During a presentation at the American Association for Cancer Research’s inaugural Advances in Malignant Lymphoma meeting, Mehta-Shah, associate professor in the Department of Medicine with Washington University School of Medicine in St. Louis, presented preliminary data showing how new pathway-dependent strategies using novel agent combinations may represent a new way to treat patients with T-cell lymphomas.
Neha Mehta-Shah, MD
There is a need for newer treatment strategies for patients with T-cell lymphoma to overcome the limitations of agents already approved, according to Neha Mehta-Shah, MD. “Our current therapies all have limited responses with the median progression-free survival (PFS) of about 4 months,” she said.
During a presentation at the American Association for Cancer Research’s inaugural Advances in Malignant Lymphoma meeting, Mehta-Shah, associate professor in the Department of Medicine with Washington University School of Medicine in St. Louis, presented preliminary data showing how new pathway-dependent strategies using novel agent combinations may represent a new way to treat patients with T-cell lymphomas.
HDAC InhibitorBased Combinations
“Two of our currently approved therapies, vorinostat [Zolinza] and romidepsin [Istodax], are both histone deacetylase [HDAC] inhibitors,” she said. “We know that they work in patients, but we don’t have a good understanding of how they work or why they work in some patients and not others.”
Romidepsin is relatively well-tolerated as a single-agent, so it has been increasingly studied in combination with other novel agents. Mehta-Shah cited a phase I/II study with cohort expansions evaluating the combination of romidepsin and the immunomodulatory agent lenalidomide (Revlimid).1Patients with relapsed/refractory T-cell lymphoma achieved an overall response rate (ORR) of 58%, but the median event-free survival (EFS) was limited to 16 weeks.
This led to the phase Ib/IIa study using romidepsin/lenalidomide with the addition of the proteasome inhibitor carfilzomib (Kyprolis) to extend the duration of remission.2
The ORR was 50% for the 16 patients with T-cell lymphoma, and the 5 patients with angioimmunoblastic T-cell lymphoma (AITL) achieved an ORR of 100%. Five patients achieved a complete response (CR) and 3 had a partial response (PR) across the histologies studied.
“Six patients went on to allogeneic transplant directly from the study, demonstrating that some of the patients who achieved a partial remission achieved a very deep partial remission,” Mehta-Shah added.
The median EFS was 9.7 weeks (95% CI, 6.0-not reached) for all patients with T-cell lymphoma and was not yet reached for responders (95% CI, 15.0- not reached).
The most common grade 3/4 adverse events (AEs) with romidepsin/lenalidomide were electrolyte abnormalities (43%), neutropenia (43%), thrombocytopenia (34%), and anemia (43%). Similar AEs were noted with the addition of carfilzomib in the triplet trial, but at slightly reduced rates. In the patients receiving romidepsin/lenalidomide/carfilzomib, grade 3/4 electrolyte abnormalities were observed in 19%, neutropenia in 30%, thrombocytopenia in 30%, and anemia in 15%. Three patients (14%) in the romidepsin/lenalidomide trial experienced grade 3/4 febrile neutropenia compared with 1 (4%) with the triplet combination.
Based on the encouraging results in patients with AITL, investigators performed a subsequent analysis of patients expressing a follicular helper T-cell (TFH) phenotype,3because the cell of origin of AITL and a subset of peripheral T-cell lymphomas (PTCL) potentially originate from these cells.
Investigators looked at 42 patients with PTCL treated with romidepsin alone or in combination. For patients with the TFH phenotype (n = 24), the ORR was 58% compared with 30% in those without the phenotype (n = 17). Additionally, 29% achieved a CR in the TFH group versus 12% in the non-TFH arm.
The median time to progression was 6 months for patients with the TFH phenotype and 2 months for those without it (HR, 0.31; P = .0046).
Patients treated with a romidepsin-containing combination regimen also showed greater responses, with an ORR of 77% versus 57% for the TFH and non-TFH groups, respectively. Six patients with the TFH phenotype experienced a CR (46%).
“Those who had TFH seemed to have an increased sensitivity to these regimens, as well as romidepsin as a single agent,” Mehta-Shah concluded.
Romidepsin and 5-Azacitidine
Apart from immunomodulatory agents, Mehta- Shah explained that HDAC inhibitors and hypomethylating agents demonstrate synergy from preclinical data. As a single agent, 5-azacitidine (Vidaza) has demonstrated antitumor activity in patients with AITL.
A phase I study evaluated this combination in 28 patients with lymphomas. Patients with T-cell lymphoma (n = 9) had an ORR of 78%, and 56% achieved a CR.4Amongst patients with any form of lymphoma (n = 28), the ORR was 23% and 21% achieved a CR.
Of note, grade 4 neutropenia and thrombocytopenia were considered dose-limiting toxicities. The most common grade ≥3 toxicities in patients with any form of lymphoma were thrombocytopenia (19%), neutropenia (6%), and febrile neutropenia (6%).
JAK-STAT Signaling
Preclinical data suggest a role for JAK/SYK inhibition as a way to disrupt the tumor microenvironment in PTCL. “JAK-STAT seems to be aberrantly expressed in T-cell lymphomas, most commonly in ALK-positive anaplastic large cell lymphoma [ALCL] as well as T-cell prolymphocytic leukemia,” Mehta-Shah said. “JAK-STAT is a driving signal for those diseases.”
She cited a phase IIa extension study evaluating the JAK/SYK inhibitor cerdulatinib (PRT062070) in patients with T-cell lymphoma.5Patients (n = 20) achieved an ORR of 35%, all of which were CRs. Additionally, 3 patients achieved stable disease. Of note, a subgroup of patients with AITL (n = 7) achieved a promising ORR of 71%.
Investigators observed grade 3/4 neutropenia in 16%, and 2 patients (8%) developed severe Nocardia infections.
PI3-Kinase Inhibitors
PI3-kinase inhibition may block malignant T-cell growth directly, and duvelisib has demonstrated clinical activity and a favorable safety profile in patients with PTCL and cutaneous T-cell lymphoma (CTCL).
In the published phase I study, investigators evaluated duvelisib in patients with relapsed/ refractory PTCL (n = 16) and CTCL (n = 19).6The ORRs for patients with PTCL and CTCL were 50.0% and 31.6%, respectively (P = .32), with CRs in 3 patients with PTCL. The median PFS was 8.3 months and 4.5 months, respectively.
Mehta-Shah noted that in preclinical studies, cell lines with a phosphorylated state of AKT were more likely to respond to duvelisib.
Investigators found potential synergy between duvelisib and romidepsin, which led to the parallel phase I study evaluating duvelisib in combination with romidepsin or bortezomib (Velcade) in relapsed/refractory T-cell lymphoma, with an expansion cohort in PTCL and CTCL (NCT02783625).7
Of the 16 patients evaluable in the romidepsin arm, the ORR was 60% and 27% achieved a CR. Conversely, the bortezomib arm (n = 17) achieved an overall response of 35% and 18% achieved a CR. Of note, the rate of liver function test (LFT) abnormalities was lower in romidepsin arm (8% vs 29%).
“Interestingly, duvelisib has known to have a great deal of colitis and LFT abnormalities, but this was not seen in the romidepsin arm of this study,” Mehta-Shah added.
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