Presentation on theme: "17th Annual International Congress on Hematologic Malignancies ® : Focus on Leukemias, Lymphomas, and Myeloma Meeting in a Box."— Presentation transcript:
17th Annual International Congress on Hematologic Malignancies ® : Focus on Leukemias, Lymphomas, and Myeloma Meeting in a Box
What Can We Learn From Multiple Myeloma Genomic Analysis? Nikhil Munshi, MD
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.
High-Risk Smoldering Myeloma – Should We Intervene Early? Ola Landgren, MD, PhD
Smoldering Myeloma 1 Kyle RA, et al. Leukemia. 2010;24: Kyle RA, et al. N Engl J Med. 2007;356: Dispenzieri A, et al. Blood. 2008;111: Perez-Persona E, et al. Blood. 2007;110: Definition of smoldering myeloma 1 –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 progression 2 –10% per year in years 0-5 –3% per year in years 6-10 –1% per year in years Risk stratification –Mayo Clinic analysis 3 stratifies patients according to their 5-yr risk of progression into 3 groups: 25% risk, 51% risk, and 76% risk –PETHEMA Study Group analysis 4 stratifies patients according to their 5-yr risk of progression into 3 groups: 4% risk, 46% risk, and 72% risk e
First Randomized Phase III Trial for Smoldering Myeloma Median time to symptomatic progression Len/dex: not yet reached Observation: 21 months 4-year overall survival Len/dex: 94% Observation: 85% Mateos MV, et al. ASH Abstract 991. HR = 5.67; P <.0001 HR = 3.5; P <.01 Lenalidomide 10 mg/day, D1-21 every 2 months Therapeutic abstention Primary endpoint: time to progression to symptomatic MM Secondary endpoints: ORR, DOR, PFS, OS, and safety and tolerability Lenalidomide 25 mg/day, D1-21 Dexamethasone 20 mg D1-D4 and D12-D15 Therapeutic abstention Randomization of high-risk smoldering MM patients: Induction: Nine 28-day cycles Maintenance: Until progression
Smoldering Myeloma Takeaways Current clinical recommendation for smoldering myeloma: no treatment unless part of a clinical trial 1 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 1 Kyle R, et al. Int’l Myeloma Working Group. Leukemia 2010.
Current Trends: Treatment Strategies for Newly Diagnosed Elderly Patients With Myeloma James Berenson, MD
Dexamethasone ± Lenalidomide SWOG S0232 Zonder JA, et al. Blood. 2010;116: Objective: to determine the efficacy and safety of Len + Dex as induction therapy in NDMM patients Primary endpoint: PFS Len + Dex (n = 97) Len: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, Three 35-day cycles Len + Dex Len: 25 mg/day, D1-21 Dex: 40 mg/day, D1-4 and day cycles until progression Dexamethasone (n = 95) Placebo: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, Three 35-day cycles Dexamethasone Placebo: 25 mg/day, D1-21 Dex: 40 mg/day, D day cycles until progression Unblinded Treatment Len: 25 mg/day, D1-28 Dex: 40 mg/day, D1-4, 9-12, Three 35-day cycles Unblinded Len + Dex Len: 25 mg/day, D1-21 Dex: 40 mg/day, D1-4 and Responding/stable disease Disease progression
Dexamethasone ± Lenalidomide SWOG S yr PFS was significantly improved with the addition of lenalidomide (78% vs 53%; P =.002) Zonder JA, et al. Blood. 2010;116: ORR = 78% ORR = 48% ORR, P <.0001 VGPR, P <.001
Lenalidomide + High-Dose Dex vs Lenalidomide + Low-Dose Dex: ECOG E4A03 Rajkumar SV, et al. Lancet Oncol. 2010;11: Arm1-yr OS2-yr OS RD (high-dose)87%75% Rd (low-dose)96%87% Survival significantly improved with Rd (low-dose) regimen (P =.0002 at 1 year) Four 28-day cycles Transplant-eligible patients can proceed to SCT 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 Lenalidomide + High-Dose Dexamethasone (RD) a Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1-4, 9-12, (n = 223) Lenalidomide + Low-Dose Dexamethasone (Rd) Len: 25 mg/day, days 1-21 Dex: 40 mg/day, days 1, 8, 15, 22 (n = 222) a Based 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.
