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Hematology. American Society of... Dec 2022Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that...
Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) carried a very poor prognosis prior to the advent of tyrosine kinase inhibitors (TKIs) that block the activity of the BCR-ABL1 oncoprotein. With improvements in TKI efficacy and allogeneic hematopoietic cell transplantation (HCT), survival has improved over the past 3 decades, and the role of chemotherapy and allogeneic HCT is now changing. Better risk stratification, the application of the third-generation TKI ponatinib, and the use of immunotherapy with the CD19-CD3 bifunctional T-cell engaging antibody blinatumomab in place of chemotherapy has made therapy for Ph+ ALL more tolerable and arguably more efficacious, especially for older patients who comprise most patients with Ph+ ALL.
Topics: Humans; Protein Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Hematopoietic Stem Cell Transplantation; Philadelphia Chromosome
PubMed: 36485090
DOI: 10.1182/hematology.2022000338 -
Cancer Gene Therapy Jan 2023The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand...
The Philadelphia (Ph) chromosome was the first translocation identified in leukemia. It is supposed to be generated by aberrant ligation between two DNA double-strand breaks (DSBs) at the BCR gene located on chromosome 9q34 and the ABL1 gene located on chromosome 22q11. Thus, mimicking the initiation process of translocation, we induced CRISPR/Cas9-mediated DSBs simultaneously at the breakpoints of the BCR and ABL1 genes in a granulocyte-macrophage colony-stimulating factor (GM-CSF) dependent human leukemia cell line. After transfection of two single guide RNAs (sgRNAs) targeting intron 13 of the BCR gene and intron 1 of the ABL1 gene, a factor-independent subline was obtained. In the subline, p210 BCR::ABL1 and its reciprocal ABL1::BCR fusions were generated as a result of balanced translocation corresponding to the Ph chromosome. Another set of sgRNAs targeting intron 1 of the BCR gene and intron 1 of the ABL1 gene induced a factor-independent subline expressing p190 BCR::ABL1. Both p210 and p190 BCR::ABL1 induced factor-independent growth by constitutively activating intracellular signaling pathways for transcriptional regulation of cell cycle progression and cell survival that are usually regulated by GM-CSF. These observations suggested that simultaneous DSBs at the BCR and ABL1 gene breakpoints are initiation events for oncogenesis in Ph+ leukemia. (200/200 words).
Topics: Humans; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Granulocyte-Macrophage Colony-Stimulating Factor; CRISPR-Cas Systems; Translocation, Genetic; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Carcinogenesis
PubMed: 35999358
DOI: 10.1038/s41417-022-00522-w -
Medical Oncology (Northwood, London,... Jul 2023Chronic myeloid leukemia (CML) is a type of blood cancer that is known to affect hematopoietic stem cells. The presence of the Philadelphia chromosome (Ph+) is the major... (Review)
Review
Chronic myeloid leukemia (CML) is a type of blood cancer that is known to affect hematopoietic stem cells. The presence of the Philadelphia chromosome (Ph+) is the major characteristic of CML. A protein expressed by the Philadelphia chromosome shows elevated tyrosine kinase activity and is considered a tumorigenic factor. The first line of therapy that had been established for CML was "imatinib," a potent tyrosine kinase inhibitor. Various other second- and third-generation TKIs are taken into account in cases of imatinib failure/resistance. With the subsequent rise in the development of tyrosine kinase inhibitors, optimization in the treatment of CML and amplified total survival were observed throughout TKI dosage. As the disease progresses, additional chromosomal abnormalities (ACAs) have been reported, but their prognostic effect and impact on the response to treatment are still unknown. However, some substantial understandings have been achieved into the disease transformation mechanisms, including the role of somatic mutations, ACAs, and several different genomic mutations that occur during diagnosis or have evolved during treatment. The acquisition of ACAs impedes CML treatment. Due to additional chromosomal lesions, there are greater chances of future disease progression at the time of CML diagnosis beyond the Ph+ translocation. The synchronous appearance of two or more ACAs leads to lower survival and is classified as a poor prognostic group. The key objective of this review is to provide detailed insights into TKIs and their role in controlling Ph+ and ACAs, along with their response, treatment, overall persistence, and survival rate.
