Treatment Options for CD30-Positive PTCL Subtypes

Steven M. Horwitz, MD

CD30-positive peripheral T-cell lymphomas (PTCL) are rare and hard to treat and in a summary of research, Steven M. Horwitz, MD, concluded at the 2018 Pan Pacific Lymphoma Conference in Maui, Hawaii, that, until better options develop, the best available strategy is standard therapy.

“Right now, you just do what you do for other types of PTCL. In our center that is CHOEP [cyclophosphamide, doxorubicin, etoposide, vincristine and prednisone] and a transplant for patients eligible for that. Some people give CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], some people don’t consolidate,” said Horwitz, an associate member of the Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York, New York.

In his review, Horwitz discussed PTCL with attention to subtypes with high CD30 expression as well as data guiding use of brentuximab vedotin (BV, Adcetris) in anaplastic large cell lymphoma (ALCL) and other types of PTCL in the relapsed and upfront settings.

Among primary cutaneous ALCL, ALCL ALK-positive and ALCL ALK-negative disease, PLTC offers the worst prognosis in the case of CD30 positivity in >80% of cells, he noted, citing data from the International T-cell Classification Project.¹

Citing a separate study, Horwitz noted 5-year overall survival (OS) of 33% of patients with ALK-positive ALCL versus 13% for ALK-negative disease by International Prognostic Index (IPI). Findings indicated that anthracycline-based regimens such as CHOP are standard first-line treatment for systemic ALCL, but are ineffective in many patients with ALK-negative ALCL, and consolidative autologous stem cell transplantation often follows.²

An investigation by the German High-Grade Non-Hodgkin Lymphoma Study Group found supportive event-free survival data for the addition of etoposide to CHOP in PTCL subtypes,³ prompting Horwitz to remark that for ALK-positive disease, “I’m starting to become more convinced that adding etoposide really helps.”

The study authors noted that results of CHOEP for patients with ALK-positive ALCL “are excellent,” although patients with ALK-negative ALCL, PTCL, or angioimmunoblastic T-cell lymphoma (AITL) do comparatively well if the IPI is low (≤ 1). The authors recommended using CHOP plus etoposide for younger patients with T-cell lymphoma as first-line therapy to potentially reduce early progression or relapse and bring more patients to transplantation.

In a 2014 paper cited by Horwitz, investigators reviewed the prognostic value of DUSP22 and TP63 rearrangements. The study included patients with ALK-negative ALCL (n = 73) and ALK-positive ALCL (n = 32). Key findings were that DUSP22 and TP63 rearrangements are present in ALK-negative ALCLs in 30% and 8% of cases, respectively, and that DUSP22 rearrangements prognosticate favorable outcomes similar to ones for ALK-positive ALCLs.⁴

Brentuximab Vedotin

“You can divide patients who are ALK-positive into a couple of genetic subtypes, and this has confounded some of our interpretation of the older literature,” Horwitz said. The findings showed that DUSP22 rearrangement is a favorable feature with ALK-positive disease, even for patients who did not undergo transplant, he added. “It would be really nice to see this confirmed in a larger study.”“When we think about relapsed patients, the data-supported targeted approach is much stronger,” Horwitz said. “The approved agents for relapsed T-cell lymphoma are mostly all comers. They don’t really sort according to subtype, with the exception of brentuximab vedotin,” which in ALCL has shown high response rates and high complete responses, he said.

A study of BV in relapsed/refractory systemic ALCL (sALCL) enrolled 58 patients, each with an average of 2 prior lines of chemotherapy. The objective response rate (ORR) was 86% (95% CI, 74.6-93.9) and the complete response (CR) rate was 57% (95% CI, 43.2-69.8). Median duration of response in patients with CR was 13.2 months.⁵

“About a quarter of patients in this study were ALK positive, and about a quarter presented with a skin lesion at baseline. The really long-term responders, the people who had multiple years of benefit, were primarily the patients who had a CR, whether you transplanted those patients or not,” Horwitz said.

“Patients had a CR and then stayed in long-term remission without any additional therapy. One of the questions was were any of those cutaneous patients? It looks like at least in the relapsed setting when you use this drug you can get long-term benefit with transplant and there’s at least a chance with ALK consolidation that patients will stay in long-term remission,” he said.

A phase II study of brentuximab in r/r PTCL showed an ORR of 54% among 13 patients with AITL; 33% of 22 patients with PTCL/nonspecified (NOS); and a CR of 38% among the AITL group and 14% among the PTCL/NOS cohort. Horwitz, lead author on the study, said 79% of individual patients (n = 29) achieved tumor reduction.¹

“This was really open to all comers. For a fair number of patients, we couldn’t find any CD30 positivity, and those were classified negative. The results are decent. In patients with even low levels of CD30 expression, the overall response rate was 41%.”

Positive findings also came from a phase I study of BV in frontline treatment of patients with CD30-positive PTCL. The study looked at BV given sequentially with CHOP or in combination with CHOP without vincristine (CHP). Responders in both arms continued with single agent BV. Investigators concluded that both regimens provided safety and manageability and delivered substantial antitumor activity in newly diagnosed patients with CD30-positive PTCL.⁶

The ORR was 100% and the CR rate was 88%. One patient with partial response converted to CR on BV monotherapy. “Most of the patients went on to receive brentuximab maintenance, and most received all 16 doses. Nobody got consolidated,” Horwitz said. “The toxicities are really what you would expect with combination chemotherapy brentuximab—nausea, peripheral neuropathy. Nothing really unexpected showed up.”

Worth waiting for will be the results of ECHELON-2, which finished accrual a year ago and randomized over 400 patients to BV plus CHP versus placebo plus CHOP, Horwitz said. The majority of patients have ALCL, either high-risk ALK-positive or ALK-negative disease.

Concluding, Horwitz said that ECHELON-2 will help to inform the debate whether a CD30-targeted approach will make a difference in aggressive T-cell lymphoma. “Once we have that, it may really change much of what we think of as the appropriate upfront treatment either for ALCL or maybe even CD30-positive PTCL.”

References

1. Horwitz SM. Therapy for CD 30+ PTCL Subtypes. In: Proceedings from the 2018 Pan Pacific Lymphoma Conference; July 16-20, 2018; Maui, Hawaii.
2. Hapgood G, Savage KJ. The biology and management of systemic anaplastic large cell lymphoma. Blood. 2015;126(1):17-25. doi: 10.1182/blood-2014-10-567461.
3. Schmitz N, Trümper L, Ziepert M, et al. Treatment and prognosis of mature T-cell and NK-cell lymphoma: an analysis of patients with T-cell lymphoma treated in studies of the German High-Grade Non-Hodgkin Lymphoma Study Group. Blood. 2010;116(18):3418-3425. doi: 10.1182/blood-2010-02-270785.
4. Parrilla Castellar ER, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):1473-1480. doi: 10.1182/blood-2014-04-571091.
5. Pro B, Advani R, Brice P, et al. Brentuximab vedotin (SGN-35) in patients with relapsed or refractory systemic anaplastic large-cell lymphoma: results of a phase II study. J Clin Oncol. 2012;30(18):2190-2196. doi: 10.1200/JCO.2011.38.0402.
6. Fanale MA, Horwitz SM, Forero-Torres A, et al. Brentuximab vedotin in the front-line treatment of patients with CD30+ peripheral T-cell lymphomas: results of a phase I study. J Clin Oncol. 2014;32(28):3137-3143. doi: 10.1200/JCO.2013.54.2456.