MSK Targeted Therapy Trials Aim to Benefit Patients with Relapsed, Refractory Peripheral T-Cell Lymphoma

By Anita Kumar, MD and Steven Horwitz, MD,

Tuesday, June 16, 2015

T cell lymphomas are rare disorders that often come back after initial chemotherapy. Despite existing therapies, relapsed and refractory peripheral T cell lymphomas (PTCL) remain an ongoing challenge. In recent years, several novel drugs — including belinostat, pralatrexate, romidepsin, and brentuximab vedotin — have been FDA-approved for the treatment of relapsed, refractory PTCL. But there remains an urgent need for novel therapeutic strategies for patients with T cell lymphoma.

In this era of personalized cancer therapy, Memorial Sloan Kettering Cancer Center (MSK) aims to treat patients with biologically targeted therapies that counteract the unique molecular or genomic drivers of the tumor. Our clinical trial portfolio includes many novel agents that potentially inhibit the underlying cellular mechanisms that fuel the uncontrolled cellular proliferation and pro-survival signaling in T cell lymphoma. Our hope is that these mechanism-based therapies will provide significant clinical benefit to patients with relapsed, refractory PTCL.


One example of mechanism-based therapy in PTCL is a phase I/II study of the drug AG-221, an inhibitor of the IDH2 mutant protein. IDH2 mutations have been found in approximately 25 percent of patients with angioimmunoblastic T cell lymphoma (AITL), and this mutation leads to elevated levels of 2-HG that cause significant derangements of cellular metabolism and promote tumorigenesis. AG-221 is a potent inhibitor of IDH2, thereby leading to the decreased production of 2-HG and restoration of normal cellular metabolism. This drug has shown promising activity in patients with refractory acute myelogenous leukemia (AML) who harbor an IDH2 mutation. The study is enrolling patients with solid tumors including glioma or AITL with IDH2 mutations.

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Another novel treatment strategy under investigation at MSK is the use of ibrutinib for the treatment of PTCL or systemic cutaneous T cell lymphoma (CTCL). Ibrutinib, an oral drug taken once daily, is shown to be safe and well tolerated in B cell malignancies. It has received FDA approval for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia, given its clinical efficacy mediated by down-regulation of the B-cell receptor pathway via inhibition of Bruton’s Tyrosine Kinase (BTK). Recent preclinical data has shown that ibrutinib not only inhibits BTK, but also irreversibly inhibits IL-2 inducible kinase (ITK).

We hypothesize that ibrutinib may provide therapeutic benefit in PTCL/CTCL by inhibiting ITK to down regulate pro-survival signaling through the T cell receptor pathway and promote host antitumor immunity with increased cytotoxic Th1 based immunity. MSK is currently enrolling relapsed, refractory PTCL/CTCL patients in a phase I study of ibrutinib to determine the optimal dose in T-cell lymphoma, assess its ability to inhibit ITK, and preliminarily evaluate its clinical efficacy.

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Carfilzomib, Romidepsin, and Lenalidomide

A final example of a new treatment approach for relapsed, refractory PTCL is a phase I/II study of combination therapy with carfilzomib, romidepsin and lenalidomide. An ongoing MSK-led study of romidepsin, a histone deactylase (HDAC) inhibitor, in combination with lenalidomide, an immune modulatory agent, has demonstrated promising clinical activity in T cell lymphoma. Preclinical research and experience from the treatment of multiple myeloma patients suggests that there is potential synergy between HDAC inhibitors, lenalidomide and proteasome inhibitors. In this study, a novel proteasome inhibitor, carfilzomib, will be used. Carfilzomib is a next-generation irreversible proteasome inhibitor that has a more favorable toxicity profile compared to bortezomib, with lesser neurotoxicity. This study represents a rationale drug combination strategy to identify a more clinically active and better-tolerated therapy in T-cell lymphoma.

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Improving Patient Outcomes

These three innovative therapies — AG-221, ibrutinib, and the combination of carfilzomib, romidepsin, and lenalidomide — are representative of the early phase clinical trial program in T cell lymphoma that include therapies hypothesized to dismantle the molecular mechanisms driving T cell lymphomagenesis. These are only a few examples of the many clinical trials and novel therapies available at MSK for patients with relapsed, refractory T cell lymphoma. With these studies, we hope to improve our understanding of T cell lymphoma pathogenesis and, most importantly, improve outcomes for patients with T cell lymphoma.

To refer a patient with T cell lymphoma, please call our lymphoma service referral line at 646-497-9137. Our T cell lymphoma specialists, including Dr. Steven Horwitz, Dr. Alison Moskowitz, and Dr. Anita Kumar, can evaluate patients for potential eligibility and treatment on the aforementioned clinical trials, as well as for other therapeutic options.

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