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