 87% with len/high-dose dex vs 96% with len/low-dose dex. aBased on the superiority of the Rd regimen, the study was stopped at a median follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy. Arm 1-yr OS 2-yr OS RD (high-dose) 87% 75% Rd (low-dose) 96% Survival significantly improved with Rd (low-dose) regimen (P = at 1 year) Rajkumar SV, et al. Lancet Oncol. 2010;11:29-37.

13 MP ± Bortezomib: VISTA Endpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS, QoL Previously untreated patients; not candidates for transplant ARM B (MP) MP: Nine 6-week cycles: Cycles 1-9 Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4 ARM A (VMP) VMP: Four 6-week cycles: Cycles 1-4 Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32; Followed by five 6-week cycles: Cycles 5-9 Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4 Max of 9 cycles (total 54 weeks) in both arms R A N D O M I Z E Study Schema: 682 patients randomized 151 centers 22 countries worldwide IDMC recommended study stop in September 2007 based on protocol-specified interim analysis VMP was significantly superior for all efficacy endpoints The VISTA trial was the pivotal trial that led to first-line approval of bortezomib in myeloma patients not eligible for transplant. In this randomized trial, bortezomib was added to standard melphalan and prednisone, first on a twice-weekly schedule (2 weeks on, 1 week off) and then to a once-weekly schedule. The dramatic results showed not only a 7.4-month improvement in median PFS with the addition of bortezomib, but also a significant 39% reduction in the risk of death. Recent follow-up results have shown that this benefit is maintained even after 5 years. Efficacy Parameter Lenalidomide Placebo HR P Value Median TTP, months 24.0 16.6 0.483 < Median OS, months NR 0.61 .008 3-yr OS: 72% in VMP arm vs 69.5% in MP arm San Miguel J, et al. N Engl J Med. 2008;359: Mateos MV, et al. J Clin Oncol. 2010;28:

14 Phase II Studies for Newly Diagnosed Multiple Myeloma
Regimen Drugs ORR CR Cybor-D1 cyclophosphamide + bortezomib + dex 93% 39% DVD2 bortezomib + pegylated liposomal doxorubicin + dex 86% 20% VRD3 bortezomib + lenalidomide + dex 100% 37% BAM4 bortezomib + ascorbic acid + melphalan → maintenance bortezomib 74% 13% BiRD5,6 clarithromycin + lenalidomide + high-dose dex 90% CRd7 carfilzomib 27 mg/m2 + lenalidomide + dex 85% CYCLONE8 carfilzomib + cyclophosphamide + thalidomide + dex 96% 29% CMP9 carfilzomib + melphalan + prednisone 89% 3% A wide variety of first-line regimens are under phase II development for the treatment of newly diagnosed multiple myeloma. All of these regimens contain 1 or 2 of the following active agents: bortezomib, lenalidomide, and carfilzomib, which is one of the most recently approved agents for myeloma. These regimens show particularly promising response rates, with one of the carfilzomib regimens – carfilzomib + lenalidomide + dexamethasone – producing a 100% response rate and an 85% complete response rate in a phase I/II trial. 1Reeder CB, et al. ASCO Abstract 8517. 2Berenson JR, et al. Br J Haematol. 2011;155:580-7. 3Richardson PG, et al. Blood. 2009;114:501-2. 4Berenson JR, et al. Eur J Haematol. 2009;82:433-9. 5Niesvizky R, et al. Blood. 2008;111: 6Rossi A, et al. ASCO Abstract 8008. 7Jakubowiak AJ, et al. Blood. 2012;120: 8Mikhael J, et al. ASCO Abstract 8010. 9Kolb B, et al. ASCO Abstract 8009.

15 Novel Combinations and New Drugs for Elderly Patients With Myeloma
Approved drugs Novel combinations Modifications of dose and schedule Improve efficacy Better tolerability Drugs in development Similar targets Proteasome inhibitors - carfilzomib (FDA-approved!), ixazomib IMiDs - pomalidomide (FDA-approved!) New classes of agents Monoclonal antibodies - anti-CS-1 (elotuzumab), anti-CD40 (dacetuzumab), anti-CD38 mTOR inhibitors - temsirolimus PI3K inhibitors - perifosine HDAC inhibitors - vorinostat, romidepsin, panobinostat To summarize, elderly patients can be treated by novel combinations of drugs available for use or they can have their current regimens modified by dose and/or schedule in order to improve efficacy and tolerability. There are a number of drugs in development for this patient population, including second- and third-generation proteasome inhibitors and IMiDs, as well as new classes of agents, such as mTOR inhibitors, PI3K inhibitors, HDAC inhibitors, and a variety of monoclonal antibodies.

16 Maintenance Therapy – Is It for Everyone?
Nikhil Munshi, MD Dr Nikhil Munshi discussed the evidence for maintenance therapy for myeloma patients.

17 Maintenance Therapy for Multiple Myeloma
Purpose is to prolong remission duration and life expectancy Requires periodic follow-up to monitor toxicity and response Patient must have: Disease that is in remission (undetectable or at a low level) Recovered from all previous toxicities Maintenance agent must have: Minimal toxicity or at least not overlapping with the toxicity of the induction regimen Convenient dosing Convenient route of administration The purpose of maintenance therapy is to prolong remission duration, and hopefully to prolong life expectancy as well. As we will see, maintenance therapy has a decided benefit for patients with multiple myeloma, but it does have specific requirements, for both the patient and the maintenance regimen. For patients to be considered for maintenance therapy, they must have disease that is in remission and they must have recovered from all previous toxicities. The maintenance regimen must be associated with minimal toxicity, or at the very least not have overlapping toxicity with the induction regimen, and it must have a convenient dosing and route of administration.

18 Lenalidomide Maintenance After Transplant: CALGB 100104
Restaging Days 90–100 Registration Randomization D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better  1 yr from start of therapy > 2 x 106 CD34 cells/kg Mel 200 ASCT Placebo CR PR SD Lenalidomide 10 mg/d with ↑↓ (5–15 mg) To determine the potential benefit of lenalidomide maintenance therapy following transplantation, the CALGB performed this placebo-controlled trial in myeloma patients achieving at least stable disease after transplant. Patients receiving maintenance lenalidomide had a 46-month median time to progression, compared to 27 months in patients receiving placebo, a difference that was statistically significant. An overall survival benefit was also established, with lenalidomide producing an absolute improvement in OS of 8%, for a P value of .027. Efficacy Parameter Lenalidomide Placebo HR P Value Median TTP, months 46 27 -- < .0001 3-yr OS 88% 80% 0.62 .027 McCarthy PL, et al. N Engl J Med. 2012;366:

19 Lenalidomide Maintenance Following Lenalidomide Consolidation: IFM 2005-02
Phase III randomized, placebo-controlled trial N= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008 Patients age < 65 years, with nonprogressive disease, ≤ 6 months after ASCT in first line Randomization: stratified according to Beta-2m, del13, VGPR Consolidation: Lenalidomide alone 25 mg/day po days 1-21 of every 28 days for 2 months Arm A = Placebo (N=307) until relapse Arm B = Lenalidomide (N=307) 10-15 mg/d until relapse The French IFM trial was somewhat different from the previous lenalidomide maintenance trial, in that all patients received 2 cycles of consolidation lenalidomide prior to randomization to lenalidomide maintenance or placebo. This trial demonstrated a 17-month improvement in PFS, which had a P value < Overall survival did not show a significant difference between groups, but a more recent analysis suggests that the 2 overall survival curves may be starting to separate. Future analyses will determine whether this regimen can produce an overall survival advantage. Primary endpoint: PFS Secondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide… PFS significantly prolonged with lenalidomide maintenance compared with placebo (41 vs 24 months; P < 10-9) OS not significantly different between groups (P = .79) Attal M, et al. Proc International Myeloma Workshop 2011. McCarthy P, et al. Proc International Myeloma Workshop 2011.

20 Lenalidomide Maintenance in Patients Ineligible for Transplant: MM-015
Double- Blind Treatment Phase Open- Label Extension Phase Cycles (28 day) 1-9 Cycles 10+ MPR-R Maintenance M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 Lenalidomide R: 10 mg/day po , days 1-21 10 mg/day days 1 - 21 MPR RANDOMIZATION Lenalidomide M: 0.18 mg/kg, days 1-4 Disease (25 mg/day) P: 2 mg/kg, days 1-4 Placebo Progression +/- R: 10 mg/day po , days 1-21 Dexamethasone As already discussed, the MM-015 trial is a 3-arm trial designed to assess the addition of lenalidomide to melphalan and prednisone (MP) in elderly, transplant-ineligible patients, either as concomitant therapy (MPR) or as concomitant therapy followed by maintenance lenalidomide (MPR-R). Just focusing on the maintenance aspect of the study, results show that the addition of maintenance lenalidomide after MPR induction therapy produced a significant 65% reduction in the risk of progression. Moreover, this PFS benefit was seen across all patient subgroups, including those with renal insufficiency, those achieving only a PR with induction therapy, and those with advanced-stage disease. MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 Placebo PBO: days 1 -21 PFS significantly prolonged with the addition of lenalidomide maintenance following MPR induction therapy (HR = 0.349; P < .001) PFS benefit maintained across patient subgroups Palumbo A, et al. N Engl J Med. 2012;366:

21 Maintenance Lenalidomide and Second Primary Malignancies
Both CALGB and IFM showed increased risk of second primary malignancies compared with placebo (23 vs 6 and 18 vs 4, respectively)1,2 MM-015 also showed increase in frequency of second primary malignancies with lenalidomide use (n=12, MPR-R; n=10, MPR; n=4, MP) A concern with any maintenance therapy is toxicity, and maintenance lenalidomide appears to be associated with secondary cancers. Both of the maintenance lenalidomide studies in patients after transplant (CALGB and IFM ) showed an increased risk of second primary malignancies compared with placebo (23 vs 6 and 18 vs 4, respectively). MM-015, the maintenance lenalidomide study in nontransplant patients, also appeared to show an increase in secondary primary malignancies in the lenalidomide-containing arms (12 and 10 vs 4 in the MP arm). However, this study also demonstrates that the vastly greater danger to these patients is progressive disease or death from myeloma, suggesting that although maintenance lenalidomide comes with a slightly elevated risk of secondary malignancies, its benefits still outweigh the risks. 1Attal M, et al. Proc International Myeloma Workshop 2011. 2McCarthy P, et al. Proc International Myeloma Workshop Palumbo A, et al. N Engl J Med. 2012;366:

22 PAD + Bortezomib Maintenance vs VAD + Thalidomide Maintenance: HOVON Trial
MM Stage II or III, Age 18–65 Bortezomib 1.3 mg/m2 IV Doxorubicin 9 mg/m2 Dexameth 40 mg Randomization 3 x VAD 3 x PAD CAD + GCSF CAD + GCSF MEL PBSCT MEL PBSCT In GMMG 2nd MEL PBSCT Allogeneic Tx In GMMG 2nd MEL PBSCT Next, we move on to the question of maintenance bortezomib. The HOVON trial randomized myeloma patients to VAD (a vincristine-based chemotherapy regimen) or PAD induction therapy, which replaces vincristine with bortezomib. All patients then received transplantation, which was followed by thalidomide maintenance (for VAD patients) or bortezomib maintenance (for PAD patients). The bortezomib arm showed a significant improvement in both PFS and OS. However, the study design prohibits any conclusions from being drawn about maintenance bortezomib, since it was not rigorously controlled. Rather, the most important point of this study is the conclusion that bortezomib can be tolerated as maintenance therapy, at least when using this regimen of 1.3 mg/m2 every other week. Thalidomide maintenance 50 mg/day for 2 yrs Bortezomib maintenance 1.3 mg/m2/2 weeks for 2 yrs Efficacy Parameter PAD → bortezomib VAD → thalidomide P Value 3-yr PFS 48% 42% .005 3-yr OS 78% 71% .02 Sonneveld P, et al. ASH Abstract 40.

23 Bortezomib + Thalidomide vs Bortezomib + Prednisone as Maintenance: GEM2005MAS65
Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trial Maintenance Bort/Thal (VT) Bort/Pred (VP) Induction (6 cycles) Bort/Mel/Pred (VMP) Bort/Thal/Pred (VTP) vs No significant differences between VMP and VTP in ORR (80% and 81%) and CR rate (20% and 27%) This next study asks whether 2 maintenance therapies – thalidomide and bortezomib – can be safely and effectively combined. This Spanish trial of 260 elderly patients with untreated myeloma randomized patients first to the bortezomib-containing VMP induction regimen or to VTP, which contains both bortezomib and thalidomide. After this stage, patients were again randomized to receive either bortezomib/prednisone maintenance or bortezomib/thalidomide maintenance. Bortezomib maintenance was administered on days 1, 4, 8, and 11 every 3 months. No difference in either ORR or CR was observed between the VMP and VTP induction regimens, but it is interesting to note that either maintenance therapy regimen produced an increase in complete responses. No significant PFS difference was observed between the 2 maintenance therapy regimens, with the bortezomib/thalidomide arm showing a 39-month PFS and the bortezomib/prednisone arm showing a 32-month PFS. The bortezomib/thalidomide arm also showed a slight increase in toxicity (12% vs 8%), which would be expected based on the toxicity profiles of the 2 agents. Arm ORR CR Median PFS VT maintenance 95% 46% 39 months VP maintenance 97% 39% 32 months Mateos MV, et al. Lancet Oncol. 2010;10:

24 Conclusions About Maintenance Therapy for Multiple Myeloma
Maintenance therapy prolongs PFS. Low-dose oral agents preferable for maintenance therapy. Both bortezomib and lenalidomide are useful maintenance agents and may need to be combined for patients with high-risk disease. Slight increase in incidence of secondary malignancy after lenalidomide maintenance. Overall, everyone who meets prerequisites for maintenance therapy should be considered candidates for treatment. In conclusion, the data presented demonstrate that maintenance therapy prolongs PFS and supports the notion that low-dose oral agents are preferable for maintenance therapy. Both bortezomib and lenalidomide are useful maintenance agents, and these 2 agents may need to be combined for patients with high-risk disease. There is a slight increase in the incidence of secondary malignancy after lenalidomide maintenance. So, should everyone be treated with maintenance therapy? Overall, everyone who meets the prerequisites for maintenance therapy – achieving at least a PR and having resolution of prior toxicities -- should be considered candidates for maintenance treatment. The real question is not if maintenance therapy should be given, but how long.

25 How to Best Use New Proteasome Inhibitors and IMiDs in Myeloma
Sundar Jagannath, MD Dr Sundar Jagannath closed the myeloma session by discussing how best to use new proteasome inhibitors and IMiDs in myeloma.

26 Pivotal Trial of Immunomodulatory Agent Pomalidomide: MM-002
Primary endpoint: PFS Secondary endpoints: ORR, DOR, OS, and safety Randomization Progressive disease Progressive disease Option to add LoDEXa (40 mg/week) POM (4 mg days 1–21 of 28-day cycles) Discontinue and follow-up for survival and subsequent treatment Pomalidomide is an immunomodulatory agent – or IMiD – that was approved by the FDA for treatment of myeloma in February 2013 on the basis of the following trial. MM-002 randomized relapsed or refractory patients to pomalidomide alone, dosed 4 mg daily for 3 of 4 weeks, or to pomalidomide + low-dose dexamethasone. Patients in the single-agent arm could add low-dose dexamethasone upon progression, and nearly 60% of these patients ended up doing so. POM (4 mg days 1–21 of 28-day cycles) + LoDEXa (40 mg/week) Aspirin (80–100 mg) or equivalent mandated for all patients. aPatients aged > 75 yrs had starting DEX dose of 20 mg/week.

27 MM-002: Response Rates Median number of cycles received = 5 (range, 1-28) Disease control rate = 81% overall Response POM + LoDEX (n=113) POM (n=108) ORR (%) 34 15 CR (%) 3 1 PR (%) 31 14 MR (%) 12 16 SD (%) 37 48 PD (%) 6 10 Median time to ORR, months 1.9 3.7 Median duration of response, months 8.3 8.8 The response rate of the combination arm was more than double that of the pomalidomide-alone arm – 34% vs 15%, with a disease control rate of 83% and 80%, respectively. The median duration of response was similar between groups – 8.3 months for the combination arm and 8.8 months for the single-agent arm. This suggests that, although the addition of dexamethasone increases the response rate, it is the pomalidomide that produces the prolonged duration of the response. Jagannath S, et al. ASH Abstract 450.

28 MM-002: PFS, OS, and Safety Efficacy Parameter POM + LoDEX POM HR P Value Median PFS, months 4.6 2.6 0.67 .002 Median OS, months 16.5 13.6 0.92 .609 Age ≤ 65 years Age > 65 years Grade 3/4 AEs ≥ 20% POM + LoDEX (n=61) POM (n=68) (n=51) (n=39) Hematologic Neutropenia Anemia Thrombocytopenia 46 26 18 40 24 35 20 59 21 Nonhematologic Pneumonia Dyspnea 16 7 10 29 8 The addition of low-dose dexamethasone did produce a significant 2-month improvement in PFS. An improvement in overall survival is not evident, likely because nearly 60% of patients in the single-agent arm ended up adding dexamethasone upon progression. Pomalidomide is generally well tolerated, causing less neutropenia than lenalidomide and less neuropathy than thalidomide, even in this relapsed/refractory population. In the combination arm, grade 3/4 neutropenia was 46% and neuropathy was 0% (13% grade 1/2). Pneumonia appears to be slightly elevated in the older patients, as is neutropenia in the single-agent arm. Other AEs of clinical relevance in POM +/- LoDEX: Febrile neutropenia: 3% Peripheral neuropathy (grade1/2): 13% (none > grade 2) DVT: 2% Jagannath S, et al. ASH Abstract 450.

