Impact Of Induction Regimen and Consolidative Stem Cell Transplantation In Patients With Double Hit Lymphoma (DHL): A Large Multicenter Retrospective Analysis

Abstract

Background DHL are high-grade B-cell lymphomas (BCL) characterized by dual gene rearrangements (RA) of MYC and either BCL2 or BCL6. Outcomes are typically dismal, particularly when treated with R-CHOP, as compared to those observed in patients (pts) with similar histologies without dual RA. Few reports have evaluated the use of intensive induction regimens, with or without consolidative stem cell transplantation (SCT). We sought to evaluate the role of intensive induction as well as SCT, and to investigate predictors of outcome in DHL. Methods This study was an IRB-approved retrospective analysis across 15 centers. Cases were diagnosed between 2000-2012 as aggressive BCL harboring RA, by FISH, of MYC along with RA of BCL2 and/or BCL6. Pts were treated with either R-CHOP, or one of the following intensified regimens: R-HyperCVAD, R-EPOCH, R-CODOX-M/IVAC, R-ICE. Survival was estimated using Kaplan Meier method, and comparisons made with log rank test. Multivariable analysis (MVA) was performed using the Cox proportional hazard regression. Results One hundred six pts were analyzed. Median age at diagnosis was 60; 59% were male. The majority had DHL characterized by RA of MYC and BCL2 (77%); the remainder showed RA of MYC and BCL6 (10%), or all three (12%). History of indolent lymphoma was present in 29 pts (27%). The most common histology was DLBCL in 56 pts (53%), followed by BCL unclassifiable (BCLU) in 45 (42%), and Burkitt-like in 5 (5%). Thirty six pts (33%) received R-CHOP, 33 (31%) R-EPOCH, and 28 (36%) R-Hyper-CVAD or CODOX-M/IVAC. Fourteen pts (13%) were consolidated with SCT (n=1 allo and n=13 auto SCT); all were treated with intensive induction. Three additional pts underwent SCT in partial remission or progressive disease following R-CHOP induction. The median PFS and OS for the entire cohort were 8.8 mo and 12 mo, respectively (Table 1); of the 24 pts (23%) alive and without progression, median follow-up was 19 mo. R-EPOCH was superior in achieving complete response (CR) compared with R-CHOP (P 0.01), and trended towards significance compared with pts receiving other intensive induction (P 0.07). Additionally, primary refractory disease, observed in 37 pts (34.5%), occurred less frequently in pts receiving R-EPOCH compared to R-CHOP (P .005) or other intensive regimens (P 0.03); induction regimen did not impact OS in patients not receiving SCT (P 0.7; Fig 1). SCT in first remission was associated with improved OS (P 0.02), and PFS (P 0.006) compared with induction alone. However, among pts achieving CR, SCT was not associated with improved OS compared with observation (P 0.22; Fig 2). Pts with prior history of indolent NHL did not fare worse than those with de novo DHL (P 0.5). No difference in OS was observed based on histology (P 0.2). The following factors were evaluated in MVA: prior indolent lymphoma, histological subtype, IPI>/=3, primary refractory disease, type of induction (R-CHOP vs intensified), and consolidative SCT. Only primary refractory disease (P<0.0001) predicted for inferior OS. Consolidative SCT did not improve OS on MVA (P 0.13). Conclusions In this analysis of DHL, primary refractory disease was the primary predictor of OS. Pts achieving CR did not appear to benefit from consolidative SCT, though our analysis was limited by the fact that pts receiving SCT are often highly selected (for chemosensitivity, age, comorbidities) and in this study, by the low number of pts receiving SCT. R-EPOCH was associated with a decreased rate of primary refractory disease compared to other regimens, and increased rate of CR compared to R-CHOP, but the lack of clear survival benefit suggests that relapsed disease offsets early benefit. Our analysis confirms the generally poor outcomes for pts with DHL, though a subset with chemosensitive disease has an improved prognosis, likely due to favorable disease biology. Further investigation on the role of SCT and of novel agents is needed for this high-risk population. ^Three patients untreated, one received multiple regimens Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Petrich:Genetech: Consultancy, Honoraria. Fenske:Seattle Genetics : Consultancy, Honoraria. Smith:Seattle Genetics, Inc.: Research Funding; Spectrum: Consultancy; Cephalon: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; GlaxoSmith Kline: Speakers Bureau. Evens:Seattle Genetics: Consultancy, Honoraria; Millennium: Consultancy, Honoraria, Research Funding; Ziopharm, Inc: Research Funding; Celgene: Consultancy, Honoraria.