Topics: Humans; Tyrosine Kinase Inhibitors; Philadelphia Chromosome; Imatinib Mesylate; Chromosome Aberrations; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Kinase Inhibitors
PubMed: 37439908
DOI: 10.1007/s12032-023-02116-4 -
Technology in Cancer Research &... 2023Central nervous system leukemia (CNSL) is the most common extramedullary relapse site in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic...
Comparison of the Efficacy and Safety of Ponatinib and Dasatinib in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia With Central Nervous System Relapse: A Retrospective Study.
INTRODUCTION
Central nervous system leukemia (CNSL) is the most common extramedullary relapse site in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukemia (ALL), with a poor prognosis and high relapse rate.
METHODS
We characterized the clinical data of 21 Ph-positive B-ALL patients to analyze the efficacy and safety of ponatinib for patients with central nervous system relapsed Ph-positive ALL retrospectively.
RESULTS
There were 11 males and 10 females in the cohort, and their median age was 45 (9-58) years old. The total CR (complete remission) rate was 90.5%. All 9 patients achieved CR in the ponatinib group, and 10 patients achieved CR in the dasatinib group (100% vs 83.3%, respectively; = .486) and minimal residual disease-positive CR in the ponatinib group and dasatinib group (88.9% vs 58.3%, = .178). The medium time after achieving CR was 5 and 8 weeks ( = .047). The total median overall survival (OS) was 31.1 months, and the 3-year OS was 49.0%. The median relapse-free survival (RFS) was 31.0 months, and the 3-year RFS was 45.2%. Patients in the ponatinib group showed a significantly longer OS than those patients in the dasatinib group with (medium OS not reached vs 27.6 months, = .045) or without (medium OS not reached vs 27.6 months, = .039) T315I mutations. The median RFS between the ponatinib group and the dasatinib group with T315I was not reached and 16.2 months, = .065. The median RFS between the ponatinib group and the dasatinib group without T315I was not reached and 16.2 months, = .036. No treatment-related deaths were observed during the therapy.
CONCLUSION
(1) Ph-positive CNSL patients seemed to have a high rate of response and postinduction MRD negativity with ponatinib and dasatinib, but ponatinib seemed to show a shorter time to achieve remission than dasatinib. (2) Ponatinib maintenance treatment might show superior survival for Ph-positive CNSL patients with or without the T315I mutation. (3) Ponatinib and dasatinib seemed to be both safe for the clinical application of Ph-positive CNSL.
Topics: Male; Female; Humans; Middle Aged; Child; Adolescent; Young Adult; Adult; Dasatinib; Retrospective Studies; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Fusion Proteins, bcr-abl; Central Nervous System; Protein Kinase Inhibitors
PubMed: 36959735
DOI: 10.1177/15330338231165866 -
Current Hematologic Malignancy Reports Jun 2023Despite progress in the treatment of pediatric B-cell acute lymphoblastic leukemia (ALL) and PH + ALL, fewer advancements have been for older adults with PH-negative... (Review)
Review
PURPOSE OF REVIEW
Despite progress in the treatment of pediatric B-cell acute lymphoblastic leukemia (ALL) and PH + ALL, fewer advancements have been for older adults with PH-negative B-cell ALL. Treatment of this population is mired by higher incidence of poor risk biologic features, increased incidence of medical comorbidities, and higher rates of treatment-related mortality (TRM). Here, we review the difficulties in managing elderly patients with PH-negative ALL.
