3What Can We Learn From Multiple Myeloma Genomic Analysis? Nikhil Munshi, MDDr Nikhil Munshi presented a lecture discussing what we can learn from multiple myeloma genomic analysis.
4Genomic Analysis Takeaways Methods of genomic analysisEstablished techniques: cytogenetics, FISHEmerging techniques: RNA- and DNA-based arrays, transcript- processing arrays, genomic sequencing, and proteomicsCurrent goals of genomic analysis in myelomaUnderstand the biology of myelomaIdentify risk categories to improve prognosticationIdentify and validate novel targetsDevelop biologic agents that target the myeloma cellUltimately, develop personalized therapyCurrently, 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.
5High-Risk Smoldering Myeloma – Should We Intervene Early? Ola Landgren, MD, PhDNext, Dr Ola Landgren discussed high-risk smoldering myeloma and whether or not we should intervene early in the disease course.
6Smoldering Myeloma Definition of smoldering myeloma1 Serum monoclonal IgG or IgA ≥ 3 g/dL and/or clonal bone marrow plasma cells ≥ 10% ANDAbsence of end-organ damage (ie, hypercalcemia, renal insufficiency, anemia, or bone lesions attributed to plasma cell proliferative disorder)Overall risk of progression210% per year in years 0-53% per year in years 6-101% per year in years 11-20Risk stratificationMayo Clinic analysis3 stratifies patients according to their 5-yr risk of progression into 3 groups: 25% risk, 51% risk, and 76% riskPETHEMA Study Group analysis4 stratifies patients according to their 5-yr risk of progression into 3 groups: 4% risk, 46% risk, and 72% riskeTo 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:
7First Randomized Phase III Trial for Smoldering Myeloma Randomization of high-risk smoldering MM patients:Median time to symptomatic progressionLen/dex: not yet reachedObservation: 21 months4-year overall survivalLen/dex: 94%Observation: 85%Lenalidomide 25 mg/day, D1-21 Dexamethasone20 mg D1-D4 and D12-D15Therapeutic abstentionInduction: Nine 28-day cyclesLenalidomide 10 mg/day, D1-21 every 2 monthsTherapeutic abstentionMaintenance: Until progressionPrimary endpoint: time to progression to symptomatic MMSecondary endpoints: ORR, DOR, PFS, OS, and safety and tolerabilityThis 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 < .0001HR = 3.5; P < .01Mateos MV, et al. ASH Abstract 991.
8Smoldering Myeloma Takeaways Current clinical recommendation for smoldering myeloma: no treatment unless part of a clinical trial1Better understanding of pathogenesis from MGUS to myeloma needed:To develop better biological markersTo predict a patient’s risk of progressionTo develop early intervention strategiesThe 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.
9Current Trends: Treatment Strategies for Newly Diagnosed Elderly Patients With Myeloma James Berenson, MDDr James Berenson then presented information on current treatment strategies for newly diagnosed patients with myeloma, particularly the elderly.
10Dexamethasone ± Lenalidomide SWOG S0232 Len + Dex (n = 97)Len: 25 mg/day, D1-28Dex: 40 mg/day, D1-4, 9-12, 17-20Three 35-day cyclesDexamethasone (n = 95)Placebo: 25 mg/day, D1-28Dex: 40 mg/day, D1-4, 9-12, 17-20Three 35-day cyclesResponding/stablediseaseDiseaseprogressionLen + DexLen: 25 mg/day, D1-21Dex: 40 mg/day, D1-4 and 15-1828-day cycles until progressionDexamethasonePlacebo: 25 mg/day, D1-21Dex: 40 mg/day, D1-2128-day cycles until progressionUnblinded TreatmentLen: 25 mg/day, D1-28Dex: 40 mg/day, D1-4, 9-12, 17-20Three 35-day cyclesBecause 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 + DexLen: 25 mg/day, D1-21Dex: 40 mg/day, D1-4 and 15-18Objective: to determine the efficacy and safety of Len + Dex as induction therapy in NDMM patientsPrimary endpoint: PFSZonder JA, et al. Blood. 2010;116:
11Dexamethasone ± Lenalidomide SWOG S0232 1-yr PFS was significantly improved with the addition of lenalidomide (78% vs 53%; P = .002)ORR = 78%ORR, P < .0001VGPR, P < .001ORR = 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:
12Transplant-eligible patients can proceed to SCT Continue therapy until Lenalidomide + High-Dose Dex vs Lenalidomide + Low-Dose Dex: ECOG E4A03Lenalidomide + High-Dose Dexamethasone (RD)aLen: 25 mg/day, days 1-21Dex: 40 mg/day, days 1-4, 9-12, 17-20(n = 223)Transplant-eligible patients can proceed to SCTFour 28-day cyclesLenalidomide + Low-Dose Dexamethasone (Rd)Len: 25 mg/day, days 1-21Dex: 40 mg/day, days 1, 8, 15, 22(n = 222)Continue therapy untildisease progressionObjective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacyPrimary endpoint: ORR after first 4 cyclesThis 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.Arm1-yr OS2-yr OSRD (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.
