Blast Phase Chronic Myeloid Leukemia Research Articles

We describe a case of immunological rejection occurring twice after cord blood transplantation (CBT) for mixed phenotype blast phase chronic myeloid leukemia that was successfully salvaged by haploidentical peripheral blood stem cell transplantation (haplo-PBSCT) with post-transplant cyclophosphamide (PT-Cy). Pre-engraftment immune reaction (PIR) and subsequent hemophagocytic lymphohistiocytosis (HLH), likely due to HLA mismatch in the graft-versus-host (GVH) direction, lead to poor graft function (PGF) and graft failure (GF). This case highlights the pathophysiology of PIR, HLH, PGF, and GF, collectively termed "post-transplant cytokine syndrome." PT-Cy haplo-PBSCT, with wide donor availability and reduced infection risk leading to HLH via rapid engraftment, may be a suitable salvage option for post-CBT cytokine syndrome-related GF.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a key treatment for patients with chronic myeloid leukemia (CML) in blast phase (CML-BP) or tyrosine kinase inhibitor (TKI)-resistant chronic phase (CML-CP). We retrospectively analyzed 75 patients who underwent allo-HCT at four U.S. centers from 2005 to 2023. Of these, 60 had CML-BP (26 myeloid, 34 lymphoid) and 15 had TKI-resistant CML-CP. Median overall survival (OS) was 50 months in myeloid blast phase (MBP) and not reached in lymphoid blast phase (LBP) or CML-CP. MBP had higher relapse rates and inferior leukemia-free survival (LFS) compared to LBP and CML-CP. Outcomes were worse in transformed MBP versus de novo MBP, and in those with 7/7q- deletions. Post-HCT TKI maintenance did not significantly affect relapse or survival. Our findings support allo-HCT as an effective treatment option in CML-BP and TKI-resistant CML-CP, with outcomes influenced by disease biology and cytogenetic features at transformation.

Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.

We analyzed 76 patients who received a ponatinib-based regimen, either as monotherapy or in combination with chemotherapy, for chronic myeloid leukemia in myeloid blast phase (CML-MBP). The rate of morphological remission with or without count recovery (i.e. overall response rate [ORR]) was 49%. Patients who received a ponatinib-based regimen as their first therapy for CML-MBP had better ORR than those received ponatinib as salvage (60% versus 27%, respectively; p = 0.006). ORR was also higher with ponatinib combination therapy than monotherapy (54% versus 29%, respectively; p = 0.06). For the entire cohort, the median RFS and OS were 11.9 and 8.5 months, respectively. Responding patients who underwent allogeneic HSCT had superior outcomes to those who did not (2-year OS 79% versus 38%, respectively; p = 0.05). After ponatinib failure, outcomes were dismal (median OS: 3.9 months). Ponatinib-based regimens are effective in CML-MBP, especially when used as first therapy and in combination with chemotherapy, followed by HSCT.

Pediatric chronic myeloid leukemia (CML) is more aggressive than adult CML, with unique molecular characteristics and a higher propensity for lymphoid blast crisis. The application of tyrosine kinase inhibitors (TKIs) has significantly improved the prognosis of pediatric CML. Based on international consensus and clinical experience, this article proposes standardized diagnosis and treatment recommendations for pediatric CML, covering initial therapy selection, efficacy evaluation, drug switching, and management of adverse effects. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is recommended only for patients with disease progression or failure of multiple lines of TKI therapy. For children newly diagnosed with CML in accelerated phase, high-dose imatinib or second-generation TKIs are recommended as first-line therapy. Those achieving optimal responses should continue maintenance therapy, while non-responders require switching to alternative TKIs and consider allo-HSCT. For blast-phase CML, induction therapy requires a combination of TKIs and chemotherapy, with allo-HSCT serving as the core curative intervention. This article highlights common but challenging problems (poor response, drug intolerance, and disease progression) in pediatric CML treatment using three typical cases, aiming to optimize treatment strategies. Furthermore, the goal of achieving treatment-free remission needs to be further addressed through multi-center clinical studies.

