A phase II study of interrupted and continuous dose lenalidomide in relapsed/refractory Hodgkin lymphoma

Newly diagnosed classical Hodgkin lymphoma (cHL) can be cured in approximately 75–85% of patients with systemic or combined-modality frontline therapy. While novel agents such as the anti-CD30 antibody drug conjugate brentuximab vedotin (BV) and immune checkpoint inhibitors (ICI; e.g., nivolumab, pembrolizumab) are highly active in cHL and now often combined with multi-agent chemotherapy,^1,2 patients with relapsed or refractory (rel/ref) disease after salvage therapy and autologous stem cell transplantation (ASCT) have few treatment options and experience 5-year median overall survival (OS) of approximately 50%.³ Lenalidomide is an immunomodulatory agent approved for mantle cell, follicular, marginal zone, and diffuse large B-cell lymphomas, which interacts with the ubiquitin E3 ligase cereblon to degrade Ikaros family transcription factors.⁴ Given multiple immunomodulatory targets in the cHL microenvironment, we hypothesized that lenalidomide would show clinical activity in rel/ref cHL. We previously reported on standard interrupted dosing of lenalidomide (25 mg/d, days 1-21, 28-day cycles) in patients with heavily pretreated rel/ref cHL.⁵ In that cohort, the International Workshop Criteria (IWC) overall response rate (ORR) was 19% and the disease control rate (DCR; best response of complete response [CR] or partial response [PR], or stable disease [SD] ≥6 months) was 33%. Based on evidence in other malignancies that continuous lenalidomide dosing may increase efficacy,⁶ we tested a continuous dosing schedule (25 mg/d, days 1-28, 28-day cycles until progression or intolerance) in a separate cohort of patients with rel/ref cHL (clinicaltrials gov. Identifier: NCT00540007). Here we report the data from the continuous dosing cohort in the context of our previously reported findings.

Collectively, 80 patients enrolled (10/2007 to 6/2011) to the two cohorts (Online Supplementary Table S1). Patient eligibility criteria, treatment, and response assessment were previously reported with the interrupted cohort outcomes.⁵ The study was carried out in accordance with the principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and regulatory and country-specific requirements. Forty-two patients were assigned to the continuous cohort and received daily lenalidomide. Eight patients (2 from the interrupted cohort and 6 from the continuous cohort) were removed from study before receiving two cycles of lenalidomide due to cytopenias (n=2), increased aspartate transaminase/alanine transaminase (n=2), venous thrombosis (n=1), desquamating rash (n=1), consent withdrawal (n=1), and incarceration (n=1), thus were not response-evaluable per protocol. The median number of lenalidomide cycles administered in the interrupted and continuous cohorts was four (range, 1-48) and 3.5 (range, 1-61+), respectively. Median follow-up from enrollment was 16.0 months (range, 0.7-92.7).

Responses were assessed by positron emission tomography/computed tomography (PET/CT) in 45 patients and CT alone in 26 patients. Due to the time period of the study, international Workshop Criteria was used to assess responses, thus estimates of ORR here may be lower than expected if Lugano response criteria had been used. In 72 response-evaluable patients across both cohorts (Table 1), the ORR was 26% (95% confidence interval [CI]: 18-40), and DCR was 43% (95% CI: 34-58). In the continuous cohort (n=36), the ORR was 32% (95% CI: 20-50) and DCR was 49% (95% CI: 30-70), compared to an ORR of 19% (95% CI: 10-37) and DCR of 36% (95% CI: 24-57) in the interrupted cohort. Of the 13 patients achieving disease control in the continuous cohort, nine (69%) had progressed after ASCT and three (23%) were refractory to their prior therapy (Online Supplementary Table S2). One patient achieving PR was censored at the time of subsequent ASCT. One patient with SD for 2 months discontinued treatment due to cytopenias prior to a diagnosis of therapy-related acute myeloid leukemia. One patient withdrew due to pregnancy, and another patient achieved a PR lasting 84 months after previously discontinuing treatment due to Cryptococcus infection.

