Patients with chemorefractory DLBCL have a poor prognosis, rarely achieving durable responses to additional treatment with standard chemotherapy. Epigenetic dysregulation likely contributes to lymphomagenesis and chemoresistance. Distinct epigenetic signatures predicted response to the DNA methyltransferase inhibitor (MTI) azacitidine (Aza) and vorinostat (V), a histone deacytelase inhibitor (HDACi) in DLBCL cell lines. Preclinical studies suggested synergy between MTI and HDACi in chemoresistant DLBCL cell lines. We performed a phase Ib trial to evaluate the combination of Aza plus V in patients with relapsed or refractory DLBCL.
Subjects with relapsed or refractory DLBCL ineligible for (due to chemorefractory state or comorbidities) or relapsed after autologous stem cell transplant were treated with Aza and V at four different dose levels (DL). DL 1 consisted of Aza 55mg SC x 5 days plus V 300mg PO x 7 days. DL 2 consisted of Aza 75mg SC x 5 days plus V 200mg PO x 7 days. DL 3 and 4 used the same Aza doses as DL1 and 2 respectively but V was administered for 14 days. Treatment was administered on 28-day cycles. Subjects remained on treatment for a maximum of 6 cycles. Up to 8 subjects could be enrolled into each DL, depending on the toxicity and activity profile. If 2 patients developed dose-limiting toxicities (DLT), enrolment to that dose level was closed. Cycle 1 DLT was defined as any of the following treatment-related adverse events: Grade 3-4 non-hematologic toxicity excluding alopecia, nausea, or fatigue responding to maximal treatment; grade 4 neutropenia lasting longer than 7 days or failing to recover to > 1000 cells/mm3 within 14 days; grade 4 thrombocytopenia of any duration; grade 4 febrile neutropenia. Primary endpoints were safety and tolerability as well as overall response rates (ORR).
A total of 18 patients were enrolled. The median age was 66 years old (range 26-82). Subjects had received a median of 3 prior lines of treatment, including 3 that had undergone autologous stem cell transplantation. Thirteen patients were refractory to their previous treatment. Eight subjects were treated at DL1, 5 at DL2, 4 at DL3 and 1 at DL4. DL2 was closed early due to limited efficacy demonstrated with the 7-day course of V; only 1 out of 13 patients treated at DL1 and DL2 achieved an objective response. DL3 and DL4 were closed early after 2 patients at DL3 required dose reductions. The following grade 1-2 non-hematologic toxicities, independent of relation to study drugs, were experienced by at least 2 subjects: nausea (11), diarrhea (8), hypoglycemia (7), vomiting (5), renal impairment (5), raised ALP (5), fatigue (4), hyperglycemia (4), fever (3) and hyperbilirubinemia (3). One patient experienced grade 3 thromboembolism (DL1), 1 experienced grade 3 diarrhea (DL2), and 1 experienced grade 4 ALP increase (DL4). Grade 3-4 hematologic toxicity included thrombocytopenia (8), anemia (3) and neutropenia (2). A median of 2 cycles of study regimen was administered (range 1-6). One patient completed 6 cycles of treatment and 17 patients stopped treatment due to PD. There was 1 DLT at DL1. Only one subject had an objective response (PR at DL2) and 3 subjects had stable disease. The trial was stopped prematurely because of low clinical activity and poor tolerability. Interestingly, 7 patients (2 with relapsed disease and 5 with disease refractory to prior pre-study therapy) received treatment post-study. Retrospective review of these cases demonstrated that 2 had CR (PEP-C and R-DICE) and 3 others appeared to have had a significant clinical response (bendamustine, radioimmunotherapy, and brentuximab vedotin-PEP-C), 1 had PD (PEP-C), and 1 was not formally evaluated (bendamustine). The median OS of these 7 patients was 501 days following Aza-V.
The combination of Aza and V was poorly tolerated and had minimal clinical activity at the doses/schedules tested in this study of refractory DLBCL patients. However, we observed that several heavily pre-treated and refractory patients appeared to go on to achieve better than expected responses to the next treatment following the study regimen, perhaps consistent with a chemosensitization effect (i.e., epigenetic priming) of Aza and V. Epigenetic priming in DLBCL warrants further investigation in less refractory patients and in combination with other agents. Epigenetic profiling of patient samples derived from this trial is ongoing.
Martin:Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau. Ruan:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Seattle Genetics, Inc.: Membership on an entity’s Board of Directors or advisory committees. Furman:Celgene: Research Funding.
Asterisk with author names denotes non-ASH members.