RECENT FINDINGS
The development of novel agents has brought additional tools to the armamentarium of drugs and has changed the landscape of treatment. More recent clinical trials and future clinical trials focus on blinatumomab, inotuzomab ozogamicin (IO), and/or chimeric antigen receptor T-cell (CAR-T) either alone or integrated with dose-reduced chemotherapy regimens. The introduction of novel agents/therapies and incorporation into our current treatment paradigms may finally offer an avenue to improve the dismal outcomes seen in this population.
Topics: Humans; Child; Aged; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Receptors, Chimeric Antigen; Antibodies, Bispecific
PubMed: 36877337
DOI: 10.1007/s11899-023-00691-x -
Leukemia & Lymphoma Jun 2023Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B cell ALL with distinct genotypes, unified by gene expression profile similar to... (Review)
Review
Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk subgroup of B cell ALL with distinct genotypes, unified by gene expression profile similar to Ph-positive ALL, but lacking the fusion. Ph-like ALL patients respond inadequately to conventional chemotherapy with higher rates of induction failure, persistent measurable residual disease, and lower survival rates compared to other B cell ALL subtypes. Considering Ph-like ALL's chemo-refractory nature, there is an interest in pursuing innovative therapeutic approaches to treat, including the combination of tyrosine kinase inhibitors with frontline regimens, and early introduction of novel antibody-drug conjugates and immunotherapies. Accurate diagnosis and disease-risk stratification are key to increase access for high-risk patients to allogeneic hematopoietic cell transplantation in their first complete remission. In this review, we will discuss our current knowledge of pathogenesis of Ph-like ALL, diagnostic strategies, as well as emerging data on new and current treatment strategies for this disease.
Topics: Humans; Adult; Philadelphia Chromosome; Philadelphia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Remission Induction; Protein Kinase Inhibitors
PubMed: 37021793
DOI: 10.1080/10428194.2023.2197538 -
Hematology (Amsterdam, Netherlands) Dec 2023Myelodysplastic syndromes (MDS) refer to a set of clonal hematopoietic disorders with fusion transcript as disease progression. Breakpoint cluster region/abelson ()... (Review)
Review
Myelodysplastic syndromes (MDS) refer to a set of clonal hematopoietic disorders with fusion transcript as disease progression. Breakpoint cluster region/abelson () fusion mostly occurs during the progressive phase from MDS to higher stages and acute leukemia transformation. Besides, it is extremely rare reported on the diagnosis of MDS. Here, the first case of transformation of de nove philadelphia (Ph)-positive MDS to chronic myeloid leukemia (CML) with rapid progression to acute myeloid leukemia (AML) was reported. Fluorescence in situ hybridization (FISH) analysis revealed an atypical positive signal (2R2G1Y) that accounted for 3% at the diagnosis of MDS and increased to 21.4% at information to CML. The result of multiplex reverse transcriptase polymerase chain reaction (RT-PCR) indicated a rearrangement of e19a2 (p230 ). The treatment with 400 mg of imatinib daily at the transformation from MDS to CML led to a hematological response. However, the patient stopped taking imatinib due to the worsening of cytopenias after five weeks of therapy and rapid progression to AML in another two months. The treatment with azacitidine (AZA) and venetoclax (VEN) achieved partial remission (PR). Unfortunately, the patient relapsed six months after PR and died shortly thereafter. In addition, another 16 cases of adult cases that reported MDS with de nove Ph-positive were also reviewed to learn about clinical features and outcomes.
