PURPOSE: We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials. PATIENTS AND METHODS: This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome. RESULTS: With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction. CONCLUSION: MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.

Dana Farber Cancer Institute Boston Children's Hospital Boston MA

Great Ormond Street Hospital London United Kingdom

Lund University Lund Sweden

MacKay Memorial Hospital Taipei Taiwan

National University of Singapore Singapore

Northern Institute for Cancer Research Newcastle University Newcastle upon Tyne United Kingdom

Princess Máxima Centre for Pediatric Oncology Utrecht the Netherlands

Robert Debré Hospital and Paris Diderot University Paris France

Saitama Children's Medical Center Saitama Japan

St Anna's Children's Hospital and Medical University of Vienna Vienna Austria

St Jude Children's Research Hospital and University of Tennessee Health Science Center Memphis TN

Tel Aviv University Tel Aviv Israel

University Hospital Motol and Charles University Prague Czech Republic

University of Kiel and University Medical Center Schleswig Holstein Kiel Germany

University of Milano Bicocca Monza Italy

University of Padova Padova Italy

J Clin Oncol. 2019 Apr 1;37(10):763-764. doi: 10.1200/JCO.19.00143. PubMed

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Pui CH, Williams DL, Raimondi SC, et al. : Hypodiploidy is associated with a poor prognosis in childhood acute lymphoblastic leukemia. Blood 70:247-253, 1987 PubMed

Pui CH, Carroll AJ, Raimondi SC, et al. : Clinical presentation, karyotypic characterization, and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or hypodiploid less than 45 line. Blood 75:1170-1177, 1990 PubMed

Heerema NA, Nachman JB, Sather HN, et al. : Hypodiploidy with less than 45 chromosomes confers adverse risk in childhood acute lymphoblastic leukemia: A report from the Children’s Cancer Group. Blood 94:4036-4045, 1999 PubMed

Raimondi SC, Zhou Y, Mathew S, et al. : Reassessment of the prognostic significance of hypodiploidy in pediatric patients with acute lymphoblastic leukemia. Cancer 98:2715-2722, 2003 PubMed

Harrison CJ, Moorman AV, Broadfield ZJ, et al. : Three distinct subgroups of hypodiploidy in acute lymphoblastic leukaemia. Br J Haematol 125:552-559, 2004 PubMed

Nachman JB, Heerema NA, Sather H, et al. : Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood 110:1112-1115, 2007 PubMed PMC

Holmfeldt L, Wei L, Diaz-Flores E, et al. : The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 45:242-252, 2013 PubMed PMC

Pui CH, Yang JJ, Hunger SP, et al. : Childhood acute lymphoblastic leukemia: Progress through collaboration. J Clin Oncol 33:2938-2948, 2015 PubMed PMC

Schultz KR, Devidas M, Bowman WP, et al. : Philadelphia chromosome-negative very high-risk acute lymphoblastic leukemia in children and adolescents: Results from Children’s Oncology Group Study AALL0031. Leukemia 28:964-967, 2014 PubMed PMC

Oliansky DM, Camitta B, Gaynon P, et al. : Role of cytotoxic therapy with hematopoietic stem cell transplantation in the treatment of pediatric acute lymphoblastic leukemia: Update of the 2005 evidence-based review. Biol Blood Marrow Transplant 18:505-522, 2012 PubMed

Pui CH, Pei D, Coustan-Smith E, et al. : Clinical utility of sequential minimal residual disease measurements in the context of risk-based therapy in childhood acute lymphoblastic leukaemia: A prospective study. Lancet Oncol 16:465-474, 2015 PubMed PMC

Pui CH, Pei D, Raimondi SC, et al. : Clinical impact of minimal residual disease in children with different subtypes of acute lymphoblastic leukemia treated with Response-Adapted therapy. Leukemia 31:333-339, 2017 PubMed PMC

O’Connor D, Enshaei A, Bartram J, et al. : Genotype-specific minimal residual disease interpretation improves stratification in pediatric acute lymphoblastic leukemia. J Clin Oncol 36:34-43, 2018 PubMed PMC

Schrappe M, Bleckmann K, Zimmermann M, et al. : Reduced-intensity delayed intensification in standard-risk pediatric acute lymphoblastic leukemia defined by undetectable minimal residual disease: Results of an international randomized trial (AIEOP-BFM ALL 2000). J Clin Oncol 36:244-253, 2018 PubMed

Pieters R, de Groot-Kruseman H, Van der Velden V, et al. : Successful therapy reduction and intensification for childhood acute lymphoblastic leukemia based on minimal residual disease monitoring: Study ALL10 from the Dutch Childhood Oncology Group. J Clin Oncol 34:2591-2601, 2016 PubMed

Roberts KG, Li Y, Payne-Turner D, et al. : Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia. N Engl J Med 371:1005-1015, 2014 PubMed PMC

Pui CH, Roberts KG, Yang JJ, et al. : Philadelphia chromosome-like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk 17:464-470, 2017 PubMed PMC

Roberts KG, Pei D, Campana D, et al. : Outcomes of children with BCR-ABL1–like acute lymphoblastic leukemia treated with risk-directed therapy based on the levels of minimal residual disease. J Clin Oncol 32:3012-3020, 2014 PubMed PMC

Mullighan CG, Jeha S, Pei D, et al. : Outcome of children with hypodiploid ALL treated with risk-directed therapy based on MRD levels. Blood 126:2896-2899, 2015 PubMed PMC

Shaffer LG, Slovak ML and Campbell LJ (eds): An International System for Human Cytogenetic Nomenclature. Basel, Switzerland, Karger, 2009.

Simon R, Makuch RW: A non-parametric graphical representation of the relationship between survival and the occurrence of an event: Application to responder versus non-responder bias. Stat Med 3:35-44, 1984 PubMed

Klein JP, Logan B, Harhoff M, et al. : Analyzing survival curves at a fixed point in time. Stat Med 26:4505-4519, 2007 PubMed

Rebora P, Galimberti S, Valsecchi MG: Using multiple timescale models for the evaluation of a time-dependent treatment. Stat Med 34:3648-3660, 2015 PubMed

Vora A, Goulden N, Mitchell C, et al. : Augmented post-remission therapy for a minimal residual disease-defined high-risk subgroup of children and young people with clinical standard-risk and intermediate-risk acute lymphoblastic leukaemia (UKALL 2003): A randomised controlled trial. Lancet Oncol 15:809-818, 2014 PubMed

Attarbaschi A, Panzer-Grümayer R, Mann G, et al. : Minimal residual disease-based treatment is adequate for relapse-prone childhood acute lymphoblastic leukemia with an intrachromosomal amplification of chromosome 21: The experience of the ALL-BFM 2000 trial. Klin Padiatr 226:338-343, 2014 PubMed

Stanulla M, Dagdan E, Zaliova M, et al. : IKZF1plus defines a new minimal residual disease-dependent very-poor prognostic profile in pediatric B-cell precursor acute lymphoblastic leukemia. J Clin Oncol 36:1240-1249, 2018 PubMed

Reference deleted.

Qian M, Cao X, Devidas M, et al. : TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol 36:591-599, 2018 PubMed PMC

Mehta PA, Zhang MJ, Eapen M, et al. : Transplantation outcomes for children with hypodiploid acute lymphoblastic leukemia. Biol Blood Marrow Transplant 21:1273-1277, 2015 PubMed PMC

Maude SL, Laetsch TW, Buechner J, et al. : Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med 378:439-448, 2018 PubMed PMC

Gökbuget N, Dombret H, Bonifacio M, et al. : Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood 131:1522-1531, 2018 PubMed PMC

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