29 Pomalidomide + Low-Dose DEX vs High-Dose DEX: MM-003
(n = 302) POM: 4 mg/day D1-21 + LoDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1, 8, 15, 22 RANDOMIZATION 2:1 Follow-up for OS and SPM until 5 years post enrollment (n = 153) HiDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1-4, 9-12, 17-20 28-day cycles PD* or intolerable AE PD* Companion trial MM-003C POM 21/28 days MM-003 is a phase III trial in which patients with disease that was refractory to both bortezomib and lenalidomide were randomized 2:1 to pomalidomide + low-dose dexamethasone or high-dose dexamethasone alone. Thromboprophylaxis indicated for those receiving POM or with DVT history Stratification Age (≤ 75 vs > 75 yrs) Number of prior Tx ( 2 vs > 2) Disease population *Progression of disease independently adjudicated in real-time

30 MM-003: PFS and OS Arm POM + LoDEX n = 302 HiDEX n=153 HR P Value
Median PFS, months ITT population Refractory to bortezomib Refractory to lenalidomide Refractory to both 3.6 3.7 3.2 1.8 1.7 0.45 0.47 0.38 0.48 < .001 Median OS, months NR 7.8 8.1 8.6 7.4 0.53 0.56 0.39 .037 .003 The combination therapy of pomalidomide + low-dose dexamethasone produces a significant PFS advantage of approximately 1.5 months, regardless of the patient subset examined. A significant improvement in overall survival was also observed across patient subgroups. Dimopoulos MA, et al. ASH Abstract LBA-6.

31 Pivotal Trial of Proteasome Inhibitor Carfilzomib: 003-A1
MM: Progressive disease > 2 prior therapy lines including bortezomib, thalidomide or lenalidomide, an alkylating agent, and anthracycline alone or in combination 003-A0 003-A1 Carfilzomib 20 mg/m2 days 1, 2, 8, 9, 15, 16 every 28 days N = 46 Carfilzomib Dose escalation to 27 mg/m2 after cycle 1 up to 12 cycles N = 266 Primary Endpoint: ORR Secondary Endpoints: clinical benefit rate (≥ minimal response), DOR, PFS, OS, and safety The pivotal trial of carfilzomib, the other recently approved myeloma agent, was conducted in myeloma patients who were heavily pretreated, progressing after at least 2 prior lines of therapy. Patients received carfilzomib at 20 mg/m2 on days 1 and 2 weekly for 3 of 4 weeks. The dose was then escalated to 27 mg/m2 for up to 12 cycles.

32 Single-Agent Carfilzomib Pivotal Trial: Efficacy
Response Carfilzomib (N=257) ORR 24% Clinical benefit rate 34% Duration of response 8.3 months Median PFS 3.7 months Median OS 15.6 months Despite the heavily pretreated nature of these patients, they achieved an ORR of 24%, had a duration of response that was nearly identical to that of pomalidomide, and had promising median PFS – 3.7 months – and OS – 15.6 months. These data suggest that this agent will improve the outcomes of patients with myeloma. Siegel DS, et al. Blood. 2012;120:

33 Single-Agent Carfilzomib Pivotal Trial: Safety
Adverse Event Grade 3/4 AEs N =266 Hematologic Anemia Thrombocytopenia Lymphopenia Neutropenia 24% 29% 20% 11% Nonhematologic Fatigue Dyspnea Upper respiratory tract infection Headache 7.5% 3.4% 4.5% 1.9% Other Febrile neutropenia Peripheral neuropathy 0.8% 1.1% Grade 3/4 hematologic adverse events were common but manageable in this population. There were relatively low levels of grade 3/4 fatigue and dyspnea, although grade 1/2 dyspnea was rather common. Congestive heart failure was present but uncommon (3.8%). Other AEs (any grade) of clinical relevance: Dyspnea in 34%; 17% due to carfilzomib CHF in 3.8%; myocardial infarction or cardiac arrest in 2.3% Siegel DS, et al. Blood. 2012;120:

34 Multiple Myeloma Takeaways
Genomic analysis is an important area of research that is expanding rapidly, but to date it has had limited use in the myeloma clinic, restricted to its ability to predict survival on the basis of gene expression profiling. Active monitoring remains optimal approach for smoldering myeloma, although this may change in the future with further examination of lenalidomide/dexamethasone treatment. Elderly patients with newly diagnosed multiple myeloma can be treated with a number of distinct regimens, depending on their comorbidities and performance status. These include lenalidomide/low-dose dexamethasone and VMP (bortezomib, melphalan, and prednisone). Maintenance therapy with a convenient, low-toxicity regimen is suggested for all myeloma patients meeting the following criteria: achievement of remission and no ongoing toxicity. Proteasome inhibitor carfilzomib and IMiD pomalidomide recently granted accelerated approval by FDA for treatment of relapsed/refractory myeloma, on the basis of promising response rates, and PFS and OS results in this heavily pretreated population. Genomic analysis is an important area of research that is expanding rapidly, but to date it has had limited use in the myeloma clinic, restricted to its ability to predict survival on the basis of gene expression profiling. Active monitoring remains as the optimal approach for smoldering myeloma, although this may change in the future with further examination of lenalidomide/dexamethasone treatment. Elderly patients with newly diagnosed multiple myeloma can be treated with a number of distinct regimens, depending on their comorbidities and performance status. These include lenalidomide/low-dose dexamethasone, and VMP (bortezomib, melphalan, and prednisone). Maintenance therapy with a convenient, low-toxicity regimen is suggested for all myeloma patients meeting the following criteria: achievement of remission and no ongoing toxicity. The proteasome inhibitor carfilzomib and the IMiD pomalidomide have recently been granted accelerated approved by the FDA for the treatment of relapsed/refractory myeloma, on the basis of promising response rates, and PFS and OS results in this heavily pretreated population.

35 The next section of slides summarizes the lectures on lymphoma.

36 Initial Management of Peripheral T-Cell Lymphoma: If CHOP Is No Good, What Is?
Steven M. Horwitz, MD Dr Steven Horwitz kicked off the T-cell lymphoma section by discussing the initial management of peripheral T-cell lymphoma.

37 Peripheral T-Cell Lymphoma Summary
With PTCL, first-line CHOP produces ORR of %, CR of %, and durable remissions <20-30%. For most patients, CHOP is inadequate. Adding therapy to a CHOP backbone is feasible but: (1) benefit not equivalent in all subtypes,1 and (2) toxicity soon outweighs benefit because regimen operating near MTD.2,3 ASCT has shown promise in some upfront trials with PTCL.4,5 Potential approaches to explore: CHOP + etoposide CHOP + novel agent (ie, brentuximab data very encouraging) CHOP → maintenance therapy ASCT Entirely new regimen Current standard of care should be clinical trial, whenever possible. 1Kim SJ. Eur J Cancer. 2012;48: 2Kim JG, et al. Cancer Chemother Pharmacol. 2007;60: 3Gallamini A, et al. Blood. 2007;110: 4Reimer P, et al. J Clin Oncol. 2009;27: 5d’Amore F, et al. J Clin Oncol. 2012;30:

38 Management of Cutaneous T-Cell Lymphoma
Lauren Pinter-Brown, MD, FACP Dr Lauren Pinter Brown ended the T-cell lymphoma section by exploring the management of CTCL.

39 Treatment and Supportive Care of Cutaneous T-Cell Lymphoma
Treatment of mycosis fungoides and Sezary’s syndrome generally involves skin-directed therapy for early-stage (IA-IIA) and systemic therapy for later stages (≥IIB) or when skin-directed therapy fails. Skin-directed therapies: topical agents (corticosteroids, imiquimod, chemotherapy, retinoids), phototherapy, radiation therapy Systemic therapies: extracorporeal photochemotherapy, retinoids, interferon-alpha or gamma, alemtuzumab, denileukin diftitox (not currently available), HDAC inhibitors, chemotherapy Treatment considerations: stage, route (oral vs topical vs systemic), rapidity of response, availability (geographically or due to cost), and comorbidities Supportive care: Pruritus: distinguish generalized from localized; treat with moisturizers, emollients, and barrier protection, as well as topical steroids, camphor/menthol, others Infection: crucial to avoid central lines and maintain skin barrier. Consider bleach baths.

40 Treatment of CD30+ Lymphoproliferative Disorders
Lymphomatoid papulosis: Treatment options: watch and wait (most cases), methotrexate, phototherapy, interferon Rapid relapse off treatment, so maintenance therapy necessary 10%-20% of these cases associated with Hodgkin lymphoma, mycosis fungoides, or ALCL, so follow-up required Primary cutaneous ALCL: Treatment options: skin-directed therapy, surgical resection, XRT, chemotherapy only with extracutaneous involvement (CHOP not recommended), retinoids, interferon, thalidomide, steroids, excimer laser. 90% 5-year overall survival Spontaneous remission possible

41 How I Manage Early-Stage Diffuse Large B-Cell Lymphoma
Daniel O. Persky, MD Dr Daniel Persky started the B-cell lymphoma section by explaining how he manages patients with early-stage DLBCL.

