Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Pediatric Patients with Treatment Related Myelodysplastic Syndrome or Acute Myelogenous Leukemia (tMDS/AML)
Authors: Kobos Rachel , Steinherz Peter G , Kernan Nancy A , Prockop Susan E , Scaradavou Andromachi , Small Trudy N , Shukla Neerav , Khalaf Ramzi , O'Reilly Richard J. , Boulad Farid 
Published: October 2019

Abstract
Abstract 2363
The development of tMDS/tAML is a complication that can occur following chemotherapy (CT) or radiation (RT) therapy. Therapeutic approaches for such patients (pts) have included both CT and/or HSCT, with overall successful outcome in 30–35% of pts. From October 1994 to September 2009, 22 pts with tMDS/tAML received an allogeneic HSCT at our institution. The median age at presentation of primary disease was 15 years (range 3 months–26 years). The median age at time of HSCT was 21 years (range 8–29 years). There were 11 males and 11 females. Therapy related MDS/AML developed following RT and/or CT in pts with cancer (n=19) or a non-malignant disease (n=3). The initial malignancies consisted of Osteosarcoma (OS) n=5, Neuroblastoma (NB) n=3, Ewing Sarcoma n=3, Rhabdomyosarcoma n=2, Desmoplastic Round Cell Tumor n=1, Malignant Fibrous Histiocytoma n=1, Hodgkin Lymphoma n=1, Non-Hodgkin Lymphoma n=1, and AML n=1.
Five pts proceeded to HSCT without induction chemotherapy, at which time four pts had refractory anemia (RA) and one pt had AML. The other 17 pts were treated with chemotherapy prior to transplant; 14 received high dose cytarabine at 3g/m2/dose every 12 hours × 4 doses with 13 pts achieving morphologic remission or secondary RA. Conditioning regimens were selected according to previous therapies: three pts had a total body irradiation (TBI) containing regimen; 11 pts received busulfan (Bu) (0.8mg/kg/dose every 6 hours × 10 doses) melphalan (Mel) (70mg/m2/dose × 2 doses) fludarabine (Flu) (25mg/m2/dose × 5 doses) for cytoreduction; and eight pts received myeloablative regimens containing Bu and/or Mel and/or thiotepa with doses modified for organ toxicity. Sixteen pts received T-cell depleted (TCD) bone marrow (n=2) or peripheral blood stem cell (PBSC) (n=14) grafts (including 11 pts following Bu-Mel-Flu); four received unmodified bone marrow (n=3) or PBSC (n=1); and two received a double umbilical cord blood transplant (DUCBT). Donors included HLA-matched (n=9), or mismatched related donors (n=3), HLA-matched (n=4), or mismatched (n=4) unrelated donors or DUCBT (n=2). Disease status at time of HSCT was: morphologic and cytogenetic CR (n=12); RA with positive cytogenetics (n=6); and refractory disease (n=4).
The median follow up is 5.9 years (2.2-15.7 years). The five-year overall survival (OS) and disease free survival (DFS) rates for the entire group are 56.6% with 12 pts alive without evidence of either primary disease or tMDS/tAML. The OS and DFS rate for the 11 pts who received the Bu-Mel-Flu cytoreduction with TCD grafts was 54.5%. Ten pts died. Cause of death was relapse of MDS/AML (n=5) or of primary disease (n=2), GVHD (n=2), and infection (n=1). Four pts developed grade II-IV acute graft versus host disease (GVHD). Two pts recovered and two pts died from infectious complications related to GVHD. One patient developed localized chronic GVHD which resolved. Variables associated with a favorable outcome included: disease status with DFS of 63% for pts in RA or CR at HSCT compared to 0% for pts with >5% residual blasts in the bone marrow (p=0.04); age with DFS of 70% for pts <21 years old compared to 40% for pts ≥21 years old (p=0.51); and normalization of cytogenetic abnormalities with DFS of 50% for pts with normal cytogenetics compared to 33% for pts with persistent abnormalities (p=0.49).
Our results suggest that the strategy of induction with high dose cytarabine-based chemotherapy followed by allogeneic stem cell transplantation improves the overall outcomes for pts with tMDS/tAML to those obtained in pts transplanted for primary MDS/AML. In addition, the use of T-cell depleted transplant may decrease the toxicity of transplantation in heavily pre-treated pts without increase in relapse rate.

Disclosures:
No relevant conflicts of interest to declare.