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Cureus Apr 2024Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), resulting from the t(9;22)(q34;q11.2)...
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome (Ph), resulting from the t(9;22)(q34;q11.2) translocation. Imatinib, a tyrosine kinase inhibitor (TKI), has revolutionized the treatment of CML. However, despite the initial response, some patients may progress to an advanced stage, such as a blast crisis. We report a 40-year-old female who presented with CML chronic phase (CP) taking imatinib 400 mg/day and achieved a complete hematological response (CHR) after one month of treatment. She achieved a suboptimal response in the third month (BCR-ABL positive 10.29% IS). However, five months into therapy, she developed a sudden lymphoid blast crisis with chromosomal aberrations involving chromosomes 10 and 12. Molecular analysis detected concomitant L248V with partial exon 4 deletion and E225V mutations within the BCR-ABL1 fusion gene. The patient received intensive chemotherapy and dasatinib. We report the first case of concomitant mutation of L248V with partial exon 4 deletion and E255V on BCR-ABL1 gene mutation, which contributes to a sudden precursor B-cell lymphoid blast crisis.
PubMed: 38800235
DOI: 10.7759/cureus.58972 -
Kidney International May 2024Acute kidney injury (AKI) is a common and devastating complication of hospitalization. Here, we identified genetic loci associated with AKI in patients hospitalized...
Acute kidney injury (AKI) is a common and devastating complication of hospitalization. Here, we identified genetic loci associated with AKI in patients hospitalized between 2002-2019 in the Million Veteran Program and data from Vanderbilt University Medical Center's BioVU. AKI was defined as meeting a modified KDIGO Stage1 or more for two or more consecutive days or kidney replacement therapy. Control individuals were required to have one or more qualifying hospitalizations without AKI and no evidence of AKI during any other observed hospitalizations. Genome-wide association studies (GWAS), stratified by race, adjusting for sex, age, baseline estimated glomerular filtration rate (eGFR), and the top ten principal components of ancestry were conducted. Results were meta-analyzed using fixed effects models. In total, there were 54,488 patients with AKI and 138,051 non-AKI individuals included in the study. Two novel loci reached genome-wide significance in the meta-analysis: rs11642015 near the FTO locus on chromosome 16 (obesity traits) (odds ratio 1.07 (95% confidence interval, 1.05-1.09)) and rs4859682 near the SHROOM3 locus on chromosome 4 (glomerular filtration barrier integrity) (odds ratio 0.95 (95% confidence interval, 0.93-0.96)). These loci colocalized with previous studies of kidney function, and genetic correlation indicated significant shared genetic architecture between AKI and eGFR. Notably, the association at the FTO locus was attenuated after adjustment for BMI and diabetes, suggesting that this association may be partially driven by obesity. Both FTO and the SHROOM3 loci showed nominal evidence of replication from diagnostic-code-based summary statistics from UK Biobank, FinnGen, and Biobank Japan. Thus, our large GWA meta-analysis found two loci significantly associated with AKI suggesting genetics may explain some risk for AKI.
PubMed: 38797326
DOI: 10.1016/j.kint.2024.04.019 -
Genes Apr 2024Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal...
Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder characterized by the presence of the Philadelphia chromosome, a product of the reciprocal translocation t(9;22)(q34;q11), in the BCR and ABL genes. These rearrangements in both genes lead to the formation of various fusion mRNA products, with preferential expression of , , and other mRNA variants, combined with additional chromosomal abnormalities. Notably, the distribution and frequency of different mRNA variants vary in different populations. However, studies concerning this in Mexico are limited, and the results have been inconclusive. This study therefore aimed to determine the distribution of mRNA variants in different clinical phases of CML and their effect on hematological parameters and patient survival. This study included 33 patients, whose demographic, clinical, and molecular data on mRNA variants and hematological parameters were collected to identify potential associations. A total of 84.8% (n = 28) of patients had translocation and increased platelet and basophil counts. The most frequent mRNA variant was (64.3%), followed by (28.6%) and (3.6%). Concerning the clinical phases of CML, 75.8% (n = 25), 21.2% (n = 7), and 3% (n = 1) of patients were in the chronic, blast, and accelerated phases, respectively. Moreover, the mRNA variant was more commonly identified in patients in the chronic phase. No correlation was observed between mRNA variant expression and patient survival. However, was indicative of patients with longer survival as well as those treated with imatinib or nilotinib. Additionally, platelet count could be a marker of translocation.
Topics: Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Female; Male; Middle Aged; Fusion Proteins, bcr-abl; Adult; Aged; RNA, Messenger; Imatinib Mesylate; Translocation, Genetic; Young Adult
PubMed: 38790196
DOI: 10.3390/genes15050567 -
HemaSphere May 2024Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high-risk...
Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL) is recognized for its genetic and clinical diversity. In this study, we identified a novel high-risk subset of Ph-like ALL, characterized by the activation of oncogenic signaling and the inactivation of the tumor suppressor gene , resulting in a dismal outcome. The association between cytogenetic aberrations and clinical features was assessed on a cohort of 191 patients with Ph-like ALL. Our findings revealed that patients with inactivation of combined with activation of oncogenic signaling ( rearrangements or high expression) had the worst outcome (3-year overall survival [OS] of 28.8% vs. 80.1% for others, < 0.001; 2-year event-free survival [EFS] of 6.5% vs. 57.0% for others, < 0.001). Multivariable analysis demonstrated that this high-risk feature was an independent inferior prognostic factor (adjusted hazard ratio for OS = 4.55, 95% confidence interval [CI]: 2.35-8.81, < 0.001; adjusted hazard ratio for EFS = 3.27, 95% CI: 1.99-5.39, < 0.001). Allogeneic hematopoietic stem cell transplantation was associated with improved prognoses in patients within the high-risk subgroup. In conclusion, this study identified a clinically distinct entity that possesses effective prognostic features and provides potential guidance for refining risk stratification in Ph-like ALL.
PubMed: 38774654
DOI: 10.1002/hem3.82 -
Expert Review of Hematology Jul 2024The treatment outcomes for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have improved with various tyrosine kinase inhibitors (TKIs) and... (Review)
Review
Is intensive chemotherapy and allogeneic stem cell transplantation mandatory for curing Philadelphia chromosome-positive acute lymphoblastic leukemia in young patients in the era of multitarget agents?
INTRODUCTION
The treatment outcomes for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) have improved with various tyrosine kinase inhibitors (TKIs) and bispecific T-cell engagers. Although allogeneic stem cell transplantation (allo-SCT) is the standard treatment for young patients with Ph+ALL, its role remains debatable in the era of TKIs and blinatumomab.
AREAS COVERED
There are some issues regarding Ph+ALL. First, do young patients require intensive chemotherapy (IC) in the era of multitarget agents? Second, which TKI is preferred for frontline therapy? Third, should allo-SCT be performed in patients achieving complete remission with ponatinib and IC? Fourth, can chemo-free treatment lead to a cure without allo-SCT? We searched relevant literature from the last 30 years on PubMed; reviewed the role of chemo-free therapies and combinations of ponatinib and IC; and assessed the necessity of allo-SCT in young patients with Ph+ALL.
EXPERT OPINION
Allo-SCT may not be needed, even in young patients with Ph+ALL treated with ponatinib-based IC or combined ponatinib and blinatumomab as frontline therapy. When adopting a ponatinib-based chemo-minimized regimen for induction, allo-SCT is needed with posttransplant ponatinib maintenance. Continuous exposure to ponatinib at pre- or post-transplant is regarded as one of the most important factor for the success of treatment.
Topics: Humans; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Transplantation, Homologous; Philadelphia Chromosome; Hematopoietic Stem Cell Transplantation; Protein Kinase Inhibitors; Antibodies, Bispecific; Antineoplastic Combined Chemotherapy Protocols; Pyridazines; Treatment Outcome; Molecular Targeted Therapy; Combined Modality Therapy; Imidazoles
PubMed: 38755522
DOI: 10.1080/17474086.2024.2357273 -
Oncology Research and Treatment May 2024Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and...
A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus...
INTRODUCTION
Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE.
METHODS
Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21.
CONCLUSION
This trial will answer several major questions in the treatment of Ph+ALL.
PubMed: 38754400
DOI: 10.1159/000539391 -
Japanese Journal of Clinical Oncology May 2024In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase...
Real-world outcomes of ponatinib treatment in 724 patients with CML and Ph+ ALL: a post-marketing surveillance study with a special interest in arterial occlusive events in Japan.
BACKGROUND
In September 2016, ponatinib was approved in Japan for the treatment of patients with chronic myeloid leukemia with resistance/intolerance to prior tyrosine kinase inhibitors and patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoblastic leukemia.
METHODS
We conducted a post-marketing all-case surveillance to study the safety and efficacy of ponatinib in clinical practice, focusing on arterial occlusive events.
RESULTS
Data from 724 patients were collected for 2 years from the initiation of ponatinib. The arterial occlusive events were reported in 6.49% (47/724) with an exposure-adjusted incidence rate of 6.8/100 person-years. The risks associated with arterial occlusive events were age and comorbidities including hypertension and diabetes. At 104 weeks, the cumulative major molecular response rate in patients with chronic-phase chronic myeloid leukemia was 67.2% and the complete cytogenetic response in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia was 80.0%. Furthermore, the estimated 1-year overall survival rate was 98.5% for chronic-phase chronic myeloid leukemia and 68.6% for Philadelphia chromosome-positive acute lymphoblastic leukemia.
