Purpose To review the impact of collaborative studies on advances in the biology and treatment of acute lymphoblastic leukemia (ALL) in children and adolescents. Methods A review of English literature on childhood ALL focusing on collaborative studies was performed. The resulting article was reviewed and revised by the committee chairs of the major ALL study groups. Results With long-term survival rates for ALL approaching 90% and the advent of high-resolution genome-wide analyses, several international study groups or consortia were established to conduct collaborative research to further improve outcome. As a result, treatment strategies have been improved for several subtypes of ALL, such as infant, MLL-rearranged, Philadelphia chromosome–positive, and Philadelphia chromosome–like ALL. Many recurrent genetic abnormalities that respond to tyrosine kinase inhibitors and multiple genetic determinants of drug resistance and toxicities have been identified to help develop targeted therapy. Several genetic polymorphisms have been recognized that show susceptibility to developing ALL and that help explain the racial/ethnic differences in the incidence of ALL. Conclusion The information gained from collaborative studies has helped decipher the heterogeneity of ALL to help improve personalized treatment, which will further advance the current high cure rate and the quality of life for children and adolescents with ALL.

Key Points• Although the risk of ALL relapse is significantly higher in children with DS, goodprognosis subgroups have been identified. • Patients with DS-ALL have higher treatment-related mortality throughout the treatment period independent of the therapeutic regimen.Children with Down syndrome (DS) have an increased risk of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). The prognostic factors and outcome of DS-ALL patients treated in contemporary protocols are uncertain. We studied 653 DS-ALL patients enrolled in 16 international trials from 1995 to 2004. Non-DS BCP-ALL patients from the Dutch Child Oncology Group and Berlin-Frankfurt-Münster were reference cohorts. DS-ALL patients had a higher 8-year cumulative incidence of relapse (26% 6 2% vs 15% 6 1%, P < .001) and 2-year treatment-related mortality (TRM) (7% 6 1% vs 2.0% 6 <1%, P < .0001) than non-DS patients, resulting in lower 8-year event-free survival (EFS) (64% 6 2% vs 81% 6 2%, P < .0001) and overall survival (74% 6 2% vs 89% 6 1%, P < .0001). Independent favorable prognostic factors include age <6 years (hazard ratio [HR] 5 0.58, P 5 .002), white blood cell (WBC) count <10 3 10 9 /L (HR 5 0.60, P 5 .005), and ETV6-RUNX1 (HR 5 0.14, P 5 .006) for EFS and age (HR 5 0.48, P < .001), ETV6-RUNX1 (HR 5 0.1, P 5 .016) and high hyperdiploidy (HeH) (HR 5 0.29, P 5 .04) for relapse-free survival. TRM was the major cause of death in ETV6-RUNX1 and HeH DSALLs. Thus, while relapse is the main contributor to poorer survival in DS-ALL, infection-associated TRM was increased in all protocol elements, unrelated to treatment phase or regimen. Future strategies to improve outcome in DS-ALL should include improved supportive care throughout therapy and reduction of therapy in newly identified good-prognosis subgroups. (Blood. 2014; 123(1):70-77)

PURPOSE Infant acute lymphoblastic leukemia (ALL) is characterized by KMT2A ( MLL) gene rearrangements and coexpression of myeloid markers. The Interfant-06 study, comprising 18 national and international study groups, tested whether myeloid-style consolidation chemotherapy is superior to lymphoid style, the role of stem-cell transplantation (SCT), and which factors had independent prognostic value. MATERIALS AND METHODS Three risk groups were defined: low risk (LR): KMT2A germline; high risk (HR): KMT2A-rearranged and older than 6 months with WBC count 300 × 109/L or more or a poor prednisone response; and medium risk (MR): all other KMT2A-rearranged cases. Patients in the MR and HR groups were randomly assigned to receive the lymphoid course low-dose cytosine arabinoside [araC], 6-mercaptopurine, cyclophosphamide (IB) or experimental myeloid courses, namely araC, daunorubicin, etoposide (ADE) and mitoxantrone, araC, etoposide (MAE). RESULTS A total of 651 infants were included, with 6-year event-free survival (EFS) and overall survival of 46.1% (SE, 2.1) and 58.2% (SE, 2.0). In West European/North American groups, 6-year EFS and overall survival were 49.4% (SE, 2.5) and 62.1% (SE, 2.4), which were 10% to 12% higher than in other countries. The 6-year probability of disease-free survival was comparable for the randomized arms (ADE+MAE 39.3% [SE 4.0; n = 169] v IB 36.8% [SE, 3.9; n = 161]; log-rank P = .47). The 6-year EFS rate of patients in the HR group was 20.9% (SE, 3.4) with the intention to undergo SCT; only 46% of them received SCT, because many had early events. KMT2A rearrangement was the strongest prognostic factor for EFS, followed by age, WBC count, and prednisone response. CONCLUSION Early intensification with postinduction myeloid-type chemotherapy courses did not significantly improve outcome for infant ALL compared with the lymphoid-type course IB. Outcome for infant ALL in Interfant-06 did not improve compared with that in Interfant-99.

Key Points• BCR-ABL1-like signature and IKZF1 deletions are clinically important to identify high-risk acute lymphoblastic patients.Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the cooccurrence and independent prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1-negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1-negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies. (Blood. 2013;122(15):2622-2629