13MP ± Bortezomib: VISTAEndpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS, QoLPreviously untreated patients;not candidates for transplantARM B (MP)MP: Nine 6-week cycles: Cycles 1-9Melphalan 9mg/m2 and prednisone 60mg/m2 days 1-4ARM A (VMP)VMP: Four 6-week cycles: Cycles 1-4Bortezomib 1.3mg/m2 days 1, 4, 8, 11, 22, 25, 29, 32;Followed by five 6-week cycles: Cycles 5-9Bortezomib 1.3mg/m2 days 1, 8, 22, 29; Melphalan 9mg/m2 and prednisone 60mg/m2 once daily on days 1–4Max of 9 cycles (total 54 weeks) in both armsRANDOMIZEStudy Schema:682 patients randomized151 centers22 countries worldwideIDMC recommended study stop in September 2007 based on protocol-specified interim analysisVMP was significantly superior for all efficacy endpointsThe 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 ParameterLenalidomidePlaceboHRP ValueMedian TTP, months24.016.60.483<Median OS, monthsNR0.61.0083-yr OS: 72% in VMP arm vs 69.5% in MP armSan Miguel J, et al. N Engl J Med. 2008;359:Mateos MV, et al. J Clin Oncol. 2010;28:
14Phase II Studies for Newly Diagnosed Multiple Myeloma RegimenDrugsORRCRCybor-D1cyclophosphamide + bortezomib + dex93%39%DVD2bortezomib + pegylated liposomal doxorubicin + dex86%20%VRD3bortezomib + lenalidomide + dex100%37%BAM4bortezomib + ascorbic acid + melphalan → maintenance bortezomib74%13%BiRD5,6clarithromycin + lenalidomide + high-dose dex90%CRd7carfilzomib 27 mg/m2 + lenalidomide + dex85%CYCLONE8carfilzomib + cyclophosphamide + thalidomide + dex96%29%CMP9carfilzomib + melphalan + prednisone89%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.
15Novel Combinations and New Drugs for Elderly Patients With Myeloma Approved drugsNovel combinationsModifications of dose and scheduleImprove efficacyBetter tolerabilityDrugs in developmentSimilar targetsProteasome inhibitors - carfilzomib (FDA-approved!), ixazomibIMiDs - pomalidomide (FDA-approved!)New classes of agentsMonoclonal antibodies - anti-CS-1 (elotuzumab), anti-CD40 (dacetuzumab), anti-CD38mTOR inhibitors - temsirolimusPI3K inhibitors - perifosineHDAC inhibitors - vorinostat, romidepsin, panobinostatTo 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.
16Maintenance Therapy – Is It for Everyone? Nikhil Munshi, MDDr Nikhil Munshi discussed the evidence for maintenance therapy for myeloma patients.
17Maintenance Therapy for Multiple Myeloma Purpose is to prolong remission duration and life expectancyRequires periodic follow-up to monitor toxicity and responsePatient must have:Disease that is in remission (undetectable or at a low level)Recovered from all previous toxicitiesMaintenance agent must have:Minimal toxicity or at least not overlapping with the toxicity of the induction regimenConvenient dosingConvenient route of administrationThe 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.
18Lenalidomide Maintenance After Transplant: CALGB 100104 RestagingDays 90–100RegistrationRandomizationD-S Stage 1-3, < 70 years> 2 cycles of inductionAttained SD or better 1 yr from start of therapy> 2 x 106 CD34 cells/kgMel 200ASCTPlaceboCRPRSDLenalidomide10 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 ParameterLenalidomidePlaceboHRP ValueMedian TTP, months4627--< .00013-yr OS88%80%0.62.027McCarthy PL, et al. N Engl J Med. 2012;366:
19Lenalidomide Maintenance Following Lenalidomide Consolidation: IFM 2005-02 Phase III randomized, placebo-controlled trialN= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008Patients age < 65 years, with nonprogressive disease, ≤ 6 months after ASCT in first lineRandomization: stratified according to Beta-2m, del13, VGPRConsolidation:Lenalidomide alone 25 mg/day podays 1-21 of every 28 days for 2 monthsArm A = Placebo(N=307)until relapseArm B = Lenalidomide(N=307)10-15 mg/d until relapseThe 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: PFSSecondary 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.
20Lenalidomide Maintenance in Patients Ineligible for Transplant: MM-015 Double-Blind Treatment PhaseOpen-LabelExtension PhaseCycles (28day) 1-9Cycles 10+MPR-RMaintenanceM:0.18 mg/kg, days 1-4P:2 mg/kg, days 1-4LenalidomideR:10 mg/day po, days 1-2110 mg/daydays 1-21MPRRANDOMIZATIONLenalidomideM:0.18 mg/kg, days 1-4Disease(25 mg/day)P:2 mg/kg, days 1-4PlaceboProgression+/-R:10 mg/day po, days 1-21DexamethasoneAs 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.MPM:0.18 mg/kg, days 1-4P:2 mg/kg, days 1-4PlaceboPBO:days 1-21PFS significantly prolonged with the addition of lenalidomide maintenance following MPR induction therapy (HR = 0.349; P < .001)PFS benefit maintained across patient subgroupsPalumbo A, et al. N Engl J Med. 2012;366:
21Maintenance 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)1,2MM-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:
22PAD + Bortezomib Maintenance vs VAD + Thalidomide Maintenance: HOVON Trial MM Stage II or III, Age 18–65Bortezomib1.3 mg/m2 IVDoxorubicin9 mg/m2Dexameth40 mgRandomization3 x VAD3 x PADCAD + GCSFCAD + GCSFMEL PBSCTMEL PBSCTIn GMMG 2ndMEL PBSCTAllogeneic TxIn GMMG 2ndMEL PBSCTNext, 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 yrsBortezomib maintenance1.3 mg/m2/2 weeks for 2 yrsEfficacy ParameterPAD → bortezomibVAD → thalidomideP Value3-yr PFS48%42%.0053-yr OS78%71%.02Sonneveld P, et al. ASH Abstract 40.