CONCLUSIONS
This surveillance demonstrated that ponatinib has a favorable safety and efficacy profile in Japanese patients and also showed the necessity of closely monitoring arterial occlusive events in older adults and patients with predisposing factors for atherosclerosis.
PubMed: 38747937
DOI: 10.1093/jjco/hyae061 -
Clinical Laboratory May 2024The goal was to improve the clinical cognition of Ph-positive mixed phenotype acute leukemia and avoid misdiagnosis or delayed diagnosis.
BACKGROUND
The goal was to improve the clinical cognition of Ph-positive mixed phenotype acute leukemia and avoid misdiagnosis or delayed diagnosis.
METHODS
The clinical manifestations and laboratory results (bone marrow cell morphology, multiparameter flow cytometry, and cytogenetics) of a case of Ph-positive mixed phenotype acute leukemia were analyzed, and related literature was reviewed.
RESULTS
Blood routine: WBC 386.35 x 109/L, HGB 117.00 g/L, PLT 31 x 109/L; 80% of the original cells can be seen by artificial classification. Morphological examination of bone marrow cells showed that the proliferation of nucleated cells was obviously active, and the original cells accounted for 76%. The size of the original cells was somewhat uniform, most of the cells had less mass, were stained light grayish blue, the cytoplasm particles were not obvious, the nuclei were mostly round or quasi-round, some of them showed distortion and nuclear notch, and the chromatin was coarse. Some of the cells were rich in mass, small azurin granules were seen, the nuclei were regular, most of them were round, the chromatin was fine, the myeloperoxidase and esterase staining were negative, the eosinophils accounted for 2.5%, and the basophils accounted for 0.5%. Flow cytometry immunotyping: Two groups of abnormal cells were seen in the bone marrow. 1. A group included 12.32% of nuclear cells and showed abnormal myeloid primitive cell phenotype. Main expression: CD117, CD34, CD38, HLA-DR, CD33, CD64, CD123, weak expression: CD13, CD19. 2. The other group included 45.61% of the nuclear cells and had a B-lymphoblastic phenotype. Main expression: CD34, CD38, HLA-DR, CD123, CD19, CD10, CD9, cCD79a, TDT, weak expression of CD13, CD22. Mixed phenotype acute leukemia (M/B) immunophenotype was considered. Chromosome: 46,XY,t(9; 22)(q34;q11.2) [20]. BCR-ABL (P210) fusion gene was positive.
CONCLUSIONS
Mixed phenotype acute leukemia (MPAL) is a rare type of malignant hematologic disease. Its diagnosis is based on the comprehensive evaluation of bone marrow cell morphology, immunophenotype, molecular and cytogenetic features.
Topics: Humans; Phenotype; Flow Cytometry; Male; Immunophenotyping; Bone Marrow Cells; Philadelphia Chromosome; Leukemia, Biphenotypic, Acute; Leukemia; Adult; Female; Middle Aged
PubMed: 38747916
DOI: 10.7754/Clin.Lab.2023.231220 -
BioRxiv : the Preprint Server For... Apr 2024Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in , the microtubule-associated...
Frontotemporal dementia (FTD) and Alzheimer's disease are the most common forms of early-onset dementia. Dominantly inherited mutations in , the microtubule-associated protein tau gene, cause FTD and parkinsonism linked to chromosome 17 (FTDP-17). Individuals with FTDP-17 develop abundant filamentous tau inclusions in brain cells. Here we used electron cryo-microscopy to determine the structures of tau filaments from the brains of individuals with mutations V337M and R406W. Both mutations gave rise to tau filaments with the Alzheimer fold, which consisted of paired helical filaments in all V337M and R406W cases and of straight filaments in two V337M cases. We also identified a new assembly of the Alzheimer fold into triple tau filaments in a V337M case. Filaments assembled from recombinant tau(297-391) with mutation V337M had the Alzheimer fold and showed an increased rate of assembly.
PubMed: 38746388
DOI: 10.1101/2024.04.29.591661 -
Journal of Nanobiotechnology May 2024Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph) leukemia. However, a series of issues, including drug...
Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph leukemic cell lines for gene therapy of Ph leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph leukemia, but also enabled gene therapy against a less druggable target.
Topics: Fusion Proteins, bcr-abl; Animals; Humans; Mice; Cell Line, Tumor; Nanoparticles; Ubiquitin-Protein Ligases; Gene Silencing; RNA, Small Interfering; NEDD8 Protein; Mice, Inbred BALB C; Apoptosis; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Genetic Therapy; Cell Proliferation; Female
PubMed: 38741123
DOI: 10.1186/s12951-024-02505-5