MP ± Bortezomib: VISTA 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: Previously untreated patients; not candidates for transplant Efficacy ParameterLenalidomidePlaceboHRP Value Median TTP, months < Median OS, monthsNR ►Endpoints: Primary: TTP; Secondary: CR, ORR, TTR, DOR, PFS, TNT, OS, QoL ARM B (MP) MP: Nine 6-week cycles: Cycles 1-9 Melphalan 9mg/m 2 and prednisone 60mg/m 2 days 1-4 ARM A (VMP) VMP: Four 6-week cycles: Cycles 1-4 Bortezomib 1.3mg/m 2 days 1, 4, 8, 11, 22, 25, 29, 32; Melphalan 9mg/m 2 and prednisone 60mg/m 2 days 1-4 Followed by five 6-week cycles: Cycles 5-9 Bortezomib 1.3mg/m 2 days 1, 8, 22, 29; Melphalan 9mg/m 2 and prednisone 60mg/m 2 once daily on days 1–4 Max of 9 cycles (total 54 weeks) in both arms RANDOMIZERANDOMIZE ►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
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
Maintenance Therapy – Is It for Everyone? Nikhil Munshi, MD
Maintenance Therapy for Multiple Myeloma Maintenance therapy: –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
Lenalidomide Maintenance After Transplant: CALGB McCarthy PL, et al. N Engl J Med. 2012;366: Efficacy ParameterLenalidomidePlaceboHRP Value Median TTP, months4627--< yr OS88%80% Restaging Days 90–100 RegistrationRandomization D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better 1 yr from start of therapy > 2 x 10 6 CD34 cells/kg Mel 200 ASCT CRPRSD Lenalidomide 10 mg/d with ↑↓ (5–15 mg) Placebo
Lenalidomide Maintenance Following Lenalidomide Consolidation: IFM PFS significantly prolonged with lenalidomide maintenance compared with placebo (41 vs 24 months; P < ) OS not significantly different between groups (P =.79) Attal M, et al. Proc International Myeloma Workshop McCarthy P, et al. Proc International Myeloma Workshop Primary endpoint: PFS Secondary endpoints: CR rate, TTP, OS, feasibility of long-term lenalidomide… 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) mg/d until relapse
Lenalidomide Maintenance in Patients Ineligible for Transplant: MM-015 Palumbo A, et al. N Engl J Med. 2012;366: PFS significantly prolonged with the addition of lenalidomide maintenance following MPR induction therapy (HR = 0.349; P <.001) PFS benefit maintained across patient subgroups MP M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 PBO: days 1-21 MPR M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 Placebo MPR-R M: 0.18 mg/kg, days 1-4 P: 2 mg/kg, days 1-4 R: 10 mg/day po, days 1-21 RANDOMIZATION Double-Blind Treatment Phase Disease Progression Maintenance Lenalidomide (25 mg/day) +/- Dexamethasone Open-Label Extension Phase Lenalidomide 10 mg/day days 1-21 Cycles (28day) 1-9Cycles 10+
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) 1 Attal M, et al. Proc International Myeloma Workshop McCarthy P, et al. Proc International Myeloma Workshop Palumbo A, et al. N Engl J Med. 2012;366:
PAD + Bortezomib Maintenance vs VAD + Thalidomide Maintenance: HOVON Trial Sonneveld P, et al. ASH Abstract 40. Efficacy ParameterPAD → bortezomibVAD → thalidomideP Value 3-yr PFS48%42% yr OS78%71%.02 MM Stage II or III, Age 18–65 CAD + GCSF 3 x VAD CAD + GCSF 3 x PAD MEL PBSCT In GMMG 2 nd MEL PBSCT In GMMG 2 nd MEL PBSCT Thalidomide maintenance 50 mg/day for 2 yrs Allogeneic Tx Bortezomib maintenance 1.3 mg/m 2 /2 weeks for 2 yrs Bortezomib1.3 mg/m 2 IV Doxorubicin9 mg/m 2 Dexameth40 mg Randomization
Bortezomib + Thalidomide vs Bortezomib + Prednisone as Maintenance: GEM2005MAS65 ArmORRCRMedian PFS VT maintenance95%46%39 months VP maintenance97%39%32 months Mateos MV, et al. Lancet Oncol. 2010;10: No significant differences between VMP and VTP in ORR (80% and 81%) and CR rate (20% and 27%) Maintenance Bort/Thal (VT) Bort/Pred (VP) Bort/Thal (VT) Bort/Pred (VP) Induction (6 cycles) Bort/Mel/Pred (VMP) Bort/Thal/Pred (VTP) vs Series of 260 elderly untreated MM patients included in the GEM2005 Spanish trial
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.
