Ohio State's 2016 ASH Review T-cell Disorders

The Ohio StateUniversity ComprehensiveCancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute
T-cell Disorders
Pierluigi Porcu, MD
Professor of Medicine
Division of Hematology
Comprehensive Cancer Center

 #253 Safe and Effective Treatment of Patients with PTCL with the Novel HDAC Inhibitor, Belinostat, in
Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial (23 patients)
 #340 Addition of Etoposide to CHOP Is Associated with Improved Outcome in Adult ALCL Patients: A
Nordic Lymphoma Group Study
 #341 First Multicenter, Randomized Phase 3 Study in Pts with Relapsed/Refractory PTCL: Alisertib
(MLN8237) Versus Investigator's Choice (Lumiere trial; NCT01482962)
 #586 The Combination of Brentuximab Vedotin (Bv) and Bendamustine (B) Demonstrates Marked Activity
in Heavily Treated Patients with Relapsed or Refractory Hodgkin Lymphoma and ALCL: Results of an
International Multi Center Phase I/II Experience
 #1537 Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab Vedotin in
Combination with CHP: 3-Year Durability and Survival Follow-up
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ASH - 2015 Presentations on Peripheral T-cell Lymphoma

 #1501 Event-Free Survival at 12 Months and Subsequent Overall Survival in Patients with PTCL
 #3937 Phase II Study of the Fondazione Italiana Linfomi on Gemcitabine Plus Romidepsin (GEMRO
Regimen) in Relapsed and Refractory PTCL Patients (20 patients)
 #3987 High Response Rate of Romidepsin in Combination with ICE (Ifosfamide, Carboplatin and
Etoposide) in Patients with Relapsed or Refractory PTCL: Updates of Phase I Trial (17 patients)
 #3947 Accuracy of PET Imaging to Detect Bone Marrow Clearance in Patients with PTCL
 #3952 Patterns of Treatment for Newly Diagnosed and R/R PTCL in the Community Setting
 #3993 Development of Masitinib for the Treatment of PTCL
 #1467 Inhibition of ITK-Mediated Chemoresistance By Ibrutinib in T-Cell Disorders
 #315 Subgroups of T-PLL Discovered By High-Throughput Ex Vivo Drug Testing and Genetic Profiling
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ASH - 2015 Presentations on Peripheral T-cell Lymphoma

 #1485 High-Depth, Targeted, Next Generation Sequencing Identifies Novel Genetic Alterations in
Cutaneous T-Cell Lymphoma
 #4403 Allogeneic Hematopoietic Cell Transplantation (HCT) for Advanced Mycosis Fungoides and
Sezary Syndrome (MF/SS): Impact of Increasing the Use of Unrelated Donors (UD) - the EBMT
Lymphoma Working Party Experience
 #2724 Phase I Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in
Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma
 #2677 Results from a Phase 1/2, Open-Label, Dose-Finding Study of Pralatrexate and Oral
Bexarotene in Patients with Relapsed/Refractory Cutaneous T-Cell Lymphoma
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ASH - 2015 Presentations on Cutaneous T-cell Lymphomas

 Belinostat: Pan HDACi recently approved in the U.S. for R/R PTCL based on results from pivotal
Phase 2 BELIEF study (O'Connor et al, JCO, 2015) which showed ORR 25.8%, durable benefit,
and good tolerability
 Study design:
 Sponsor: Spectrum
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#253 Safe and Effective Treatment of Patients with PTCL with the Novel HDAC Inhibitor,
Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

 A total of 23 patients were enrolled in the study (10 PTCL, 9 AITL, 3 ALCL)
 Part A = Maximum Tolerated Dose (MTD) of the Bel-CHOP combination (11 patients)
 Part B = Expansion Phase (12 more patients)
 MTD = 1000 mg/m2 on Days 1-5 (Cohort 5)
 Only DLT was in Cohort 3 (G3 Nausea and Vomiting).
 18/23 patients (78%) completed all 6 cycles of Bel-CHOP, 87% completing at least 4 cycles.
 10 patients (43%) had at least 1 serious adverse event (SAE); 18 (78%) had at least one G3/4 AE
 Most frequent G3/4 AEs = neutropenia (26%), anemia (22%), leukopenia (17%).
 ORR = 89% (16/18 patients that completed End of Study Visit )
 CR = 72% (n=13)
 PR = 17% (n=3)
 Progressive disease = 2 patients.
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#253 Safe and Effective Treatment of Patients with PTCL with the Novel HDAC Inhibitor,
Belinostat, in Combination with CHOP: Results of the Bel-CHOP Phase 1 Trial

