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The Evolving Role of Hematopoietic Stem Cell Transplantation in Philadelphia-like Acute Lymphoblastic Leukemia: From High-Risk Standard to Precision Strategies
by
, , and
Matteo Molica
1,*
,
Claudia Simio
1,
Laura De Fazio
1,
Caterina Alati
2,
Marco Rossi
1 and
Massimo Martino
2
1
Department of Hematology-Oncology, Azienda Universitaria Ospedaliera Renato Dulbecco, 88100 Catanzaro, Italy
2
Hematology and Stem Cell Transplantation and Cellular Rerapies Unit (CTMO), Department of Hemato-Oncology and Radiotherapy, Grande Ospedale Metropolitano “Bianchi-Melacrino-Morelli”, Presidio Morelli, 89128 Reggio Calabria, Italy
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(19), 3237; https://doi.org/10.3390/cancers17193237 (registering DOI)
Submission received: 28 August 2025
/
Revised: 29 September 2025
/
Accepted: 4 October 2025
/
Published: 5 October 2025
(This article belongs to the Special Issue Hematopoietic Stem Cell Transplant in Hematological Malignancies)
Simple Summary
Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk form of B-cell ALL, characterized by kinase-activating genetic alterations and a poor response to conventional chemotherapy. This review analyzes the role of allogeneic hematopoietic stem cell transplantation (allo-HSCT), highlighting that transplantation in first remission may improve survival in patients with high molecular risk or positive measurable residual disease (MRD). Personalized therapeutic approaches based on genomic profiling and MRD assessment are becoming essential. New strategies, such as immunotherapy, TKIs, JAK inhibitors, and CAR-T cells, may improve clinical outcomes and, in some cases, prevent the need for allo-HSCT.
Abstract
Background: Philadelphia-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype of B-cell ALL characterized by a gene expression profile similar to BCR::ABL1-positive leukemia, but lacking the BCR::ABL1 fusion gene. It is frequently associated with kinase-activating alterations, such as CRLF2 rearrangements, JAK-STAT pathway mutations, and ABL-class fusions. Patients with Ph-like ALL typically experience poor outcomes with conventional chemotherapy, underscoring the need for intensified and targeted therapeutic approaches. Methods: This review summarizes current evidence regarding the role of hematopoietic stem cell transplantation (HSCT) in patients with Ph-like ALL. We analyzed retrospective cohort studies, registry data, and ongoing clinical trials, focusing on transplant indications, molecular risk stratification, measurable residual disease (MRD) status, timing of transplant, and post-transplant strategies. Results: Retrospective data suggest that HSCT in first complete remission (CR1) may improve survival in patients with high-risk molecular lesions or MRD positivity at the end of induction. However, the lack of prospective data specific to Ph-like ALL limits definitive conclusions. Post-transplant relapse remains a challenge, and novel strategies, including the use of tyrosine kinase inhibitors or JAK inhibitors as post-HSCT maintenance therapy, are being explored. Emerging immunotherapies, such as chimeric antigen receptor (CAR) T cells, may reshape the therapeutic landscape and potentially alter the indications for transplantation. Conclusions: HSCT remains a crucial therapeutic option for selected patients with Ph-like ALL, particularly those with poor molecular risk features or persistent MRD. However, further prospective studies are needed to evaluate the indication for HSCT in CR1 and the potential integration of transplantation with targeted and immunotherapeutic strategies. Personalized treatment approaches based on genomic profiling and MRD assessment are essential to improve outcomes in this high-risk subset.
