A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia

Michael J. Burke, Jatinder K. Lamba, Stanley Pounds, Xueyuan Cao, Yogita Ghodke-Puranik, Bruce R. Lindgren, Brenda J. Weigel, Michael R. Verneris, Jeffrey S. Miller

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Abstract

DNA hypermethylation and histone deacetylation are pathways of leukemia resistance. We investigated the tolerability and efficacy of decitabine and vorinostat plus chemotherapy in relapse/refractory acute lymphoblastic leukemia (ALL). Decitabine (15 mg/m2 iv) and vorinostat (230 mg/m2 PO div BID) were given days 1-4 followed by vincristine, prednisone, PEG-asparaginase, and doxorubicin. Genome wide methylation profiles were performed in 8 matched patient bone marrow (BM) samples taken at day 0 and day 5 (postdecitabine). The median age was 16 (range, 3-54) years. All patients had a prior BM relapse, with five relapsing after allogeneic transplant. The most common nonhematological toxicities possibly related to decitabine or vorinostat were infection with neutropenia (grade 3; n=4) and fever/neutropenia (grade 3, n=4; grade 4, n=1). Of the 13 eligible patients, four achieved complete remission without platelet recovery (CRp), two partial response (PR), one stable disease (SD), one progressive disease (PD), two deaths on study and three patients who did not have end of therapy disease evaluations for an overall response rate of 46.2% (CRp+PR). Following decitabine, significant genome-wide hypo-methylation was observed. Comparison of clinical responders with nonresponders identified methylation profiles of clinical and biological relevance. Decitabine and vorinostat followed by re-Induction chemotherapy was tolerable and demonstrated clinical benefit in relapsed patients with ALL. Methylation differences were identified between responders and nonresponders indicating interpatient variation, which could impact clinical outcome. This study was registered at www.clinicaltrials.gov as NCT00882206.

Original languageEnglish (US)
Pages (from-to)889-895
Number of pages7
JournalAmerican Journal of Hematology
Volume89
Issue number9
DOIs
StatePublished - Jan 1 2014

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decitabine
Combination Drug Therapy
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Methylation
Neutropenia
Bone Marrow
Genome
Therapeutics
Recurrence
Induction Chemotherapy
Vincristine
Prednisone
Histones
Doxorubicin
Leukemia
Fever
Blood Platelets
vorinostat
Transplants
Drug Therapy

All Science Journal Classification (ASJC) codes

  • Hematology

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A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia. / Burke, Michael J.; Lamba, Jatinder K.; Pounds, Stanley; Cao, Xueyuan; Ghodke-Puranik, Yogita; Lindgren, Bruce R.; Weigel, Brenda J.; Verneris, Michael R.; Miller, Jeffrey S.

In: American Journal of Hematology, Vol. 89, No. 9, 01.01.2014, p. 889-895.

Research output: Contribution to journalArticle

Burke, MJ, Lamba, JK, Pounds, S, Cao, X, Ghodke-Puranik, Y, Lindgren, BR, Weigel, BJ, Verneris, MR & Miller, JS 2014, 'A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia', American Journal of Hematology, vol. 89, no. 9, pp. 889-895. https://doi.org/10.1002/ajh.23778
Burke, Michael J. ; Lamba, Jatinder K. ; Pounds, Stanley ; Cao, Xueyuan ; Ghodke-Puranik, Yogita ; Lindgren, Bruce R. ; Weigel, Brenda J. ; Verneris, Michael R. ; Miller, Jeffrey S. / A therapeutic trial of decitabine and vorinostat in combination with chemotherapy for relapsed/refractory acute lymphoblastic leukemia. In: American Journal of Hematology. 2014 ; Vol. 89, No. 9. pp. 889-895.
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