42 Current Treatment Paradigm for Early-Stage DLBCL
Early-stage DLBCL is curable malignancy, with >50% cure rate and a 70%-90% 5-year OS.1 Differences in outcomes arise from variations in radiation therapy quality and patient selection Early-stage disease has pattern of late relapses Addition of rituximab to chemotherapy modestly improved PFS outcomes in early-stage disease, but has not improved OS.2,3 Another option for early-stage DLBCL is R-CHOP x 3-4 (short course) → IFRT, which showed favorable results in a retrospective comparison to standard R-CHOP.4 Regimen 3-yr PFS 3-yr OS R-CHOP x 3-4 → IFRT 90% 96% R-CHOP x 6-8 74% 86% 1Miller TP. J Clin Oncol. 2004;22: 2Ketterer N, et al. Ann Oncol. 2013;24: 3Pfreundschuh M, et al. Lancet Oncol. 2011;12: 4Terada Y, et al. ASH Abstract 1628.

43 Novel Approaches for Early-Stage DLBCL
Radioimmunotherapy consolidation: SWOG 0313:1 CHOP x 3 + IFRT → ibritumomab: 4-yr est. PFS = 84% E3402:2 R-CHOP → ibritumomab → IFRT (if PET+): 4-yr PFS = 88%, OS = 98% PET risk-adapted therapy – mid-treatment PET prognostically significant in DLBCL3,4 BCCA experience:5 R-CHOP x 3 → PET. If PET+, go on to IFRT. If PET‒, receive R-CHOP x 1 Ongoing phase II trial, S1001, will test this PET risk-adapted approach in early-stage DLBCL, with PET+ population receiving R-CHOP x 3 → IFRT → ibritumomab Result PET – n=103 PET + n=30 P Value 3-yr TTP 92% 60% .09 3-yr OS 96% 83% .1 1Miller TP, et al. ASH Abstract 3598. 2Witzig T, et al. ASH Abstract 2687. 3Haioun C, et al. Blood. 2005;106: 4Spaepen K, et al. Ann Oncol. 2002;13: 5Sehn et al, Lugano Abstract 052; Sehn LH, et al. Lugano Abstract 028.

44 Biology of Early-Stage DLBCL
DLBCL molecularly heterogeneous with different 5-year survivals:1 Primary mediastinal: 64% Germinal center B-cell-like (GCB): 59% Activated B-cell-like (ABC): 30% GCB appears more prevalent in early-stage disease2 and with superior survival3 after R-CHOP compared with ABC Bottom line: Biology of early-stage DLBCL needs further exploration. 1Rosenwald A, et al. J Exp Med. 2003;198: 2Lenz G, et al. N Engl J Med. 2008;359: 3Lenz G, et al. N Engl J Med. 2010;362:

45 Advanced-Stage DLBCL Craig Moskowitz, MD
Dr Craig Moskowitz then presented a lecture on advanced-stage DLBCL.

46 R-CHOP Regimens for Advanced-Stage DLBCL
R-CHOP21 vs R-CHOP14 phase III studies GELA:1 3-yr EFS similar (60% vs 56%; HR = 1.04; P = .76) UK:2 2-yr OS similar (81% vs 83%; HR = 0.95; P = .70) Current strategy: R-CHOP21 x 6-8 cycles → 2nd-line treatment if < CR3 MSKCC:4 R-CHOP → ibritumomab For those receiving RIT, 2-yr PFS = 79%, 2-yr OS = 84% Led to current US phase III trial: R-CHOP → ibritumomab consolidation in elderly DLBCL 1Delarue R, et al. Lancet Oncol. 2013;14: 2Cunningham D, et al. ASCO Abstract 8000. 3NCCN NHL guidelines 4Hamlin PA, et al. ASH Abstract 1793.

47 Risk-Adapted Therapy for Advanced-Stage DLBCL
MSKCC : MSKCC : ICE x 2 RICE x 1 HDT/ASCT ICE x 3 followed by observation Bx + Bx - PET - Repeat Bx + R-C1000HOuncappedP-14 x 4 Results showed no difference in PFS among:1 PET-negative PET-positive/biopsy-negative PET-positive/biopsy-positive Results showed 4-yr OS > 80% and 4-yr PFS > 70% R-R-C1000HOuncappedP-14 x 3 C1000HOuncappedP-21 x 1 + PET - Repeat Bx Bx - Bx + ≥80% Ki <80% Augmented RICE x 2 followed by HDT/ASCT Augmented RICE x 2 followed by observation ICE x 3 followed by observation 1Moskowitz et al. Lancet Oncol. 2010;28:

48 Dose-Adjusted EPOCH-R for Advanced-Stage DLBCL
CALGB phase II study1 Excellent 5-yr results in overall population OS = 84% PFS = 81% EFS = 75% However, high-risk disease associated with worse outcomes than other subgroups IPI high-risk group, OS = 43% ABC OS inferior to GCB (P = .04) Ki67 < 60% OS inferior to ≥ 60% (P = .05) Ongoing phase III CALGB 50303: dose-adjusted EPOCH-R vs R-CHOP21 1Wilson WH, et al. Haematologica. 2012;97:

49 Relapsed DLBCL in the Rituximab Era
Anas Younes, MD Dr Anas Younes then summarized relapsed DLBCL in the rituximab era.

50 Salvage Phase III Trials in Relapsed DLBCL: R-ICE + BEAM/ASCT Remains Standard
CORAL:1 Randomized patients who relapsed after CHOP ±R to R-ICE or R- DHAP. Those achieving CR or PR then received BEAM ASCT. No difference between salvage therapies in OS (P = .49) or PFS (P = .44). Among those who relapsed within 12 months after diagnosis, prior rituximab associated with poor EFS (P = .001). Among those who relapsed more than 12 months after diagnosis, prior rituximab status had no impact on EFS (P = .11). Bio-CORAL:2 subset of patients from CORAL trial with histologic material available. Tumors classified as GCB or ABC. Among those receiving R-ICE, histologic type did not impact PFS (P = .82) or OS (P = .96). Among those receiving R-DHAP, patients with GCB tumors had significantly better PFS (P = .005) and potentially better OS (P = .06) compared with patients with ABC tumors. 1Gisselbrecht, et al. J Clin Oncol. 2010;28: 2Thieblemont et al. J Clin Oncol. 2011;29:

51 Relapsed DLBCL Summary
As frontline therapy is changing based on tumor oncogenic properties, the same should be done for salvage therapy and conditioning regimens. To achieve higher ORRs with salvage therapy and better ASCT outcome, patients should be pre-selected based on predictive biomarkers. Randomized biomarker-driven salvage dynamic combination regimens will need to be examined using innovative trial designs, such as shown below. Lymphoma PI3K/AKT/mTOR JAK/STAT BCR Biomarker - It is likely that all salvage regimens are equal. P-PRAS40 + pSTAT3 + P-CD19 + RCHOP RCHOP + Drug A RCHOP RCHOP + Drug C RCHOP RCHOP + Drug D RCHOP

52 New Directions in Follicular Lymphoma
Bruce D. Cheson, MD Dr Bruce Cheson described new directions in the management of follicular lymphoma.

53 Antibodies in Follicular Lymphoma
GA101: Anti-CD20 antibody Antibody-drug conjugates DCDT2980S: anti-CD22 linked to MMAE. Showed CR in 2 of 3 patients with DLBCL and 1 PR in patient with FL in phase I testing3 DCDT4501A: anti-CD79b linked to MMAE. Showed responses in 5 of 8 patients at first assessment in phase I testing4 Ongoing randomized crossover trial: Trial Treatment n (FL) ORR GAUGIN1 (BO20999) GA101 low-dose 14 36% GA101 high-dose 20 60% GAUSS2 GA101 74 43% rituximab 75 39% Arm A: R (d1) + DCDT2980S (d2) Q 21 days Response PD Arm B: R (d1) + DCDT4501A (d2) Q 21 days Response 1Salles GA, et al. ASH Abstract 268. 2Sehn LH, et al. ASH Abstract 269. 3Advani R, et al. ASH Abstract 59. 4Palanca-Wessels MC, et al. ASH Abstract 56.

54 Small-Molecule Inhibitors in Follicular Lymphoma
Ibrutinib (PCI-32765): BTK inhibitor produced 54% ORR in overall B-cell malignancy population and 38% in FL.1 Duration of response impressive, particularly in FL, where multiple patients continue to receive ibrutinib after ≥2 years Idelalisib (GS-1101): PI3K delta inhibitor IPI-145: PI3K delta and gamma inhibitor In phase I testing, IPI-145 showed early signs of clinical activity across multiple heme malignancies.3 Phase I Treatment2 Decreased Adenopathy ORR 1-yr PFS Idelalisib + rituximab 97% 77% 82% Idelalisib + bendamustine 85% 90% Idelalisib + bendamustine/rituximab 100% 78% 1Advani RH, et al. J Clin Oncol. 2013;31:88-94. 2Fowler NH, et al. ASH Abstract 3645. 3Kahl B, et al. Lugano Abstract 066.

