Pembrolizumab and Involved Site Radiation Therapy Alone As an Alternative to Transplant in Patients with Localized Failure Following Chemotherapy for Hodgkin Lymphoma: A Prospective Multicenter Phase II Study

Background: Chemotherapy followed by autologous stem cell transplant (ASCT) is standard of care for relapsed/refractory Hodgkin Lymphoma (HL). In a phase II study, we evaluated pembrolizumab with involved site radiation therapy (ISRT) as an alternative salvage approach for localized favorable relapse.

Methods: Patients with relapsed/refractory stage IA/IIA, non-bulky (<10cm) HL after one line of therapy received positron emission tomography-computed tomography (PETCT) simulation followed by pembrolizumab 200mg IV every 21 days for 4 cycles and PETCT simulation 2-3 weeks later. Patients then received ISRT per response as follows: 1) 20 Gy for complete metabolic response (CMR) defined by Deauville Score (DS) 1-3; 2) 30 Gy for partial metabolic response (PMR) or stable disease (SD) (DS 4-5) and negative biopsy; or 3) 36-40 Gy for PMR/SD and positive biopsy. Patients who progressed (PD) were taken off study. PETCT was done 4-6 weeks after ISRT to document response. The primary endpoint was CMR rate after pembrolizumab-RT. Secondary endpoints were response to single agent pembrolizumab, 2-year progression free survival (PFS), and toxicity.

Results: 18 of planned 22 patients enrolled so far, with median age 37 (range 22-66). 3 (17%) had stage I, 14 (78%) stage II, and 1 had an unspecified limited stage at initial diagnosis. Frontline therapy was chemotherapy alone in 15 (83%) and combined modality in 3 (17%). 16 (89%) received adriamycin/bleomycin/vinblastine/dacarbazine (ABVD), 12 (67%) with <6 cycles. 13 (72%) had relapsed and 5 (28%) had refractory disease.

Of the 15 evaluable patients (3 still on therapy), 5 (33%) had CMR after pembrolizumab, 3 (20%) had PMR/SD with negative biopsy, 4 (27%) had PMR with positive biopsy, and 3 (20%) had PD. 12 patients proceeded to ISRT, of whom 5 (42%) with CMR received 20 Gy, 3 (25%) with PMR/SD and negative biopsy received 30 Gy, and 4 (33%) with PMR/SD and positive biopsy received 36-40 Gy. 10 (83% of these pts, 67% overall) achieved CMR. After median follow up of 42 months (3-82), 2-year PFS was 67% (95% CI 47-95).

3 patients progressed on pembrolizumab and 3 relapsed after a median of 12 months (range 7-70) from completion of pembrolizumab-RT. Among the 6 patients with PD during or after pembrolizumab-RT, 3 are currently in remission while the status for the other 3 is unknown. Subsequent treatment for the 3 patients currently in remission included pembrolizumab plus gemcitabine/vinorelbine/liposomal doxorubicin followed by ASCT (n=1), brentuximab vedotin (BV) plus nivolumab followed by ASCT (n=1) and 2 doses of BV followed by additional RT (n=1).

Immune-related toxicities were 3 (17%) grade 1 rash, and 2 (12%) grade 2 hypo/hyperthyroidism. Grade >2 toxicities were 1 (6%) grade 3 headache and 1 (6%) grade 4 lipase elevation.

Conclusion: Pembrolizumab-RT yielded excellent CMR rates and minimal toxicity. These data suggest pembrolizumab-RT as a potential alternative to high dose chemotherapy and ASCT in localized, favorable relapsed/refractory HL. Enrollment to the study continues.