Front‐line, dose‐escalated immunochemotherapy is associated with a significant progression‐free survival advantage in patients with double‐hit lymphomas: a systematic review and meta‐analysis

“…Overall, the current meta‐analysis included 394 patients. The 2 largest studies, reported by Oki et al () and Gandhi et al (), accounted for more than half of these patients. The majority of patients with DHL had stage III/IV disease, intermediate or high International Prognostic Index score and elevated serum lactate dehydrogenase at first diagnosis.…”

“…However, the study did report the number of patients at risk at each time point, so the number of censored and observed events within each time interval was able to be calculated (Appendix S1). In the remaining five studies, DHL‐ and treatment‐specific KM curves were either not reported or were illegible to determine individual event or censoring times (Abramson et al , ; Gandhi et al , ; Navarro et al , ; Sun et al , ; Cohen et al , ). Thus, aggregate survival data were used for these studies and were incorporated into the model as median survival time or percent surviving at follow‐up time (Appendix S1).…”

MYC‐associated and double‐hit lymphomas: A review of pathobiology, prognosis, and therapeutic approaches

“…68 Given the retrospective nature of these reports, it is very likely that the patients who received escalated induction therapy, HDT-ASCT, and/or allo-SCT were chosen based on such fea-tures as younger age, better performance status, and (in the case of SCT) based on response to induction therapy, each of which correlates with more favorable disease characteristics and with improved clinical outcomes. Moreover, the lack of a survival benefit associated with escalated induction regimens observed in the studies by Gandhi and colleagues and Oki et al, 56,67 despite favorable CR rates, suggests that relapse of DHL offsets most, if not all, early benefit of intensification. The role of escalated induction therapy for those patients who have double-expressing lymphoma or DHL, as defined by MYC GOC criteria, remains poorly explored.…”

“…Existing data suggest that this is a rare phenomenon and carries a poor prognosis, although whether such patients fare worse than those with DHL is not known. 55,56 The observation that IHC routinely detects a greater proportion of both MYC and BCL2 overexpression compared with FISH techniques raises an important question: is expression of both MYC and BCL2 protein (as detected by IHC) prognostically relevant independent of genetic rearrangements? In fact, there is now a growing body of data supporting the notion that patients with this socalled double protein-expressing or, simply, double-expressing lymphoma have a poor prognosis on par with FISHdefined DHL; however, there is significant discordance on the degree of immunohistochemical positivity associated with adverse outcomes.…”

‘Double‐Hit’ cytogenetic status may not be predicted by baseline clinicopathological characteristics and is highly associated with overall survival in B cell lymphoma patients

“…Accordingly, there is a strong rationale for offering intensive first‐line therapies to patients with MYC‐ rearranged DLBCL (including DH), and the use of dose‐adjusted EPOCH‐R (etoposide, predisone, vincristine, cyclophosphamide, doxorubicin, rituximab; NCT01092182) is currently being evaluated in a multi‐centre phase 2 clinical trial. Consolidative haematopoietic cell transplantation in first remission may lead to prolonged overall survival in DH lymphoma patients, although the benefit of this strategy remains unclear (Gandhi et al , ; Howlett et al , ; Oki et al , ). Furthermore, preclinical data suggests that newly‐developed BCL2 antagonists, such as the BH3‐mimetics, have activity in BCL2/MYC overexpressing mouse models with and without the addition of other anti‐lymphoma therapy (Mason et al , ; Vandenberg & Cory, ).…”