23Bortezomib + Thalidomide vs Bortezomib + Prednisone as Maintenance: GEM2005MAS65 Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trialMaintenanceBort/Thal(VT)Bort/Pred(VP)Induction(6 cycles)Bort/Mel/Pred(VMP)Bort/Thal/Pred(VTP)vsNo 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.ArmORRCRMedian PFSVT maintenance95%46%39 monthsVP maintenance97%39%32 monthsMateos MV, et al. Lancet Oncol. 2010;10:
24Conclusions 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.
25How to Best Use New Proteasome Inhibitors and IMiDs in Myeloma Sundar Jagannath, MDDr Sundar Jagannath closed the myeloma session by discussing how best to use new proteasome inhibitors and IMiDs in myeloma.
26Pivotal Trial of Immunomodulatory Agent Pomalidomide: MM-002 Primary endpoint: PFSSecondary endpoints: ORR, DOR, OS, and safetyRandomizationProgressive diseaseProgressive diseaseOption to add LoDEXa (40 mg/week)POM (4 mg days 1–21 of 28-day cycles)Discontinue and follow-up for survival and subsequent treatmentPomalidomide 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.
27MM-002: Response RatesMedian number of cycles received = 5 (range, 1-28)Disease control rate = 81% overallResponsePOM + LoDEX(n=113)POM (n=108)ORR (%)3415CR (%)31PR (%)3114MR (%)1216SD (%)3748PD (%)610Median time to ORR, months1.93.7Median duration of response, months8.38.8The 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.
28MM-002: PFS, OS, and SafetyEfficacy ParameterPOM + LoDEXPOMHRP ValueMedian PFS, months220.127.116.11.002Median OS, months16.518.104.22.1689Age ≤ 65 yearsAge > 65 yearsGrade 3/4 AEs ≥ 20%POM + LoDEX(n=61)POM(n=68)(n=51)(n=39)HematologicNeutropeniaAnemiaThrombocytopenia462618402435205921NonhematologicPneumoniaDyspnea16710298The 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.
29Pomalidomide + 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, 22RANDOMIZATION 2:1Follow-up for OS and SPM until 5 years post enrollment(n = 153)HiDEX: 40 mg (≤ 75 yrs) mg (> 75 yrs) D1-4, 9-12, 17-2028-day cyclesPD* or intolerable AEPD*Companion trial MM-003CPOM 21/28 daysMM-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 historyStratificationAge (≤ 75 vs > 75 yrs)Number of prior Tx ( 2 vs > 2)Disease population*Progression of disease independently adjudicated in real-time
30MM-003: PFS and OS Arm POM + LoDEX n = 302 HiDEX n=153 HR P Value Median PFS, monthsITT populationRefractory to bortezomibRefractory to lenalidomideRefractory to both22.214.171.124.81.70.450.470.380.48< .001Median OS, monthsNR126.96.36.199.40.530.560.39.037.003The 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.
31Pivotal Trial of Proteasome Inhibitor Carfilzomib: 003-A1 MM: Progressive disease> 2 prior therapy linesincluding bortezomib, thalidomide or lenalidomide,an alkylating agent,and anthracycline alone or in combination003-A0003-A1Carfilzomib20 mg/m2 days 1, 2, 8, 9, 15, 16 every 28 daysN = 46CarfilzomibDose escalation to 27 mg/m2 after cycle 1 up to 12 cyclesN = 266Primary Endpoint: ORRSecondary Endpoints: clinical benefit rate (≥ minimal response), DOR, PFS, OS, and safetyThe 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.
32Single-Agent Carfilzomib Pivotal Trial: Efficacy ResponseCarfilzomib(N=257)ORR24%Clinical benefit rate34%Duration of response8.3 monthsMedian PFS3.7 monthsMedian OS15.6 monthsDespite 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:
33Single-Agent Carfilzomib Pivotal Trial: Safety Adverse EventGrade 3/4 AEsN =266HematologicAnemiaThrombocytopeniaLymphopeniaNeutropenia24%29%20%11%NonhematologicFatigueDyspneaUpper respiratory tract infectionHeadache7.5%3.4%4.5%1.9%OtherFebrile neutropeniaPeripheral neuropathy0.8%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 carfilzomibCHF in 3.8%; myocardial infarction or cardiac arrest in 2.3%Siegel DS, et al. Blood. 2012;120:
34Multiple 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.
35The next section of slides summarizes the lectures on lymphoma.
36Initial Management of Peripheral T-Cell Lymphoma: If CHOP Is No Good, What Is? Steven M. Horwitz, MDDr Steven Horwitz kicked off the T-cell lymphoma section by discussing the initial management of peripheral T-cell lymphoma.