55 Apoptosis-Inducing Agents and IMiDs in Follicular Lymphoma
ABT-199:1 apoptosis-inducing agent Lenalidomide:2 IMiD tested in combination with rituximab for untreated indolent lymphoma in phase II study: Results led to ongoing RELEVANCE phase III trial: R2 = rituximab + lenalidomide Population N ORR SD Gr 3/4 Treatment-Related AEs in >2 Patients Overall (R/R NHL) 23 48% 30% 10% anemia FL 8 12% 88% NR Population N ORR SD 2-yr PFS Overall (untreated indolent NHL) 103 90% 8% 83% FL 46 98% 2% 89% R2 R2 maintenance 1st line FL N=1000 R R + chemo Rituximab maintenance 1Davids MS, et al. ASH Abstract 304. 2Fowler NH, et al. ASH Abstract 901.

56 Management of Hodgkin Lymphoma in the Elderly
Paul A. Hamlin, MD Dr Paul Hamlin presented a lecture concerning the management of Hodgkin lymphoma in elderly patients.

57 Hodgkin Lymphoma: Differences in the Elderly Subset
Approximately 20% of all HL patients are > 60 years old, but few are enrolled in clinical trials. HL biological factors in the older patient: Advanced stage1 More aggressive histology1 B symptoms1 EBV positivity associated with worse disease-specific survival and OS2 Bleomycin produces high incidence of toxicity in elderly.3 Elderly outcomes: Elderly patients have worse outcomes in clinical trials than younger patients.4 A study in Scotland of 674 patients with HL who were ≥ 60 years old reported a 5-year survival of only 35%.5 1Word, et al. ASH Abstract 3648. 2Jarrett, et al. Blood. 2005;106: 3Evens AM. ASCO Post. 2012;3. 4Proctor SJ, et. al. Crit Rev Oncol Hematol. 2009;71: 5Proctor SJ, et al. Eur J Haematol. 2005;(suppl 66):63-7.

58 Reduced-Intensity Therapy for Hodgkin Lymphoma
Reduced-intensity regimens: CVP/CEB VBM VEPEMB ChIVPP Less-toxic regimens produce more relapses. CVP/CEB produces 73% remission rate and is well tolerated (4% toxic death), but relapses are high (5-yr RFS 47%)1 Phase II SHIELD study used VEPEMB2 Population Receiving VEPEMB N CR 3-yr OS 3-yr PFS Patients with early-stage disease 31 74% 81% Patients with advanced-stage disease 72 61% 66% 58% 1Levis A, et al. Haematologica 1996;81:450-6. 2Proctor SJ, et al. Blood. 2012;119:

59 Anthracycline-Containing Therapy in Hodgkin Lymphoma
ChIVPP/ABV COPP/ABVD ABVD Stanford V BEACOPP GHSD10 and 11: ABVD1 In patients age ≥ 60, ABVD associated with 14% dose reductions and delays, 68% grade 3/4 toxicity, and 5% treatment-related mortality. NLSG: ChIVPP vs ChIVPP/ABV2 Retrospective analysis In patients age ≥ 60, those receiving ChIVPP/ABV had better 5-yr OS than those receiving ChIVPP (67% vs 30%; P = .0086). Both OS (39% vs 87%) and EFS (31% vs 75%) worse in patients age ≥ 60 compared with patients age < 60. 1Boll B, et al. J Clin Oncol. 2013;31: 2Weekes CD, et al. J Clin Oncol. 2002;20:

60 Death due to acute toxicity
Anthracycline-Containing Therapy in Hodgkin Lymphoma ABVD vs Stanford V1 Analysis of patients age ≥ 60 treated on randomized E2496 trial (n=44) Among older patients, no survival difference between ABVD and Stanford V Compared with younger patients, older patients had worse treatment-related mortality (9% vs 0.3%), 5-yr OS (58% vs 90%), and 5-yr FFS (48% vs 74%). GHSD HD9elderly: COPP/ABVD vs BEACOPP2 Analysis of patients age years from randomized HD9 clinical trial BEACOPP associated with lower relapse rate (12% vs 23%), but at cost of increased toxicity Treatment N CR 5-yr OS 5-yr FFTF Death due to acute toxicity COPP-ABVD 26 77% 50% 46% 8% BEACOPP 42 76% 21% 1Evens AM, et al. Br J Haematol. 2013;161:76-86. 2Ballova V, et al. Ann Oncol. 2005;16:

61 Relapsed and Refractory HL: Will We Be Able to Avoid Transplant?
Craig Moskowitz, MD Dr Craig Moskowitz presented a debate on the optimal transplant strategies for the localized relapse of Hodgkin lymphoma.

62 Transplantation for Relapsed/Refractory Hodgkin Lymphoma
Current status of transplantation for relapsed/refractory HL: Toxicity and cost markedly decreased, but relapse rate remains relatively constant Standard conditioning regimens remain the same (CBV or BEAM) PFS = 30%-50% Adding more chemotherapy agents or escalating the dose has had minimal value Adverse prognostic factors in patients with relapsed/refractory disease (MSKCC model):1 B symptoms (night sweats, weight loss, fever without infection) Extranodal disease Complete remission duration < 1 year 1Moskowitz CH, et al. Blood. 2001;97:

63 FDG-PET to Identify Patients Needing Additional Salvage Therapy
Normalization of PET prior to transplant is predictive of survival1 and identifies patients with excellent outcomes MSKCC Protocol for relapsed/refractory HL: Repeat biopsy, determine risk factors Staging evaluation: FDG PET, diagnostic CT CAP, BM Bx Results showed patients transplanted after standard or GVD salvage chemotherapy had EFS > 80%, compared with 29% EFS for patients with PET positivity.2 Arm A = 0 or 1 risk factors Standard ICE x 1 Augmented ICE x 1 PBPC collection Arm B = 2 risk factors Augmented ICE x 2 PBPC collection Induction: Nine 28-day cycles POD on ICE Restaging: FDG-PET, CT CAP PET negative PET positive GVD x 4 Restaging Radiotherapy, if applicable HDT/ASCT CR, PR, MR POD off study 1Moskowitz AJ, et al. Blood. 2010;116: 2Moskowitz CH et al. Blood. 2012;119:

64 FDG-PET to De-escalate Salvage Therapy in Hodgkin Lymphoma
Pre-transplant FDG-PET highly predictive of post-transplant outcome, so perhaps PET can be used to identify patients appropriate for de-escalated salvage therapy. Brentuximab vedotin (SGN-35): Antibody directed against CD30 (antigen highly expressed on HL surface) conjugated to MMAE, an anti-tubulin agent. Well tolerated and highly active in HL following transplant failure ORR = 75% and CR = 34% in phase II study of q3w dosing in relapsed/refractory HL1 Also being studied with qw dosing (3 wk on, 1wk off) 1Chen RW, et al. ASCO Abstract 8031.

65 Current/Proposed Brentuximab Clinical Trials in Relapsed/Refractory HL
MSKCC ongoing trial First treatment following upfront therapy Proposed international trial adding RT Nodal-only relapse, RT-naïve patients Weekly SGN-35 x 2 Weekly SGN-35 x 2 + PET - + PET - RT alone Augmented ICE x 2 Platinum-based salvage x 2 randomize PET - HDT/ASCT PET - HDT/ASCT + + Further treatment according to treating physician Further treatment according to treating physician

66 New Directions in Hematologic Malignancies
Jonathan W. Freidberg, MD (Aurora kinase inhibition) Jennifer R. Brown, MD, PhD (Kinase inhibitors in lymphoma) Anas Younes, MD (JAK inhibition in lymphoma) Andre Goy, MD (IMiDs in lymphoma) A number of faculty presented individual lectures about promising novel agents in the treatment of hematologic malignancies.

67 Aurora Kinase Inhibition With Alisertib
Key to the cell cycle, regulating mitotic entry/progression, centrosome maturation/separation, G2/M transition, chromosome alignment, and cytokinesis Present in aggressive T and B cell NHL Alisertib is an Aurora A kinase small-molecule inhibitor. Alisertib clinical development in T-cell lymphoma: Showed 57% ORR (4/7) in T-cell lymphomas in phase II NHL testing1 Ongoing SWOG 1108, a phase II study in relapsed/refractory PTCL Ongoing phase III study in PTCL: alisertib vs investigator’s choice Alisertib clinical development in B-cell lymphoma: Because of preclinical synergy with vincristine, a phase I/II study is ongoing, testing alisertib, vincristine, and rituximab in patients with relapsed/refractory aggressive B-cell lymphomas. 1Friedberg J, et al. ASH Abstract 95.

