Outcomes for Double Hit Lymphoma Patients Identified Via Routine Vs Selective Testing for MYC Rearrangement

Abstract

Introduction Patients (pts) diagnosed with double hit lymphoma (DHL) are reported to experience poor survival outcomes following first-line treatment with R-CHOP, although survival may be improved with receipt of intensive front-line immunochemotherapy. These results may be altered by selection bias, as prior retrospective series of DHL pts did not report performing routine cytogenetic testing to identify those with DHL. We hypothesized that outcomes might differ for DHL pts identified after the implementation of routine testing at our institution. Methods In January of 2015, our institution began routine testing for MYC-rearrangement (R) by fluorescence in situ hybridization (FISH) for all newly-diagnosed cases of DLBCL and HGBL/BCLU, with reflex testing for BCL2-R and BCL6-R by FISH if positive for MYC-R. Prior to this, FISH for MYC-R, BCL2-R and/or BCL6-R was performed at the discretion of the treating physician or interpreting hematopathologist. Pts included in our analysis were diagnosed with DHL from May 2009 through July 2018. Inclusion criteria were adults treated with first-line curative-intent immunochemotherapy. Exclusion criteria were HIV-associated lymphoma, primary CNS or testicular lymphoma, post-transplant lymphoproliferative disorder, and incomplete clinicopathologic and outcomes data. Primary outcome measures were progression free survival (PFS) and overall survival (OS) in the pre-January 2015 selective testing (ST) and post-January 2015 routine testing (RT) cohorts. Data were censored on 5/31/19. Results Sixty-five pts were included in the analysis. The ST and RT cohorts did not differ significantly on the baseline characteristics of age, sex, stage, performance status, B symptoms, elevated LDH, extranodal disease, stage III/IV, blood or bone marrow involvement, International Prognostic Index score, Ki67, cell of origin, expression of MYC or BCL2 protein or the combination, time from diagnosis to treatment >14 days, disease bulk > 7.5 cm, transformation from an indolent lymphoma, or front-line treatment with R-CHOP vs intensive immunochemotherapy. Eighty percent (n=52) of pts received intensive front-line immunochemotherapy, most with R-EPOCH (n=42). Median length of follow-up was 32 months (61 months for ST and 24 months for RT). The RT group had a longer 2-year PFS 70% vs 43%, p=0.02; univariate hazard ratio (HR) for progression 2.4, 95% confidence interval (CI) 1.1-5.4, p=0.03, (Figure 1A). The only other variable associated with progression was presence of extranodal disease (HR 2.35, 95% CI 1.0-5.4, p=0.047). In a multivariate model, both ST and the presence of extra-nodal disease were independently associated with progression at 2 years (HR 2.84, 95% CI 1.3-6.4, p=0.012 and HR 2.79, 95% CI 1.2-6.5, p=0.018, respectively). Longer OS was observed with RT (median OS NR vs 16 months, 2-year OS 72% vs 41%, p=0.008; HR 2.97 95% CI 1.3-6.9, p=0.012, Figure 1B). No other factors were associated with longer OS. For pts who relapsed after first-line therapy, survival was poor with a median OS after relapse of 6 and 5 months in the RT and ST groups (p=0.11). When limiting the analysis to only those pts treated with intensive immunochemotherapy, median PFS and OS remained significantly longer for the RT group (2-year PFS 70% vs 38%, p=0.01; median OS NR vs 16 months and 2-year OS 74% vs 38%, p=0.007). Post-relapse survival was similarly poor for those treated with intensive induction regardless of RT vs ST (median post-relapse OS 6 vs 5 months, p=0.1). Conclusions Long-term survival may be improved for DHL pts identified through routine as opposed to selective FISH testing. These data could serve as a new baseline for outcomes of DHL pts identified in this manner. Survival outcomes for our cohort of pts treated with intensive immunochemotherapy are similar to those for DHL pts reported in a recent prospective multicenter study of front-line R-EPOCH (Lancet Haematol. 2018 Dec;5(12):e609-e617). While we suspected that the poorer outcomes experienced by ST pts may have been due to high-risk clinicopathologic factors that contributed to selection bias in testing, this does not seem to be the case for any measured factors. It may be that variation in additional molecular features within this high-risk cytogenetic population could explain differences in survival, and next generation sequencing analysis of DHL patient tissue specimens is planned. Disclosures Dwivedy Nasta: Celgene: Honoraria; ATARA: Research Funding; Pharmacyclics: Research Funding; Rafael: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; 47 (Forty Seven): Research Funding; Millenium/Takeda: Research Funding; Debiopharm: Research Funding; Aileron: Research Funding. Schuster:Merck: Honoraria, Research Funding; Novartis: Honoraria, Patents & Royalties: Combination Therapies of CAR and PD-1 Inhibitors with royalties paid to Novartis, Research Funding; Loxo Oncology: Honoraria; Pharmacyclics: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Nordic Nanovector: Honoraria; AstraZeneca: Honoraria; Pfizer: Honoraria; Acerta: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Chong:Merck: Research Funding; Tessa: Consultancy; Novartis: Consultancy. Rhodes:DAVA Oncology: Honoraria. Landsburg:Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Seattle Genetics: Speakers Bureau; Triphase: Research Funding; Triphase: Research Funding.

