How I treat high risk DLBCL in first line? Greg Nowakowski, MD - PowerPoint PPT Presentation

How I treat high risk DLBCL in first line? Greg Nowakowski, MD Director, Aggressive Lymphoma Program Mayo Clinic Rochester, Minnesota

DLBCL Outcomes in Mayo Clinic Lymphoma SPORE Database

Heterogeneity of outcomes in DLBCL Two broad strategies: 1.0 • Target both subgroups .9 – possibly overtreating RCHOP RCHOP insufficient “sufficient group” .8 Target RCHOP “insufficient” group • .7 Time to progression provided .6 – it can be identified .5 – It cab be targeted .4 .3 RCHOP sufficient .2 .1 0.0 Time (years) 0 2 4 6 8 10

Heterogeneity of outcomes in DLBCL 1.0 • Clinical factors .9 – IPI (R-IPI) RCHOP insufficient • Interim PET scan .8 • GEP .7 Time to progression – ACB vs GCB .6 • Protein expression .5 – MYC and BCL2 .4 • Chromosomal alterations .3 RCHOP sufficient – MYC, BCL2, BCL6 .2 • Deep sequencing .1 mutation/combined expression 0.0 Time (years) analysis 0 2 4 6 8 10

Double hit lymphoma • “High grade B -cell lymphoma (HGBL) with MYC and BCL2 and/or BCL6 rearrangements” - entity in the 2016 revision of the World Health Organization Classification of Lymphoid Neoplasms • Rearrangements as opposed to expression • Outcomes have been reported to be poor Swerdlow SH, Campo E, Pileri SA, et al. Blood. 2016;127:2375-2390. J Clin Onc 2012 Oct 1; 30(28): 3452 – 3459.

MYC, BCL2, and BCL6 • MYC is a transcription factor: – Involved in cell cycle regulation, DNA damage repair, metabolism, protein synthesis, and response to stress – MYC rearranged in 7-12% of DLBCL; GCB or ABC subtype – In normal cells MYC activates the TP53 pathway • 1/3 of MYC- rearranged DLBCL’s have concurrent TP53 inactivating mutations • BCL2 has an anti-apoptotic function – BCL2 rearranged in 14-21% of DLBCL; GCB subtype • BCL6 is a transcription repressor – Overexpression prevents apoptosis – BCL6 rearranged in 23-32% of DLBCL; ABC or GCB subtype – Does not inhibit TP53

Mayo Clinic Lymphoma Database DHL/THL, Event-Free Survival and Overall Survival (n=100) Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

Not All DH/THL Are Created Equal Event Free Survival (EFS) of Newly Diagnosed vs. Transformation Patients P=0.0008 Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

EFS by Treatment P=0.10 Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

EFS Age < 60 Years by Treatment P=0.11 Haematologica. 2018; 103:doi:10.3324/haematol.2018.190157

Phase III study of R-CHOP vs DA-EPOCH-R in patients with untreated DLBCL (CALGB/Alliance 50303) Study schema Event-free survival 0.8 Key eligibility criteria R R-CHOP (N=524) Probability event free A 6 cycles •Age ≥18 years 0.6 N D • Stage II or higher newly 1:1 O diagnosed DLBCL (Stage M 0.4 I I PMBCL) Z • ECOG PS 0 – 2 E • Fresh/frozen tumor biopsy DA-EPOCH-R Median follow-up 5.0 years 0.2 6 cycles (4 cores) HR=1.14 (0.82 – 1.61) R-CHOP p=0.4386 DA-EPOCH-R + 0.0 0 1 2 3 4 5 Years from Study Entry Bartlett, Wilson et al. ASH 2016. Abstract 469.

