mantle cell lymphoma 2019 · mantle cell lymphoma 2019: new agents michael e. williams, md, scm...
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Mantle Cell Lymphoma 2019: New Agents
Michael E. Williams, MD, ScMByrd S. Leavell Professor of MedicineChief, Hematology/Oncology DivisionPhysician Lead, Cancer Service LineUniversity of Virginia Cancer Center
Charlottesville, Virginia
Disclosures: Michael E. Williams, MD, ScM
• Clinical trial grant support to the University of Virginia: • Allos, Celgene, Gilead, Janssen, Novartis, Pharmacyclics, TG
Therapeutics
• Honoraria:• Xian Janssen
• Consultant: • Abbvie, Astra-Zeneca, Celgene, Janssen, Kite, Juno, TG Therapeutics,
Gilead Sciences, Verastem, Seattle Genetics, Sandoz
MCL Challenges
• Biologic and clinical heterogeneity• Better treatment endpoints• Improve duration of response• Optimize use of stem cell transplantation• Optimize use of targeted agents• Chemotherapy-free regimens• Cure
MCL: Typical Presentation• 74% male, average age 63 years
– Usually stage III-IV disease– MIPI scores may correlate with outcome
• Diffuse adenopathy, splenomegaly• Extranodal disease, especially GI tract• Clinically and biologically heterogeneous
– Blastoid variant is more aggressive– Complex karyotype or p53 mutation carry
poorer prognosis
Pathogenesis and Progression of Mantle Cell Lymphoma
M. Dreyling et al. Ann Oncol 2014
Indolent MCLClinical features:
– Splenomegaly– Minimal or no
adenopathy– Leukemic phase– May be confused
with CLL– Observe without
treatment if no symptoms
Molecular features:– Mutated IgVH genes– No p53 mutations– Few chromosomal
changes other than the t(11;14)
– SOX11 negative
Martin P, et al. J Clin Oncol.2009; 27:1209-1213.
Fernandez V, et al. Cancer Res. 2010;70:1408-1418.
MCL Initial Therapy: 2019• Watch/Wait patients
– indolent subtype, low tumor burden, asymptomatic (~20% of patients)
• Younger, fit patients, < 60-65 y– Rituximab plus a high-dose cytarabine -based
regimen (e.g.,R-DHAX) à Auto SCTà Maint. Rituximab (LeGouill et al, NEJM 2017)
– Is ASCT needed if MRD negative after induction therapy? (ECOG 5141)
– Non-HiDAC regimens also utilized pre-ASCT
A Randomized Phase III Trial of Consolidation with Autologous Hematopoietic Cell Transplantation Followed
by Maintenance Rituximab vs. Maintenance Rituximab Alone for Patients with Mantle Cell Lymphoma In Minimal
Residual Disease-Negative First Complete Remission:ECOG 5141
Intergroup study in Mantle Cell Lymphoma
Timothy Fenske, MD; Medical College of Wisconsin (ECOG)Brian Till, MD University of Washington (SWOG)
Kristie Blum, MD; The Ohio State University (Alliance)Brad Kahl, MD; Washington University (ECOG)
E5141 Study Schema: MCL
Initial therapy in older MCL patients: 2019
1. BR (Bendamustine-rituximab)
2. R-CHOP3. VR-CAP (Bortezomib plus R-CHP)4. R-BAC500 (BR plus cytarabine 500 mg/m2)
5. R2 (Lenalidomide-rituximab)
6. Clinical trial (e.g., BTKi, or BTKi combined with anti-CD20 or venetoclax)
Summary of non-intensive MCL induction regimens*
N Age ORR CR mPFS
R-CHOP 244 66 89% 42% (CT) 14.4 mo
