Abstract IA21: Biomarker-informed studies in peripheral T-cell lymphoma
Authors: Horwitz Steven M. 
Published: December 2020

Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of non-Hodgkin's lymphomas (NHL) with 29 distinct subtypes (counting provisional entities) in the latest WHO classification (1). Historically, therapeutic approaches for PTCL were derived from aggressive B-cell lymphomas. More recent therapies have been studied specifically in PTCL with four drugs approved by the FDA in the last decade, including pralatrexate, romidepsin, brentuximab vedotin (ALCL only), and belinostat (2-5). The most frequent approach to studying new agents has been empiric with some continued success in identifying additional tools, with “all-comer” overall response rates between 25-30% and only moderate durability (median PFS 2.5-4 months). The one standardly used exception is the CD30 targeted antibody drug conjugate brentuximab vedotin. When the CD30 target is strongly and consistently expressed as in anaplastic large-cell lymphoma, brentuximab vedotin is remarkably active with an overall response rate of 86% (57% CR) and a median PFS &gt;12 months (4). Brentuximab vedotin has activity in other variably CD30-expressing PTCL including AITL, PTCL-NOS, and MF, although the consistency, depth, and duration of responses are less than those seen in ALCL (6-7). Whether those differences are explained primarily by the density and intensity of target as opposed to the underlying biology of those diseases is unclear. Nonetheless, when BV was added to upfront chemotherapy for patients with untreated PTCL, and enriched for those with CD30 expression, significant improvements in PFS and OS were seen with the greatest benefit for those with ALCL (8).

In an attempt to expedite our understanding and application of new therapies in T-cell lymphoma, we expanded and formalized a clinical research partnership in part supported by an LLS SCOR grant (Translational Discovery in Peripheral T-cell lymphoma; PI David Weinstock) to prospectively incorporate correlative science plans and institute standards of sample collection into new clinical trials of targeted agents.

Several of our initial trials have shown efficacy at times in subtype-specific ways. The SYK/JAK inhibitor cerdulatinib (NCT01994382) showed particular activity in AITL and intriguing but transient activity in several subjects with strong syk-expressing g/d TCLs but an absence of activity in those with PTCL-NOS (9). For the Pi3K d/g inhibitor duvelisib as part of combination therapy (NCT02783625), the responses and complete responses were consistent across subtypes (10). In that trial over 80% of subjects had samples collected, and RNAseq, whole-exome sequencing, and multicolor immunofluorescence are being conducted. For the trial of ruxolitinib, we set out to both test a prespecified hypothesis and collect tissues pretreatment, on treatment, and at relapse to assess additional predicators of response and understand mechanisms of resistance. In this study (NCT02974647, PI Alison Moskowitz). We divided patients into cohorts based on presence of JAK/STAT mutation (Cohort 1), absence of mutation but presence of phosphorylated (p)STAT3 or pSTAT5 by IHC/phosphoflow (Cohort 2), or neither (Cohort 3). As hypothesized, absence of either pathway activation or mutation was associated with low rates of response, and preliminary assessment of pretreatment biopsies by multicolor immunofluorescence identified pS6 as a predictive biomarker to inform subsequent studies of ruxolitinib in PTCL (11).

These early attempts have demonstrated a proof of principle that biomarker-driven hypotheses can be embedded into prospective clinical trials of PTCL and adequate sample collection is feasible. These samples allow us to best match therapies to patients and, critically, by obtaining samples on treatment and at progression, provide the best opportunity to understand mechanisms of resistance to facilitate the design of combination therapies.

References:

1. Swerdlow et al. Blood 2016;127(20):2375–90.

2. O'Connor et al. JCO 2011;29(9):1182-9.

3. Coiffier et al. JCO 2012;30(6):631-6.

4. Pro et al. JCO 2012;30(18):2190-6.

5. O'Connor et al. JCO 2013;31.

6. Horwitz et al. Blood. 2014;123:3095-3100.

7. Kim et al. JCO 2015;33:3750-8.

8. Horwitz et al. Lancet 2019.

9. Horwitz et al. ASH 2019;a 466.

10. Horwitz et al. ASH 2018;a683.

11. Moskowitz et al. ASH 2019;A4019.

Citation Format: Steven M. Horwitz. Biomarker-informed studies in peripheral T-cell lymphoma [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA21.