Transplant in DH/THL Landsburg DJ et al. ASH 2016

How do I treat DHL frontline? • Patients <60 yo R-CODOX-M/IVAC • > 60 RCHOP, RCHOP with ASCT consolidation or DAEPOCH-R Current US Intergroup Study DAEPOCH-R+ venetoclax DHL R DAEPOCH-R Select by GEP – real DLBCL time R-CHOP21 + ventoclax Double Ineligible R “expresser” 6 x R-CHOP21

DLBCL Molecular Subtypes Two major molecular subtypes: • Activated B-cell like (ABC) – B-cell receptor driven • Germinal center B-cell like (GCB) Lenz et al. N Engl J Med 2008;359:2313 – 2323.

Pathways with therapeutic potential in ABC DLBCL Figure from: Roschewski et al. Nat Rev Clin Oncol 2014;11:22 – 25.

XR-CHOP(s) What X? • Bortezomib: Bor-RCHOP (Phase 2/3) • Ibrutinib: IR-CHOP (Phase 3) • Everolimus: EveR-CHOP (Phase 1b) • Lenalidomide: R2-CHOP (Phase 3)

PYRAMID: Non-GCB DLBCL Study design PFS Prospective randomized, open-label, Phase II study 1.0 Bortezomib 1.3 mg/m 2 i.v. 0.9 Days 1, 4 + 0.8 R-CHOP* 21 days x 6 cycles 0.7 PFS probability Treatment-naïve, (n = 92) 0.6 non-GCB DLBCL 0.5 by Hans IHC with measurable disease, 0.4 ECOG PS 0 – 2 0.3 R-CHOP* R-CHOP VR-CHOP (N=183) 0.2 (N=91) (N=92) Treatment group: Censored observations: 21 days x 6 cycles 25% 18% 0.1 Events R-CHOP VR-CHOP R-CHOP VR-CHOP (n = 91) 0.0 Limits: 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Time to event (months) Patients at risk: • Patient selection in the PYRAMID trial may R-CHOP 91 72 65 61 57 50 37 28 22 15 5 2 0 0 0 0 VR-CHOP 92 75 72 66 61 51 38 27 24 13 7 2 2 1 0 0 have played a role  R-CHOP alone produced better outcomes than expected • 2-year PFS: 78% R-CHOP vs 82% VR-CHOP • IHC based on Hans algorithm – HR (95% CI): 0.73 (0.43 – 1.24); p=0.611 Leonard JP, et al. Blood 2015;126:811a. VR-CHOP, bortezomib, rituximab, cyclophosphamide, (Updated data presented in oral presentation at ASH annual meeting) hydroxydaunorubicin, vincristine, prednisone.

REMoDL trial 74.3% 70.1% 5 x R-CHOP Rando- HR=0.841, p=0.225 Patients misation with Stratified for DLBCL Con- R- 5 x R-CHOP + in need molecular sent CHOP bortezomib of full phenotype 1.3 mg/m 2 #1 course and IPI days 1+8 of R- CHOP ABC: N=244 GCB: N=475 (stage Biopsy sent to II Ax -IV) HMDS for molecular profiling DASL, cDNA-mediated annealing, selection, extension and ligation; HMDS, Haematological Malignancy Diagnostic Service. Davies AJ, et al. ICML 2017. Abstract 121. Updated data presented at ICML.

DLBCL Molecular Subtypes and Outcomes Lenz et al. N Engl J Med 2008;359:2313 – 2323.

