Dose Intensive Induction Followed By Allogeneic Stem Cell Transplantation More Than Doubles Progression-Free and Overall Survival In “Double-Hit” Lymphoma (DHL)

Abstract

Introduction There is a growing awareness of the molecular heterogeneity of DLBCL beyond the GC and non-GC well established subtypes. “Double-hit” lymphoma (DHL) harboring rearrangements of c-Myc and BCL2 have been clearly associated with a poor prognosis. It is well recognized that these pts do poorly with R-CHOP and typically cannot be salvaged using ASCT in the relapse setting. Small series suggest that dose-intensive (DI) strategies may lead to better outcomes in the frontline setting and that some pts achieve durable disease control after allogeneic SCT in the relapse setting. We report here one of the largest series of consecutive DHL pts treated with a DI approach followed by allogeneic SCT and compare outcomes to a similar pt population treated with standard dose (SD) chemotherapy. Methods We conducted a retrospective cohort study of DHL pts to evaluate clinical outcomes stratified by chemotherapy intensity ± SCT treated at John Theurer Cancer Center (JTCC) between 4/09-6/13. DHL was defined by the presence of c-Myc rearrangement (FISH) in combination with rearrangement of BCL2 (FISH) or BCL2 over expression (IHC). Primary study endpoints were PFS and OS assessed by chart review and SSDI database. Investigators were blinded to clinical outcomes. A group of hematopathologists reviewed all cases to verify DHL status (also blinded to outcome). Statistical tests included a two-sample t-test to compare baseline characteristics between groups and Kaplan-Meier and Cox regression survival analyses (med follow up 7.9 months, max follow up 46 months). Results Among the 280 pts with either DLBCL or FL treated between 4/09-6/13 at JTCC, 37 pts (12%) were identified as DHL [100% c-Myc + rearrangement by FISH; 86% t(14;18) + rearrangement by FISH and 95% BCL2 over expression by IHC]. These included 68% de novo DHL: 68% DLBCL, 24% FL, 8% transformed FL and 82% were of germinal center cell origin (Hans). Baseline pt characteristics included med age 60 yr (range 23-84), 57% males, 60% aaIPI ≥3, 93% stage III-IV, 29% BM involvement, 76% bulky disease, 61% extra-nodal disease, med LDH 899 (range 419-8276) and med Ki-67 was 85% (range 20-99%). Treatment regimens included a DI regimen in 66% (n=24) [R-hyper-CVAD, R-CODOX-M/IVAC (Magrath Regimen), DA-R-EPOCH] or a SD regimen in 33% (n=12) [mostly R-CHOP, R-EPOCH (not DA), R-ESHAP]. Of the DI group, 42% of pts underwent SCT as consolidation (73% allogeneic, 27% autologous). Allogeneic SCT included: 25% URD, 75% myeloablative conditioning (Flu/Mel, Cy/TBI, BEAM). There were no significant differences between DI vs. SD groups in terms of pt age, stage, LDH, cell of origin, number of cycles of chemotherapy or Ki-67 (p=NS). Med PFS for the entire cohort was 30.2 months. When stratified by chemotherapy intensity, there was a significant difference in PFS for the DI vs. SD treatment group [46 vs. 8 months, HR 0.26, p=0.005]. The added benefit of SCT was demonstrated when pts were stratified by transplantation status (Figure 1): med PFS for DI with SCT, DI without SCT, and SD were 46, 14.8 and 4.9 months, respectively [DI with SCT vs. SD, HR 0.079, p=0.016; DI without HSCT vs. SD, HR 0.53, p=0.237]. Med OS for SD group was 11.1 months, while med OS for the DI ± SCT groups has not been reached (Figure 2) [DI with SCT vs. SD, HR 0.13, p=0.05; DI without HSCT vs. SD, HR 0.73, p=0.6]. Conclusions As previously recognized, DHL do very poorly with SD alone. DI strategies with allogeneic SCT lead to significantly longer PFS and OS. Though our series is a retrospective analysis and numbers remain small, this is a relatively large series of “true DHL” (with 100% c-Myc rearrangement by FISH and 86% t(14;18) translocation), a situation where no treatment has demonstrated long term benefit. The effect of DLI (a few relapses post-SCT converted to CR after DLI) and the durability of PFS support a GVL effect of allogeneic SCT in DHL. Prospective screening for DHL is warranted in high risk B-cell NHL particularly based on high Ki-67. Additional studies are needed to confirm the benefit of allogeneic SCT consolidation after DI induction therapy. Disclosures: No relevant conflicts of interest to declare.

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

“…Two authors of the 11 included studies provided additional IPD data on request (Howlett et al , ; Landsburg et al , ). Individual event or censoring times were estimated from the reported Kaplan–Meier (KM) survival curves of 3 of the remaining 8 studies, simulating IPD (Johnson et al , , ; Green et al , ).…”

“…Nearly all patients were MYC and BCL2 positive by rearrangement (97%). Further, 11 patients were BCL 2 positive by IHC (Abramson et al , ; Howlett et al , ). Baseline characteristics for patients included in this analysis are outlined in Table .…”

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

“…In another single‐center experience, Howlett and colleagues presented data on 37 patients with FISH‐defined DHL, observing that intensified regimens followed by SCT (most were allogeneic [allo]‐SCTs; hazard ratio, 0.079; P =.016), but not early intensification without transplantation (hazard ratio, 0.53; P =.237), were associated with improved PFS compared with R‐CHOP alone. However, no direct comparison of patients who received intensified regimens and subsequent SCT, compared with those who received intensified induction regimens without SCT, was offered in that analysis.…”

‘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, ).…”