68 Kinase Inhibitors in Lymphoma
Ibrutinib Bruton’s tyrosine kinase (BTK) small-molecule irreversible inhibitor Efficacy in FL: 55% ORR and 12.3 months DOR1 Efficacy in ABC DLBCL: 41% ORR (compared with 5% ORR for GCB)2 Efficacy in phase II relapsed or refractory MCL: 66.1% ORR3 Idelalisib (GS-1101, CAL-101) PI3Kδ small-molecule inhibitor Efficacy in MCL and indolent lymphoma: 62% ORR for each4 Efficacy in MCL in combination with everolimus, bortezomib, or bendamustine/rituximab: 46% ORR5 1Fowler NH, et al. ASH Abstract 156. 2Wilson WH, et al. ASH Abstract 686. 3Wang M, et al. ASH Abstract 904. 4Kahl B, et al. ASH Abstract 1777. 5Wagner-Johnston N, et al. ASCO Abstract 8501.

69 JAK and STAT Inhibitors
JAK/STAT signaling Janus kinase 2 (JAK2) and Signal Transducers and Activators of Transcription (STAT) pathways important to pathogenesis of hematologic malignancies JAK2, STAT3, and STAT6 frequently overexpressed in HL and NHL JAK2 inhibition in vitro associated with reduced proliferation in numerous lymphoma cell lines SB1518 is a JAK2 small-molecule inhibitor. Phase I study of daily SB1518 in 35 patients with relapsed lymphoma provided proof of principle of therapeutic value of inhibiting the JAK/STAT pathway in lymphoma.1 Ongoing phase II study of ruxolitinib (JAK inhibitor already approved for the treatment of myelofibrosis) will provide additional information on potential value of targeting these pathways in DLBCL and PTCL. 1Younes A, et al. Lugano Abstract 157.

70 IMiDs in Lymphoma Lenalidomide is an immunomodulatory agent with pleiotropic effects not completely understood. Effects include increases in T-cell activation, NK- mediated killing, immune synapse formation, and APC function in B cells. Currently approved for use in multiple myeloma, MDS, and MCL and has activity across broad range of lymphomas Received approval in June 2013 for MCL based on MCL-001, a phase II study showing a 28% ORR and a median DOR of 16.6 months in heavily pretreated patients In 46 FL patients, lenalidomide + rituximab produced a 98% ORR1 RELEVANCE: ongoing phase III trial of 1000 patients with untreated FL R-chemo → maint R (2 yrs) vs R + Len → maint R (2 yrs) + Len (1 yr) Len monotherapy activity in DLBCL appears to be concentrated within non-GCB population of relapsed/refractory patients (ORR, 53% vs 9%)2 R2-CHOP (RCHOP + R and Len maint) produced a 100% ORR and 77% CR in DLBCL3 Len-RICE shows promise (8/13 CR) as salvage therapy in DLBCL4 1Fowler NH, et al. ASH Abstract 901. 2Hernandez-Ilizaliturri, et al. Cancer. 2011;117(22): 3Reddy NM, et al. ASH Abstract 3668. 4Feldman et al. ASH Abstract 3710.

71 Lymphoma Takeaways Strategies being tested to replace CHOP for PTCL, including ASCT and CHOP + novel agents. Treatment of CTCL continues to involve skin-directed therapy for early-stage disease and systemic therapy for later stages. Novel approaches for early-stage DLBCL include radioimmunotherapy consolidation and PET risk-adapted therapy. PET risk-adapted therapy also being studied for advanced-stage DLBCL, as is dose-adjusted EPOCH-R. Randomized biomarker-driven combination regimens need to be examined for relapsed DLBCL using innovative trial designs. New agents under investigation for follicular lymphoma include GA101, IPI- 145, Ibrutinib, idelalisib, ABT-199, and ADCs DCDT2980S and DCDT4501A. Reduced-intensity therapies being examined in the elderly HL population. Strategies to improve ASCT in relapsed/refractory HL include pre-transplant PET imaging and inclusion of brentuximab vedotin into salvage therapy. Many promising agents under investigation for treatment of hematologic malignancies, including radioimmunoconjugates, antibody-drug conjugates, aurora kinase inhibitors, BTK inhibitors, PI3K inhibitors, JAK inhibitors, and IMiDs.

72 Leukemia & Myeloproliferative neoplasms
The next section of slides summarizes the lectures on lymphoma.

73 Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase? Imatinib
Harry P. Erba, MD, PhD

74 Optimal First-Line CML Therapy: Cure Rate and OS Improvement
When choosing an optimal therapy for CML, there are several considerations: Can it provide a cure? Nearly 40% of patients from STIM trial who discontinued imatinib after sustained complete molecular response (CMR) of ≥ 2 years maintained CMR,1 but trial had short median follow-up of only 30 months, so premature to call those patients cured. Can it improve overall survival (OS)? Randomized TKI trials likely never be able to show survival advantage because of crossover, inherent to all of these trials. IRIS trial: no OS improvement of imatinib vs IFN/Ara-C2 because of the frequency of crossover from IFN/Ara-C to imatinib ENESTnd: no difference in OS of imatinib vs nilotinib (300 mg) after 3 years (94% vs 95%; P = .44)3 DASISION: no difference in OS of imatinib vs dasatinib (95% vs 95%; data still immature)4 1Mahon FX, et al. ASH Abstract 603. 2Druker BJ, et al. N Engl J Med. 2006;355: 3Kantarjian HM, et al. ASH Abstract 1676. 4Kantarjian HM, et al. Blood. 2012;119:

75 Optimal First-Line CML Therapy: Achievement of Remission and Tolerability
Can it improve remission rate? Although major molecular response (MMR) at 24 months is inferior with imatinib, MMR offers no advantage over CCyR in defining long-term outcomes.3 Shown above, no/modest differences in complete cytogenetic response (CCyR) present at 24 months between imatinib and 2nd-generation TKIs Can it improve tolerability? No clear tolerability advantage of 2nd-generation TKIs over imatinib Safety profiles different but overall AE incidences similar1,2 Imatinib has no known late complications, unlike dasatinib and nilotinib Trial Experimental TKI MMR at 12 Months vs Imatinib MMR at 24 Months vs Imatinib P Value at 24 Months DASISION1 dasatinib 46% vs 28% 64% vs 46% < .0001 ENESTnd2 nilotinib 300 mg 55% vs 27% 73% vs 53% Trial Experimental TKI CCyR at 12 Months vs Imatinib CCyR at 24 Months vs Imatinib P Value at 24 Months DASISION1 dasatinib 85% vs 73% 85% vs 82% NS ENESTnd4 nilotinib 300 mg 80% vs 65% 87% vs 77% .0018 1Kantarjian HM, et al. Blood. 2012;119: 2Saglio G, et al. ASH Abstract 452. 3Jabbour E, et al. J Clin Oncol. 2011;29: 4Kantarjian HM, et al. Lancet Oncol. 2011;12:

76 Progression to AP/BP vs Imatinib
Optimal First-Line CML Therapy: Prevention of Progression and Cost of Therapy Can it prevent progression? Imatinib may permit more progressions to accelerated-phase/blast- phase (AP/BP) than dasatinib or nilotinib. Does it have an acceptable cost? Imatinib will be generic in 2015. Guidelines suggest that if BCR-ABL/ABL ratio > 10% at 3 months, then switch therapy to 2nd-generation agent,3 showing that patients who have suboptimal response to imatinib can then switch to a 2nd- generation TKI. Trial Experimental TKI Progression to AP/BP vs Imatinib P Value DASISION1 dasatinib 3.5% vs 5.8% NR ENESTnd2 nilotinib 300 mg 3.2% vs 6.7% .0496 1Kantarjian HM, et al. Blood. 2012;119: 2Saglio G, et al. ASH Abstract 452. 3NCCN CML guidelines. Version

77 Imatinib as First-Line CML Therapy: Summary
Cytogenetic and molecular response rates higher with nd-generation TKIs compared with imatinib for first-line treatment of adults with CML in chronic phase (CML-CP) at early time points, but advantage may disappear at later time points. Imatinib remains standard of care for the initial therapy of adults with CML-CP based on long-term follow-up data, OS, PFS, and tolerability.