37Peripheral 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.2,3ASCT has shown promise in some upfront trials with PTCL.4,5Potential approaches to explore:CHOP + etoposideCHOP + novel agent (ie, brentuximab data very encouraging)CHOP → maintenance therapyASCTEntirely new regimenCurrent 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:
38Management of Cutaneous T-Cell Lymphoma Lauren Pinter-Brown, MD, FACPDr Lauren Pinter Brown ended the T-cell lymphoma section by exploring the management of CTCL.
39Treatment 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 therapySystemic therapies: extracorporeal photochemotherapy, retinoids, interferon-alpha or gamma, alemtuzumab, denileukin diftitox (not currently available), HDAC inhibitors, chemotherapyTreatment considerations: stage, route (oral vs topical vs systemic), rapidity of response, availability (geographically or due to cost), and comorbiditiesSupportive care:Pruritus: distinguish generalized from localized; treat with moisturizers, emollients, and barrier protection, as well as topical steroids, camphor/menthol, othersInfection: crucial to avoid central lines and maintain skin barrier. Consider bleach baths.
40Treatment of CD30+ Lymphoproliferative Disorders Lymphomatoid papulosis:Treatment options: watch and wait (most cases), methotrexate, phototherapy, interferonRapid relapse off treatment, so maintenance therapy necessary10%-20% of these cases associated with Hodgkin lymphoma, mycosis fungoides, or ALCL, so follow-up requiredPrimary 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 survivalSpontaneous remission possible
41How I Manage Early-Stage Diffuse Large B-Cell Lymphoma Daniel O. Persky, MDDr Daniel Persky started the B-cell lymphoma section by explaining how he manages patients with early-stage DLBCL.
42Current Treatment Paradigm for Early-Stage DLBCL Early-stage DLBCL is curable malignancy, with >50% cure rate and a 70%-90% 5-year OS.1Differences in outcomes arise from variations in radiation therapy quality and patient selectionEarly-stage disease has pattern of late relapsesAddition of rituximab to chemotherapy modestly improved PFS outcomes in early-stage disease, but has not improved OS.2,3Another 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.4Regimen3-yr PFS3-yr OSR-CHOP x 3-4 → IFRT90%96%R-CHOP x 6-874%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.
43Novel 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 DLBCL3,4BCCA experience:5 R-CHOP x 3 → PET. If PET+, go on to IFRT. If PET‒, receive R-CHOP x 1Ongoing phase II trial, S1001, will test this PET risk-adapted approach in early-stage DLBCL, with PET+ population receiving R-CHOP x 3 → IFRT → ibritumomabResultPET –n=103PET +n=30P Value3-yr TTP92%60%.093-yr OS96%83%.11Miller 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.
44Biology of Early-Stage DLBCL DLBCL molecularly heterogeneous with different 5-year survivals:1Primary 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 ABCBottom 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:
45Advanced-Stage DLBCL Craig Moskowitz, MD Dr Craig Moskowitz then presented a lecture on advanced-stage DLBCL.
46R-CHOP Regimens for Advanced-Stage DLBCL R-CHOP21 vs R-CHOP14 phase III studiesGELA: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 < CR3MSKCC:4 R-CHOP → ibritumomabFor those receiving RIT, 2-yr PFS = 79%, 2-yr OS = 84%Led to current US phase III trial:R-CHOP → ibritumomab consolidation in elderly DLBCL1Delarue R, et al. Lancet Oncol. 2013;14:2Cunningham D, et al. ASCO Abstract 8000.3NCCN NHL guidelines4Hamlin PA, et al. ASH Abstract 1793.
47Risk-Adapted Therapy for Advanced-Stage DLBCL MSKCC :MSKCC :ICE x 2RICE x 1HDT/ASCTICE x 3followed byobservationBx +Bx -PET-Repeat Bx+R-C1000HOuncappedP-14 x 4Results showed no difference in PFS among:1PET-negativePET-positive/biopsy-negativePET-positive/biopsy-positiveResults showed 4-yr OS > 80% and 4-yr PFS > 70%R-R-C1000HOuncappedP-14 x 3C1000HOuncappedP-21 x 1+PET-Repeat BxBx -Bx +≥80% Ki <80%AugmentedRICE x 2followed byHDT/ASCTAugmentedRICE x 2followed byobservationICE x 3followed byobservation1Moskowitz et al. Lancet Oncol. 2010;28:
48Dose-Adjusted EPOCH-R for Advanced-Stage DLBCL CALGB phase II study1Excellent 5-yr results in overall populationOS = 84%PFS = 81%EFS = 75%However, high-risk disease associated with worse outcomes than other subgroupsIPI 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-CHOP211Wilson WH, et al. Haematologica. 2012;97:
49Relapsed DLBCL in the Rituximab Era Anas Younes, MDDr Anas Younes then summarized relapsed DLBCL in the rituximab era.
50Salvage 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:
51Relapsed 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.LymphomaPI3K/AKT/mTORJAK/STATBCRBiomarker -It is likely that all salvage regimens are equal.P-PRAS40 +pSTAT3 +P-CD19 +RCHOPRCHOP +Drug ARCHOPRCHOP +Drug CRCHOPRCHOP +Drug DRCHOP
52New Directions in Follicular Lymphoma Bruce D. Cheson, MDDr Bruce Cheson described new directions in the management of follicular lymphoma.
