Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Christopher C. Dvorak, Prakash Satwani, Elliot Stieglitz, Mitchell S. Cairo, Ha Dang, Qinglin Pei, Yun Gao, Donna Wall, Tali Mazor, Adam B. Olshen, Joel S. Parker, Samir Kahwash, Betsy Hirsch, Susana Raimondi, Neil Patel, Micah Skeens, Todd Cooper, Parinda A. Mehta, Stephan A. Grupp, Mignon L. Loh

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


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.

Original languageEnglish (US)
Article numbere27034
JournalPediatric Blood and Cancer
Issue number7
StatePublished - Jul 2018

Bibliographical note

Funding Information:
The authors thank Bryan Langholz, Mark Krailo, Lu Chen, and Todd Alonzo for additional statistical support and advice. Research reported in this publication was supported by the Children's Oncology Group and the National Clinical Trials Network (NCTN) of the National Cancer Institute (NCI) of the National Institutes of Health (NIH) under grants number U10CA98543, U10CA98413, U10CA180886, U10CA180899, CA21765, CA36401, and U01GM92666. Further support was from the St. Baldrick's Foundation, the Leukemia and Lymphoma Society (ES, MLL), and NIH/NCI 5P30CA082103 (AO). The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health.

Funding Information:
Grant sponsor: National Institutes of Health (NIH); Grant numbers: U10CA98543, U10CA98413, U10CA180886, U10CA180899, CA21765, CA36401, and U01GM92666; Grant sponsor: Leukemia and Lymphoma Society; Grant number: NIH/NCI 5P30CA082103.

Publisher Copyright:
© 2018 Wiley Periodicals, Inc.


  • conditioning regimens
  • hematopoietic cell transplantation
  • juvenile myelomonocytic leukemia
  • mutant allele burden


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