How to Best Use New Proteasome Inhibitors and IMiDs in Myeloma Sundar Jagannath, MD
Pivotal Trial of Immunomodulatory Agent Pomalidomide: MM-002 Aspirin (80–100 mg) or equivalent mandated for all patients. a Patients aged > 75 yrs had starting DEX dose of 20 mg/week. Randomization Progressive disease Primary endpoint: PFS Secondary endpoints: ORR, DOR, OS, and safety POM (4 mg days 1–21 of 28-day cycles) Option to add LoDEX a (40 mg/week) POM (4 mg days 1–21 of 28-day cycles) + LoDEX a (40 mg/week) Discontinue and follow- up for survival and subsequent treatment
Median number of cycles received = 5 (range, 1-28) Disease control rate = 81% overall Jagannath S, et al. ASH Abstract 450. MM-002: Response Rates Response POM + LoDEX (n=113) POM (n=108) ORR (%)3415 CR (%)31 PR (%)3114 MR (%)1216 SD (%)3748 PD (%)610 Median time to ORR, months Median duration of response, months
MM-002: PFS, OS, and Safety Age ≤ 65 yearsAge > 65 years Grade 3/4 AEs ≥ 20% POM + LoDEX (n=61) POM (n=68) POM + LoDEX (n=51) POM (n=39) Hematologic Neutropenia Anemia Thrombocytopenia Nonhematologic Pneumonia Dyspnea Other AEs of clinical relevance in POM +/- LoDEX: –Febrile neutropenia: 3% –Peripheral neuropathy (grade1/2): 13% (none > grade 2) –DVT: 2% Efficacy ParameterPOM + LoDEXPOMHRP Value Median PFS, months Median OS, months Jagannath S, et al. ASH Abstract 450.
Pomalidomide + Low-Dose DEX vs High-Dose DEX: MM-003 (n = 302) POM: 4 mg/day D LoDEX: 40 mg (≤ 75 yrs) 20 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) 20 mg (> 75 yrs) D1-4, 9-12, day cycles PD* or intolerable AE PD* Companion trial MM-003C POM 21/28 days Stratification Age (≤ 75 vs > 75 yrs) Number of prior Tx ( 2 vs > 2) Disease population Thromboprophylaxis indicated for those receiving POM or with DVT history *Progression of disease independently adjudicated in real-time
Dimopoulos MA, et al. ASH Abstract LBA-6. MM-003: PFS and OS Arm POM + LoDEX n = 302 HiDEX n=153 HRP Value Median PFS, months ITT population Refractory to bortezomib Refractory to lenalidomide Refractory to both <.001 Median OS, months ITT population Refractory to bortezomib Refractory to lenalidomide Refractory to both NR <
Pivotal Trial of Proteasome Inhibitor Carfilzomib: 003-A1 Carfilzomib 20 mg/m 2 days 1, 2, 8, 9, 15, 16 every 28 days N = 46 Carfilzomib 20 mg/m 2 days 1, 2, 8, 9, 15, 16 every 28 days N = 46 MM: Progressive disease > 2 prior therapy lines including bortezomib, thalidomide or lenalidomide, an alkylating agent, and anthracycline alone or in combination MM: Progressive disease > 2 prior therapy lines including bortezomib, thalidomide or lenalidomide, an alkylating agent, and anthracycline alone or in combination Carfilzomib Dose escalation to 27 mg/m 2 after cycle 1 up to 12 cycles N = 266 Carfilzomib Dose escalation to 27 mg/m 2 after cycle 1 up to 12 cycles N = A0 003-A1 Primary Endpoint: ORR Secondary Endpoints: clinical benefit rate (≥ minimal response), DOR, PFS, OS, and safety
Siegel DS, et al. Blood. 2012;120: Single-Agent Carfilzomib Pivotal Trial: Efficacy Response Carfilzomib (N=257) ORR24% Clinical benefit rate34% Duration of response8.3 months Median PFS3.7 months Median OS15.6 months
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% Siegel DS, et al. Blood. 2012;120: 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%
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.