VR-CAP 243 65 92% 53% (CT) 24.7 mo
BR** 188 70 ~90% ~45% (CT) 35-48 mo
RBAC500 57 71 91% 91% (PET) Not reached
*no maintenance therapy**pooled data from 3 trials
Sustained remission with Lenalidomide plus Rituximab as initial therapy of MCL
J Ruan et al, NEJM 2015; JCO 2018
• n=38, median f/u 64 mo. (21-78 mo.)• ORR 92%, CR 64% (by PET +/- BM; med. 11 mo. to reach CR)
• 3 yr PFS 80%, OS 90%• 5 yr estimated PFS 64%, OS 77%
– 8/10 patients in CR @ 3 yr are MRD negative– No difference in ORR for Low- vs High-risk MIPI– No correlation with Ki-67 score
• Toxicity: – Grade 3-4 neutropenia 50%, thrombocytopenia 13%– 1 pancreas cancer, 6 non-inv. skin cancer– Grade 3 infection in 3 pts
• Relapsing pts respond to second line Rx
ECOG Trial: E1411 - Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma
REGISTRATION
BR x 6
BVR x 6
Lenalidomide + Rituximab
BR = Bendamustine, Rituximab V= Bortezomib
Randomized phase II, N ~ 328; 82 eligible per arm
BR x 6
BVR x 6
Lenalidomide + Rituximab
Rituximab
Rituximab
M. Smith, Study PI; accrual completed September 2016
E1411 - Phase 2 Intergroup Trial: Initial Therapy of Mantle Cell Lymphoma
REGISTRATION
BR x 6
BVR x 6
Lenalidomide + Rituximab
BR = Bendamustine, Rituximab V= Bortezomib
Randomized phase II, N ~ 328; 82 eligible per arm
BR x 6
BVR x 6
Lenalidomide + Rituximab
Rituximab
Rituximab
M. Smith, Study PI; accrual completed September 2016
As of Oct. 2019, at 89% for events, anticipated data analysis Spring 2019
Treatment options in relapsed MCL
• Younger, fit patient, including post-ASCT– Consider allo SCT, with curative intent
• Older or less fit patients– Depends on initial therapy and prior response– Clinical trial preferred– Ibrutinib, Acalabrutinib, Lenalidomide/Ritux,
Venetoclax +/- anti-CD20, Bortezomib/Ritux
• Elderly, serious coexisting illness– BTKi or rituximab, palliate symptoms
P. Perez-Galan et al. Blood. 2011
The B-cell receptor pathway is activated in most B-cell malignancies
OverexpressedDown-regulated
Modified from P. Perez-Galan et al. Blood. 2011
The B-cell receptor pathway : Selected Inhibitors
Fostamatinib,Entospletinib
Ibrutinib,Acalabrutinib,Zanabrutinib
Idelalisib,Duvelisib, Copanlisib
Everolimus,Temsirolimus
Venetoclax
Bortezomib,Carfilzomib,Ixazomib
Targeted, non-Chemotherapy Approaches for Relapsed/Refractory MCL
Agent N Response Rate mDOR
Bortezomib 155 33% 9.2 months
Temsirolimus 54 22% 7.1 months
Lenalidomide 134 28% 16.6 months
Lenalidomide-rituximab
52 57% 18.9 months
Idelalisib 40 40% 4 months
Ibrutinib 111 68% 17.5 months
Acalabrutinib 124 81% 72% at 12 m
Venetoclax 28 75% 12 months
Ibrutinib-Venetoclax 24 71% (all CR) 80% at 12 m
PFS and OS by Prior Line of TherapyPooled analysis of 3 studies in Relapsed/Refractory MCL (n=370)
§ Median PFS was nearly 3 years in patients with 1 prior line of therapy
PFS
Median 33.6 mo(19.4-42.1)
Median 8.4 mo (7.1-12.8)
Median PFS overall (95% CI): 13.0 (8.4-16.8) months
Median OS overall (95% CI): 26.7 (22.5-38.4) months
Patients censored from OS analysis upon study discontinuation. CI, confidence interval; NE, not estimable.
