Chromatin Remodeling Therapy and Capizzi Methotrexate in Treatment-Related MDS/AML
Authors: Aftandilian Catherine , Sakamoto Kathleen M. , Davis Kara L. , Dahl Gary Van Houten , Lacayo Norman J. 
Published: October 2019

Abstract
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 aspiration revealed a hypercellular marrow with 18% blasts, increased marrow fibrosis and cytogenetics with a complex del(7q)/+8 clone, consistent with t-MDS. He received Treatment B, and a bone marrow evaluation on day 25 showed a hemodilute specimen with MRD <0.1%. He then received vincristine and methotrexate on day 35 followed by erwinia on day 36. Repeat bone marrow evaluation on day 42 again showed a hypocellular marrow with MRD of <0.1%. He went on to receive another cycle of vincristine and methotrexate followed by days 1 through 5 of Treatment B. Bone marrow evaluation on day 29 showed a hypocellular marrow with insufficient viable cells for MRD analysis.
The patient received an alpha/beta T cell depleted haploidentical transplant. He remains in morphologic remission with no evidence of disease more than 3 months after HCT.
Treatment-related MDS/AML remains a devastating complication of osteosarcoma treatment with no standard treatment. The two cases presented here demonstrated good response to a novel combination of therapy with decitabine/vorinostat followed by Capizzi methotrexate. Given the significant toxicity associated with most regimens for t-MDS/t-AML, this regimen should be considered when first line salvage chemotherapy has failed. The precise regimen as well as the optimal number of cycles prior to stem cell transplant should be evaluated in the context of a clinical trial.

Disclosures
No relevant conflicts of interest to declare.