Initial Management of Peripheral T-Cell Lymphoma: If CHOP Is No Good, What Is? Steven M. Horwitz, MD
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. 1 Kim SJ. Eur J Cancer. 2012;48: Kim JG, et al. Cancer Chemother Pharmacol. 2007;60: Gallamini A, et al. Blood. 2007;110: Reimer P, et al. J Clin Oncol. 2009;27: d’Amore F, et al. J Clin Oncol. 2012;30:
Management of Cutaneous T-Cell Lymphoma Lauren Pinter-Brown, MD, FACP
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.
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
How I Manage Early-Stage Diffuse Large B-Cell Lymphoma Daniel O. Persky, MD
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 1 Miller TP. J Clin Oncol. 2004;22: Ketterer N, et al. Ann Oncol. 2013;24: Pfreundschuh M, et al. Lancet Oncol. 2011;12: Terada Y, et al. ASH Abstract Regimen3-yr PFS3-yr OS R-CHOP x 3-4 → IFRT90%96% R-CHOP x 6-874%86%
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 DLBCL 3,4 ‒ 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 1 Miller TP, et al. ASH Abstract Witzig T, et al. ASH Abstract Haioun C, et al. Blood. 2005;106: Spaepen K, et al. Ann Oncol. 2002;13: Sehn et al, Lugano Abstract 052; Sehn LH, et al. Lugano Abstract 028. Result PET – n=103 PET + n=30P Value 3-yr TTP92%60%.09 3-yr OS96%83%.1
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 disease 2 and with superior survival 3 after R-CHOP compared with ABC Bottom line: Biology of early-stage DLBCL needs further exploration. 1 Rosenwald A, et al. J Exp Med. 2003;198: Lenz G, et al. N Engl J Med. 2008;359: Lenz G, et al. N Engl J Med. 2010;362:
Advanced-Stage DLBCL Craig Moskowitz, MD
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 < CR 3 ‒ 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 1 Delarue R, et al. Lancet Oncol. 2013;14: Cunningham D, et al. ASCO Abstract NCCN NHL guidelines Hamlin PA, et al. ASH Abstract 1793.
Risk-Adapted Therapy for Advanced-Stage DLBCL MSKCC : MSKCC : 1 Moskowitz et al. Lancet Oncol. 2010;28: Results showed no difference in PFS among: 1 PET-negative PET-positive/biopsy-negative PET-positive/biopsy-positive ICE x 2 RICE x 1 HDT/ASCT ICE x 3 followed by observation Bx + Bx - PET - Repeat Bx + R-C 1000 HO uncapped P-14 x 4 Augmented RICE x 2 followed by HDT/ASCT ICE x 3 followed by observation Bx + Bx - PET - Repeat Bx + R-R-C 1000 HO uncapped P-14 x 3 C 1000 HO uncapped P-21 x 1 Augmented RICE x 2 followed by observation ≥80% Ki-67 <80% Results showed 4-yr OS > 80% and 4-yr PFS > 70%
Dose-Adjusted EPOCH-R for Advanced-Stage DLBCL CALGB phase II study 1 ‒ 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 1 Wilson WH, et al. Haematologica. 2012;97:
Relapsed DLBCL in the Rituximab Era Anas Younes, MD
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. 1 Gisselbrecht, et al. J Clin Oncol. 2010;28: Thieblemont et al. J Clin Oncol. 2011;29:
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 - P-PRAS40 + pSTAT3 + P-CD19 + RCHOP RCHOP + Drug A RCHOP RCHOP + Drug C RCHOP RCHOP + Drug D RCHOP
New Directions in Follicular Lymphoma Bruce D. Cheson, MD
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 testing 3 ‒ DCDT4501A: anti-CD79b linked to MMAE. Showed responses in 5 of 8 patients at first assessment in phase I testing 4 ‒ Ongoing randomized crossover trial: TrialTreatmentn (FL)ORR GAUGIN 1 (BO20999) GA101 low-dose1436% GA101 high-dose2060% GAUSS 2 GA % rituximab7539% 1 Salles GA, et al. ASH Abstract Sehn LH, et al. ASH Abstract Advani R, et al. ASH Abstract Palanca-Wessels MC, et al. ASH Abstract 56. Arm A: R (d1) + DCDT2980S (d2) Q 21 days Arm B: R (d1) + DCDT4501A (d2) Q 21 days Response PD
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 Treatment 2 Decreased AdenopathyORR1-yr PFS Idelalisib + rituximab97%77%82% Idelalisib + bendamustine97%85%90% Idelalisib + bendamustine/rituximab100%77%78% 1 Advani RH, et al. J Clin Oncol. 2013;31: Fowler NH, et al. ASH Abstract Kahl B, et al. Lugano Abstract 066.