 Population-based study, Swedish and Danish Lymphoma Registries
 Goal: analyzing outcome and risk factors for survival in patients with systemic ALCL (ALK+ and ALK-)
 Adult (>18 years) patients with ALCL diagnosed between 2000 and 2010
 Primary cutaneous ALCL cases excluded.
 No central review of pathology
 N = 371 patients (ALK+ ALCL N=122; ALK- N=216; ALK unknown N=33)
 Largest cohort of adult ALCL patients published
 The median follow-up 7.2 years
 ALK+ patients younger than ALK- patients (median age 40 versus 66 years, p<0.001
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#340 Addition of Etoposide to CHOP Is Associated with Improved Outcome in
Adult ALCL Patients: A Nordic Lymphoma Group Study

 118/328 assessable patients relapsed or progressed (ALK+ n=20, ALK- n= 83, ALK u n=15)
 5-yr OS and PFS, respectively were 78% and 64% in ALK+ ALCL, 37% and 32% in ALK- ALCL and 27%
and 25% in ALK u ALCL.
 Data on primary treatment available in 341/371 patients (92%). The majority of patients (n=278, 82%) was
treated with CHOP (N=233) or CHOEP (N=108).
 Up-front ASCT performed in 38 patients with ALK- ALCL (most CHOEP) and 6 patients with ALK+ ALCL.
 Independent variable in multivariable analysis were:
1. Treatment with CHOEP = better OS (HR 0.48 95% CI 0.32-0.74, p=0.001)
2. Increasing NCCN-IPI score (HR [for each increment] 1.6 95% CI 1.5-1.8, p<0.001) = inferior OS.
 Risk factors for worse OS by multivariable analysis for patients treated with CHOEP:
 Age (HR 2.9 95% CI 1.5-5.3, p=0.001)
 ALK-negativity (HR 2.6 95% CI 1.2-6.0, p=0.020)
 Elevated LDH (HR 2.1 95% CI 1.0-4.3, p=0.047)
 Assigning 0,1 and 2 points for age <40, 40-60 and 60-75, 1 for ALK-, and 1 for LDH, a new score identified
4 groups with different OS. Patients with a score of 3 or 4 had a similar OS.
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 CONCLUSIONS
 Study confirms the favorable outcome of ALK+ ALCL patients and the association with low-risk features
 Addition of etoposide to CHOP was independently associated with a superior OS
 Addition of etoposide to CHOP, if tolerated, is an important component in the treatment of ALCL
 When adjusting for this treatment modification, the impact of ALK-expression on OS was mitigated.
 Risk analysis in the CHOEP treatment group: age, ALK-, LDH independent risk factors for OS
 Novel prognostic score proposed
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 Alisertib investigational, oral, selective inhibitor of Aurora A kinase, key mitotic regulator
overexpressed/amplified in various cancers, including lymphomas.
 Phase 2 data with single-agent alisertib in R/R NHL (Friedberg et al JCO 2014) and R/R PTCL (Barr et al
JCO 2015) suggested promising antitumor activity.
 This international phase 3 trial evaluated single-agent alisertib vs investigator's choice in pts with R/R
PTCL, and was the first initiated randomized trial in this setting.
 Eligibility:
 Adult pts with R/R PTCL
 ≥1 prior systemic therapy
 Measurable disease by 2007 IWG criteria
 Tumor biopsy for central hematopathology review
 ECOG PS 0–2
 No prior exposure to comparator drug (pralatrexate, romidepsin, or gemcitabine)
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#341 First Multicenter, Randomized Phase 3 Study in Pts with Relapsed/Refractory
PTCL: Alisertib (MLN8237) Versus Investigator's Choice (Lumiere trial; NCT01482962)

