Post-Transplant Pembrolizumab Consolidation Improves PFS in Relapsed/Refractory Hodgkin Lymphoma

In patients with high-risk, relapsed/refractory classical Hodgkin lymphoma (cHL) who have undergone autologous hematopoietic cell transplantation (AHCT), consolidation therapy with the PD-1 inhibitor pembrolizumab resulted in high progression-free survival (PFS) rates, according to findings from a small phase II study published in Blood.

“The options for treatment after AHCT are brentuximab vedotin or no consolidation,” lead author Philippe Armand, MD, PhD, of Dana-Farber Cancer Institute in Boston, told ASH Clinical News. The results compared favorably to those expected with either approach, he added. “The expected PFS [at 18 months] for this patient population without post-AHCT brentuximab, based on historical data, was estimated to be approximately 60%, compared with 80% in our study.”

The phase II trial enrolled 30 patients (median age = 33 years; range = 20-69 years) with cHL that relapsed or was refractory to frontline therapy. All participants had undergone AHCT, achieved partial/complete metabolic response after salvage therapy and prior to AHCT, and were receiving no additional therapy after AHCT.

Eligible patients could not have received more than three lines of therapy prior to enrollment. Study treatment was initiated within 21 days of discharge after AHCT; patients received a total of eight cycles of pembrolizumab, administered at 200 mg per dose every three weeks.

The most common firstline therapy was ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine; 77%), and the most common salvage therapy was ICE (ifosfamide, carboplatin, etoposide; 50%). In addition, six patients (20%) had received PD-1 blockade as part of salvage therapy.

This patient population had high-risk disease, the authors noted. Approximately 90% of patients had at least one of the defined five risk factors for patients with cHL undergoing AHCT:

  • primary refractory disease or relapse within 12 months of receiving frontline therapy
  • residual postsalvage FDG avid disease
  • greater than one salvage regimen required to achieve remission
  • extranodal disease at relapse
  • B symptoms at relapse

Treatment with pembrolizumab began at a median of 34 days (range = 27-43 days) after AHCT. Although most patients (77%) completed all eight treatment cycles, seven patients did not complete the study regimen due to toxicity (n=4), patient choice (n=2), and progressive disease (n=1).

Twenty-four participants (80%) experienced a grade ≥2 adverse event (AE), and nine (30%) experienced at least one grade ≥3 AE. In total, the investigators observed 14 grade 3 treatment-related AEs (TRAEs) and six grade 4 TRAEs, with no grade 5 AEs on this study.

The most common grade ≥2 TRAEs included leukopenia (n=23), neutropenia (n=17), and transaminitis (n=17).  Five AEs led to discontinuation: grade 2 pneumonitis (n=1), grade 2 diplopia (n=1), grade 3 pneumonitis (n=1), and grade 3 transaminitis (n=2).

Efficacy was measured through PET and CT scans conducted at baseline, then 10 and 22 weeks after treatment initiation. Tumor assessments also were conducted at 12 months and 18 months after AHCT.

At baseline, two patients had post-AHCT residual disease before pembrolizumab initiation, and both achieved complete response (CR) following three pembrolizumab treatment cycles. One of the patients who achieved CR at three cycles remained in CR after 18 months, while the other patient remained in CR at 12 months and was subsequently lost to follow-up.

“The study provides assurance that the use of PD-1 blockade [as consolidation after transplant] appears safe and has promising efficacy.”

—Philippe Armand, MD, PhD

Most patients (n=26; 87%) were in CR at 12 months; all but five patients remained in CR through 18 months of follow-up. The five patients with relapsed disease experienced a relapse at a median of six months (range = 3-18 months) after AHCT.

“The study therefore met its primary endpoint,” the authors noted. “Even if the two patients lost to follow-up at 12 months were considered PFS events, the 18-month progression-free rate (77%) would still have met the primary endpoint.”

Using a 19-month timepoint to account for the variability of the exact time of the “18-month” restaging, the investigator estimated that the PFS rate was 81% overall. The 19-month PFS rate also was high in patients with at least two high-risk disease factors (83%).

While these response and survival outcomes appeared to improve on outcomes seen previously with brentuximab vedotin consolidation, the study was not powered to test this comparison. “It is challenging to establish the relevant historical comparison PFS rate, given the difference in eligibility criteria and risk mix of this study compared with prior publications,” the authors added.

“The study provides assurance that the use of PD-1 blockade appears safe and has promising efficacy,” Dr. Armand concluded. “However, because this trial was a single-arm study and enrolled only 30 patients, it will be critical to confirm the potential benefit of post-transplantation pembrolizumab consolidation in comparative studies. Ideally, this could be done through a phase III study that compares the addition of PD-1 blockade to standard of care after AHCT.”

The authors report relationships with Merck, which sponsored the trial.

Reference

Armand P, Chen YB, Redd RA, et al. PD-1 blockade with pembrolizumab for classical Hodgkin lymphoma after autologous stem cell transplantation. Blood. 2019 April 5. [Epub ahead of print]

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