53Antibodies in Follicular Lymphoma GA101: Anti-CD20 antibodyAntibody-drug conjugatesDCDT2980S: anti-CD22 linked to MMAE. Showed CR in 2 of 3 patients with DLBCL and 1 PR in patient with FL in phase I testing3DCDT4501A: anti-CD79b linked to MMAE. Showed responses in 5 of 8 patients at first assessment in phase I testing4Ongoing randomized crossover trial:TrialTreatmentn (FL)ORRGAUGIN1 (BO20999)GA101 low-dose1436%GA101 high-dose2060%GAUSS2GA1017443%rituximab7539%Arm A: R (d1) +DCDT2980S (d2)Q 21 daysResponsePDArm B: R (d1) +DCDT4501A (d2)Q 21 daysResponse1Salles 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.
54Small-Molecule Inhibitors in Follicular Lymphoma Ibrutinib (PCI-32765): BTK inhibitor produced 54% ORR in overall B-cell malignancy population and 38% in FL.1Duration of response impressive, particularly in FL, where multiple patients continue to receive ibrutinib after ≥2 yearsIdelalisib (GS-1101): PI3K delta inhibitorIPI-145: PI3K delta and gamma inhibitorIn phase I testing, IPI-145 showed early signs of clinical activity across multiple heme malignancies.3Phase I Treatment2Decreased AdenopathyORR1-yr PFSIdelalisib + rituximab97%77%82%Idelalisib + bendamustine85%90%Idelalisib + bendamustine/rituximab100%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.
55Apoptosis-Inducing Agents and IMiDs in Follicular Lymphoma ABT-199:1 apoptosis-inducing agentLenalidomide: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 + lenalidomidePopulationNORRSDGr 3/4 Treatment-Related AEs in >2 PatientsOverall (R/R NHL)2348%30%10% anemiaFL812%88%NRPopulationNORRSD2-yr PFSOverall(untreated indolent NHL)10390%8%83%FL4698%2%89%R2R2 maintenance1st lineFLN=1000RR +chemoRituximab maintenance1Davids MS, et al. ASH Abstract 304.2Fowler NH, et al. ASH Abstract 901.
56Management of Hodgkin Lymphoma in the Elderly Paul A. Hamlin, MDDr Paul Hamlin presented a lecture concerning the management of Hodgkin lymphoma in elderly patients.
57Hodgkin 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 stage1More aggressive histology1B symptoms1EBV positivity associated with worse disease-specific survival and OS2Bleomycin produces high incidence of toxicity in elderly.3Elderly outcomes:Elderly patients have worse outcomes in clinical trials than younger patients.4A study in Scotland of 674 patients with HL who were ≥ 60 years old reported a 5-year survival of only 35%.51Word, 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.
58Reduced-Intensity Therapy for Hodgkin Lymphoma Reduced-intensity regimens:CVP/CEBVBMVEPEMBChIVPPLess-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%)1Phase II SHIELD study used VEPEMB2Population Receiving VEPEMBNCR3-yr OS3-yr PFSPatients with early-stage disease3174%81%Patients with advanced-stage disease7261%66%58%1Levis A, et al. Haematologica 1996;81:450-6.2Proctor SJ, et al. Blood. 2012;119:
59Anthracycline-Containing Therapy in Hodgkin Lymphoma ChIVPP/ABVCOPP/ABVDABVDStanford VBEACOPPGHSD10 and 11: ABVD1In 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/ABV2Retrospective analysisIn 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:
60Death due to acute toxicity Anthracycline-Containing Therapy in Hodgkin LymphomaABVD vs Stanford V1Analysis of patients age ≥ 60 treated on randomized E2496 trial (n=44)Among older patients, no survival difference between ABVD and Stanford VCompared 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 BEACOPP2Analysis of patients age years from randomized HD9 clinical trialBEACOPP associated with lower relapse rate (12% vs 23%), but at cost of increased toxicityTreatmentNCR5-yr OS5-yr FFTFDeath due to acute toxicityCOPP-ABVD2677%50%46%8%BEACOPP4276%21%1Evens AM, et al. Br J Haematol. 2013;161:76-86.2Ballova V, et al. Ann Oncol. 2005;16:
61Relapsed and Refractory HL: Will We Be Able to Avoid Transplant? Craig Moskowitz, MDDr Craig Moskowitz presented a debate on the optimal transplant strategies for the localized relapse of Hodgkin lymphoma.