 Study Design:
 Stratification: Nodal vs Extranodal, IPI 0/1/2 vs 3/4/5, North America + EU vs Rest of World
 Randomized (1:1) to Alisertib 50 mg PO bid on d 1–7 in 21d cycles vs. investigator's choice
 Pralatrexate, Romidepsin, or Gemcitabine (all at standard dosing schedule)
 Treated until disease progression, unacceptable toxicity, or 2 yrs (extendable if benefit shown).
 Crossover to other drug not permitted.
 Primary endpoints: ORR (CR+PR) and PFS by IWG criteria per central (IRC) assessment.
 Secondary endpoints: OS, DOR, and safety.
 Adaptive sample size reassessment approach, with two interim analyses (IA1, futility; IA2) and one final analysis
 Sample size: 80% power for ORR (assumed 55% alisertib vs 30% comparator); ~85% power for PFS
 Assumed 55% ORR for alisertib vs 30% ORR for comparator
 Planned final analysis N=354 randomized pts + N=261 PFS events
 PFS analysis at IA2 could determined futility assessment (reported at ASH)
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 Results: 238 pts randomized across 27 countries (120 alisertib, 118 comparator)
 Baseline characteristics were balanced between arms (alisertib vs comparator)
 Median age 63 vs 64 yrs
 Male 68% vs 64%
 Ann Arbor stage III/IV 74% vs 72%
 Bone marrow involvement 29% vs 35%.
 Efficacy:
 ORR: 33% alisertib vs 43% comparator (OR 0.65 [95% CI: 0.34–1.23]), 16% vs 25% CR
 Median duration of follow-up 9.5 vs 9.2 mos
 Median PFS 3.7 vs 3.4 mos (HR 0.939 [95% CI: 0.681–1.293])
 Median OS was 9.9 vs 12.2 mos (HR 0.901 [95% CI: 0.607–1.337]
 Median treatment duration with alisertib vs comparator was 12 vs 10 weeks
 Overall safety and rates of specific Aes similar between the two arms
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 Conclusions:
 Alisertib showed activity in R/R PTCL, but….
 No significant efficacy benefit vs comparator
 Based on IA2, there was a low probability of claiming superiority of alisertib for PFS at the final analysis
 Per IDMC recommendation enrollment stopped at 271 pts and pts deriving benefit continue on treatment.
 The study was unblinded and final data are pending.
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 Phase 1 trial of brentuximab vedotin (BV) in sequence with CHOP or in combination with CHP (no
vincristine) in treatment-naive pts with PTCL, including systemic ALCL (Fanale 2014)
 Updated durability data and peripheral neuropathy resolution from the combination-therapy arm of this trial
 Analysis set consisted of pts who received BV+CHP x 6 cycles, q3wk.
 Pts who achieved at least PR could receive up to 10 additional cycles of single-agent BV (1.8 mg/kg q3wk)
 ALK+ ALCL pts must have IPI score ≥2
 No centralized response assessment
 Efficacy endpoints included PFS and OS
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#1537 Frontline Treatment of CD30+ Peripheral T-Cell Lymphomas with Brentuximab
Vedotin in Combination with CHP: 3-Year Durability and Survival Follow-up

 Cohort size N= 26
 ALCL (n=19; 3ALK+, 16 ALK-), PTCL-NOS (n=2), AITL (n=2), ATLL (n=2), and EATL (n=1)
 OR rate = 100%; CR rate = 88%
 Treatment-emergent adverse events >G3: febrile neutropenia, neutropenia, anemia and pulm. embolism
 Peripheral neuropathy (any grade): 73%
 20 pts on study, median observation time = 38.7 months (range, 4.6 to 44.3)
 3 yr OS: 80% (95% CI: 59, 91 months)
 Median PFS not reached.
 Twenty one pts received a median of 10 doses (range, 1-10) of BV post BV-CHP
 Nine/19 (47%) ALCL and 5/7 (71%) non-ALCL pts have not experienced disease progression or death
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 Eighteen of 19 (95%) patients experienced either complete resolution (n=7, 37%) or improvement by at
least 1 grade level (n=11, 58%) in neuropathy
 There were a total of 44 PN events of which 23 (52%) resolved and 14 (32%) improved
 Five pts (19%) who experienced disease progression post-treatment received subsequent BV
 Three patients received stem cell transplants (1 autologous, 2 allogenic)
 No patients received a consolidative ASCT in first remission
 Conclusions:
 Durable remissions observed with BV-CHP in newly diagnosed pts with PTCL
 After >3 years of follow-up, clinical outcomes compare favorably with historical data in PTCL pts.
 An ongoing randomized trial with 450 pts is comparing BV+CHP with CHOP for the frontline treatment of
CD30+ PTCL (ClinicalTrials.gov NCT01777152)
 Final results from this trial are expected in 2017 to 2018.
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Progression-Free Survival: BV-CHP

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Ohio State's 2016 ASH Review T-cell Disorders

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