Treatment of chronic myeloid leukemia has improved significantly with the introduction of tyrosine kinase inhibitors (TKIs), and treatment guidelines based on numerous clinical trials are available for chronic phase disease. However for CML in the blast phase (CML-BP), prognosis remains poor and treatment options are much more limited. The spectrum of treatment strategies for children and adolescents with CML-BP has largely evolved empirically and includes treatment principles derived from adult CML-BP and pediatric acute leukemia. Given this heterogeneity of treatment approaches, we formed an international panel of pediatric CML experts to develop recommendations for consistent therapy in children and adolescents with this high-risk disease based on the current literature and national standards. Recommendations include detailed information on initial diagnosis and treatment monitoring, differentiation from Philadelphia-positive acute leukemia, subtype-specific selection of induction therapy, and combination with tyrosine kinase inhibitors. Given that allogeneic hematopoietic stem cell transplantation currently remains the primary curative intervention for CML-BP, we also provide recommendations for the timing of transplantation, donor and graft selection, selection of a conditioning regimen and prophylaxis for graft-versus-host disease, post-transplant TKI therapy, and management of molecular relapse. Management according to the treatment recommendations presented here is intended to provide the basis for the design of future prospective clinical trials to improve outcomes for this challenging disease.

• MeSH
• Leukemia, Myeloid, Acute * MeSH
• Blast Crisis therapy   MeSH
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive * drug therapy   diagnosis   MeSH
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Graft vs Host Disease * MeSH
• Prognosis MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH
• Adolescent MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

• MeSH
• Child MeSH
• Adult MeSH
• Gene Rearrangement * MeSH
• Infant MeSH
• Humans MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor genetics   MeSH
• Follow-Up Studies MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma genetics   pathology   MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Retrospective Studies MeSH
• Trans-Activators genetics   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• Biomarkers, Tumor MeSH
• Trans-Activators MeSH
• ZNF384 protein, human MeSH Browser

Recently, we described B-cell precursor acute lymphoblastic leukemia (BCP-ALL) subtype with early switch to the monocytic lineage and loss of the B-cell immunophenotype, including CD19 expression. Thus far, the genetic background has remained unknown. Among 726 children consecutively diagnosed with BCP-ALL, 8% patients experienced switch detectable by flow cytometry (FC). Using exome and RNA sequencing, switch was found to positively correlate with three different genetic subtypes: PAX5-P80R mutation (5 cases with switch out of 5), rearranged DUX4 (DUX4r; 30 cases of 41) and rearranged ZNF384 (ZNF384r; 4 cases of 10). Expression profiles or phenotypic patterns correlated with genotypes, but within each genotype they could not identify cases who subsequently switched. If switching was not taken into account, the B-cell-oriented FC assessment underestimated the minimal residual disease level. For patients with PAX5-P80R, a discordance between FC-determined and PCR-determined MRD was found on day 15, resulting from a rapid loss of the B-cell phenotype. Discordance on day 33 was observed in all the DUX4r, PAX5-P80R and ZNF384r subtypes. Importantly, despite the substantial phenotypic changes, possibly even challenging the appropriateness of BCP-ALL therapy, the monocytic switch was not associated with a higher incidence of relapse and poorer prognosis in patients undergoing standard ALL treatment.

• MeSH
• PAX5 Transcription Factor genetics   MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * MeSH
• B-Lymphocytes MeSH
• Immunophenotyping MeSH
• Humans MeSH
• Mutation MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma * diagnosis   genetics   MeSH
• Neoplasm, Residual MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• PAX5 Transcription Factor MeSH
• PAX5 protein, human MeSH Browser

Traditionally, genetic abnormalities detected by conventional karyotyping, fluorescence in situ hybridization, and polymerase chain reaction divided childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) into well-established genetic subtypes. This genetic classification has been prognostically relevant and thus used for the risk stratification of therapy. Recently, the introduction of genome-wide approaches, including massive parallel sequencing methods (whole-genome, -exome, and -transcriptome sequencing), enabled extensive genomic studies which, together with gene expression profiling, largely expanded our understanding of leukemia pathogenesis and its heterogeneity. Novel BCP-ALL subtypes have been described. Exact identification of recurrent genetic alterations and their combinations facilitates more precise risk stratification of patients. Discovery of targetable lesions in subsets of patients enables the introduction of new treatment modalities into clinical practice and stimulates the transfer of modern methods from research laboratories to routine practice.

• Keywords
• acute lymphoblastic leukemia, children, massive parallel sequencing, new BCP-ALL subtypes,
• MeSH
• Acute Disease MeSH
• Child MeSH
• Exome genetics   MeSH
• Genomics methods   MeSH
• Risk Assessment methods   MeSH
• Humans MeSH
• Precursor B-Cell Lymphoblastic Leukemia-Lymphoma classification   genetics   MeSH
• Gene Expression Profiling MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH