German Hodgkin Study Group Phase I Trial Of Doxorubicin, Vinblastine, Dacarbazine, and Lenalidomide (AVD-Rev) For Older Hodgkin Lymphoma Patients

Patients above 60 years of age account for up to one third of all patients with Hodgkin Lymphoma (HL). ABVD is considered standard of care for this patient cohort; however, both outcome and feasibility are poor, since tolerability of cytotoxic drugs is often markedly decreased. A major limitation is pulmonary toxicity due to bleomycin. We thus aimed at improving the ABVD regimen by replacing bleomycin with the immunomodulatory drug lenalidomide (Revlimid^®, AVD-Rev), which has shown promising activity as single agent in HL.

We initiated the GHSG AVD-Rev dose finding trial (NCT01569204) for patients between 60 and 76 years of age, with first diagnosis of early unfavorable- or advanced-stage HL, good performance status (ECOG/WHO ≤2), and without evidence of severe organ dysfunction. Prophylactic anticoagulation (ASA or heparin) was mandatory.

Depending on stage and response at interim staging, patients received four to eight cycles of AVD-Rev (standard-dose AVD on day 1 and 15 of a 28 days cycle and lenalidomide daily from day 1 to 21) followed by radiotherapy The daily lenalidomide dose for the first patient was 5 mg, and there were 8 possible dose levels ranging from 5 mg to 40 mg. Subsequently, all incoming information on dose limiting toxicities (DLT) during the first 4 cycles of therapy was used for dose level determination for the next patient using the EWOC (Escalation with Overdose Control) method. Critical adverse events including thromboembolism ≥CTC Grade II, hematological toxicity such as severe cytopenia (ANC< 500/µl >7days with G-CSF support and thrombocytopenia below 25.000/µl ≥ 1 day), and resulting complications such as neutropenic fever and prolonged therapy delay were considered as dose limiting toxicities.

25 patients with a median age of 67 years (range 61-76) and with a CIRS-G comorbidity scoring of up to 7 points (n=2, range 0-7) were recruited and assigned to dose levels 5 mg (n=1), 10 mg (n=1), 15 mg (n=1), 20 mg (n=6), and 25 mg (n=16). Fifteen patients were male, 68% had advanced stage disease, and 80% had B-symptoms at diagnosis.

After DLT evaluation of 20 patients, a pre-specified stopping criterion was reached and the recommended dose for a phase II trial was 25 mg.

Dose delivery was high with a mean relative dose intensity of 91% (all dose levels, range: 63-104%, median: 97%), however at least one CTC Grade III-IV toxicity occurred in all 22 patients who were treated at dose levels 20 mg and 25 mg, and 16 of these patients had a CTC Grade IV toxicity. Dose limiting toxicities were observed in 2 of 6 (33%) and 8 of 16 (50%) patients at 20 mg and 25 mg, respectively, and were mainly hematologic but also included 3 thromboembolic events despite documented ASA prophylaxis. No DLT occurred in patients treated with <20 mg lenalidomide. Of note in these highly vulnerable patients, no treatment related deaths occurred.

Overall response rates were 79% for all evaluable patients (19/24) and 86% (18/21) in patients treated with at least 20 mg lenalidomide. After 12 months median observation time, 5 patients had a disease progression and 3 patients died. The one-year estimates for progression-free an overall survival are 69% [95%-CI: 50-91%] and 91% [95%-CI: 79-100%], respectively.

AVD-Rev is feasible and effective in this vulnerable population of older Hodgkin patients. We thus recommend this regimen for further evaluation in a phase II study.

Böll:Celgene: Travel Grant Other. von Tresckow:Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Engert:Seattle Genetics, Inc.: Honoraria, Research Funding.