Table 1.Response rates for entire cohort and per protocol response-evaluable patients for interrupted and continuous cohorts.

In the continuous cohort, median duration of response (DOR) was 8.1 months (range, 4-73), and median time-to-treatment failure (TTF) in patients achieving disease control was 8.3 months (range, 4-73) (Online Supplementary Figure S1A). The previously reported interrupted cohort median DOR was 6 months (range, 4-24) (Online Supplementary Figure S1B), and median TTF in patients achieving disease control was 15 months (range, 4-43).⁵ Survival was analyzed on an intention-to-treat basis. Median progression-free survival (PFS) was 3.7 months for both the continuous (95% CI: 1.8-7.7) and interrupted cohorts (95% CI: 1.8-4.6) (Figure 1A). The median OS was 35.9 months (95% CI: 17.7-not estimated [NE]) for the continuous cohort, 19.6 months (95% CI: 15.3-29.0) for the interrupted cohort, and 23.7 months (95% CI: 17.4-35.6) for the entire study population across both cohorts (Figure 1B). Both cohorts had exceptional long-term responders. Two patients receiving interrupted lenalidomide had a TTF of 30 and 46 months. Both patients had received ≥4 prior therapies including ASCT and were refractory to their previous treatment. Two patients on continuous lenalidomide had long-term responses, one for 24 months (CR), having relapsed after three prior treatments including ASCT. The second patient (PR) remained on treatment for 73 months before discontinuation due to Cryptococcus infection. This patient progressed 11 months later and was subsequently treated with multiple therapies including BV and nivolumab, all of which their disease was refractory to or relapsed again within 12 months.

Figure 1.Intention-to-treat survival analysis by cohort. (A) Progression-free survival. (B) Overall survival.

Lenalidomide was generally well-tolerated with both dosing schedules. The most frequent grade 3-4 adverse events (AE) across both cohorts were neutropenia (48%), leukopenia (29%), thrombocytopenia (23%), lymphopenia (23%), and anemia (19%). Grade 3-4 AE frequencies were similar between the dosing cohorts (Table 2). In the continuous cohort, dose reductions occurred due to cytopenias (n=3) and skin ulceration (n=1). Eight patients discontinued treatment for cytopenias (n=4), vertigo (n=1), myelodysplasia (n=1), pregnancy (n=1), or rash (n=1) at a median of 5.7 months (range, 3.6-73.0). In the interrupted cohort, dose reductions (n=7) and treatment discontinuations (n=4) were previously noted.⁵ The median time on therapy for patients who discontinued was 5.7 months (range, 3.6-71.5).

Prior studies in rel/ref cHL explored changes in plasma/ serum levels of CCL17/TARC as a biomarker of response. In the continuous cohort, we observed a trend (P=0.07) of decreasing CCL17/TARC levels from C1D1 to C1D15 in responding patients (Online Supplementary Figure S1C). Data from the combined cohorts revealed significant associations between decreasing CCL17/TARC levels from C1D1 to C1D15 in responding patients (P=0.014), as well as lower CCL17/TARC levels at C1D15 in responding versus C1D15 in non-responding patients (P=0.017) (Online Supplementary Figure S1D).

This study represents the largest reported group of patients with rel/ref cHL treated with single-agent lenalidomide, which exhibited an ORR of 26% and DCR of 43% across 72 evaluable patients treated with either interrupted or continuous dosing. Compared to interrupted dosing, continuous dosing resulted in a modest, although not statistically significant, increase in ORR (32% vs. 19%) and DCR (49% vs. 33%). Median PFS was identical at 3.7 months. Both cohorts had exceptional long-term responders. Eleven patients had previously received BV and either progressed on or within 6 months of discontinuing BV. Three of these patients responded to lenalidomide: one PR (9.3 months) and two CR (10 and 48 months). Thus, in heavily pretreated patients, lenalidomide resulted in modest activity overall, with several exceptional responders.