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: R 2 = rituximab + lenalidomide PopulationNORRSD Gr 3/4 Treatment-Related AEs in >2 Patients Overall (R/R NHL)2348%30%10% anemia FL812%88%NR 1 Davids MS, et al. ASH Abstract Fowler NH, et al. ASH Abstract 901. PopulationNORRSD2-yr PFS Overall (untreated indolent NHL) 10390%8%83% FL4698%2%89% 1 st line FL N=1000 R2R2 R + chemo R 2 maintenance Rituximab maintenance R
Management of Hodgkin Lymphoma in the Elderly Paul A. Hamlin, MD
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 stage 1 ‒ More aggressive histology 1 ‒ B symptoms 1 ‒ EBV positivity associated with worse disease-specific survival and OS 2 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 1 Word, et al. ASH Abstract Jarrett, et al. Blood. 2005;106: Evens AM. ASCO Post. 2012;3. 4 Proctor SJ, et. al. Crit Rev Oncol Hematol. 2009;71: Proctor SJ, et al. Eur J Haematol. 2005;(suppl 66):63-7.
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 VEPEMB 2 1 Levis A, et al. Haematologica 1996;81: Proctor SJ, et al. Blood. 2012;119: Population Receiving VEPEMBNCR3-yr OS3-yr PFS Patients with early-stage disease3174%81%74% Patients with advanced-stage disease7261%66%58%
Anthracycline-Containing Therapy in Hodgkin Lymphoma Anthracycline-containing therapy: ‒ ChIVPP/ABV ‒ COPP/ABVD ‒ ABVD ‒ Stanford V ‒ BEACOPP GHSD10 and 11: ABVD 1 ‒ 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/ABV 2 ‒ 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 < Boll B, et al. J Clin Oncol. 2013;31: Weekes CD, et al. J Clin Oncol. 2002;20:
1 Evens AM, et al. Br J Haematol. 2013;161: Ballova V, et al. Ann Oncol. 2005;16: Anthracycline-Containing Therapy in Hodgkin Lymphoma ABVD vs Stanford V 1 ‒ 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 HD9 elderly : COPP/ABVD vs BEACOPP 2 ‒ 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 TreatmentNCR5-yr OS5-yr FFTFDeath due to acute toxicity COPP-ABVD2677%50%46%8% BEACOPP4276%50%46%21%
Relapsed and Refractory HL: Will We Be Able to Avoid Transplant? Craig Moskowitz, MD
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 1 Moskowitz CH, et al. Blood. 2001;97:
FDG-PET to Identify Patients Needing Additional Salvage Therapy Normalization of PET prior to transplant is predictive of survival 1 and identifies patients with excellent outcomes MSKCC Protocol for relapsed/refractory HL: 1 Moskowitz AJ, et al. Blood. 2010;116: Moskowitz CH et al. Blood. 2012;119: Results showed patients transplanted after standard or GVD salvage chemotherapy had EFS > 80%, compared with 29% EFS for patients with PET positivity. 2 Restaging: FDG-PET, CT CAP PET negative Arm A = 0 or 1 risk factors Standard ICE x 1 Augmented ICE x 1 PBPC collection Repeat biopsy, determine risk factors Staging evaluation: FDG PET, diagnostic CT CAP, BM Bx Induction: Nine 28-day cycles Arm B = 2 risk factors Augmented ICE x 2 PBPC collection PET positive Radiotherapy, if applicable HDT/ASCT POD on ICE GVD x 4 Restaging CR, PR, MR POD off study
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 HL 1 Also being studied with qw dosing (3 wk on, 1wk off) 1 Chen RW, et al. ASCO Abstract 8031.
