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 Journal Article


Authors: Moskowitz, A. J.; Schöder, H.; Yahalom, J.; Mccall, S. J.; Fox, S. Y.; Gerecitano, J.; Grewal, R.; Hamlin, P. A.; Horwitz, S.; Kobos, R.; Kumar, A.; Matasar, M.; Noy, A.; Palomba, M. L.; Perales, M. A.; Portlock, C. S.; Sauter, C.; Shukla, N.; Steinherz, P.; Straus, D.; Trippett, T.; Younes, A.; Zelenetz, A.; Moskowitz, C. H.
Article Title: 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 18F-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/m2 in combination with mesna 5000 mg/m2 continuous infusion over 24 h, days 1 and 2; one dose of carboplatin AUC 5, day 3; three doses of etoposide 200 mg/m2 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. © 2015 Elsevier Ltd.
Keywords: adolescent; adult; clinical article; aged; prednisone; constipation; drug tolerability; neutropenia; cancer recurrence; salvage therapy; doxorubicin; diarrhea; drug dose reduction; cancer radiotherapy; cytarabine; rituximab; cancer staging; positron emission tomography; carboplatin; dacarbazine; multiple cycle treatment; phase 2 clinical trial; sensory neuropathy; etoposide; leukopenia; nausea; neuropathy; thrombocytopenia; vomiting; myalgia; cyclophosphamide; melphalan; vincristine; autologous stem cell transplantation; continuous infusion; carmustine; chlormethine; ifosfamide; procarbazine; vinblastine; hodgkin disease; arthralgia; coughing; dyspnea; febrile neutropenia; hyperglycemia; hypomagnesemia; pruritus; rash; drug fatality; feasibility study; add on therapy; radiation dose fractionation; fluorodeoxyglucose f 18; bleomycin; hypoglycemia; progressive multifocal leukoencephalopathy; mesna; alopecia; plerixafor; skin infection; hypocalcemia; filgrastim; anorectal disease; brentuximab vedotin; intention to treat analysis; human; male; female; priority journal; article
Journal Title: Lancet Oncology
Volume: 16
Issue: 3
ISSN: 1470-2045
Publisher: Elsevier Science, Inc.  
Date Published: 2015-03-01
Start Page: 284
End Page: 292
Language: English
DOI: 10.1016/s1470-2045(15)70013-6
PROVIDER: scopus
PUBMED: 25683846
DOI/URL:
Notes: Export Date: 2 April 2015 -- Source: Scopus
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MSK Authors
  1. Joachim Yahalom
    455 Yahalom
  2. Carol Portlock
    198 Portlock
  3. Tanya M Trippett
    109 Trippett
  4. Craig Moskowitz
    388 Moskowitz
  5. Ariela Noy
    225 Noy
  6. Maria Lia Palomba
    163 Palomba
  7. Steven M Horwitz
    408 Horwitz
  8. Ravinder K Grewal
    66 Grewal
  9. Heiko Schoder
    330 Schoder
  10. Craig Steven Sauter
    199 Sauter
  11. Andrew D Zelenetz
    599 Zelenetz
  12. Miguel-Angel Perales
    454 Perales
  13. Alison Moskowitz
    179 Moskowitz
  14. Paul Hamlin
    186 Hamlin
  15. Matthew J Matasar
    149 Matasar
  16. David J Straus
    245 Straus
  17. Peter G Steinherz
    190 Steinherz
  18. Susan J McCall
    14 McCall
  19. Rachel Kobos
    67 Kobos
  20. Neerav Shukla
    86 Shukla
  21. Anita Kumar
    67 Kumar
  22. Anas Younes
    246 Younes
  23. Stephanie Yvonne Fox
    5 Fox