Feasibility of Interim PET-Adapted Therapy in HIV-Positive Patients with Advanced Hodgkin Lymphoma (HL): Sub-Analysis of SWOG S0816 Phase 2 Trial

Background: The risk of HL is 10-fold higher in HIV-infected individuals than in the background population. Patients with HIV-HL typically present with advanced stage disease and frequent extranodal sites of involvement, accounting for higher risk scores than HIV-negative counterparts. Despite that, the prognosis of HIV-HL in the HAART era has been favorable. Standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) results in complete response rates (74%) and five-year overall survival (80%) similar to those in non-HIV-HL. Thus, as in HIV-negative HL, exploration of response-adapted therapy in HIV-HL is well-justified. PET imaging after 2 cycles of chemotherapy was found to be a strong predictor of treatment outcome in patients with non-HIV-HL. Here, for the first time, we report on the outcomes of HIV-positive patients enrolled on S0816, a multicenter Phase 2 trial of response-adapted therapy of stage III-IV HL using interim FDG-PET imaging.

Methods: HIV-positive patients aged 18-60 with previously untreated stage III-IV classical HL were eligible. Patients with multi-drug resistant HIV or concurrent AIDS-defining conditions were excluded. All patients received 2 cycles of ABVD followed by an interim PET, reviewed centrally. Patients with negative PET (Deauville≤3) subsequently received 4 additional cycles of ABVD, while PET-positive patients received 6 cycles of BEACOPP standard regimen (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine and prednisone).

Results: 12 patients with HIV-HL received study treatment. Median age was 44.6 years (range, 25 to 50 years), 83.3% were male. 11/12 (91.6%) patients presented with bulky lymphadenopathy (≥10 cm) and 50% had poor risk international prognostic score (IPS≥4). 6/12 (50%) patients manifested B-symptoms and 33.3% had bone marrow involvement by HL. Where information was available, most patients (7/9, 77.8%) received concurrent HAART during chemotherapy. Median CD4 count prior to registration was 165/µL (range, 22-400/µL), and <100/µL in 5/12 pts (41.7%).

All HIV-HL patients successfully completed 2 initial cycles of ABVD. Gr 4 neutropenia and gr 3 febrile neutropenia were common during this treatment (66% and 25%, respectively). 10/12 (83.3%) patients achieved PET-negative status and 2 remained PET-positive with Deauville scores of 4 and 5. All PET-negative patients continued therapy with ABVD. Of those, nine completed the 4 cycles of treatment and one discontinued early for progressive disease 4 months after registration on study. Of the PET-positive patients, one elected to receive ABVD therapy off the study protocol, while the other completed 6 cycles of BEACOPP; both achieved a partial response. Thus, following ABVD therapy, 82% of patients achieved complete response and 18% - partial response. With median follow-up of 31 months (range, 5.4-38.1 months) all study patients are alive. Two patients developed progressive disease, with the estimated progression-free survival of 83% at 2 years (95% CI, 46.1 to 95.3%). Most grade 3-4 adverse events with continued therapy were neutropenia (72.7%) and febrile neutropenia (27.2%), while other toxicities were uncommon (see Table). All 12 patients experienced at least one grade 3-4 toxicity during study treatment. 3 patients (25%) required dose reductions due to febrile neutropenia (N=2) and neuropathy (N=1).

Conclusions. ABVD is highly effective in patients with advanced stage poor-risk HIV-HL and induces PET-negative responses at a similar rate without undue added toxicity as compared to non-HIV patients in a prospective trial setting. As response-adapted therapy evolves to be a standard approach for HIV-negative patients with advanced stage HL, the results of S0816 study presented here support a similar investigative approach in patients with HIV-HL, with the goal of reducing long-term toxicity. The role of intensified chemotherapy regimens in patients with HIV-HL who do not achieve PET-negative status needs further study. 

Toxicity	Grade 3, N (%)	Grade 4, N (%)
Anemia	2 (18.2)	2 (18.2)
Febrile neutropenia	3 (27.2)	-
Lymphopenia	1 (9.1)	2 (18.2)
Neutropenia	2 (18.2)	6 (54.5)
Thrombocytopenia	1 (9.1)	-
Infection	2 (18.2)	-
Anorexia	1 (9.1)	-
Dizziness	1 (9.1)	-
Fatigue	1 (9.1)	-
Hypophosphatemia	1 (9.1)	-
Musculoskeletal pain	1 (9.1)	-
Thrombosis	1 (9.1)	-