62Transplantation for Relapsed/Refractory Hodgkin Lymphoma Current status of transplantation for relapsed/refractory HL:Toxicity and cost markedly decreased, but relapse rate remains relatively constantStandard conditioning regimens remain the same (CBV or BEAM)PFS = 30%-50%Adding more chemotherapy agents or escalating the dose has had minimal valueAdverse prognostic factors in patients with relapsed/refractory disease (MSKCC model):1B symptoms (night sweats, weight loss, fever without infection)Extranodal diseaseComplete remission duration < 1 year1Moskowitz CH, et al. Blood. 2001;97:
63FDG-PET to Identify Patients Needing Additional Salvage Therapy Normalization of PET prior to transplant is predictive of survival1 and identifies patients with excellent outcomesMSKCC Protocol for relapsed/refractory HL:Repeat biopsy, determine risk factorsStaging evaluation: FDG PET, diagnostic CT CAP, BM BxResults showed patients transplanted after standard or GVD salvage chemotherapy had EFS > 80%, compared with 29% EFS for patients with PET positivity.2Arm A = 0 or 1 risk factorsStandard ICE x 1Augmented ICE x 1PBPC collectionArm B = 2 risk factorsAugmented ICE x 2PBPC collectionInduction: Nine 28-day cyclesPOD on ICERestaging: FDG-PET, CT CAPPET negativePET positiveGVD x 4RestagingRadiotherapy, if applicableHDT/ASCTCR, PR, MRPODoff study1Moskowitz AJ, et al. Blood. 2010;116:2Moskowitz CH et al. Blood. 2012;119:
64FDG-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 failureORR = 75% and CR = 34% in phase II study of q3w dosing in relapsed/refractory HL1Also being studied with qw dosing (3 wk on, 1wk off)1Chen RW, et al. ASCO Abstract 8031.
65Current/Proposed Brentuximab Clinical Trials in Relapsed/Refractory HL MSKCC ongoing trialFirst treatment following upfront therapyProposed international trial adding RTNodal-only relapse, RT-naïve patientsWeekly SGN-35 x 2Weekly SGN-35 x 2+PET-+PET-RT aloneAugmented ICE x 2Platinum-basedsalvage x 2randomizePET-HDT/ASCTPET-HDT/ASCT++Further treatmentaccording totreating physicianFurther treatmentaccording totreating physician
66New 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.
67Aurora Kinase Inhibition With Alisertib Key to the cell cycle, regulating mitotic entry/progression, centrosome maturation/separation, G2/M transition, chromosome alignment, and cytokinesisPresent in aggressive T and B cell NHLAlisertib 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 testing1Ongoing SWOG 1108, a phase II study in relapsed/refractory PTCLOngoing phase III study in PTCL: alisertib vs investigator’s choiceAlisertib 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.
68Kinase Inhibitors in Lymphoma IbrutinibBruton’s tyrosine kinase (BTK) small-molecule irreversible inhibitorEfficacy in FL: 55% ORR and 12.3 months DOR1Efficacy in ABC DLBCL: 41% ORR (compared with 5% ORR for GCB)2Efficacy in phase II relapsed or refractory MCL: 66.1% ORR3Idelalisib (GS-1101, CAL-101)PI3Kδ small-molecule inhibitorEfficacy in MCL and indolent lymphoma: 62% ORR for each4Efficacy in MCL in combination with everolimus, bortezomib, or bendamustine/rituximab: 46% ORR51Fowler 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.
69JAK and STAT Inhibitors JAK/STAT signalingJanus kinase 2 (JAK2) and Signal Transducers and Activators of Transcription (STAT) pathways important to pathogenesis of hematologic malignanciesJAK2, STAT3, and STAT6 frequently overexpressed in HL and NHLJAK2 inhibition in vitro associated with reduced proliferation in numerous lymphoma cell linesSB1518 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.1Ongoing 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.
70IMiDs in LymphomaLenalidomide 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 lymphomasReceived 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 patientsIn 46 FL patients, lenalidomide + rituximab produced a 98% ORR1RELEVANCE: 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%)2R2-CHOP (RCHOP + R and Len maint) produced a 100% ORR and 77% CR in DLBCL3Len-RICE shows promise (8/13 CR) as salvage therapy in DLBCL41Fowler 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.
71Lymphoma TakeawaysStrategies 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.
72Leukemia & Myeloproliferative neoplasms The next section of slides summarizes the lectures on lymphoma.
73Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase? Imatinib Harry P. Erba, MD, PhD
74Optimal 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 imatinibENESTnd: no difference in OS of imatinib vs nilotinib (300 mg) after 3 years (94% vs 95%; P = .44)3DASISION: no difference in OS of imatinib vs dasatinib (95% vs 95%; data still immature)41Mahon 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:
75Optimal 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.3Shown above, no/modest differences in complete cytogenetic response (CCyR) present at 24 months between imatinib and 2nd-generation TKIsCan it improve tolerability?No clear tolerability advantage of 2nd-generation TKIs over imatinib Safety profiles different but overall AE incidences similar1,2Imatinib has no known late complications, unlike dasatinib and nilotinibTrialExperimental TKIMMR at 12 Months vs ImatinibMMR at 24 Months vs ImatinibP Value at 24 MonthsDASISION1dasatinib46% vs 28%64% vs 46%< .0001ENESTnd2nilotinib 300 mg55% vs 27%73% vs 53%TrialExperimental TKICCyR at 12 Months vs ImatinibCCyR at 24 Months vs ImatinibP Value at 24 MonthsDASISION1dasatinib85% vs 73%85% vs 82%NSENESTnd4nilotinib 300 mg80% vs 65%87% vs 77%.00181Kantarjian 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:
76Progression to AP/BP vs Imatinib Optimal First-Line CML Therapy: Prevention of Progression and Cost of TherapyCan 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.TrialExperimental TKIProgression to AP/BP vs ImatinibP ValueDASISION1dasatinib3.5% vs 5.8%NRENESTnd2nilotinib 300 mg3.2% vs 6.7%.04961Kantarjian HM, et al. Blood. 2012;119:2Saglio G, et al. ASH Abstract 452.3NCCN CML guidelines. Version
77Imatinib 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.
78Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase? Second-Generation TKIs Michael J. Mauro, MD
79Prediction 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:1More recently discovered that early reduction in BCR-ABL/ABL transcript levels correlates with survival:2NCCN guidelines now recommend switching TKIs if BCR-ABL transcript levels > 10% at 3 months.3Time PointEarly ResponseMMR %P Value3 months> 2-log reduction100%< .0010- to 2-log reduction54%6 months86%0%Time PointEarly BCR-ABL/ ABL Level8-yr OSP Value3 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
80Is 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.1YES! 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.2Months on TreatmentPatients Not in CCyR (n)Event (%)31092364734122638MMR After 12 MonthsAP/BP (%)P ValueYes1.0004No101Quintas-Cardama A, et al. Blood. 2009;113:2Hughes T, et al. Blood. 2010;116:
81Why Dasatinib and Nilotinib for First-Line Therapy? Both dasatinib and nilotinib produce more favorable early responses than imatinib.1-4Both dasatinib and nilotinib associated with less transformation to AP/BP than imatinib.5,6Currently no prognostic tool validated to determine who needs additional therapy.Efficacy Measure at 12 MonthsNilotinibImatinibP ValueDasatinibCCyR80%65%< .00185%73%.0002MMR55%27%46%28%< .0001CMR11%1%~5%NSTrialExperimental TKITransformation to AP/BP (%) vs ImatinibP ValueDASISIONdasatinib2.3% vs 5%NSENESTndnilotinib 300 mg0.7% vs 6.0%.00031Saglio 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.
82Dasatinib 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.1,2Dasatinib and nilotinib safety data less mature, but dasatinib associated with pulmonary arterial hypertension3 and nilotinib associated with peripheral arterial disease.4TKI discontinuation holds promise. Of 25 patients who discontinued dasatinib or nilotinib, 73% maintained MMR after 6 months.5Final 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.
83Alessandra Ferrajoli, MD Treatment for Elderly Chronic Lymphocytic Leukemia: Is There a Standard?Alessandra Ferrajoli, MD
84Considerations in the Treatment of Elderly Patients With CLL Nearly 80% of patients with CLL are ≥ 65 years old at diagnosis.1Survival for patients aged years with CLL is poorer than with age-matched controls.2Number of comorbidities increases with age in patients with CLL.3CIRS (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 onlySlow go: use reduced-intensity therapyGo go: use standard therapyPhysically 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).41SEER cancer statistics2Shanafelt T, et al. Cancer. 2010;116:3Cramer P, et al. ASH Abstract 2840.4Hallek M, et al. Lancet. 2010;376:
85First-Line Treatment of Elderly Patients With Comorbidities CLL208: R-chlorambucilPhase II trial of 100 patients showed 80% ORR and 12% CR.1Median PFS 23.9 months; median OS not reached.1Rituximab + GM-CSFTrial of patients ≥ age 70 years showed 68% ORR and 6% CR.2R + GM-CSF well tolerated, with 2% grade 3/4 neutropenia the only grade 3/4 AE.2CLL11: chlorambucil vs R-chlorambucil vs GA101-chlorambucil3LenalidomidePhase II study of 60 patients age ≥ 65 years produced 65% ORR and % CR. CR rate increased over time to 38%.4Median PFS = 52 months; median OS not reached.4Efficacy MeasureGA101 + Chlor vs ChlorP ValueR + Chlor vs ChlorORR, %75.5 vs 30.2NR65.9 vs 30.0Median PFS, months23.0 vs 10.9< .000115.7 vs 10.91Hillmen 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:
86Targeted Therapy for CLL: Focusing on the B Cell Receptor Pathway Jennifer R. Brown, MD, PhD
87Therapies 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.1Phase 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%.2Approximately 35% of patients relapsed in irst 12 months, after which a plateau through 28 months.2Ongoing phase III idelalisib trial in CLL:Idelalisib + BR vs placebo + BR in previously treated CLL1Brown JR, et al. ASCO Abstract 7003.2Barrientos JC, et al. ASCO Abstract 7017.
88Therapies 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/refractory1Most 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.Efficacyat 26 MonthsTNR/ROveralldel17pdel11qNo delIgVH MutIGVH UnmutEst. PFS96%75%57%73%93%83%72%Est. OS70%85%82%1Byrd JC, et al. ASH Abstract 189.