Paediatric blast-phase chronic myeloid leukaemia (CML-BP) is a rare and serious condition. Of 231 paediatric patients enrolled in the German CML-PAED-II registry between January 2007 and September 2023, 25 individuals (11%) were diagnosed with CML-BP. To identify genetic variants associated with early onset and disease transformation, we performed whole genome sequencing (WGS), deep targeted sequencing and cytogenetic analyses in 19 cases with de novo (n = 11) or secondary (n = 8) CML-BP and sufficient available biomaterial. Copy number variants (CNVs) were more frequent than single nucleotide variants (SNVs) and more prevalent in secondary than in de novo CML-BP. Recurrent pathogenic somatic SNVs were observed in ABL1 (n = 5, 24%), RUNX1 (n = 2, 12%) and ASXL1 (n = 2, 12%). Nine patients (47%) carried pathogenic germline (n = 8) or somatic (n = 1) variants in either of the genes ATM, CHEK2, FANCM, HERC2, NBN, RAD54B, RECQL4, SETD2 or TP63 belonging to the DNA damage response (DDR). Within a comparison cohort of 19 patients with chronic phase paediatric CML, only one individual (5%) exhibited a pathogenic DDR germline variant. Our study provides novel pathogenetic insights into paediatric CML-BP. The identification of pathogenic DDR-associated germline variants suggests a genetic predisposition with potential implications for patients and families concerning cancer treatment and surveillance.

NAMPT-mediated deacetylation of HCLS1 protein promotes clonogenic growth of pediatric CML cells.

A combination of tyrosine kinase inhibitors and chimeric antigen receptor (CAR) T cells has made a breakthrough in refractory or relapsed Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, it remains unclear if this treatment in newly diagnosed Ph-positive ALL is associated with high rates of complete molecular remission (CMR) and leukemia-free survival. To evaluate the efficacy and safety of dasatinib in combination with CAR T cells as frontline therapy in adults with newly diagnosed Ph-positive ALL. This trial was conducted at a single center, the First Affiliated Hospital of Zhejiang University School of Medicine. Patients were enrolled in this phase 2, single-arm nonrandomized clinical trial between March 5, 2021, and April 13, 2024. The data cutoff date was February 10, 2025. The data analysis was conducted on February 11, 2025. The median duration of follow-up was 23.9 (range, 7.3-47.7) months. A total of 29 adults with newly diagnosed Ph-positive ALL and adequate organ function were screened for eligibility, and 1 patient who received a diagnosis of blast-phase chronic myeloid leukemia was excluded. Dasatinib was administered with a 2-week vindesine and dexamethasone regimen as induction, followed by sequential CD19 and CD22 CAR T-cell therapies and single-agent dasatinib maintenance. The primary end point was CMR rate after CD19 CAR T-cell therapy. CMR was defined as undetectable BCR/ABL1 transcripts as measured by quantitative reverse transcription polymerase chain reaction with a sensitivity of 10-4 in the bone marrow. Twenty-eight patients (median [range] age, 48.5 [18.0-69.0] years; 10 female individuals [36%]) were enrolled, and 1 patient withdrew after induction. The CMR rate was 25% (7 of 28) after induction and increased to 85% (23 of 27) after CD19 CAR T-cell therapy. Twenty-five patients (89.3%) received sequential CD22 CAR T-cell therapy, and the CMR rate was 76% (19 of 25). Of the 52 CAR T-cell therapies, only 21 cases of grade 1 cytokine release syndrome occurred. After a median follow-up of 23.9 (range, 7.3-47.7) months, the 2-year overall survival and leukemia-free survival were 92%. The results of this nonrandomized clinical trial suggest that the combination of dasatinib and CAR T-cell therapy showed encouraging efficacy in newly diagnosed Ph-positive ALL with acceptable toxic effects. Further studies with larger cohorts and longer follow-up durations are needed. ClinicalTrials.gov Identifier: NCT04788472.

Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer1,2. However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81 years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1, were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3–14 years (confidence interval 2–16 years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.

Chronic myeloid leukemia in the blast phase (BP-CML) remains challenging despite advancements in tyrosine kinase inhibitors (TKIs). This study retrospectively assessed BP-CML patients who underwent allogeneic stem cell transplantation (allo-SCT) from June 2009 to December 2022. Thirty-three patients were included and the median age was 41 years, with a predominantly male cohort. Myeloablative conditioning and peripheral blood stem cells were used in the majority of the patients. The estimated 2-year overall survival (OS) was 48.3% of the cohort. Relapse occurred in 48.5% of patients, typically within 3 months post-transplant. Post-transplant TKI maintenance showed a significant association with improved OS (p-value = 0.001). The study highlights the need for early intervention and optimized post-transplant maintenance to improve outcomes.