OS
Median NR (36.0-NE)
Median 22.5 mo(16.2-26.7)
S. Rule, et al. Brit J Haematol 2017
Acalabrutinib
• Second generation BTK inhibitor– FDA Approved in Mantle cell lymphoma with at least one prior
therapy– Dose: 100 mg twice daily until unacceptable toxicity or
progression• More specific for BTK, fewer off target effects than ibrutinib
– Less TEK kinase inhibition
Herman S, CCR 2017
Acalabrutinib in relapsed or refractory mantle cell lymphoma (ACE-LY-004): a single-arm, phase 2 trial
Wang M, et al. Lancet 2018
Acalabrutinib in R/R MCL
Compared to ibrutinib (n=370, pooled data, 3 trials) more favorable patient population in the acalabrutinib trial (n=124)
Rule S, et al. Brit J Haematol 2017;Wang M, et al. Lancet 2018
Ibrutinib560 mg/day
Acalabrutinib100 mg 2x/day
Med age 67.5 68 (61-75)
Median prior lines of therapy
2 (1-9) 2 (1-2)
sMIPI high 32% 17%
sMIPI int 45% 44%
sMIPI low 24% 39%
Blastoid 12% NR
Prior SCT 34% 18%
Refractory NR 24%
Acalabrutinib vs. Ibrutinib in MCL
• Acalabrutinib appears to have better safety profile– Very infrequent atrial fibrillation and bleeding events– More headache with acalabrutinib
• Acalabrutinib was used in less heavily pre-treated patients– Can’t say that it is more effective in MCL as yet– Head-to-head trial of ibrutinib vs acalabrutinib (ACE-CL-006)
enrolled high-risk, relapsed CLL; results pending• In MCL, both agents have efficacy, choose based on patient
factors• If a patient fails a BTK inhibitor, consider switch to venetoclax • If a BTK inhibitor is stopped for toxicity, use the alternative BTK
agent• Acala plus BR, and other combinations, in current clinical trials
Zanabrutinib in patients with relapsed/refractory mantle cell lymphoma
Y Song, et al, Abstract 015ICML Lugano 2019
• Single-agent phase 2 study, 160 mg bid• Given until intolerance or progression• n=86 enrolled in 13 centers in China• Median f/u 13.9 mo (0.3-18 mo)• Zana d/c in 19 (22%) due to progression and
in 9.3% due to toxicity• ORR 84.7%, CR 76.5%, median PFS 16.7 m• AE: neutropenia, thrombocytopenia,
infections; no Afib, grade 3 bleed in 2.3%
COMBINATION OF IBRUTINIB WITH RITUXIMAB (IR) IS HIGHLY EFFECTIVE IN PREVIOUSLY UNTREATED
ELDERLY (>65 YEARS) PATIENTS (PTS) WITH MANTLE CELL LYMPHOMA (MCL) – PHASE II TRIAL
Jain P, et al. MD Anderson Cancer CenterAbstract 011
ICML 2019, Lugano
Front-line ibrutinib plus rituximab in MCL
Response CR PR Stable disease
ORR
IR combo 69% 26% 5% 95%
MRD neg. 65%
• n= 42 (blastoid and Ki67> 50% excluded)• Median age 71y (range 65-84), ECOG PS 0-1=98%• Ibrut 560mg/d x 28 d, then start Rituximab x 2y
• Treatment continued until intolerance or progression• 23/42 (55%) required dose reduction of ibrutinib• Median duration on study = 19 mo; 4 PD, 2 deaths
Venetoclax
BH3-only family member proteins include BIM, BAD, PUMA, and NOXA
Venetoclax Binds to and Inhibits Overexpressed
BCL-2
Venetoclax
BH3-only
BAK BCL-2 BCL-2
An Increase in BCL-2 Expression Allows the Cancer Cell to Survive
Mitochondria
Pro-apoptotic Proteins
(BAX, BAK)
Anti-apoptotic Proteins(BCL-2)
21Apoptosis is Initiated
Apoptosome
APAF-1
Cytochrome c
Active Caspase
Procaspase
3
BAX
Courtesy of Dr. Sven deVos, UCLA
• FDA-approved for CLL/SLL, with or without del 17p, with at least 1 prior therapy;
• Approved Nov. 2018 for AML pts > 75y in combination with aza, decitabine or AraC
Venetoclax Monotherapy in NHLDavids M, JCO 2017
Venetoclax Monotherapy in NHLDavids M, JCO 2017
Revised Dose Ramp-Up to Mitigate the Risk of Tumor Lysis Syndrome When Initiating Venetoclax in Patients With Mantle Cell Lymphoma
MS Davids, G von Keudell, CA Portell, JB Cohen, et alJ Clin Oncol 2018; 36: 3525-7
Original Article
Ibrutinib plus Venetoclax for the Treatment of Mantle-Cell Lymphoma
Constantine S. Tam, M.B., B.S., M.D., Mary Ann Anderson, M.B., B.S., Ph.D., Christiane Pott, M.D., Ph.D., Rishu Agarwal, M.B., B.S., Sasanka Handunnetti, M.B.,
B.S., Rodney J. Hicks, M.B., B.S., Kate Burbury, M.B., B.S., Gillian Turner, B.N., M.I.P.H., Juliana Di Iulio, Ph.D., Mathias Bressel, M.Sc., David Westerman, M.B., B.S., Stephen Lade, M.B., B.S., Martin Dreyling, M.D., Sarah-Jane Dawson, M.B.,
B.S., Ph.D., Mark A. Dawson, M.B., B.S., Ph.D., John F. Seymour, M.B., B.S., Ph.D., and Andrew W. Roberts, M.B., B.S., Ph.D.
