High-Dose Cytarabine Is Indispensable for the Survival of Children with Myeloid Leukemia of Down Syndrome Despite Negative Minimal Residual Disease Post-Induction

Abstract

Introduction. Myeloid leukemia in children with Down syndrome (ML-DS) is a unique subtype of acute myeloid leukemia, distinguished by an earlier age of onset (under 4 years of age); somatic mutations of GATA1; hypersensitivity of leukemic blasts to cytarabine and other chemotherapeutic agents; lack of CNS involvement; and superior event-free survival (EFS, 85-90% at 5 years). Due to these excellent outcomes, successive protocols by the Children's Oncology Group (COG) have aimed for a reduction of treatment intensity but continue to include a course containing high-dose cytarabine (HD-AraC) for all patients, which is associated with the bulk of infectious toxicity. COG AAML1531 is the first study to evaluate differential treatment for ML-DS patients based on risk-stratification. We report the outcomes for patients with Standard Risk (SR) ML-DS enrolled on AAML1531, who were treated without inclusion of HD-AraC (https://clinicaltrials.gov/ct2/show/NCT02521493?term=AAML1531&rank=1). Methods. Patients older than 90 days and younger than 4 years of age with ML-DS were eligible, including those presenting with myelodysplastic syndrome (< 20% blasts in the bone marrow) and trisomy 21 mosaicism. Pathological and cytogenetic data were reviewed centrally. All patients received the same first course of induction therapy (cytarabine 200 mg/m2/24h IV as continuous infusion, day 1-4; daunorubicin 20 mg/m2IV, day 1-4; thioguanine 50 mg/m2/dose PO twice daily, day 1-4; and a single dose of age-based intrathecal cytarabine on day 1). After this first course, measureable residual disease (MRD) in the bone marrow by multi-dimensional flow cytometry in a reference laboratory was used for risk stratification. Patients with negative MRD (<0.05%) were assigned to Standard Risk (SR) therapy, which was modeled after the AAML0431 predecessor study, but with further reduction of treatment by omission of the course containing HD-AraC/E. coli asparaginase (Induction II of AAML0431). Courses #2 and #3 of SR therapy were identical to the first course except that no further intrathecal chemotherapy was administered. Courses #4 and #5 (cytarabine 100 mg/m2/24h IV as continuous infusion day 1-7; etoposide 125 mg/m2 IV, day 1-3) were identical to the corresponding courses of AAML0431. For patients younger than 36 months, chemotherapy doses were calculated based on weight. Use of dexrazoxane during anthracycline-containing courses was at the discretion of the treating center but was captured by the data collection of the study. Patients with positive MRD (>0.05%) after the first course were assigned to the High Risk (HR) Arm and received intensified therapy (equivalent to that used for non-DS AML). Accrual to the HR arm is ongoing. Results. Interim analysis of SR therapy was performed after 50% of expected EFS events had occurred as of June 30, 2018. The observed EFS was 89.3 +/- 6.1% at 2 years from study entry and significantly lower than expected for comparable MRD-negative patients whose treatment in predecessor study AAML0431 included a course of HD-AraC/E. coliasparaginase (p=0.0002). OS at 2 years was 88.7 +/- 6.8%. Among a total of 114 SR ML-DS patients, 11 developed a relapse, all within the first year from study entry (range 136-327 days). OS at 1 year from relapse was 9.1 +/- 17.3%. Based on the results of interim analysis, the SR arm of AAML1531 was closed to accrual due to lack of efficacy. Cytogenetic analysis showed that complex karyotypes (defined as >3 independent abnormalities including >1 structural one) were significantly more frequent in SR patients who relapsed (40%, n=10) compared to SR patients who did not (9%; n=100; p=0.017). The most common abnormalities were trisomies (61% of cases) of chromosomes 3 and 8, and a gain of a fourth copy of chromosome 21. Monosomy 7 was present in 20% of relapsed vs. 5% of patients without a relapse (p=0.122). Conclusions. MRD measured by multi-dimensional flow cytometry is insufficient to identify a subset of ML-DS patients for whom HD-AraC/E.coliasparaginase can be eliminated from treatment. Cytogenetic profiling may aid in further refining risk-based subsets of ML-DS patients. Additional approaches to risk stratification of ML-DS should be pursued, which take into account the emerging genetic events that co-operate with mutant GATA1 in the development of ML-DS. At this time, HD-AraC/E.coli asparaginase should be included in the treatment of ML-DS, regardless of MRD. Disclosures Druley: Washington University: Employment; ArcherDX Inc.: Employment, Equity Ownership. Loken:Hematologics, Inc: Employment, Equity Ownership. Eidenschink Brodersen:Hematologics, Inc: Employment.

Clonal Myeloproliferative Disorders in Patients with Down Syndrome—Treatment and Outcome Results from an Institution in Argentina

“…Complex karyotypes have been reported to be associated with an unfavorable therapy outcome in adult and childhood malignant myeloid disorders [66][67][68]. Worse outcomes related to CK were previously observed in DS-AML [23,41], although another group could not associate CK with worse OS, EFS or CIR [57]. In this report, CK, as well as non-megakaryoblastic immunophenotype and older age, were identified as poor prognostic factors.…”

“…Also, only one patient of sporadic DS-AML aged 11 years old presented a favorable cytogenetic rearrangement [6,33,37,58,60]. As previously described, the incidence of chromosomal abnormalities was higher in AML than in TAM patients [22,61], being +8 the most frequent chromosome alteration = [30,[33][34][35]37,41,57,59,60].…”

“…Less treatment-related mortality (TRM) was described when more time is given for marrow recovery [35,37,40]. Several treatment groups have identified incorporation of High-Dose Cytarabine (HDARA-C) as responsible for better outcomes in DS-AML [27,31,37,41]. In the ML-BFM98 study [42], the cumulative doses of anthracyclines and cytarabine were reduced compared to the BFM93 study omitting the HAM block, and high cure rates were achieved.…”

Gain of chromosome 21 in hematological malignancies: lessons from studying leukemia in children with Down syndrome

“…Due to concerns regarding increased treatment-related toxicity in children with ML–DS [ 28 – 30 ], sequential protocols successfully reduced cumulative exposure to several agents including daunorubicin, etoposide, and intrathecal cytarabine without impacting on overall outcome [ 13 , 14 , 26 , 27 ]. High-dose cytarabine was established as an important component of therapy, with early administration leading to improved outcomes [ 13 ] and subsequent attempts to omit high-dose cytarabine in standard-risk patients resulting in significantly lower event-free survival [ 31 ]. Several studies have identified older age as an unfavorable independent prognostic feature [ 26 , 27 , 32 ].…”

Treatments for children and adolescents with AML

“…Instead, intensification included two cycles of cytarabine and etoposide. Currently, the first prospective trial based on risk stratification in this patient group is being conducted through an assessment of MRD levels at the end of induction I [ 45 ].…”