Brentuximab Vedotin and CHP Combination Leads to Lasting Remissions in Peripheral T-Cell Lymphomas

Half of patients with peripheral T-cell lymphomas (PTCLs) who were treated with brentuximab vedotin in combination with CHP (cyclophosphamide, doxorubicin, prednisone) remained in remission for almost five years, according to long-term follow-up from a phase I trial of this frontline regimen.1

The report, published in Blood by Michelle A. Fanale, MD, of the University of Texas MD Anderson Cancer Center, updates previously published findings, in which all 26 participants responded to brentuximab vedotin plus CHP. The initial trial protocol evaluated both CHP and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) but, because a high number of participants had disease progression while receiving CHOP, enrollment in this arm was terminated.2

The study included 26 treatment-naïve patients (median age = 55.5 years; range = 21-82 years) with CD30-positive PTCL; 19 (73%) had systemic anaplastic large-cell lymphoma (ALCL; including 16 with ALK-positive disease) and the remaining seven (27%) had other CD30-positive PTCLs.

Per study protocol, participants received brentuximab vedotin 1.8 mg/kg and standard-dose CHP every three weeks for six cycles. If patients experienced an objective response, they received up to 10 cycles of brentuximab vedotin as a single agent.

After receiving a median of 13 cycles (range = 3-16 cycles) of brentuximab vedotin, all patients (100%) achieved an objective response, including 24 complete remissions (CRs; 92%) and two partial remissions. After a median follow-up of 59.6 months (range = 4.6-66.0 months), 12 patients (46%) experienced progressive disease or died, including 10 with ALCL (the other 2 patients had non-ALCL disease).

Five patients (19%) died during long-term follow-up (4 with ALK-negative ALCL and 1 with enteropathy-associated T-cell lymphoma); four deaths were disease-related and the other was caused by respiratory failure. “No progression or death was observed beyond 35 months,” the researchers reported.

Among the patients whose disease progressed, eight (31%) received subsequent therapy: three (38%) underwent hematopoietic cell transplantation and four (50%) received initial single-agent brentuximab vedotin.

After approximately five years of follow-up, 13 patients (50%) remained in remission without receiving any new anti-cancer therapy; all had achieved CR, including nine with systemic ALCL (3 with ALK-positive disease) and four with other diagnoses. In this cohort, progression-free survival values ranged from 37.8 months to more than 66 months.

The long-term results of this phase I study are “very encouraging,” Laurie H. Sehn, MD, MPH, told ASH Clinical News when asked for comment on the study’s findings. However, she added that the findings “will require further validation within the context of a randomized controlled trial before [frontline brentuximab vedotin + CHP] is routinely used in clinical practice.” (Read more from Dr. Sehn in “Perspectives” at the end of this article.)

The median overall survival (OS) was not reached during follow-up; the estimated five-year OS was 79 percent (95% CI 53-92) for patients with ALCL and 83 percent (95% CI 27-97) for patients with non-ALCL disease. Those with ALK-positive disease appeared to have more favorable outcomes than those with ALK-negative ALCL, the researchers noted.

Among patients still in remission at last follow-up, disease stage at diagnosis tended to be earlier and baseline International Prognostic Index score tended to be lower. Those remaining in remission received a median of 16 treatment cycles (range = 6-16 cycles), compared with 10 cycles (range = 3-16 cycles) for those who were not in remission.

Nineteen patients, including 12 who remained in remission, experienced treatment-related peripheral neuropathy, which is a known adverse event associated with brentuximab vedotin. At last follow-up, 10 participants (53%) had ongoing peripheral neuropathy. Most cases of peripheral neuropathy were grade 1 or 2 (n=17), but two patients experienced a grade 3 reaction. The median time to onset of peripheral neuropathy was 11 weeks (range = 0-34 weeks), and almost all patients (n=18; 95%) had resolution or improvement in peripheral neuropathy symptoms during treatment (within a median of 4.2 months and 2.6 months, respectively; ranges not provided). Nine patients had full resolution.

The study is limited by its small patient population and lack of a comparator arm. Based on the results of this study, investigators initiated a randomized, phase III trial comparing frontline brentuximab vedotin plus CHP and brentuximab vedotin plus CHOP for patients with PTCL. The authors expect the results to be published soon.

Seattle Genetics and Millennium Pharmaceuticals provided funding for the study.

The authors report financial support from Bristol-Myers Squibb, Merck, Seattle Genetics (of which three authors were employees), Takeda, ADC Therapeutics, Aileron Therapeutics, Celgene, Forty Seven, Infinity/Verastem, Kyowa Hakko Kirin, Millennium, and Spectrum. Seattle Genetics provided editorial support.


References

  1. Fanale MA, Horwitz SM, Forero-Torres A, et al. Five-year outcomes for frontline brentuximab vedotin with CHP for CD30-expressing peripheral T-cell lymphomas. Blood. 2018. [Epub ahead of print]
  2. 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;32:3137-43.

“With a median follow-up time of five years, the high initial response rate observed [with frontline brentuximab vedotin plus CHP] has proven durable in a high proportion of patients. The overall safety profile of this regimen appeared reasonable, compared with standard CHOP and more favorable than intensive approaches such as upfront autologous hematopoietic cell transplantation. It is reassuring that most patients who experienced peripheral neuropathy had improvement or resolution of symptoms over time. Overall, outcome appears favorable, compared with historical expectations with standard CHOP, but these findings will require further validation within the context of a randomized, controlled trial (e.g., the phase III ECHELON-2 trial that was recently completed). It will be important to assess the role of this regimen, compared with standard therapy in a larger cohort of patients. In particular, its merit will need to be considered separately in patients with ALCL, as well as the various subtypes of non-ALCL PTCL.”

Laurie H. Sehn, MD, MPH, Blood associate editor and chair of the Lymphoma Tumour Group at BC Cancer Agency

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