New Therapies Being Developed Rapidly for Relapsed Hodgkin Lymphoma

Ranjana Advani, MD

In relapsed classical Hodgkin lymphoma (HL), the era of therapies post-brentuximab vedotin (BV) is developing rapidly. Novel salvage approaches are showing high rates of response, and checkpoint inhibitors have already been approved for the treatment of patients with relapsed HL following autologous stem cell transplant (ASCT) and BV, said Ranjana Advani, MD, at the NCCN’s 12th Annual Congress on Hematologic Malignancies.¹

The time to relapse after ASCT determines outcome, with median overall survival increasing from 0.7 years when relapse occurs within 3 months of ASCT to 4.6 years when time to relapse exceeds 12 months. Many pathogenic pathways have been identified in HL, leading to “a plethora of drugs being developed like we’ve never had before,” said Advani, a professor of lymphoma at Stanford Cancer Institute.

BV has FDA approved for patients with classical HL after failure of ASCT or multi-agent chemotherapy, and as maintenance treatment in patients who are at high risk of relapse or progression post-ASCT consolidation. Five-year results obtained in a phase II clinical trial of BV show that 38% of patients who achieve complete response (CR) have remained in remission >5 years and may be cured.

ATHERA was a double-blind, placebo-controlled, randomized phase III study conducted in high-risk patients after ASCT.² Investigator-assessed 2-year progression-free survival (PFS) favored maintenance BV over placebo (65% vs 45%), with the greatest benefit of BV observed in the highest-risk group as identified by relapse or refractory within 12 months after frontline therapy, not achieving CR to salvage therapy, receipt of ≥2 salvage regimens, or extranodal involvement.

Current salvage therapies cause significant hematologic toxicity and as many as half of treated patients have functional imaging-positive disease. BV is a good candidate for first-line salvage therapy because it has a favorable toxicity profile and high efficacy in the post-ASCT setting, said Advani. Adaptive trial designs are examining the use of rituximab (Rituxan) alone followed by salvage chemotherapy if the patient is positive by functional imaging, or sparing chemotherapy and going straight to ASCT if negative by functional imaging. Using this approach, about one-third of patients can avoid chemotherapy, she said.

An emerging prognostic marker in relapsed/refractory HL is baseline metabolic tumor volume; patients with low metabolic tumor volume appear to do just as well as those who are negative by PET scans going into transplant. “Because brentuximab is easy to give and it’s active, there have been a number of studies combining it with different chemotherapy backbones to see if the complete remission rate can be improved beyond what you would see with brentuximab alone or chemotherapy alone,” said Advani.

The response rate to BV plus bendamustine is high but infusion-related toxicities require premedication. BV combined with etoposide, methylprednisolone, cytarabine, and cisplatin (ESHAP) is associated with a CR rate of about 70%,³ and when BV is combined with ifosfamide, carboplatin, and etoposide (ICE), the CR rate approaches 90%.⁴ Whether these high response rates translate into improved survival is not yet known.

PD-L1 is universally expressed on Hodgkin Reed Sternberg cells through 9p24.1 amplification. Binding of PD-1 to its ligand inhibits T-cell activation, allowing tumors to evade the immune response. After failure of both ASCT and BV, nivolumab (Opdivo) was associated with a 6-month PFS of 77% and a median duration of response of 7.8 months.⁵ The response to pembrolizumab (Keytruda) in relapsed/refractory classical HL is similar. The CR rate is about 20% with both of these checkpoint inhibitors.⁶

In the current treatment era of novel therapeutics, outcomes in patients who have progressed after ASCT have improved. The logical next step is to try to improve response further by combining novel agents, said Advani. In a phase I/II study, the overall response rate was 90% with a combination of BV plus nivolumab as first-line salvage therapy, with complete metabolic response doubled from about 30% with each agent individually to 62% when used in combination.⁷ After ASCT failure, this same combination produced similar overall response and CR rates.⁸ “The follow-up of these newer approaches incorporating either brentuximab or checkpoint inhibitors is not mature enough to say whether or not they will translate into improved long-term outcomes,” said Advani, adding that the use of the novel agents in the relapsed/refractory setting is still considered experimental.

Other novel therapies being evaluated include HDAC inhibitors such as mocetinostat and panobinostat. The latter agent, when combined with ICE, was not more effective than ICE alone in a randomized phase II trial in patients with relapsed or refractory classic HL.⁹

The response rate to everolimus (Afinitor) exceeds 40%. Because the PI3K/mTOR inhibitors are approved for other indications, they represent an option in patients in whom ASCT or immune checkpoint inhibition has failed, she said.

A pilot study of ruxolitinib (Jakafi) showed antitumor activity in 3 of 7 patients with HL, including 3 partial responses at the end of the second cycle, and no grade 3/4 toxicity was observed. This study serves as the basis of a phase II trial of JAK inhibition in recurrent classic HL.¹⁰

The discovery of crosstalk between Hodgkin Reed Sternberg cells and the tumor microenvironment has led to lenalidomide (Revlimid) being studied in patients with relapsed/refractory HL. In one study of patients who were treated with a median of 4 prior therapies, the median PFS and median OS with lenalidomide were 4 months and 20 months, respectively.¹¹

The response to chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory HL has not been as robust as in large-cell lymphoma. Efforts to improve the efficacy of CAR T cells by overcoming inhibition, increasing migration, and supplementing CAR T cells with counter inhibitory factors are under investigation.

References

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8. Diefenbach CS, Hong F, David KA, et al. A phase I study with an expansion cohort of the combination of ipilimumab and nivolumab and brentuximab vedotin in patients with relapsed/refractory Hodgkin lymphoma: a trial of the ECOG-ACRIN Cancer Research Group (E4412 arms D and E). In: Proceedings from the 58th ASH Annual Meeting & Exposition; December 2-6, 2016; San Diego, CA. Abstract 1106.
9. Hu B, Younes A, Westin JR, et al. Phase-I and randomized phase-II trial of panobinostat in combination with ICE (ifosfamide, carboplatin, etoposide) in relapsed or refractory classical Hodgkin lymphoma. Leuk Lymph. 2017; doi: 10.1080/10428194.2017.1359741.
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