First‐line treatment of double‐hit and triple‐hit lymphomas: Survival and tolerance data from a retrospective multicenter French study

“…On the other hand, this may result in a bias with a dilution of the most aggressive cases over time. Frosh et al showed that DHL identified with a routine FISH technique resulted in longer patient survival than DHL identified by selective FISH 15 . Such generalization of FISH technique however raises the question of the management of localized cases of DHL and THL (Stage I/II Ann Arbor).…”

Altered pathways and targeted therapy in double hit lymphoma

“…DHITsig positive patients had dismal outcomes after being treated with R-CHOP in terms of DSS (BioElectric Massage) (pos vs neg, 63% vs 90%), 5-year PFS (pos vs neg, 53% vs 79%), and OS (pos vs neg, 60% vs 83%). Several literature highlighted the importance of risk stratification depending on molecular features like GEP (gene expression profile), instead of merely genetic translocation status, to avoid missing out on a cluster of high-risk patients while exposing low-risk ones to excessive therapies [ 27 , 28 ].…”

“…To avoid the late diagnosis, the study result supports the performance of the routine FISH test in all DLBCL patients, which considerably improves the outcome of DHL (ST vs RT: 2-year RFS, 38% v 70% and 2-year overall survival, 38% v 74%). At the same time, routine testing identified a cohort of low-risk DHL patients and the lack of benefit from intensive immunochemotherapy [ 28 ]. Independent research further stratifies DHL into high-risk and low-risk (DHIT + SIG) subgroups, suggesting tremendous heterogenicity lies in the DHL cohort [ 26 ].…”

Molecular Risk Stratification in Aggressive B-Cell Lymphomas

“…Despite there being no relevant differences in measured baseline clinicopathologic features or in rates of treatment with intensive first-line immunochemotherapy, patients with DHL who were identified by ST as opposed to RT had a 2-year relapse-free survival (RFS) of 43% versus 70% and a higher risk of 2-year relapse and death, even when accounting for clinical, pathologic, and treatment factors in a multivariable model. 11 These results did not change when considering only the 80% of patients treated with intensive immunochemotherapy in each group (2-year RFS, 38% v 70% and 2-year overall survival, 38% v 74%). In addition, for patients in the RT cohort, those who received R-CHOP compared with those who received intensive first-line immunochemotherapy experienced similar 2-year RFS (80% v 70%) as well as 2year overall survival (67% v 74%), suggesting a possible lack of survival benefit from using intensive first-line immunochemotherapy in the RT cohort.…”