Kelly W. Maloney

Chromosomal rearrangements are initiating events in acute lymphoblastic leukaemia (ALL). Here using RNA sequencing of 560 ALL cases, we identify rearrangements between MEF2D (myocyte enhancer factor 2D) and five genes (BCL9, CSF1R, DAZAP1, HNRNPUL1 and SS18) in 22 B progenitor ALL (B-ALL) cases with a distinct gene expression profile, the most common of which is MEF2D-BCL9. Examination of an extended cohort of 1,164 B-ALL cases identified 30 cases with MEF2D rearrangements, which include an additional fusion partner, FOXJ2; thus, MEF2D-rearranged cases comprise 5.3% of cases lacking recurring alterations. MEF2D-rearranged ALL is characterized by a distinct immunophenotype, DNA copy number alterations at the rearrangement sites, older diagnosis age and poor outcome. The rearrangements result in enhanced MEF2D transcriptional activity, lymphoid transformation, activation of HDAC9 expression and sensitive to histone deacetylase inhibitor treatment. Thus, MEF2D-rearranged ALL represents a distinct form of high-risk leukaemia, for which new therapeutic approaches should be considered.

genes vs flow cytometry (FC) for measurable residual disease (MRD) detection at the end of induction chemotherapy in pediatric patients with newly diagnosed B-ALL. Six hundred nineteen paired pretreatment and end-of-induction bone marrow samples from Children's Oncology Group studies AALL0331 (clinicaltrials.gov #NCT00103285) (standard risk [SR]; with MRD by FC at any level) and AALL0232 (clinicaltrials.gov #NCT00075725) (high risk; with day 29 MRD <0.1% by FC) were evaluated by HTS and FC for event-free (EFS) and overall survival (OS). HTS and FC showed similar 5-year EFS and OS for MRD-positive and -negative patients using an MRD threshold of 0.01%. However, there was a high discordant rate with HTS identifying 55 (38.7%) more patients MRD positive at this threshold. These discrepant patients have worse outcomes than FC MRD-negative patients. In addition, the increased analytic sensitivity of HTS permitted identification of 19.9% of SR patients without MRD at any detectable level who had excellent 5-year EFS (98.1%) and OS (100%). The higher analytic sensitivity and lower false-negative rate of HTS improves upon FC for MRD detection in pediatric B-ALL by identifying a novel subset of patients at end of induction who are essentially cured using current chemotherapy and identifying MRD at 0.01% in up to one-third of patients who are missed at the same threshold by FC.

Durable remissions in children with acute lymphoblastic leukemia (ALL) require a 2-year maintenance phase that includes daily oral 6-mercaptopurine (6MP). Adherence to oral 6MP among Asian-American and African-American children with ALL is unknown. We enrolled 298 children with ALL (71 Asian Americans, 68 African Americans, and 159 non-Hispanic whites) receiving oral 6MP for the maintenance phase. Adherence was measured electronically for 39 803 person-days. Adherence declined from 95.0% (month 1) to 91.8% (month 5, P < .0001). Adherence rates were significantly (P < .0001) lower in Asian Americans (90.0% ± 4.9%) and African Americans (87.1% ± 4.4%), as compared with non-Hispanic whites (95.2% ± 1.3%). Race-specific sociodemographic characteristics helped explain poor adherence (African Americans: low maternal education [less than a college degree: 78.9%, vs at least college degree: 94.6%; P < .0001]; Asian Americans: low-income households [<$50 000: 84.5%, vs ≥$50 000: 96.7%; P = .04]; households without mothers as full-time caregivers [85.6%] vs households with mothers as full-time caregivers [97.2%; P = .05]). Adherence rate below 90% was associated with increased relapse risk (hazard ratio, 3.9; P = .01). Using an adherence rate <90% to define nonadherence, 20.5% of the participants were nonadherers. We identify race-specific determinants of adherence, and define a clinically relevant level of adherence needed to minimize relapse risk in a multiracial cohort of children with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00268528.