Topics: Humans; Philadelphia Chromosome; Imatinib Mesylate; Fusion Proteins, bcr-abl; In Situ Hybridization, Fluorescence; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Myelodysplastic Syndromes; Leukemia, Myeloid, Acute; Cell Transformation, Neoplastic; Karyotype
PubMed: 37288817
DOI: 10.1080/16078454.2023.2220220 -
Annals of Hematology Sep 2023Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype with a poor prognosis under conventional chemotherapy. Ph-like ALL has a... (Review)
Review
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subtype with a poor prognosis under conventional chemotherapy. Ph-like ALL has a similar gene expression profile to Philadelphia chromosome-positive (Ph+) ALL, but is highly heterogeneous in terms of genomic alterations. Approximately 10-20% of patients with Ph-like ALL harbor ABL class (e.g. ABL1, ABL2, PDGFRB, and CSF1R) rearrangements. Additional genes that form fusion genes with ABL class genes are still being researched. These aberrations result from rearrangements including chromosome translocations or deletions and may be targets of tyrosine kinase inhibitors (TKIs). However, due to the heterogeneity and rarity of each fusion gene in clinical practice, there is limited data on the efficacy of tyrosine kinase inhibitors. Here, we report three cases of Ph-like B-ALL with ABL1 rearrangements treated with the dasatinib backbone for the CNTRL::ABL1, LSM14A::ABL1, and FOXP1::ABL1 fusion genes. All three patients achieved rapid and profound remission with no significant adverse events. Our findings suggest that dasatinib is a potent TKI for the treatment of ABL1-rearranged Ph-like ALL and can be used as a first-line treatment option for such patients.
Topics: Humans; Dasatinib; Philadelphia Chromosome; Fusion Proteins, bcr-abl; Protein Kinase Inhibitors; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Repressor Proteins; Forkhead Transcription Factors
PubMed: 37103615
DOI: 10.1007/s00277-023-05236-z -
Clinical Lymphoma, Myeloma & Leukemia Apr 2024The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed...
BACKGROUND
The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes.
PATIENTS AND METHODS
We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL.
RESULTS
Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10, including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen.
CONCLUSION
Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings.
Topics: Humans; Aged; Inotuzumab Ozogamicin; Retrospective Studies; Philadelphia Chromosome; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Antibodies, Bispecific; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Cardiovascular Diseases
PubMed: 38212207
DOI: 10.1016/j.clml.2023.12.016 -
Cancer Medicine Jan 2021The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our...
The epidemiology, genetics, and thrombosis risk of MPNs among Arabs are largely unknown. This may be attributed to scarce epidemiological data, particularly from our region. Our study included 381 Kuwaiti nationals with Ph-negative MPNs and a confirmed driver mutation involving JAK2 (exon 12 14), CALR, or MPL. This first regional study examines the demographics, clinical parameters, and thrombosis-related attributes of the participants. This study reported a median age of 58 years, with females and males representing 54.9% and 45.1%, respectively. ET was the most frequent subtype of Ph-negative MPNs in our population, accounting for 52.0% of the cases, followed by PV, found in 34.6% of the participants, and PMF, found in 8.4% of participants. The crude annual cumulative incidence of Ph-negative MPNs in Kuwait ranged from 0.674 to 3.177 per 100,000 population across the study period. The most common driver mutation was JAK2V617F, with a frequency of 89.5%. At diagnosis, 19.2% of the patients presented with unexplained thrombosis, and almost half were of arterial origins. Males were more likely to present with arterial thrombosis than females (61.5% vs. 35.3%), whereas venous thrombotic events were more common in females than in males (47.1% vs. 17.9%; p-value = 0.025). Ph-negative MPNs in Kuwait are rare; however, thrombosis is a frequent complication, being documented in up to 19.2% of cases at presentation, more commonly at arterial sites. These findings call for thorough evaluation of patients with unexplained derangements in their hematological parameters during follow-ups.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Arterial Occlusive Diseases; Calreticulin; Child; Child, Preschool; Female; Genetic Predisposition to Disease; Humans; Incidence; Infant; Infant, Newborn; Janus Kinase 2; Kuwait; Male; Middle Aged; Mutation; Myeloproliferative Disorders; Philadelphia Chromosome; Receptors, Thrombopoietin; Registries; Risk Assessment; Risk Factors; Thrombosis; Venous Thromboembolism; Young Adult
PubMed: 33280271
DOI: 10.1002/cam4.3633