89IMiDs and Combinations: How to Integrate Into Standard CLL Therapy Alessandra Ferrajoli, MD
90Lenalidomide Monotherapy in CLL Properties of lenalidomide treatmentNormalization of peripheral blood lymphocytes and T cells1,2Improvement in serum Igs2Single-agent lenalidomide as salvage therapy:Lenalidomide monotherapy as frontline therapy for CLL (n = 25):5PR = 56%Tumor flare = 88%Grade 3/4 neutropenia = 72%ResponseRPCI3n = 45MDACC1n = 44CLL-014n = 52ORR47%32%12%CR9%7%0%SD18%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:
91Lenalidomide Combination Therapy in CLL Lenalidomide + fludarabine + rituximab in untreated CLLPhase !/II study: ORR = 56%, but combination too toxic, with myelosuppression and idiosyncratic drug reaction as DLTs.1REVLIRIT: Combination followed by lenalidomide and rituximab maintenance therapy. Dosages more tolerable; ORR = 87%, CR = 49%, MRDneg = 29%.2Lenalidomide + rituximab in frontline CLL3Phase 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).GroupNORRCRAge < 65 years4095%20%Age ≥ 65 years2978%7%Overall6988%15%1Brown JR, et al. Leukemia. 2010;24:2Egle A, et al. ASH Abstract 292.3James DF, et al. ASH Abstract 291.
92Lenalidomide Combination Therapy in CLL Lenalidomide + rituximab in relapsed CLL1Phase II study of 59 patients who received prior purine analog therapyMedian 2 prior regimens; 93% prior FCR, PCR, CFAR, or OFARNo grade 3/4 tumor flare; combination well toleratedDeletion 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 CLL2Phase II trial of 34 patients who received prior purine analog therapy (100% received FCR).TreatmentORRCRMedian TTF3-yr OSLenalidomide + rituximab66%12%17.4 months71%TreatmentORRCRMedian PFS2-yr OSLenalidomide + ofatumumab68%24%16 months73%1Badoux XC, et al. J Clin Oncol. 2013;31:2Ferrajoli A, et al. ASH Abstract 720.
93Management of Patients With MDS Refractory to Hypomethylating Agents David Steensma, MD
94Hypomethylating Agents for MDS: Response to Treatment Treatment with hypomethylating agents (HMAs; azacitidine and decitabine):Improves survival by 9 months in high-risk patients1Delays progression to AML by 4-6 months2Improves quality of life3Has low early treatment-related mortality4However, it also:Produces low CR rate5,6Produces hematologic responses in only 30%-60% of patients7,8Has variable duration of response9Is associated with poor survival –< 6 months – after HMA failure101Fenaux 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:
95Hypomethylating Agents for MDS: Outcomes After HMA Failure Common reasons for azacitidine failure:1Primary failure (progression or stable disease): 55%Secondary failure (initial response, then progression or stable disease): 36%Intolerance: 9%Outcomes after HMA failure:HMAMedian OS1-yr OSAzacitidineHigh risk1Intermediate-1 risk2Low risk25.6 months15 months46 months29%NRDecitabineIntermediate-1 to high risk34.3 months28%1Prebet T, et al. J Clin Oncol. 2013;29:2Mishra A, et al. ASH Abstract 2815.3Jabbour E, et al. Cancer. 2010;116:
96Hypomethylating 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 FailureMedian OS, months1Allogeneic transplant19.5Clinical trial with investigational agent13.2Intensive cytotoxic chemotherapy8.9Low-dose chemotherapy7.3Supportive care4.1Rigosertib 1800 mg/24h as 72h continuous infusiondays 1, 2, and 3 of a 2-week cycleRandomize2:1Best supportive care or low-dose cytarabinePrimary endpoint: OSSecondary endpoints: IWG 2006 response, AEs1Prebet T, et al. J Clin Oncol. 2011;29:
97BiTE Antibodies for Treatment of ALL Daniel J. DeAngelo, MD, PhD
98Bispecific 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.
99Blinatumomab 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.1Patients 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.TreatmentMolecular CRDFS AfterMedian 15 Months FUBlinatumomab80%60%1Topp MS, et al. J Clin Oncol. 2011;29:
100Blinatumomab 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 phaseCohort 115 µg/m2/dPrimary endpoint: CR and CRh* ratewithin 2 cyclesCohort 3extension phase5-15 µg/m2/dCohort 2a5-15 µg/m2/dScreening & enrollmentSafety evaluationN=36Cohort 2bµg/m2/dCohort 2 was selected as dosage for extension phase because it had lowest incidence of treatment-emergent AEs.TreatmentCRMolecular Remission in Pts with CR/CRh*Median RFSMedian OSBlinatumomab69%88%7.6 months9.8 months*CRh = CR with only partial hematologic recovery
101A Critical Evaluation of the Role of JAK2 Inhibitors for Myeloproliferative Neoplasms Ruben Mesa, MD
102JAK2 Inhibitors and Myelofibrosis Ruxolitinib – approved by FDA in 2011 for myelofibrosisCOMFORT 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).1,2SAR – 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.3Pacritinib – in phase III testingIn a phase II study of 34 patients, pacritinib reduced splenomegaly by ≥ 25% in one-third of patients.4CYT387 – in phase II testingPhase 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.51Verstovsek 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.
103Ruxolitinib 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.1Clinically meaningful improvements in pruritus, night sweats, and bone pain sustained through week 1441In phase III testing (RESPONSE and RELIEF)Essential thrombocythemiaOf 39 patients, 79% achieved ≥ 50% reduction in platelets during ruxolitinib use.2Ruxolitinib in phase III testing (RELIEF)1Verstovsek S, et al. ASH Abstract 804.2Verstovsek S, et al. ASH Abstract 313.
104Leukemia 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.