Pathway-Dependent Strategies Using Novel Combinations May Represent a New Plan of Attack in Treating T-Cell Lymphomas

Publication
Article
Targeted Therapies in OncologyAugust 2018
Volume 7
Issue 8

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 Inhibitor—Based 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.

References:

  1. Mehta-Shah N, Lunning MA, Boruchov AM, et al. A phase I/II trial of the combination of romidepsin and lenalidomide in patients with relapsed/ refractory lymphoma and myeloma: activity in T-cell lymphoma. J Clin Oncl. 2015;33(suppl 14; abstr 8521). doi: 10.1200/jco.2015.33.15_suppl.8521.
  2. Mehta-Shah N, Moskowitz AJ, Lunning M, et al. A phase Ib/lla trial of the combination of the romidepsin, lenalidomide and carfilzomib in patients with relapsed/refractory lymphoma shows complete responses in relapsed and refractory T-cell lymphomas. Blood. 2016;128(22):2991. bloodjournal.org/content/128/22/2991.
  3. Ghione P, Ozkaya N, Faruque P, et al. Romidepsin activity in T follicular helper (TFH)-phenotype PTCL versus non TFH treated on the same clinical trials. J Clin Oncol. 2018;36(suppl; abstr 7509). meetinglibrary.asco.org/ record/159474/abstract.
  4. Falchi L, Lue JK, Amengual JE, et al. A phase I/II study of oral 5-azacitidine and romidepsin in patients with lymphoid malignancies reveals promising activity in pretreated peripheral T-cell lymphoma (PTCL). Blood. 2017;130(1):1515. bloodjournal.org/content/130/Suppl_1/1515?sso-checked=true.
  5. Horwitz S, Hamlin PA, Feldman TA, et al. The novel SYK/JAK inhibitor cerdulatinib demonstrates good tolerability and clinical response in a phase IIa study in relapsed/refractory peripheral T-cell lymphoma. Presented at: 23rd Congress of EHA; June 14-17, 2018; Stockholm, Sweden. Abstract PF261.
  6. Horwitz SM, Hoch R, Porcu P, et al. Activity of the PI3-kinase inhibitor duvelisib in a phase I trial and preclinical models of T-cell lymphoma. Blood. 2018;131(8):888-889. doi: 10.1182/blood-2017-08-802470.
  7. Moskowitz AJ, Koch R, Mehta-Shah N, et al. In vitro, in vivo, and parallel phase i evidence support the safety and activity of duvelisib, a PI3K- δ,γ inhibitor, in combination with romidepsin or bortezomib in relapsed/ refractory t-cell lymphoma. Blood. 2017;130(suppl 1):819.
Related Videos
Stephen T. Oh, MD, PhD, an expert on myelofibrosis
Stephen T. Oh, MD, PhD, an expert on myelofibrosis
Stephen T. Oh, MD, PhD, an expert on myelofibrosis
Stephen T. Oh, MD, PhD, an expert on myelofibrosis
Stephen T. Oh, MD, PhD, an expert on myelofibrosis
Stephen T. Oh, MD, PhD, an expert on myelofibrosis
Related Content