78 Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase? Second-Generation TKIs
Michael J. Mauro, MD

79 Prediction of Outcome Based on Early Response to Therapy
Initially discovered that early reduction in BCR-ABL/ABL transcript levels correlates with later achievement of MMR:1 More recently discovered that early reduction in BCR-ABL/ABL transcript levels correlates with survival:2 NCCN guidelines now recommend switching TKIs if BCR-ABL transcript levels > 10% at 3 months.3 Time Point Early Response MMR % P Value 3 months > 2-log reduction 100% < .001 0- to 2-log reduction 54% 6 months 86% 0% Time Point Early BCR-ABL/ ABL Level 8-yr OS P Value 3 months < 9.84% 93% < .001 > 9.84% 57% 1Branford S, et al. Leukemia. 2003;17: 2Marin D, et al. J Clin Oncol. 2012;30:232-8. 3NCCN CML guidelines. Version

80 Is Early Response to Therapy Really Important?
YES! Patients who don’t achieve CCyR after 12 months of treatment have greater risk of an event (loss of response, disease progression, or death) than those who don’t achieve CCyR after 3 months.1 YES! Patients who don’t achieve MMR after 12 months of treatment have greater risk of progression to AP/BP than those who do achieve MMR.2 Months on Treatment Patients Not in CCyR (n) Event (%) 3 109 23 6 47 34 12 26 38 MMR After 12 Months AP/BP (%) P Value Yes 1 .0004 No 10 1Quintas-Cardama A, et al. Blood. 2009;113: 2Hughes T, et al. Blood. 2010;116:

81 Why Dasatinib and Nilotinib for First-Line Therapy?
Both dasatinib and nilotinib produce more favorable early responses than imatinib.1-4 Both dasatinib and nilotinib associated with less transformation to AP/BP than imatinib.5,6 Currently no prognostic tool validated to determine who needs additional therapy. Efficacy Measure at 12 Months Nilotinib Imatinib P Value Dasatinib CCyR 80% 65% < .001 85% 73% .0002 MMR 55% 27% 46% 28% < .0001 CMR 11% 1% ~5% NS Trial Experimental TKI Transformation to AP/BP (%) vs Imatinib P Value DASISION dasatinib 2.3% vs 5% NS ENESTnd nilotinib 300 mg 0.7% vs 6.0% .0003 1Saglio G, et al. N Engl J Med. 2010;362: 2Kantarjian HM, et al. Blood. 2012;119: 3Kantarjian HM, et al. Lancet Oncol. 2011;12: 4Hochhaus A, et al. EHA Abstract 484. 5Kantarjian HM, et al. ASCO Abstract 6510. 6Larson RA, et al. ASCO Abstract 6511.

82 Dasatinib and Nilotinib for First-Line Therapy: Remaining Questions and Summary
Safety of long-term use of dasatinib and nilotinib needs further study. Imatinib has no known late effects of chronic use.1,2 Dasatinib and nilotinib safety data less mature, but dasatinib associated with pulmonary arterial hypertension3 and nilotinib associated with peripheral arterial disease.4 TKI discontinuation holds promise. Of 25 patients who discontinued dasatinib or nilotinib, 73% maintained MMR after 6 months.5 Final thoughts: Perhaps rather than managing treatment failures, may be preferable to focus on prevention of treatment failure. 1Gambacorti-Passerini C, et al. JNCI. 2011;103: 2Gambacorti-Passerini C, et al. ASH Abstract 3766. 3Montani D, et al. Circulation. 2012;125: 4Le Coutre P, et al. JNCI. 2011;103: 5Rea D, et al. ASH Abstract 604.

83 Alessandra Ferrajoli, MD
Treatment for Elderly Chronic Lymphocytic Leukemia: Is There a Standard? Alessandra Ferrajoli, MD

84 Considerations in the Treatment of Elderly Patients With CLL
Nearly 80% of patients with CLL are ≥ 65 years old at diagnosis.1 Survival for patients aged years with CLL is poorer than with age-matched controls.2 Number of comorbidities increases with age in patients with CLL.3 CIRS (Cumulative Illness Rating Scale), a measure of chronic illness burden, can be used to divide elderly patients into 3 categories: No go: use supportive therapy only Slow go: use reduced-intensity therapy Go go: use standard therapy Physically fit patients with no significant comorbidities and excellent renal function can receive standard FCR therapy, as shown by the CLL8 study in which addition of rituximab to FC produced a doubling of the CR rate (44% vs 22%; P < .0001).4 1SEER cancer statistics 2Shanafelt T, et al. Cancer. 2010;116: 3Cramer P, et al. ASH Abstract 2840. 4Hallek M, et al. Lancet. 2010;376:

85 First-Line Treatment of Elderly Patients With Comorbidities
CLL208: R-chlorambucil Phase II trial of 100 patients showed 80% ORR and 12% CR.1 Median PFS 23.9 months; median OS not reached.1 Rituximab + GM-CSF Trial of patients ≥ age 70 years showed 68% ORR and 6% CR.2 R + GM-CSF well tolerated, with 2% grade 3/4 neutropenia the only grade 3/4 AE.2 CLL11: chlorambucil vs R-chlorambucil vs GA101-chlorambucil3 Lenalidomide Phase II study of 60 patients age ≥ 65 years produced 65% ORR and % CR. CR rate increased over time to 38%.4 Median PFS = 52 months; median OS not reached.4 Efficacy Measure GA101 + Chlor vs Chlor P Value R + Chlor vs Chlor ORR, % 75.5 vs 30.2 NR 65.9 vs 30.0 Median PFS, months 23.0 vs 10.9 < .0001 15.7 vs 10.9 1Hillmen P, et al. ASH Abstract 697. 2Ferrajoli A, et al. Paper submitted. 3Goede V, et al. ASCO Abstract 7004. 4Badoux XC, et al. Blood. 2011;118:

86 Targeted Therapy for CLL: Focusing on the B Cell Receptor Pathway
Jennifer R. Brown, MD, PhD

87 Therapies Targeting BCR Pathway: Idelalisib
PI3Kδ inhibitor; BID dosing. Unique response pattern: causes simultaneous decline in lymphadenopathy (sustained over treatment) and increase in lymphocytosis (transient). Single-agent idelalisib produced 56% ORR, 81% nodal response, and median PFS of 17 months in relapsed/refractory CLL.1 Phase Ib study of idelalisib in combination with rituximab and/or bendamustine in relapsed/refractory CLL: Patients from each group achieved nodal responses and ORR ≥ 78%.2 Approximately 35% of patients relapsed in irst 12 months, after which a plateau through 28 months.2 Ongoing phase III idelalisib trial in CLL: Idelalisib + BR vs placebo + BR in previously treated CLL 1Brown JR, et al. ASCO Abstract 7003. 2Barrientos JC, et al. ASCO Abstract 7017.

88 Therapies Targeting BCR Pathway: Ibrutinib
BTK inhibitor; QD dosing. Phase II monotherapy study (N=116) of 3 groups of patients: treatment-naïve ≥ age 65 years, relapsed/refractory, and high-risk relapsed/refractory1 Most grade 3/4 AEs ≤ 5% incidence; neutropenia ~20% and infection ~40% in RR group. One death due to pneumonia in R/R group. Sustained improvements observed in hemoglobin and platelets for most relapsed patients with cytopenias. 68% ORR in treatment-naïve patients and 71% in R/R patients. Even patients with bulky disease or del17p had good responses. Lymphocytosis occurred in most patients but normalized by 12 months. Ongoing phase III ibrutinib trials in CLL: BR ± ibrutinib in R/R CLL and ibrutinib vs chlorambucil in elderly CLL. Efficacy at 26 Months TN R/R Overall del17p del11q No del IgVH Mut IGVH Unmut Est. PFS 96% 75% 57% 73% 93% 83% 72% Est. OS 70% 85% 82% 1Byrd JC, et al. ASH Abstract 189.

89 IMiDs and Combinations: How to Integrate Into Standard CLL Therapy
Alessandra Ferrajoli, MD

90 Lenalidomide Monotherapy in CLL
Properties of lenalidomide treatment Normalization of peripheral blood lymphocytes and T cells1,2 Improvement in serum Igs2 Single-agent lenalidomide as salvage therapy: Lenalidomide monotherapy as frontline therapy for CLL (n = 25):5 PR = 56% Tumor flare = 88% Grade 3/4 neutropenia = 72% Response RPCI3 n = 45 MDACC1 n = 44 CLL-014 n = 52 ORR 47% 32% 12% CR 9% 7% 0% SD 18% 25% 58% 1Ferrajoli A, et al. Blood. 2008;111: 2Badoux XC, et al. Blood. 2011;118: 3Chanan-Khan AA, et al. J Clin Oncol. 2006;24: 4Wendtner CM, et al. Leuk Lymphoma. 2012;53: 5Chen CI, et al. J Clin Oncol. 2011;29:

91 Lenalidomide Combination Therapy in CLL
Lenalidomide + fludarabine + rituximab in untreated CLL Phase !/II study: ORR = 56%, but combination too toxic, with myelosuppression and idiosyncratic drug reaction as DLTs.1 REVLIRIT: Combination followed by lenalidomide and rituximab maintenance therapy. Dosages more tolerable; ORR = 87%, CR = 49%, MRDneg = 29%.2 Lenalidomide + rituximab in frontline CLL3 Phase II study of 69 patients, divided by age (65 years) into 2 groups: Ongoing phase III lenalidomide trials in CLL: Lenalidomide vs chlorambucil as frontline therapy. Lenalidomide as maintenance (1 after 1st-line and 1 after 2nd-line). Group N ORR CR Age < 65 years 40 95% 20% Age ≥ 65 years 29 78% 7% Overall 69 88% 15% 1Brown JR, et al. Leukemia. 2010;24: 2Egle A, et al. ASH Abstract 292. 3James DF, et al. ASH Abstract 291.