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 Further treatment according to treating physician HDT/ASCT PET - - Augmented ICE x 2 + Weekly SGN-35 x 2 + Further treatment according to treating physician HDT/ASCT PET - - Platinum-based salvage x 2 + Weekly SGN-35 x 2 + RT alone randomize
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)
Aurora Kinase Inhibition With Alisertib Aurora kinase ‒ 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 testing 1 ‒ 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. 1 Friedberg J, et al. ASH Abstract 95.
Kinase Inhibitors in Lymphoma Ibrutinib ‒ Bruton’s tyrosine kinase (BTK) small-molecule irreversible inhibitor ‒ Efficacy in FL: 55% ORR and 12.3 months DOR 1 ‒ Efficacy in ABC DLBCL: 41% ORR (compared with 5% ORR for GCB) 2 ‒ Efficacy in phase II relapsed or refractory MCL: 66.1% ORR 3 Idelalisib (GS-1101, CAL-101) ‒ PI3Kδ small-molecule inhibitor ‒ Efficacy in MCL and indolent lymphoma: 62% ORR for each 4 ‒ Efficacy in MCL in combination with everolimus, bortezomib, or bendamustine/rituximab: 46% ORR 5 1 Fowler NH, et al. ASH Abstract Wilson WH, et al. ASH Abstract Wang M, et al. ASH Abstract Kahl B, et al. ASH Abstract Wagner-Johnston N, et al. ASCO Abstract 8501.
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. 1 Younes A, et al. Lugano Abstract 157.
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% ORR 1 ‒ 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 DLBCL 3 ‒ Len-RICE shows promise (8/13 CR) as salvage therapy in DLBCL 4 1 Fowler NH, et al. ASH Abstract Hernandez-Ilizaliturri, et al. Cancer. 2011;117(22): Reddy NM, et al. ASH Abstract Feldman et al. ASH Abstract 3710.
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.
LEUKEMIA & MYELOPROLIFERATIVE NEOPLASMS
Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase? Imatinib Harry P. Erba, MD, PhD
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-C 2 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 1 Mahon FX, et al. ASH Abstract Druker BJ, et al. N Engl J Med. 2006;355: Kantarjian HM, et al. ASH Abstract Kantarjian HM, et al. Blood. 2012;119:
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 similar 1,2 ‒ Imatinib has no known late complications, unlike dasatinib and nilotinib Optimal First-Line CML Therapy: Achievement of Remission and Tolerability 1 Kantarjian HM, et al. Blood. 2012;119: Saglio G, et al. ASH Abstract Jabbour E, et al. J Clin Oncol. 2011;29: Kantarjian HM, et al. Lancet Oncol. 2011;12: Trial Experimental TKI MMR at 12 Months vs Imatinib MMR at 24 Months vs Imatinib P Value at 24 Months DASISION 1 dasatinib46% vs 28%64% vs 46%<.0001 ENESTnd 2 nilotinib 300 mg55% vs 27%73% vs 53%<.0001 Trial Experimental TKI CCyR at 12 Months vs Imatinib CCyR at 24 Months vs Imatinib P Value at 24 Months DASISION 1 dasatinib85% vs 73%85% vs 82%NS ENESTnd 4 nilotinib 300 mg80% vs 65%87% vs 77%.0018
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 ‒ 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. Optimal First-Line CML Therapy: Prevention of Progression and Cost of Therapy 1 Kantarjian HM, et al. Blood. 2012;119: Saglio G, et al. ASH Abstract NCCN CML guidelines. Version Trial Experimental TKI Progression to AP/BP vs ImatinibP Value DASISION 1 dasatinib3.5% vs 5.8%NR ENESTnd 2 nilotinib 300 mg3.2% vs 6.7%.0496
Imatinib as First-Line CML Therapy: Summary Cytogenetic and molecular response rates higher with 2nd-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.
