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ASH 2019: PTCL
Key PTCL Studies Presented at ASH 2019

Released: December 06, 2019

Barbara Pro
Barbara Pro, MD
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Introduction
It is an exciting time in the treatment of peripheral T-cell lymphomas (PTCL), and innovative new data are being presented at the upcoming ASH 2019 meeting. I would like to share some of the abstracts that I believe represent important advances in the field.

Exploratory Analysis of Frontline Treatment With Brentuximab Vedotin Plus CHP in Patients With CD30+ PTCL: ECHELON-2
In the ECHELON-2 trial, patients with PTCL and ≥ 10% CD30 expression who received frontline treatment with brentuximab vedotin plus CHP achieved significantly longer PFS and OS vs those treated with CHOP. Data from a subset analysis that examined the impact of consolidated stem cell transplant (SCT) vs no transplant in patients who achieved a CR with brentuximab vedotin plus CHP will be presented at ASH 2019.

According to this subset analysis, both patients with ALK‑negative anaplastic large‑cell lymphoma (ALCL) and other types of PTCL benefited from undergoing SCT if they were in CR. A total of 67% (76/113) of patients with ALK‑negative ALCL achieved a CR, and 36% of them (27/76) received SCT. The subset analysis showed that the median PFS for patients who underwent SCT was not reached vs 55.6 months for patients without SCT, suggesting that patients who underwent SCT did better. Similarly, 59% of patients in the non-ALCL group (38/64) achieved CR and 29% (11/38) received SCT, with a PFS not reached in the SCT group vs 33 months for patients without SCT. Of note, in both groups, patients who underwent SCT were younger, with median ages of 50 years and 57 years in the ALK‑negative ALCL and non-ALCL groups, respectively, which may have affected the results.

Another important aspect of this study is that the investigators examined practice patterns worldwide. Patients treated in Asian countries (Japan, South Korea, and Taiwan) with both ALK‑negative ALCL and non-ALCL were less likely to undergo SCT (13% and 12%) vs those treated outside of Asia (32% and 23%). This highlights that the practice of using SCT varies worldwide, another possible confounder for international studies examining the impact of SCT consolidation.

Dual SYK/JAK Inhibitor Cerdulatinib in PTCL and CTCL
An interim analysis of the phase II study of the SYK/JAK inhibitor cerdulatinib in patients with relapsed/refractory PTCL and cutaneous T‑cell lymphoma (CTCL) will be presented at ASH 2019. The rationale for using this agent is that SYK expression is observed in PTCL and CTCL and the JAK/STAT pathway appears to be very important in the pathogenesis of these diseases. Cerdulatinib is a small-molecule reversible ATP competitive inhibitor of both SYK and JAK that is taken orally. This analysis includes 61 patients with PTCL and 37 patients with CTCL who were treated with this agent.

In the PTCL cohort, the ORR was 35%, similar to that observed with other drugs approved to treat this disease. Of interest, responses were higher for patients with either angioimmunoblastic T‑cell lymphoma (AITL) or T‑cell lymphoma with the T follicle or helper subtype, with an ORR of 55%, with an impressive CR rate of 41% in responders. Overall, the treatment was very well tolerated; the most common adverse events were lipase and amylase increases without clinical pancreatitis. I believe these data represent promising activity of this agent in this setting, with a very good toxicity profile.

In the CTCL cohort, the ORR was also 35%, with a subset analysis showing that patients with mycosis fungoides may be able to achieve higher responses as their ORR was 45%. For patients with Sézary syndrome, the ORR was only 17%, with no CR. 

Nivolumab in Patients With Relapsed/Refractory PTCL
Another study to be aware of is with the checkpoint inhibitor nivolumab in patients with relapsed/refractory PTCL. The rationale for using nivolumab in this setting is that preclinical data showed that PD-L1 can be overexpressed in PTCL; therefore, checkpoint inhibitors were hypothesized to possibly have efficacy in this disease.

In this study, nivolumab was given at a flat dose of 240 mg every 2 weeks for 8 cycles, followed by monthly treatments with 48 mg IV. Of the 12 patients who received at least 1 cycle of nivolumab included in this analysis, the ORR was 33%, with 1 CR, and a median response duration of 3.6 months. With the low response and duration and hyperprogressive disease in 4 of the 12 patients, the researchers ended the study. These data are very similar to those reported in a recently published study of pembrolizumab in this patient population, where the ORR was also 33% and the median PFS was approximately 3 months. This study, therefore, provides further confirmation that checkpoint inhibitors have limited activity in PTCL as monotherapy and suggests that these drugs instead should be studied in combination therapy for this disease.

Tipifarnib in Relapsed/Refractory AITL and CXCL12+ PTCL
Next we have an open-label phase II study of the novel agent tipifarnib in 50 patients with relapsed/refractory AITL and PTCL. Tipifarnib is a unique agent that inhibits the enzyme farnesyltransferase, and this inhibitor can also downregulate CXCL12, which is very important for T‑cell homing to lymphoid organs and bone marrow. This study originally accrued patients with PTCL generally; however, based on initial findings, the accrual was amended to include patients with AITL or PTCL with CXCL12 expression.

In 11 evaluable patients with AITL, there was an ORR of 45% with a clinical benefit rate (3 CR, 2 PR, 3 stable disease) of 73%. In the CXCL12 cohort, the ORR was similar at 42% (5/12) and included 3 patients with a CR.

An important aspect of this study is that they also did tumor whole exon sequencing generated by next-generation sequencing and gene expression data, which provided evidence that this AITL histology genotype, which included the expression of CXCL12 and KIR3DL, was associated with better response. Therefore, I think this study provides proof of concept that if you have a targeted agent and can identify a signal of increased activity based on the target, there is potential for improved benefit. Enrollment on this study continues, and we will wait to see whether or not these responses are durable with longer follow-up.

Dose Optimization of Duvelisib in Patients With Relapsed/Refractory PTCL
Lastly, an interesting poster will be presented at ASH 2019 on duvelisib, a PI3K gamma/delta inhibitor, which is already approved for chronic lymphocytic leukemia and other lymphomas. An earlier phase I study of this agent in 16 patients with relapsed/refractory PTCL showed an ORR of 50% with a CR rate of 19%. This trial is a follow‑up looking at 2 doses of duvelisib: 25 mg PO BID in cohort 1 (n = 20) with an option for dose escalation and 75 mg PO BID in cohort 2 (n = 13). For evaluable patients who received the 25-mg dose, the ORR was 54% and the CR rate was 38%; for evaluable patients who received the 75-mg dose, the ORR was also 54% and the CR rate was 23%.

I think this study confirms the significant activity of this PI3K inhibitor in this patient population. There are now numerous studies looking at combination therapy with this agent, and hopefully, based on this study, duvelisib will be approved for this patient population, thereby adding one more option for our patients in this disease setting.

Your Thoughts?
What PTCL studies are you most interested in at the 2019 ASH annual meeting? Please answer the polling question on your screen and share your thoughts in the comments box.

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