N Engl J MedVolume 378(13):1211-1223
March 29, 2018
Ibrutinib plus venetoclax in MCL: Study Schema
Tam CS et al. N Engl J Med 2018;378:1211-1223
24 patients; 23 relapsed or refractory; most high-risk including MIPI score and TP53 mutations
Kinetics of Response and Clearance of Minimal Residual Disease (MRD)
Tam CS et al. N Engl J Med 2018;378:1211-1223
Tam CS et al. N Engl J Med 2018;378:1211-1223
Progression-free survivalMedian follow-up 16 mo
Duration of Response
Overall survival
Tan et al, NEJM 2018
MCL: Ibrutinib plus venetoclaxn = 24
Complete response by PET/CT scan = 71%
3 non-responders
Toxicity mostly grade 1-2 diarrhea, fatigue
Grade 3-4:33% neutropenia12% diarrhea4% bleeding8% atrial fibrillation8% tumor lysis
Phase I/Ib study of Ven and Ibr
Major inclusion/exclusion • Ibrutinib naïve • Not high risk for TLS• Relapsed to >/=1 prior
chemotherapy regimen
Week 2 Week 1 Week 2 Week 3+
Ibrutinibdosing per allocation
Venetoclax 100mg
200mg200mg Arms
A, B, & D100mg
400mg Arms
C, E, & F
20mg 50mg
Week 1
Cycle 1Cycle 0
Ibrutinib 560 mg/d after 6 mo of combination therapy
Schema: 2 week ramp-up of venetoclax before ibrutinib
Phase I/Ib study of Ven and Ibr
Major inclusion/exclusion • Ibrutinib naïve • Not high risk for TLS• Relapsed to 1 prior
chemotherapy containing regimen
Week 2 Week 1 Week 2 Week 3+
Ibrutinib dosing per allocation
Venetoclax 100mg
200mg200mg Arms
A, B, & D100mg
400mg Arms
C, E, & F
20mg 50mg
Week 1
Cycle 1Cycle 0
Ibrutinib 560 mg/d after 6 months of combination therapy
Schema: 2 week ramp up venetoclax before ibrutinib
Multi-institution phase I/Ib study of ibrutinib with venetoclax in relapsed or refractory MCL. Portell et al, ASH 2019
Ibrutinib Combined With Venetoclax in R/R Mantle Cell Lymphoma (SYMPATICO)
• Initiated May 2017• Sponsor: Pharmacyclics• Phase 3 multinational, randomized, double-
blind study to compare the efficacy and safety of the combination of ibrutinib/venetoclax vs. ibrutinib/placebo in subjects with MCL
• R/R MCL, 1-5 prior treatments
Improving Outcomes in MCL: The Next 3-5 Years
• Increasing molecular and pathogenic insights
• Risk-adapted therapy, e.g. p53 mutated
• Maintenance therapies, à MRD-driven?
• Combine targeted agents, minimize standard chemotherapy and ASCT
• Rational therapeutic sequencing• Limited therapy duration