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

Media type: E-Article
Title: German Hodgkin Study Group Phase I Trial Of Doxorubicin, Vinblastine, Dacarbazine, and Lenalidomide (AVD-Rev) For Older Hodgkin Lymphoma Patients
Contributor: Böll, Boris; Plütschow, Annette; Fuchs, Michael; Eichenauer, Dennis A.; Thielen, Indra; von Tresckow, Bastian; Behringer, Karolin; Atta, Johannes; Pfreundschuh, Michael; Feuring-Buske, Michaela; Vogelhuber, Martin; Sökler, Martin; Engert, Andreas; Borchmann, Peter
imprint: American Society of Hematology, 2013
Published in: Blood
Language: English
DOI: 10.1182/blood.v122.21.3054.3054
ISSN: 0006-4971; 1528-0020
Keywords: Cell Biology ; Hematology ; Immunology ; Biochemistry
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Footnote:
Description: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Rationale</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Disclosures:</jats:title> <jats:p>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.</jats:p> </jats:sec>
Access State: Open Access

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