Have we moved beyond EPOCH for B-cell non-hodgkin lymphoma? YES!

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1 Have we moved beyond EPOCH for B-cell non-hodgkin lymphoma? YES! Christopher Flowers, MD, MSc Associate Professor Director, Lymphoma Program Department of Hematology and Oncology Emory School of Medicine 1

2 Diffuse Large B-Cell Lymphoma Peak incidence in 6th decade Heterogeneous biology and clinical outcomes Poor risk subsets - GCB vs. ABC by GEP or IHC - MYC+ / (BCL2+ &/or BCL6+) Double hit by FISH Double expression by IHC - Poor outcomes with standard therapy - No defined strategy that improves outcomes - Should be enrolled on a clinical trial - (w/ comparison to R-CHOP) 2

3 Molecularly and Clinically Distinct Subgroups in DLBCL Alizadeh et al. Nature 2000 OS Overall Survival Years Rosenwald A et al. J Exp Med 2003;198: Zhang et al. Proc Natl Acad Sci 2013 Morin et al. Blood 2013 Lohr et al. Proc Natl Acad Sci 2012 Pasqualucci et al. Nat Genet Rosenwald A et al. J Exp Med Yr OS PMBL 64% GCB 59% ABC 30% Alizadeh AA, et al. Nature. 403(6769): Rosenwald A, et al. J Exp Med. 2003;198(6): Zhang J, et al. Proc Natl Acad Sci U S A. 2013;110(4): Rosenwald Morin et al. Rd, J Exp et al. Med Blood. 2003;198: ;122(7): Lohr JG, et al. Proc Natl Acad Sci U S A. 2012;109(10): Pasqualucci L, et al. Nat Genet. 2011;43(9):

4 Molecularly and Clinically Distinct Subgroups in DLBCL Integrative Genetic and Clinical Analysis through Whole Exome Sequencing of 1001 DLBCL Patients Zhang J, et al. Blood. 2016;128: Abstract

5 Dose Adjusted R-EPOCH Impressive Outcomes in Phase 2 Clinical Trials Wilson WH, et al. Haematologica. 2012;97(5):

6 CALGB/Alliance 50303: Study Design Randomized Phase 3 study Untreated, newly diagnosed stage II-IV DLBCL (stage I PMBCL), ECOG PS 0-2, LVEF > 45%, tumor biopsies available, no CNS disease (N = 465) DA-EPOCH-R* Rituximab 375 mg/m 2 IV Cyclophosphamide 750 mg/m 2 IV Doxorubicin 10 mg/m 2 IV on Days 1-4 Etoposide 50 mg/m 2 IV on Days 1-4 Vincristine 0.4 mg/m 2 IV on Days 1-4 Prednisone 60 mg/m 2 BID on Days 1-5 G-CSF as needed SC on Days 6-12 (n = 232) R-CHOP* Rituximab 375 mg/m 2 IV Cyclophosphamide 750 mg/m 2 IV Doxorubicin 50 mg/m 2 IV Vincristine 1.4 mg/m 2 IV (max 2 mg) Prednisone 40 mg/m 2 PO on Days 1-5 G-CSF as needed SC (n = 233) 6 cycles Primary endpoint: EFS Secondary endpoints: RR OS Safety *Included CNS prophylaxis if BM/testicular involvement or elevated LDH plus 2 extranodal sites. Prophylaxis: MTX IT x 4 doses on Day 1 of Cycles 3-6. Increased 20% if ANC nadir > 0.5. De-escalated if ANC < 0.5 for > 3 days. Wilson WH, et al. Blood. 2016;128: Abstract

7 CALGB/Alliance 50303: Baseline Characteristics Characteristic R-CHOP DA-EPOCH-R P Value Median age, yrs (range) 58 (18-86) 57 (19-84).677 ECOG PS, % 0/1 2 Stage, % 1 (PMBCL) IPI criteria, % 0/ / No significant differences between treatment arms Wilson WH, et al. Blood. 2016;128: Abstract

8 CALGB/Alliance 50303: Outcomes Response, % R-CHOP DA-EPOCH-R P Value ORR CR/CRu PR SD PD 80 EFS *Median follow-up 5 yrs < 1.0 Missing data OS.983 EFS (%) R-CHOP DA-EPOCH-R HR: 1.14 (95% CI: ; P =.4386) Yrs Arm N Events, n 3 Yrs (95% CI) 5 Yrs (95% CI) R-CHOP ( ) 0.69 ( ) DA-EPOCH-R ( ) 0.66 ( ) Wilson WH, et al. Blood. 2016;128: Abstract 469. OS (%) R-CHOP DA-EPOCH-R HR: 1.18 (95% CI: ; P =.42) Yrs Arm N Events, n 3 Yrs (95% CI) 5 Yrs (95% CI) R-CHOP ( ) 0.80 ( ) DA-EPOCH-R ( ) 0.76 ( ) 8

9 CALGB/Alliance 50303: Conclusions No differences between R-CHOP vs DA-EPOCH-R for EFS and OS with 5-yr follow-up No benefit with DA-EPOCH-R identified among clinical subgroups defined by age and IPI criteria Moderately increased rates of grade 3-5 AEs in the DA-EPOCH-R arm vs R-CHOP arm (cytopenias, febrile neutropenia, neuropathy) NO Advantage demonstrated for using DA-EPOCH-R for any group of lymphoma patients Wilson WH, et al. Blood. 2016;128: Abstract

10 Dose Adjusted R-EPOCH Impressive Outcomes in Phase 2 Clinical Trials Wilson et al. Blood Dunleavey et al. NEJM Little et al. Blood

11 Dose Adjusted R-EPOCH Impressive Outcomes in Phase 2 Clinical Trials Not Supported by Randomized Phase 3 Clinical Trials!! Wilson et al. Blood Dunleavey et al. NEJM Little et al. Blood

12 Alternatives exist to Dose Adjusted R-EPOCH even for HIV-associated NHL 12

13 Petrich AM, et al. Blood. 2014;124(15):

14 Targeting Molecular Pathways in DLBCL Zhang J, et al. Blood. 2016;128: Abstract Roschewski M, et al. Nat Rev Clin Oncol. 2014;11(1):

15 Need strategies for poor risk DLBCL that improve outcomes vs. R-CHOP DA-REPOCH has not demonstrated unique benefits for any lymphoma subgroup RCT in DLBCL shows no benefit DLBCL has heterogeneous biology and clinical outcomes Poor risk subsets GCB vs. ABC by GEP or IHC MYC+ / (BCL2+ &/or BCL6+) Double hit by FISH Double expression by IHC Poor Outcomes with standard therapy Should be enrolled on a clinical trial with molecular agent + R-CHOP (w/ comparison to R-CHOP) Numerous promising agents for combinations 15

16 Emory clinical trials for DLBCL Vitamin D supplementation Drake MT, et al. J Clin Oncol. 2010;28(27): Phase 1/2 Carfilzomib + R-CHOP 16

17 Emory Lymphoma Program Program Goals: To eliminate death and suffering from lymphoma Physician Team: - Dr. Flowers Questions? Mapping Lymphoma Incidence Patterns in Georgia New NHL pts in population Kristie Blum, MD Professor of Medicine - Dr. Lechowicz - Dr. Cohen Pamela Allen, MD Northwestern University -Dr. Bernal-Mizrachi -Dr. Koff -Dr. Brian Greenwell (fellow) -Dr. Andres Chang (fellow) -Dr. Andrew Ip (fellow) 17