Therapeutic improvements in T cell lymphoproliferative diseases, including peripheral T cell lymphoma (PTCL), have not matched the tremendous advances in B cell malignancies. Although four drugs (pralatrexate, romidepsin, belinostat, and brentuximab vedotin) have been approved by the FDA for the treatment of relapsed/refractory PTCL, all except brentuximab vedotin in anaplastic large-cell lymphoma have an overall response rate (ORR) of less than 30%. Advances in PTCL have been hindered by the rarity of each individual subtype, incomplete understanding of the pathophysiology of PTCL, and lack of large clinical trials.
Fundamental new insights into the pathophysiology of PTCL have generated potentially ground-breaking therapeutic breakthroughs, however. Several PI3 kinase inhibitors are approved by the FDA to treat B cell malignancies, and recent preclinical and clinical data have demonstrated that inhibition of the gamma isoform of PI3 kinase can lead to clinically meaningful responses in PTCL.
A recent phase 1 trial reported an ORR of 50% for the PI3 kinase-delta and gamma inhibitor duvelisib in relapsed/refractory PTCL. In a companion preclinical study conducted by David Weinstock, MD, at Dana-Farber, duvelisib demonstrated potent in vitro activity in 3 of 4 PTCL cell lines characterized by constitutive phospho-AKT expression (a marker of PI3 kinase pathway activation), while duvelisib was inactive in all 7 cell lines lacking phospho-AKT, providing evidence of the on-target effect of duvelisib. A large, multicenter confirmatory trial is now ongoing. In addition, as part of a Leukemia and Lymphoma Society Specialized Center of Research (LLS SCOR) grant, Dana-Farber and a consortium of other large academic centers are exploring the combination of duvelisib and romidepsin. A preliminary analysis of this combination demonstrated an ORR of 59% with 33% complete response rate (1). The study has now been expanded to a larger patient population.
Mutation or activation of the JAK/STAT pathway is present in over 80% of PTCL. In another trial conducted as part of the LLS SCOR grant, the clinical activity of the JAK inhibitor ruxolitinib (FDA-approved for myelofibrosis and polycythemia vera) was examined in 3 cohorts of patients with: JAK/STAT pathway mutations, JAK/STAT pathway activation (without mutation), and unknown JAK/STAT status or absence of mutation/activation. The ORR was 28% in patients with JAK/STAT mutation and 29% with JAK/STAT activation. The clinical benefit rate (i.e., ORR plus stable disease for at least 6 months) was 44% with mutation and 41% with pathway activation. The response rate in patients with neither activation nor mutation (or unknown JAK/STAT status) was only 8%, again supporting an on-target effect of ruxolitinib (2). We are now launching a trial of ruxolitinib in combination with duvelisib to explore potential synergy with these agents.
The recent ECHELON-2 trial offered a much-needed source of optimism by demonstrating an overall survival advantage with the addition of brentuximab vedotin to a modified CHOP regimen (omitting vincristine) for initial treatment of CD30+ peripheral T cell lymphoma, compared to conventional CHOP without brentuximab. However, improvements over CHOP have been elusive in patients with CD30- PTCL. Researchers in Dr. Weinstock’s laboratory at Dana-Farber used functional BH3 profiling to demonstrate the activity of the MCL1 inhibitor AZD5991 in PTCL xenograft models (3). Even more importantly, CHOP and AZD5991 demonstrated tremendous synergy in these models. Dana-Farber investigators are now developing a front-line trial of CHOP-AZD5991 in PTCL.
In addition to PI3kinase, JAK/STAT, and MCL1, a variety of other targets, including IDH2, epigenetic modifiers (DNMT3A and TET2), SYK and EZH1/2 have emerged as potentially important therapeutic targets in PTCL. What was once a field with a dearth of therapeutic targets has now become a field of opportunity. Unfortunately, with each new opportunity come new challenges, including the identification of biomarkers of response/resistance and the coordination of large trials in a group of rare and increasingly diverse malignancies. Making true strides requires eliminating academic parochialism and promoting meaningful cooperation on a national scale. We are proud that the efforts of our LLS SCOR grant are starting to bring some of those aspirations to fruition.