Debate: What Is the Optimal First-Line Treatment for CML in Chronic Phase? Second-Generation TKIs Michael J. Mauro, MD
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 1 Branford S, et al. Leukemia. 2003;17: Marin D, et al. J Clin Oncol. 2012;30: NCCN CML guidelines. Version Time PointEarly ResponseMMR %P Value 3 months> 2-log reduction100%< to 2-log reduction54% 6 months> 2-log reduction86%< to 2-log reduction0% Time PointEarly BCR-ABL/ ABL Level8-yr OSP Value 3 months< 9.84%93%<.001 > 9.84%57%
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 TreatmentPatients Not in CCyR (n) Event (%) Quintas-Cardama A, et al. Blood. 2009;113: Hughes T, et al. Blood. 2010;116: MMR After 12 MonthsAP/BP (%)P Value Yes No10
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 MonthsNilotinibImatinibP ValueDasatinibImatinibP Value CCyR80%65%<.00185%73%.0002 MMR55%27%<.00146%28%<.0001 CMR11%1%<.001~5% NS TrialExperimental TKI Transformation to AP/BP (%) vs ImatinibP Value DASISIONdasatinib2.3% vs 5%NS ENESTndnilotinib 300 mg0.7% vs 6.0% Saglio G, et al. N Engl J Med. 2010;362: Kantarjian HM, et al. Blood. 2012;119: Kantarjian HM, et al. Lancet Oncol. 2011;12: Hochhaus A, et al. EHA Abstract Kantarjian HM, et al. ASCO Abstract Larson RA, et al. ASCO Abstract 6511.
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 hypertension 3 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. 1 Gambacorti-Passerini C, et al. JNCI. 2011;103: Gambacorti-Passerini C, et al. ASH Abstract Montani D, et al. Circulation. 2012;125: Le Coutre P, et al. JNCI. 2011;103: Rea D, et al. ASH Abstract 604.
Treatment for Elderly Chronic Lymphocytic Leukemia: Is There a Standard? Alessandra Ferrajoli, MD
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 1 SEER cancer statistics Shanafelt T, et al. Cancer. 2010;116: Cramer P, et al. ASH Abstract Hallek M, et al. Lancet. 2010;376:
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-chlorambucil 3 Lenalidomide –Phase II study of 60 patients age ≥ 65 years produced 65% ORR and 15% CR. CR rate increased over time to 38%. 4 –Median PFS = 52 months; median OS not reached. 4 1 Hillmen P, et al. ASH Abstract Ferrajoli A, et al. Paper submitted. 3 Goede V, et al. ASCO Abstract Badoux XC, et al. Blood. 2011;118: Efficacy Measure GA101 + Chlor vs ChlorP Value R + Chlor vs ChlorP Value ORR, %75.5 vs 30.2NR65.9 vs 30.0NR Median PFS, months23.0 vs 10.9< vs 10.9<.0001
Targeted Therapy for CLL: Focusing on the B Cell Receptor Pathway Jennifer R. Brown, MD, PhD
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 1 Brown JR, et al. ASCO Abstract Barrientos JC, et al. ASCO Abstract 7017.
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/refractory 1 –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. 1 Byrd JC, et al. ASH Abstract 189. Efficacy at 26 MonthsTN R/R Overalldel17pdel11qNo delIgV H MutIGV H Unmut Est. PFS96%75%57%73%93%83%72% Est. OS96%83%70%85%93%83%82%
IMiDs and Combinations: How to Integrate Into Standard CLL Therapy Alessandra Ferrajoli, MD
Lenalidomide Monotherapy in CLL Properties of lenalidomide treatment –Normalization of peripheral blood lymphocytes and T cells 1,2 –Improvement in serum Igs 2 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% 1 Ferrajoli A, et al. Blood. 2008;111: Badoux XC, et al. Blood. 2011;118: Chanan-Khan AA, et al. J Clin Oncol. 2006;24: Wendtner CM, et al. Leuk Lymphoma. 2012;53: Chen CI, et al. J Clin Oncol. 2011;29: Response RPCI 3 n = 45 MDACC 1 n = 44 CLL-01 4 n = 52 ORR47%32%12% CR9%7%0% SD18%25%58%
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%, MRD neg = 29%. 2 Lenalidomide + rituximab in frontline CLL 3 –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). 1 Brown JR, et al. Leukemia. 2010;24: Egle A, et al. ASH Abstract James DF, et al. ASH Abstract 291. GroupNORRCR Age < 65 years4095%20% Age ≥ 65 years2978%7% Overall6988%15%