Compared to interrupted dosing, continuous dosing resulted in modestly more toxicity-related discontinuations (n=8 vs. n=4), particularly due to cytopenias (n=4 vs. n=1). Despite this, there was a similar incidence of grade 3-4 AE overall. Our results indicate that lenalidomide’s efficacy in rel/ref cHL is similar to that reported with other novel single-agent therapies in both the post-ASCT and post-BV setting, including panobinostat, mocetinostat, and AFM13, with lenalidomide exhibiting a favorable toxicity profile.⁷ Other smaller studies have evaluated interrupted lenalidomide monotherapy in rel/ref cHL. A phase II study of 14 patients (lenalidomide 25 mg/d, days 1-21, 28-day cycles) demonstrated best responses of PR in two patients and stable disease in seven patients.⁸ A lenalidomide compassionate-use program reported an ORR of 29% (1 CR, 11 PR) in 42 patients treated similarly. Two patients transitioned to continuous lenalidomide without increased toxicity.⁹

Combining lenalidomide with other therapies is also appealing, as its immunomodulatory effects may enhance partner drugs’ anti-tumor activities. Several ongoing trials combine lenalidomide with chemotherapy or targeted agents. One study of AVD (4-8 cycles) and lenalidomide (5-25 mg/d) as frontline treatment in patients ≥60 years old with cHL reported an 80% ORR and 84% 3-year PFS.¹⁰ A phase I/ II study of bendamustine (60 mg/m², days 1/8/15) plus continuous lenalidomide (10-25 mg/d) in 15 patients with chemorefractory cHL reported a 73% ORR and 8.7-month median PFS.¹¹ A study of the mTOR inhibitor temsirolimus (25 mg intravenously weekly) and lenalidomide (20 mg/d, days 1-21, 28-day cycles) in 20 patients with cHL refractory to or relapsing after BV reported an 80% ORR and 9.2-month median PFS.¹² Not all lenalidomide combinations have been as promising. A study of 25 patients with rel/ref cHL receiving lenalidomide (20 mg, days 1-21, 28-day cycles) and panobinostat (15 mg, 3 doses/week) reported a 17% ORR, lower than the expected ORR for either monotherapy,¹³ as well as significant cytopenias and infections. The checkpoint inhibitors nivolumab and pembrolizumab, approved for treatment of rel/ref cHL, have similar CR rates (16-22%) and ORR (64-70%) in heavily pretreated patients,¹⁴ but are likely to be used in first- or second-line combinations moving forward.^2,15,16 The combination of lenalidomide and nivolumab is currently under investigation.¹⁷ Overall, lenalidomide 25 mg/d administered via interrupted (days 1-21) or continuous (days 1-28) schedule with 28-day cycles has preliminary evidence of clinical efficacy in patients with rel/ref cHL. Lenalidomide was well tolerated by the heavily pretreated patients in both cohorts, and durable responses to lenalidomide monotherapy were observed. Given the single-agent activity and observed toxicities, lenalidomide could be considered in the post-ICI/ BV setting, and future studies of combination approaches including lenalidomide are warranted, especially those incorporating immunotherapy strategies.

Table 2.Grade 3 or 4 adverse events occurring in greater than 5% of patients.

Footnotes

• Received May 2, 2023
• Accepted September 6, 2023

Correspondence

T.A. FEHNIGER - tfehnige@wustl.edu

N.L. BARTLETT - nbarlet@wustl.edu

Disclosures

TAF and NLB have received research funding from Celgene for this clinical study.

Contributions

TAF and NLB developed the concept and designed the study. TAF, AFC, KAB, TSF, DDH, AG, NW-J and NLB provided study materials or patients. TAF, MJS, SES, MPW, and NE collected and assembled data. TAF, FW, MJS, SES, NLB, MPW, NE, and DR-G analyzed and interpreted data. TAF, MPW, DAR-G, NE, NLN, BK, and NM-S wrote and edited the manuscript. TAF, MPW, DAR-G, NJS, AFC, KAB, TSF, DDH, AG, FW, SES, NW-J, NLB, NE, BK, and NM-S gave the final approval of the mansucript. All authors had access to the primary clinical trial data..

Data-sharing statement

No shared data are available.

Funding

Acknowledgments

We thank all study site personnel as well as the patients and their families for participation in this study.