Introduction: Patients (pts) infected with HIV have a 6-8 fold increased risk of classic Hodgkin lymphoma (cHL). Incidence may have increased with the implementation of combined anti-retroviral therapy (cART) in the mid 1990s. Frontline therapy for HIV-associated cHL (HIV-cHL) using, doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in the pre-cART era showed a 2 year overall survival (OS) of 48%, but outcomes are currently similar to the non-HIV population. Pts with advanced disease have a 30% chance of relapse with ABVD. Brentuximab vedotin (BV), an anti-CD30 an antibody drug conjugate that selectively induces apoptosis of CD30+ cells with a complete response of 34% in patients with relapsed/refractory cHL. An international trial of BV with doxorubicin, vinblastine, and dacarbazine (AVD) vs. ABVD is ongoing. Here we present the phase I portion of the first trial using BV with AVD in the upfront treatment of HIV-cHL. The Phase II portion is actively accruing in both the United States and France as part of an AIDS Malignancy Consortium (AMC)/Lymphoma Study Association (LYSA) collaboration.
Methods: The Phase I was a 3+3 dose de-escalation design evaluating 3 dose levels of BV (1.2 mg/kg, 0.9 mg/kg, and 0.6 mg/kg) every 2 weeks combined with standard, fixed doses of doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD) in a 28 day cycle. Eligibility: HIV+ pts diagnosed with untreated cHL stage II-IV with CD4 counts ≥50 cells/mm3 were required to take cART regimens for at least 1 week before treatment. Ritonavir, zidovidine, and cobisistat were excluded. Baseline, cycle 2, and post treatment PET/CT scans were required. Dose limiting toxicities (DLTs) were defined during cycle 1.
Results: Sixpts (5 men and 1 woman) were treated in the phase I portion from 3/2013-5/2015. Staging: II (n=1), III (n=1) IV (n=4). Pathology: mixed cellularity (n=2), nodular sclerosis (n=3), and lymphocyte depleted/mixed cellularity (n=1) HIV-cHL. The median CD4 T cell count at lymphoma diagnosis was 499 cells/mm3 (range 86-784) and the median viral load was 44 copies/ml (range 20-77). No cycle 1 DLTs were identified in the first 6 eligible patients and only 3 grade 3 adverse events in later cycles were noted, pneumonia, n=1, and neuropathy n=2, and neutropenia, n=1. In 2 pts, toxicity required delays in therapy of over 3 weeks (after c5d1 and after c6d1) resulting in subject removal from further protocol therapy. One pt had a decrease in the diffusion lung capacity for carbon monoxide (DLCO) to 65% after cycle 2, and BV was withheld while AVD continued as per protocol. Two pts were later deemed ineligible, and excluded from any analysis, due to the concomitant use of ritonavir-based cART at enrollment. Both developed febrile neutropenia and one developed a grade 3 pancreatitis during cycle 1, emphasizing the importance of not treating patients with BV + AVD with concurrent CYP3A4 inhibitors. Five of the 6 pts achieved cycle 2 PET/CT negativity as defined by a Deauville score 1-3. The PET/CT positive patient ultimately had a negative post-therapy scan. The 5 pts who completed therapy achieved CR post-therapy, and one patient has yet to complete treatment. Phase II is enrolling at BV 1.2 mg/kg in combination with AVD.
Conclusions: AVD-BV in stage II-IV HIV-cHL was well-tolerated therapy as no DLT were identified. Five of the 6 patients achieved a negative C2 PET/CT and 5/5 of the patients who completed therapy thus far achieved a CR. The recommended Phase II dose is 1.2 mg/kg +AVD every other week. The phase II portion (51 subjects) is actively accruing in both the USA and France, in an AMC/LYSA collaboration, clinicaltrials.gov NCT01771107.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.