Lenalidomide Combination Therapy in CLL Lenalidomide + rituximab in relapsed CLL 1 –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 CLL 2 –Phase II trial of 34 patients who received prior purine analog therapy (100% received FCR). 1 Badoux XC, et al. J Clin Oncol. 2013;31: Ferrajoli A, et al. ASH Abstract 720. TreatmentORRCRMedian PFS2-yr OS Lenalidomide + ofatumumab68%24%16 months73% TreatmentORRCRMedian TTF3-yr OS Lenalidomide + rituximab66%12%17.4 months71%
Management of Patients With MDS Refractory to Hypomethylating Agents David Steensma, MD
Hypomethylating Agents for MDS: Response to Treatment Treatment with hypomethylating agents (HMAs; azacitidine and decitabine): –Improves survival by 9 months in high-risk patients 1 –Delays progression to AML by 4-6 months 2 –Improves quality of life 3 –Has low early treatment-related mortality 4 However, it also: –Produces low CR rate 5,6 –Produces hematologic responses in only 30%-60% of patients 7,8 –Has variable duration of response 9 –Is associated with poor survival – < 6 months – after HMA failure 10 1 Fenaux P, et al. Lancet Oncol. 2009;10: Kantarjian H, et al. Cancer. 2006;106: Kornblith AB, et al. J Clin Oncol. 2002;20: Santos FP, et al. Expert Rev Anticancer Ther. 2010;10: Itzykson R, et al. Blood. 2011;117: Lubbert M, et al. J Clin Oncol. 2011;29: Lee JH, et al. Haematologica. 2011;96: Lyons RM, et al. J Clin Oncol. 2009;27: Steensma DP, et al. J Clin Oncol. 2009;27: Prebet T, et al. J Clin Oncol. 2013;29:
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: 1 Prebet T, et al. J Clin Oncol. 2013;29: Mishra A, et al. ASH Abstract Jabbour E, et al. Cancer. 2010;116: HMAMedian OS1-yr OS Azacitidine High risk 1 Intermediate-1 risk 2 Low risk months 15 months 46 months 29% NR Decitabine Intermediate-1 to high risk months28%
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. 1 Prebet T, et al. J Clin Oncol. 2011;29: Treatment Option After HMA FailureMedian OS, months 1 Allogeneic transplant19.5 Clinical trial with investigational agent13.2 Intensive cytotoxic chemotherapy8.9 Low-dose chemotherapy7.3 Supportive care4.1 Randomize 2:1 Rigosertib 1800 mg/24h as 72h continuous infusion days 1, 2, and 3 of a 2-week cycle Best supportive care or low-dose cytarabine Primary endpoint: OS Secondary endpoints: IWG 2006 response, AEs
BiTE Antibodies for Treatment of ALL Daniel J. DeAngelo, MD, PhD
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.
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/m 2 /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 Blinatumomab80%60% 1 Topp MS, et al. J Clin Oncol. 2011;29:
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). Screening & enrollment Safety evaluation Cohort 2b µg/m 2 /d Cohort 3 extension phase 5-15 µg/m 2 /d Dose-finding run-in phase Primary endpoint: CR and CRh* rate within 2 cycles TreatmentCR Molecular Remission in Pts with CR/CRh*Median RFSMedian OS Blinatumomab69%88%7.6 months9.8 months N=36 Cohort 2a 5-15 µg/m 2 /d Cohort 1 15 µg/m 2 /d Cohort 2 was selected as dosage for extension phase because it had lowest incidence of treatment-emergent AEs. *CRh = CR with only partial hematologic recovery
A Critical Evaluation of the Role of JAK2 Inhibitors for Myeloproliferative Neoplasms Ruben Mesa, MD
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 1 Verstovsek S, et al. N Engl J Med. 2012;366: Harrison C, et al. N Engl J Med. 2012;366: Talpaz M, et al. ASH Abstract Komrokji RS, et al. ASH Abstract Pardanani A, et al. ASH Abstract 178.
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 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) 1 Verstovsek S, et al. ASH Abstract Verstovsek S, et al. ASH Abstract 313.
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.