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Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study
Author(s) -
Dvorak Christopher C.,
Satwani Prakash,
Stieglitz Elliot,
Cairo Mitchell S.,
Dang Ha,
Pei Qinglin,
Gao Yun,
Wall Donna,
Mazor Tali,
Olshen Adam B.,
Parker Joel S.,
Kahwash Samir,
Hirsch Betsy,
Raimondi Susana,
Patel Neil,
Skeens Micah,
Cooper Todd,
Mehta Parinda A.,
Grupp Stephan A.,
Loh Mig L.
Publication year - 2018
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.27034
Subject(s) - medicine , juvenile myelomonocytic leukemia , busulfan , regimen , cyclophosphamide , hematopoietic stem cell transplantation , fludarabine , transplantation , randomized controlled trial , oncology , chemotherapy , pediatrics , surgery , stem cell , haematopoiesis , genetics , biology
Background Most patients with juvenile myelomonocytic leukemia (JMML) are curable only with allogeneic hematopoietic cell transplantation (HCT). However, the current standard conditioning regimen, busulfan‐cyclophosphamide‐melphalan (Bu‐Cy‐Mel), may be associated with higher risks of morbidity and mortality. ASCT1221 was designed to test whether the potentially less‐toxic myeloablative conditioning regimen containing busulfan‐fludarabine (Bu‐Flu) would be associated with equivalent outcomes. Procedure Twenty‐seven patients were enrolled on ASCT1221 from 2013 to 2015. Pre‐ and post‐HCT (starting Day +30) mutant allele burden was measured in all and pre‐HCT therapy was administered according to physician discretion. Results Fifteen patients were randomized (six to Bu‐Cy‐Mel and nine to Bu‐Flu) after meeting diagnostic criteria for JMML. Pre‐HCT low‐dose chemotherapy did not appear to reduce pre‐HCT disease burden. Two patients, however, received aggressive chemotherapy pre‐HCT and achieved low disease‐burden state; both are long‐term survivors. All four patients with detectable mutant allele burden at Day +30 post‐HCT eventually progressed compared to two of nine patients with unmeasurable allele burden ( P = 0.04). The 18‐month event‐free survival of the entire cohort was 47% (95% CI, 21–69%), and was 83% (95% CI, 27–97%) and 22% (95% CI, 03–51%) for Bu‐Cy‐Mel and Bu‐Flu, respectively ( P = 0.04). ASCT1221 was terminated early due to concerns that the Bu‐Flu arm had inferior outcomes. Conclusions The regimen of Bu‐Flu is inadequate to provide disease control in patients with JMML who present to HCT with large burdens of disease. Advances in molecular testing may allow better characterization of biologic risk, pre‐HCT responses to chemotherapy, and post‐HCT management.