Patients with constitutional trisomy 21 (Down syndrome [DS]) are at high risk of developing both acute lymphoblastic leukemia and myeloid leukemia (DS-ALL and ML-DS, respectively). These malignant conditions are associated with distinctive epidemiology, genetic signatures, and clinical outcomes compared to those of non-DS leukemias.1-3 DS-ALL is nearly exclusively of the B-cell lineage and occurs in children and adolescents/young adults, with extremely few cases reported in infants younger than one year. Many DS-ALL cases are cytogenetically normal, suggesting a role for activating mutations as leukemic drivers.3 Almost all ML-DS cases are of the acute megakaryoblastic subtype and occur in children younger than four years. ML-DS commonly ensues following the canonical preleukemic transient myeloproliferative disorder (TMD) characterized by somatic GATA1 mutations and is hypothesized to arise from a residual TMD population that subsequently acquires additional driver mutation(s).1, 4, 5 Patients with DS-ALL have inferior clinical outcomes versus those with non-DS-ALL, which is attributed to higher rates of treatment-associated mortality (TRM) and relapse.6, 7 Conversely, children with ML-DS have excellent chemosensitivity and high overall survival (OS), although survival of those with relapsed ML-DS is dismal.5
Attempts to reduce the treatment toxicities for pediatric patients with DS-associated leukemias have shown mixed success to date. TRM is typically due to infection and can occur during any phase of treatment, including maintenance.6 In addition to mortality resulting from the toxicity itself, individual treatment modifications in response to toxicities seem to be an important cause of lower event-free survival (EFS) in children with DS-ALL.7 Prior strategies in the Children’s Oncology Group (COG) AALL0932 and AALL1131 clinical trials to reduce anthracycline exposure, modify methotrexate dosing, decrease vincristine/glucocorticoid pulses, and intensify supportive care for patients with DS-ALL did not appreciably decrease TRM.8 The current COG AALL1731 trial further reduces chemotherapy toxicity by non-randomly assigning children with DS-ALL to three cycles of blinatumomab, a bispecific CD19×CD3 antibody immunotherapy, and omitting daunomycin in induction (all DS-ALL) and the cyclophosphamide/cytarabine-based second month of delayed intensification (high-risk DS-ALL only). Together, these two phases of treatment represent almost all of the TRM in high-risk DS-ALL.9 Preliminary analysis of interim AALL1731 data showed similar TRM rates (approximately 8%) among patients with DS-ALL on AALL1131 and AALL1731 however, and an increased blinatumomab-associated seizure risk that can be mitigated with antiepileptic drug prophylaxis.10
The reasons for the significantly higher rate of relapse in DS-ALL are likely multifactorial, including underlying leukemia biology, decreased immune surveillance compared to non-DS patients, and under-reported treatment reductions in response to adverse events.3, 6 A specific association between the distinct genetics of DS-ALL and poorer outcomes has not been established. For example, CRLF2 rearrangements with frequent JAK2 co-mutations that are associated with poor outcomes in patients with non-DS-ALL11 occur in 50 to 60 percent of DS-ALL and seem to have limited prognostic significance.6, 12, 13 Conversely, favorable genetic alterations in non-DS-ALL, such as ETV6-RUNX1 fusions, are also associated with good prognosis in DS-ALL.6, 7
Given the superior EFS of ML-DS compared to non-ML-DS, a major focus of recent clinical trials has been to reduce treatment intensity and toxicity.5, 14, 15 The COG AAML0431 trial aimed to improve EFS and reduce TRM by administering high-dose cytarabine (HiDAC) during induction II instead of intensification, decreasing total anthracycline exposure, and reducing prophylactic intrathecal chemotherapy.14 While the adjustments to anthracyclines and intrathecal chemotherapy did not affect EFS or OS, the earlier HiDAC exposure improved both metrics, though adverse events occurred more frequently during induction II.5, 14 The COG AAML1531 trial subsequently had the goal of omitting HiDAC in standard-risk patients with ML-DS who achieved measurable residual disease (MRD) less than 0.05 percent at the end of induction I.5 Unfortunately, children who did not receive HiDAC-based induction II had significantly higher relapse rates and worse EFS compared to MRD-negative patients treated on AAML0431, demonstrating that HiDAC inclusion is an essential component of ML-DS therapy.5 Interestingly, a Japanese Childhood AML Cooperative Study Group trial investigating a similar cytarabine dose-reduction reported much lower TRM and no significant differences in three-year EFS and OS,16 concordant with earlier studies.15, 17 Differences in anthracycline pharmacodynamics and other small differences among treatment protocols have been hypothesized to account for these discrepant results,18 but these effects remain difficult to isolate, and HiDAC remains essential in ML-DS therapy in the United States.
The small numbers of children with relapsed/refractory ML-DS have limited the ability to identify prognostic molecular characteristics and other biomarkers. In addition to MRD positivity, older age at diagnosis (≥4 years) has been suggested to portend an inferior prognosis,17, 19 though such ML-DS cases are usually more genetically similar to non-DS-associated AML.20 The genetic characteristics of ML-DS blasts are clearly distinct from non-ML-DS cells,5 which is consistent with the unique cellular origins of ML-DS, but the exact significance of the pathogenic GATA1 mutations remains unclear. In a phenomenon termed “silent TMD,” as many as 30 percent of neonates with DS have been reported to have GATA1 mutations without detectable TMD in peripheral blood.17, 21, 22 Interestingly, no association has been identified between specific GATA1 mutations and risk of ultimately developing ML-DS.23
Patients with relapsed DS-ALL24, 25 or ML-DS5, 19 have poor prognoses, with successful salvage (including allogeneic hematopoietic stem cell transplantation) often limited by TRM and subsequent relapses.24, 25 Exclusion of children with DS-associated leukemias from many early-phase clinical trials has hampered both access to innovative new therapies and tailored protocols focused upon DS-specific toxicity reduction.26 Emerging data encouragingly suggest that patients with relapsed/refractory DS-ALL tolerate CD19-directed cellular therapy well, which can perhaps be used as definitive therapy without hematopoietic stem cell transplantation in some patients.27 Similar advances are still needed for children with relapsed/refractory ML-DS.
Dr. Takasaki and Dr. Tasian indicated no relevant conflicts of interest.