Investigator-assessed PFS by Cell of Origin* Kaplan-Meier plot of investigator- assessed PFS by COO ABC, GCB, Unclassified, 1.0 n=243 n=540 n=150 Pts with 0.8 92 129 54 event, (37.9) (23.9) (36.0) n (%) 0.6 Probability 2-year 66.4 78.0 65.9 PFS, % 0.4 ABC (n=243) GCB (n=540) 0.2 3-year 59.3 75.0 63.2 Unclassified (n=150) PFS, % Censored 0 HR (95% CI) 0 6 12 18 24 30 36 42 48 54 60 1.70 (1.30, 2.23) ABC vs GCB Time (months) No. of patients at risk 1.57 (1.14, 2.16) ABC Unclassified vs 243 209 174 161 144 78 52 32 13 2 GCB 540 480 417 398 344 207 139 96 41 3 GCB Unclassified 150 128 111 103 86 64 42 25 9 1 *Exploratory analysis; COO classification determined for 933 pts by gene expression profiling assay (Nanostring); missing COO classifications due to: restricted Chinese export license, n=252; CD20+ DLBCL not confirmed, n=102; missing/inadequate tissue, n=131; PFS HR=0.82 (0.64, 1.04) in pts with COO classification; PFS HR=1.18 (0.85, 1.64) in pts without COO classification Vitolo et al. ASH 2016. Abstract 470.

Phoenix: Study schema 6 to 8 x R-CHOP21* + ibrutinib 560 mg daily N=400 R Non-GCB 6 to 8 x R-CHOP21 + placebo daily N=400 Select by IHC DLBCL – real time *Option for 2 additional cycles if considered standard of care per local practice Ineligible GCB • Newly diagnosed DLBCL of non-GCB type • IPI ≥ 2; ECOG PS ≤ 2; Age >18 • Primary Endpoint = EFS • N = 800 ClinicalTrials.gov Identifier: NCT02285062.

Phoenix: Study schema 6 to 8 x R-CHOP21* + ibrutinib 560 mg daily N=400 R Non-GCB 6 to 8 x R-CHOP21 + placebo daily N=400 Select by IHC DLBCL – real time *Option for 2 additional cycles if considered standard of care per local practice Ineligible GCB • Newly diagnosed DLBCL of non-GCB type • IPI ≥ 2; ECOG PS ≤ 2; Age >18 • Primary Endpoint = EFS • N = 800 ClinicalTrials.gov Identifier: NCT02285062. Press release available from: https://www.jnj.com/janssen-provides-update-on-imbruvica-ibrutinib-phase-3-phoenix-trial-in-newly-diagnosed-non-germinal-center-b-cell-non-gcb-subtype-of- diffuse-large-b-cell-lymphoma-dlbcl

Phase II studies of lenalidomide R-CHOP (R2-CHOP) in front-line DLBCL N=44 N=64 ORR 92% ORR 98% CR 86% CR 80% Nowakowski et al. J Clin Oncol 2015;33:251 – 257; Vitolo et al. Lancet Oncol 2014;15:730 – 737.

Long Term Results of R2CHOP: Combined Analysis of Two Phase 2 Studies (n=108) Overall Survival by COO (IHC) 100 100 Overall Survival by COO (Nanostring) 100 100 100 100 90 90 90 90 90 90 80 80 80 80 80 80 70 70 70 70 70 70 Event-Free Event-Free 60 60 60 60 60 60 Alive Alive Alive Alive 50 50 50 50 50 50 % % % % 40 40 % % 40 40 40 40 30 30 30 30 30 30 Outcome Events/Total Time-Point KM Est (95% CI) Nanostring Events/Total Time-Point KM Est (95% CI) 20 20 20 20 20 20 PFS 38/106 5 Years 65.4 (56.6-75.5%) COO Events/Total Time-Point KM Est (95% CI) ABC 5/22 5 Years 74.8 (57.5-97.3%) TTP 31/106 5 Years 69.9 (61.2-79.9%) Non-GCB 9/40 5 Years 75.3 (62.3-91.1%) GCB 10/30 5 Years 76.0 (62.0-93.2%) 10 10 10 10 10 10 OS 25/107 5 Years 77.4 (69.4-86.4%) GCB 15/45 5 Years 71.7 (59.2-86.9%) Unclassified 3/15 5 Years 79.0 (60.4-100.0%) Censor Logrank P-value: 0.3327 Censor Logrank P-value: 0.6580 Censor 0 0 0 0 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Years Years Years Years Years Years Castellino et al. ASCO, 2018, In Press