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Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia.

ABSTRACT: The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR-ABL1 fusion gene encoding for a chimeric BCR-ABL1 protein. It is present in 3-4% of pediatric acute lymphoblastic leukemia (Ph(+) ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph(+) ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutionized the therapy of Ph(+) ALL. Addition of the first generation ABL1 class TKI imatinib to intensive chemotherapy dramatically increased the survival for children with Ph(+) ALL and established that many patients can be cured without HSCT. In parallel, the mechanistic understanding of Ph(+) ALL expanded exponentially through careful mapping of pathways downstream of BCR-ABL1, the discovery of mutations in master regulators of B-cell development such as IKZF1 (Ikaros), PAX5, and early B-cell factor (EBF), the recognition of the complex clonal architecture of Ph(+) ALL, and the delineation of genomic, epigenetic, and signaling abnormalities contributing to relapse and resistance. Still, many important basic and clinical questions remain unanswered. Current clinical trials are testing second generation TKIs in patients with newly diagnosed Ph(+) ALL. Neither the optimal duration of therapy nor the optimal chemotherapy backbone are currently defined. The role of HSCT in first remission and post-transplant TKI therapy also require further study. In addition, it will be crucial to continue to dig deeper into understanding Ph(+) ALL at a mechanistic level, and translate findings into complementary targeted approaches. Expanding targeted therapies hold great promise to decrease toxicity and improve survival in this high-risk disease, which provides a paradigm for how targeted therapies can be incorporated into treatment of other high-risk leukemias.

SUBMITTER: Bernt KM

PROVIDER: S-EPMC3971203 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia.

Bernt Kathrin M KM Bernt Kathrin M KM Hunger Stephen P SP

Frontiers in oncology 20140325

The t(9;22)(q34;q11) or Philadelphia chromosome creates a BCR-ABL1 fusion gene encoding for a chimeric BCR-ABL1 protein. It is present in 3-4% of pediatric acute lymphoblastic leukemia (Ph(+) ALL), and about 25% of adult ALL cases. Prior to the advent of tyrosine kinase inhibitors (TKI), Ph(+) ALL was associated with a very poor prognosis despite the use of intensive chemotherapy and frequently hematopoietic stem-cell transplantation (HSCT) in first remission. The development of TKIs revolutioni ...[more]

PMID: 24724051

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Project description:Background and objective Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL Ph+) is quite rare among pediatric patients. Its management has undergone significant changes in the past few years, leading to some variability in how it is approached. At the Portuguese Oncology Institute of Porto (IPOP), a tertiary oncological center, the standard of care has been aligned with the guidelines proposed by the European intergroup study of post-induction treatment of ALL Ph+ (EsPhALL). In this study, we aimed to examine the experience and outcomes related to the treatment of pediatric patients with ALL Ph+ at IPOP. Methods This retrospective cohort study involved pediatric patients diagnosed with ALL Ph+ at IPOP between January 2008 and December 2022 and analyzed their outcomes. Results A total of 14 patients were included. IKFZ1 was altered in five patients (out of nine in whom it was searched). Five patients were treated according to EsPhALL 2004, which involved starting imatinib later in a discontinuous manner [resulting in both five-year overall survival (OS) and progression-free survival (PFS) of 60%]. The EsPhALL 2010 (preconizing a continuous imatinib regimen instead) was employed in three patients, with a five-year OS and PFS of 66.7%. All children mentioned above received cranial irradiation therapy (CRT). Finally, six were treated according to the EsPhALL 2015, which stopped including CRT in its backbone. The five-year OS was 100%, whereas every patient progressed with an increase in BCR::ABL1 levels greater than 1-log. Moreover, until 2015, all patients had been recommended to undergo allogeneic hematopoietic stem cell transplantation (alloHSCT). However, since 2015, alloHSCT has been exclusively reserved for relapsed/refractory (R/R) disease or poor responders with positive measurable residual disease (MRD). In total, alloHSCT was performed in nine patients. Conclusions Although initially associated with a poor prognosis, the ALL Ph+ paradigm is drastically shifting. Further studies will hopefully clarify the outcomes in this population and help understand the role of central nervous system (CNS) prophylaxis, alloHSCT, and MRD quantification.

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Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia.

Publications

Current concepts in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia.

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