AraC: up for down

In this issue of Blood, Hitzler et al¹ demonstrate that high-dose cytarabine (HD-AraC) is required for the best likelihood for cure in the majority of children with Down syndrome with myeloid leukemia (ML-DS).

ML-DS is a unique subtype of leukemia occurring in children with DS younger than 4 years of age. It is always characterized by somatic mutations in the megakaryocytic-erythroid transcription factor GATA1, creating a GATA1 short protein (GATA1s) lacking its aminoterminal. Additional somatic mutations, mostly activating JAK-STAT signaling and inactivating chromatin modifiers, as well as additional unbalanced chromosomal copy number changes, are often observed in the leukemic cells.^2,3 Unlike acute myeloid leukemia (AML) in children without DS, ML-DS is highly sensitive to chemotherapy, with excellent cure rates.^4,5 It is particularly sensitive to the nucleoside analog cytarabine. Research from Taub’s laboratory suggests that the absence of the full-length GATA1 leads to higher intracellular concentration and activity of cytarabine.⁶ 

High toxicity from infection has been a limiting factor in the treatment of children with DS and leukemia (both AML and acute lymphoblastic leukemia). Children with DS and leukemia are particularly susceptible to respiratory viruses, in addition to being particularly susceptible to bacterial infections.^4,7 Many of these severe infections occurred during HD-AraC courses in the prior Children’s Oncology Group AAML0431 protocol.⁴ This observation and previous reports of the ultrasensitivity of ML-DS to lower doses of cytarabine^8,9 led Hitzler et al to eliminate the HD-AraC block from therapy for the majority of patients with ML-DS with an excellent response to induction therapy. This resulted in a reduction of the total dose of cytarabine from 27.8 g/m² in the AAML0431 to 3.8 g/m². In addition, because of the rarity of central nervous system (CNS) involvement by ML-DS, intrathecal (IT) cytarabine was reduced from 2 doses to a single dose.

The interim analysis revealed decreased survival compared with the previous protocol (2-year event-free survival [EFS] of 85.6% compared with 93.5% in AAML0431), highlighting the necessity of HD-AraC for the optimal outcome in ML-DS.¹ Although the reported percentages appear disappointing, it is important to note that EFS of 85% and overall survival of 91% for children with ML-DS, while receiving only an intermediate dose of cytarabine, is remarkable, and achieving so high a cure rate is a highly desirable goal for children with non-DS AML. Thus, children with ML-DS and severe comorbidities, for whom therapy for the AML is fraught with difficulty, might benefit from a treatment protocol lacking the more toxic HD-AraC. For other patients, additional work is needed to reduce the problem of infectious complications.

Relapse/refractory ML-DS, although rare, remains a major unmet need. In the current protocol, 12 standard risk (SR) patients (out of 114) experienced a relapse, 11 in the bone marrow and one in the CNS. Only 2 survived, despite intensive relapse treatment and stem cell transplant. CNS relapses are extremely rare in ML-DS, and the occurrence of isolated CNS relapse could suggest that the 1 IT cytarabine dose administered in the current protocol was insufficient. A complex karyotype and detectable GATA1s by next-generation sequencing were more frequent among SR patients who relapsed. Future studies should focus on the pathogenesis of relapse of ML-DS, on its early detection, possibly by next-generation sequencing quantification of GATA1s levels during remission, and on novel therapies for this extremely poor prognosis subgroup of ML-DS.