Chromatin Remodeling Therapy and Capizzi Methotrexate in Treatment-Related MDS/AML

Treatment-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/t-AML) is a devastating complication for pediatric patients with osteosarcoma. Even with intensive chemotherapy, overall survival ranges from 10-26%. These regimens cause significant morbidity, poor quality of life and increased toxicity, at times precluding the ultimate goal of hematopoietic cell transplant (HCT). Chromatin remodeling therapy with decitabine and vorinostat has shown some promise in adults with relapsed/refractory AML and MDS. The synergistic combination of methotrexate and asparaginase, also referred to as ‘Capizzi methotrexate’, is not generally part of upfront treatment for AML but does have some activity in relapsed/refractory disease. Using this rationale, we report the use of this combination regimen in 2 children with t-AML where chromatin remodeling therapy with subsequent Capizzi methotrexate successfully bridged both patients to HCT. Patients were treated at Lucile Packard Children's Hospital Stanford between 2010 and 2018 for osteosarcoma and subsequently for t-AML. An overview of the treatments used is described in Table 1. An adolescent female was treated for metastatic osteosarcoma. She developed an isolated pulmonary recurrence 5 months after completing therapy. She underwent resection of her pulmonary nodule and then was enrolled on a clinical trial. Four months later, she developed another pulmonary recurrence. At this time, she began treatment with ifosfamide and etoposide. After the sixth cycle, she was noted to have blasts in her blood, and a bone marrow evaluation confirmed t-MDS. Cytogenetics were negative for deletion of 5q, 7q or MLL rearrangement. Repeat bone marrow evaluation two months later revealed progression to t-AML. She initially received 5 days of high dose cytarabine without response and was then transitioned to Treatments A and B. Bone marrow evaluation on day 30 of Treatment B showed morphologic remission with 11% MRD. She underwent Treatment C and then proceeded to a matched sibling HCT. She had no detectable osteosarcoma at the time of her transplant. The patient remained in remission from t-AML but subsequently died from recurrent osteosarcoma more than 2 years after HCT. An adolescent male was treated for non-metastatic osteosarcoma of the left distal femur with methotrexate, adriamycin, cisplatin, ifosfamide and etoposide. Six years after completing treatment, he developed weight loss, epistaxis and pancytopenia. Bone marrow a