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Phase 1 dose‐escalation trial of clofarabine followed by escalating dose of fractionated cyclophosphamide in adults with relapsed or refractory acute leukaemias
Author(s) -
Zeidan Amer M.,
Ricklis Rebecca M.,
Carraway Hetty E.,
Yun Hyun D.,
Greer Jacqueline M.,
Smith B. Douglas,
Levis Mark J.,
McDevitt Michael A.,
Pratz Keith W.,
Showel Margaret M.,
Gladstone Douglas E.,
Gore Steven D.,
Karp Judith E.
Publication year - 2012
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2012.09142.x
Subject(s) - clofarabine , medicine , cyclophosphamide , refractory (planetary science) , salvage therapy , gastroenterology , regimen , adverse effect , phases of clinical research , hematopoietic stem cell transplantation , transplantation , surgery , chemotherapy , cytarabine , physics , astrobiology
Summary The prognosis of patients with relapsed and refractory acute leukaemia ( RRAL ) is very poor. Forty patients with RRAL were enroled [28 acute myeloid leukaemia ( AML ), 12 acute lymphoblastic leukaemia ( ALL )] in this Phase 1 dose‐escalation trial of daily‐infused clofarabine ( CLO ) followed by cyclophosphamide ( CY ) for four consecutive days ( CLO ‐ CY x4). The median age was 48·5 years. The median number of prior regimens was 2 (range 1–5), and 6/40 patients (15%) had prior allogeneic haematopoietic stem cell transplant. 28/40 patients (70%) had adverse genetic features. 6/40 patients (15%) died within 60 d of induction (two infections, four progressive disease). The average time to neutrophil recovery (absolute neutrophil count ≥0·5 × 10 9 /l was 34 d, (range, 17–78). The overall response rate ( ORR ) was 33% (13/40), with seven complete remissions (18%), four complete remissions with incomplete recovery of blood counts (10%), and two partial remissions (5%). ORR was 25% (7/28), and 50% (6/12), for AML and ALL respectively. Notably, the clinical responses were independent of dose level. 7/17 patients (41%) exhibited CLO ‐mediated enhancement of CY ‐induced DNA , which was associated with, but not necessary for, improved clinical outcomes. In summary, the CLO ‐ CY x4 regimen was well tolerated and had activity in patients with RRAL , especially relapsed ALL . Therefore, CLO ‐ CY x4 can be considered a salvage therapy for adults with RRAL s, and warrants further investigations.