Chronic myeloid leukemia (CML) is a rare disease during childhood, and accelerated phase (AP) and blast phase (BP) CML, also called advanced phases, are even rarer. We retrospectively collected and analyzed clinical data of children younger than 20 years with de novo advanced-phase CML between 1996 and 2017 in Japan. Median follow-up time was 8.9 years for AP-CML (n = 15) and 3.7 years for BP-CML (n = 32). The 5-year overall survival (OS) was 93.3% for AP-CML, and 100.0% for patients who received tyrosine kinase inhibitors (TKIs) in first-line therapy (n = 10). Four of the ten patients who received TKIs in first-line therapy remained in molecular remission without transplantation (median follow-up 5.5 years). The 5-year OS of patients with BP-CML was 79.0%, and most patients received chemotherapy before transplantation, with regimen selection based on blast immunophenotype. Furthermore, among patients who received transplantation after TKI therapy, the 5-year OS was 100.0% for AP and 84.8% for BP. In conclusion, our study confirmed excellent outcomes in children with de novo advanced-phase CML, especially in the TKI-era.

Vodobatinib for patients with Philadelphia chromosome-positive chronic myeloid leukaemia resistant or intolerant to multiple lines of previous therapy: an open-label, multicentre, phase 1/2 trial.

Clinical Outcomes of De Novo Versus Transformed Myeloid Blast Phase Chronic Myeloid Leukemia Following Allogeneic Hematopoietic Cell Transplantation

Chronic myeloid leukemia (CML), a refractory leukemia stem cell (LSC) disease, is characterized by the Philadelphia chromosome (Ph) t(9;22)(q34;q11.2) that generates the gene fusion between BCR and ABL1 genes. The BCR::ABL1 fusion gene products have a constitutively activated tyrosine kinase that causes leukemogenesis of CML. Tyrosine kinase inhibitors (TKIs) are effective in chronic phase of CML (CML-CP) but ineffective in blast phase of CML (CML-BC). The mechanisms of blast crisis (BC) in CML are highly complicated. This review aims to depict several mechanisms of BC induction in CML-BP. Blast transformation is caused by various mechanisms such as genetic alterations (IKZF1, TP53, INK4-ARF and Rb), epigenetic dysfunctions (aberrant methylation of CEBPα and PU.1, and underexpression of histone demethylase RBP2), suppression of differentiation-mediated transcription factors (CEBPα, CEBPβ, PU.1 and UBE2a), abnormal splicing (IKZF1 and GSK3β) and aberrantly regulated HIF-1α in bone marrow microenvironment. To develop novel therapies against blast cells in CML-BP based on the mechanisms of blast transformation, further studies are required.

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm driven by the BCR::ABL tyrosine kinase. Tyrosine kinase inhibitors (TKIs) have significantly improved the outcome of CML patients. Dasatinib, a second-generation TKI, is highly effective but associated with off-target effects, including pulmonary toxicities. While pleural effusion induced by dasatinib has been linked to therapeutic efficacy, its role remains controversial. Severe pulmonary complications, such as diffuse alveolar hemorrhage (DAH), can lead to treatment failure and increased mortality. We report a 72-year-old man with de novo blast-phase CML on clopidogrel who developed respiratory failure due to DAH 16 days after initiating dasatinib and prednisolone as induction therapy. Immediate steroid pulse therapy with methylprednisolone (1,000 mg/day for three days) was administered, and both dasatinib and clopidogrel were discontinued. Maintenance prednisolone (1 mg/kg/day) was then tapered by 10 mg per week. The patient's symptoms and radiographic findings improved without recurrence during tapering. This case highlights the importance of early recognition and management of severe complications like DAH in patients receiving dasatinib. Careful monitoring is essential to mitigate the risk of life-threatening respiratory failure and optimize CML treatment outcomes.

Management and Outcomes of Patients Diagnosed with Chronic Myeloid Leukemia in Blast Phase: A Multicenter Analysis By the H Jean Khoury Cure CML Consortium

Long-Term Outcomes in Blastic Phase Chronic Myeloid Leukemia - One Center Experience

A Retrospective Analysis of Ponatinib-Based Therapy in Patients with Myeloid Blast Phase Chronic Myeloid Leukemia: Responses Rates, Outcomes and Patterns of Relapse

Outcomes of Accelerated and Blast Phase Chronic Myeloid Leukemia at a Tertiary Center

Evaluating the Safety of Combining Tyrosine Kinase Inhibitors with Anticoagulants in Chronic Myeloid Leukemia : A Systematic Review