PET-adapted sequential salvage therapy with brentuximab vedotin followed by augmented ifosamide, carboplatin, and etoposide for patients with relapsed and refractory Hodgkin's lymphoma: a non-randomised, open-label, single-centre, phase 2 study.

Abstract

BACKGROUND:

Pre-transplantation (18)F-fluorodeoxyglucose (FDG) PET-negativity is one of the strongest predictors of outcome after high-dose therapy and autologous stem-cell transplant (HDT/ASCT) for patients with relapsed or refractory Hodgkin's lymphoma. In this study, we assessed the feasibility and activity of PET-adapted salvage therapy with brentuximab vedotin, followed by augmented ifosfamide, carboplatin, and etoposide (ICE).

METHODS:

In this non-randomised, open-label, single-centre, phase 2 trial, we enrolled patients with relapsed or refractory Hodgkin's lymphoma who had failed one previous doxorubicin-containing chemotherapy regimen. All patients received weekly infusions of 1·2 mg/kg brentuximab vedotin on days 1, 8, and 15 for two 28 day cycles. After completion of brentuximab vedotin treatment, patients received a PET scan. Patients who achieved PET-negative status (a Deauville score of 1 or 2) proceeded directly to HDT/ASCT; those with persistent abnormalities on PET received two cycles of augmented ICE (augICE; two doses of ifosfamide 5000 mg/m(2) in combination with mesna 5000 mg/m(2) continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m(2) every 12 h, day 1) before consideration for HDT/ASCT. Only patients with persistent abnormalities on PET after brentuximab vedotin received augICE; however, all patients in the intention-to-treat population were assessed for the primary outcome, which was the proportion of patients who were PET-negative after brentuximab vedotin alone or brentuximab vedotin followed by augICE. This study is registered with ClinicalTrials.gov, number NCT01508312, and is no longer accruing patients.

FINDINGS:

Between Jan 5, 2012, and Oct 4, 2013, we enrolled 46 patients. One patient was deemed ineligible, and not evaluable, before treatment initiation owing to having nodular, lymphocyte-predominant Hodgkin's lymphoma and thus 45 patients received treatment. After brentuximab vedotin, 12 patients (27%, 95% CI 13-40) were PET-negative and proceeded to HDT/ASCT. 33 (73%, 95% CI 60-86) patients were PET-positive after brentuximab vedotin; one PET-positive patient withdrew consent, therefore 32 PET-positive patients received augICE, 22 (69%, 95% CI 53-85) of whom were PET-negative. Overall, 34 patients (76%, 95% CI 62-89) achieved PET-negativity. All 44 patients who completed treatment as per protocol proceeded to receive HDT/ASCT. Brentuximab vedotin was well tolerated and associated with few grade 3-4 adverse events including hyperglycaemia (two [4%] patients, grade 3), nausea (one [2%], grade 3), hypoglycaemia (one [2%], grade 3 and one [2%], grade 4), and hypocalcaemia (one [2%], grade 3 and one [2%], grade 4).

INTERPRETATION:

PET-adapted sequential salvage therapy with brentuximab vedotin followed by augICE resulted in a high proportion of patients with relapsed or refractory Hodgkin's lymphoma achieving PET-negativity, and therefore could optimise the chance of cure after HDT/ASCT.

FUNDING:

Seattle Genetics.

• Authors: Alison J Moskowitz, Heiko Schöder, Joachim Yahalom, Susan J McCall, Stephanie Y Fox, John Gerecitano, Ravinder Grewal, Paul A Hamlin, Steven Horwitz, Rachel Kobos, Anita Kumar, Matthew Matasar, Ariela Noy, M Lia Palomba, Miguel-Angel Perales, Carol S Portlock, Craig Sauter, Neerav Shukla, Peter Steinherz, David Straus, Tanya Trippett, Anas Younes, Andrew Zelenetz, Craig H Moskowitz
• Journal: The Lancet. Oncology (Lancet Oncol) Vol. 16 Issue 3 Pg. 284-92 (Mar 2015) ISSN: 1474-5488 [Electronic] England
• PMID: 25683846 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ltd. All rights reserved.

Chemical References

• Immunoconjugates
• Etoposide
• Brentuximab Vedotin
• Carboplatin
• Ifosfamide

Topics

• Adolescent
• Adult
• Aged
• Antineoplastic Combined Chemotherapy Protocols (adverse effects, therapeutic use)
• Brentuximab Vedotin
• Carboplatin (administration & dosage)
• Chemotherapy, Adjuvant
• Etoposide (administration & dosage)
• Feasibility Studies
• Female
• Hodgkin Disease (diagnostic imaging, drug therapy)
• Humans
• Ifosfamide (administration & dosage)
• Immunoconjugates (administration & dosage)
• Male
• Middle Aged
• Neoadjuvant Therapy
• New York City
• Positron-Emission Tomography
• Recurrence
• Salvage Therapy
• Stem Cell Transplantation
• Time Factors
• Treatment Outcome
• Young Adult