92 Lenalidomide Combination Therapy in CLL
Lenalidomide + rituximab in relapsed CLL1 Phase II study of 59 patients who received prior purine analog therapy Median 2 prior regimens; 93% prior FCR, PCR, CFAR, or OFAR No grade 3/4 tumor flare; combination well tolerated Deletion status did not impact PFS outcomes. Fludarabine-refractory patients had inferior PFS compared with patients not refractory to fludarabine (P = .019). Lenalidomide + ofatumumab in relapsed CLL2 Phase II trial of 34 patients who received prior purine analog therapy (100% received FCR). Treatment ORR CR Median TTF 3-yr OS Lenalidomide + rituximab 66% 12% 17.4 months 71% Treatment ORR CR Median PFS 2-yr OS Lenalidomide + ofatumumab 68% 24% 16 months 73% 1Badoux XC, et al. J Clin Oncol. 2013;31: 2Ferrajoli A, et al. ASH Abstract 720.

93 Management of Patients With MDS Refractory to Hypomethylating Agents
David Steensma, MD

94 Hypomethylating Agents for MDS: Response to Treatment
Treatment with hypomethylating agents (HMAs; azacitidine and decitabine): Improves survival by 9 months in high-risk patients1 Delays progression to AML by 4-6 months2 Improves quality of life3 Has low early treatment-related mortality4 However, it also: Produces low CR rate5,6 Produces hematologic responses in only 30%-60% of patients7,8 Has variable duration of response9 Is associated with poor survival – < 6 months – after HMA failure10 1Fenaux P, et al. Lancet Oncol. 2009;10: 2Kantarjian H, et al. Cancer. 2006;106: 3Kornblith AB, et al. J Clin Oncol. 2002;20: 4Santos FP, et al. Expert Rev Anticancer Ther. 2010;10:9-22. 5Itzykson R, et al. Blood. 2011;117: 6Lubbert M, et al. J Clin Oncol. 2011;29: 7Lee JH, et al. Haematologica. 2011;96: 8Lyons RM, et al. J Clin Oncol. 2009;27: 9Steensma DP, et al. J Clin Oncol. 2009;27: 10Prebet T, et al. J Clin Oncol. 2013;29:

95 Hypomethylating Agents for MDS: Outcomes After HMA Failure
Common reasons for azacitidine failure:1 Primary failure (progression or stable disease): 55% Secondary failure (initial response, then progression or stable disease): 36% Intolerance: 9% Outcomes after HMA failure: HMA Median OS 1-yr OS Azacitidine High risk1 Intermediate-1 risk2 Low risk2 5.6 months 15 months 46 months 29% NR Decitabine Intermediate-1 to high risk3 4.3 months 28% 1Prebet T, et al. J Clin Oncol. 2013;29: 2Mishra A, et al. ASH Abstract 2815. 3Jabbour E, et al. Cancer. 2010;116:

96 Hypomethylating Agents for MDS: Treatment Options After HMA Failure
Rigosertib is a multikinase inhibitor that inhibits PI3K/Akt/ERK pathway that is in phase III testing for MDS patients who have progressed after or did not respond to an HMA. Treatment Option After HMA Failure Median OS, months1 Allogeneic transplant 19.5 Clinical trial with investigational agent 13.2 Intensive cytotoxic chemotherapy 8.9 Low-dose chemotherapy 7.3 Supportive care 4.1 Rigosertib 1800 mg/24h as 72h continuous infusion days 1, 2, and 3 of a 2-week cycle Randomize 2:1 Best supportive care or low-dose cytarabine Primary endpoint: OS Secondary endpoints: IWG 2006 response, AEs 1Prebet T, et al. J Clin Oncol. 2011;29:

97 BiTE Antibodies for Treatment of ALL
Daniel J. DeAngelo, MD, PhD

98 Bispecific T-Cell Engager (BiTE) Antibodies
BiTE antibodies are bispecific antibodies that harness patient’s immune system by engaging T cells with tumor cells via variable region from a T-cell-specific antibody linked to variable region from a tumor-specific antibody. Blinatumomab is a BiTE antibody with variable regions of anti-CD3 antibody and anti-CD19 antibody linked together.

99 Blinatumomab for Treatment of ALL in Hematologic CR
Blinatumomab phase II study of 21 patients with ALL in hematologic complete remission with either molecular failure or relapse after ≥ 3 cycles of chemotherapy.1 Patients received single-agent blinatumomab 15 µg/m2/d continuous infusions 4 wk on/2 wk off. Responses were rapid, occurring within first cycle of treatment. Median DFS not yet reached. E1910: phase III study of blinatumomab in patients with newly diagnosed BCR-ABL-negative ALL. Will be followed by consolidation and maintenance chemotherapy for both groups. Treatment Molecular CR DFS After Median 15 Months FU Blinatumomab 80% 60% 1Topp MS, et al. J Clin Oncol. 2011;29:

100 Blinatumomab for Treatment of Relapsed/Refractory ALL
MT study design: Most common AEs were pyrexia, fatigue, headache, tremor, and leukopenia. Medically important AEs were cytokine release syndrome (n=3), reversible CNS AEs (n=6), and infection (n=1 death due to fungal encephalitis). Dose-finding run-in phase Cohort 1 15 µg/m2/d Primary endpoint: CR and CRh* rate within 2 cycles Cohort 3 extension phase 5-15 µg/m2/d Cohort 2a 5-15 µg/m2/d Screening & enrollment Safety evaluation N=36 Cohort 2b µg/m2/d Cohort 2 was selected as dosage for extension phase because it had lowest incidence of treatment-emergent AEs. Treatment CR Molecular Remission in Pts with CR/CRh* Median RFS Median OS Blinatumomab 69% 88% 7.6 months 9.8 months *CRh = CR with only partial hematologic recovery

101 A Critical Evaluation of the Role of JAK2 Inhibitors for Myeloproliferative Neoplasms
Ruben Mesa, MD

102 JAK2 Inhibitors and Myelofibrosis
Ruxolitinib – approved by FDA in 2011 for myelofibrosis COMFORT I and II – phase III trials of ruxolitinib vs placebo showed ruxolitinib produced dramatic reduction in splenomegaly (both P < .001), reduced overall and individual symptoms (P < .001), and improved OS (HR = 0.50 and 0.58; P ≤ .04).1,2 SAR – in phase III testing (JAKARTA) Phase II data from 31 patients showed mean spleen volume reduction of 42% in patients receiving the highest dose (500 mg daily). Also evidence of symptom improvement in majority of patients.3 Pacritinib – in phase III testing In a phase II study of 34 patients, pacritinib reduced splenomegaly by ≥ 25% in one-third of patients.4 CYT387 – in phase II testing Phase II study of 166 patients demonstrated rapid and sustained reductions in splenomegaly, marked improvement to complete resolution of constitutional symptoms by majority of patients, and increased transfusion independence.5 1Verstovsek S, et al. N Engl J Med. 2012;366: Harrison C, et al. N Engl J Med. 2012;366: 3Talpaz M, et al. ASH Abstract 2837. 4Komrokji RS, et al. ASH Abstract 282. 5Pardanani A, et al. ASH Abstract 178.

103 Ruxolitinib for Polycythemia Vera and Essential Thrombocythemia
Polycythemia vera (PV) Hydroxyurea and IFN are frontline therapies. Ongoing trial will determine standard of care for PV. Ruxolitinib examined in open-label phase II study of patients with PV refractory or intolerant to hydroxyurea. Nearly three-quarters of patients remained on-study and phlebotomy-free for ≥ 144 weeks.1 Clinically meaningful improvements in pruritus, night sweats, and bone pain sustained through week 1441 In phase III testing (RESPONSE and RELIEF) Essential thrombocythemia Of 39 patients, 79% achieved ≥ 50% reduction in platelets during ruxolitinib use.2 Ruxolitinib in phase III testing (RELIEF) 1Verstovsek S, et al. ASH Abstract 804. 2Verstovsek S, et al. ASH Abstract 313.

104 Leukemia and MPN Takeaways
Ongoing debate regarding best TKI for frontline treatment of CML-CP: imatinib or 2nd-generation agents dasatinib and nilotinib. Imatinib has excellent long-term safety, but 2nd-generation TKIs produce more early cytogenetic and molecular responses. A number of novel regimens being tested in elderly patients with CLL, including rituximab + GM-CSF, GA101 + chlorambucil, and lenalidomide. Ibrutinib and idelalisib have shown promising efficacy and safety in CLL and are currently in late-stage development for treatment of this disease. Lenalidomide, alone or in combination with other agents (primarily anti-CD20 antibodies), is currently under investigation for several CLL indications. Treatment options limited for MDS after failure of hypomethylating agents. Rigosertib is a targeted agent in phase III testing for this indication. Blinatumomab is a BiTE antibody that has demonstrated encouraging efficacy and safety for treatment of ALL and is undergoing phase III evaluation. JAK2 inhibitor ruxolitinib approved for treatment of myelofibrosis and under investigation in polycythemia vera and essential thrombocythemia. Several other JAK2 inhibitors in development for myelofibrosis.

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