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Cancers Aug 2023Chronic myeloid leukemia (CML) is treated with tyrosine kinase inhibitors (TKI) that target the pathological BCR-ABL1 fusion oncogene. The objective of this statistical... (Review)
Review
Chronic myeloid leukemia (CML) is treated with tyrosine kinase inhibitors (TKI) that target the pathological BCR-ABL1 fusion oncogene. The objective of this statistical meta-analysis was to assess the prevalence of other hematological adverse events (AEs) that occur during or after predominantly first-line treatment with TKIs. Data from seventy peer-reviewed, published studies were included in the analysis. Hematological AEs were assessed as a function of TKI drug type (dasatinib, imatinib, bosutinib, nilotinib) and CML phase (chronic, accelerated, blast). AE prevalence aggregated across all severities and phases was significantly different between each TKI ( < 0.05) for anemia-dasatinib (54.5%), bosutinib (44.0%), imatinib (32.8%), nilotinib (11.2%); neutropenia-dasatinib (51.2%), imatinib (29.8%), bosutinib (14.1%), nilotinib (14.1%); thrombocytopenia-dasatinib (62.2%), imatinib (30.4%), bosutinib (35.3%), nilotinib (22.3%). AE prevalence aggregated across all severities and TKIs was significantly ( < 0.05) different between CML phases for anemia-chronic (28.4%), accelerated (66.9%), blast (55.8%); neutropenia-chronic (26.7%), accelerated (63.8%), blast (36.4%); thrombocytopenia-chronic (33.3%), accelerated (65.6%), blast (37.9%). An odds ratio (OR) with 95% confidence interval was used to compare hematological AE prevalence of each TKI compared to the most common first-line TKI therapy, imatinib. For anemia, dasatinib OR = 1.65, [1.51, 1.83]; bosutinib OR = 1.34, [1.16, 1.54]; nilotinib OR = 0.34, [0.30, 0.39]. For neutropenia, dasatinib OR = 1.72, [1.53, 1.92]; bosutinib OR = 0.47, [0.38, 0.58]; nilotinib OR = 0.47, [0.42, 0.54]. For thrombocytopenia, dasatinib OR = 2.04, [1.82, 2.30]; bosutinib OR = 1.16, [0.97, 1.39]; nilotinib OR = 0.73, [0.65, 0.82]. Nilotinib had the greatest fraction of severe (grade 3/4) hematological AEs (30%). In conclusion, the overall prevalence of hematological AEs by TKI type was: dasatinib > bosutinib > imatinib > nilotinib. Study limitations include inability to normalize for dosage and treatment duration.
PubMed: 37686630
DOI: 10.3390/cancers15174354 -
Frontiers in Oncology 2023Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT)...
INTRODUCTION
Myelofibrosis (MF) is a rare hematopoietic stem cell disorder progressing to bone marrow (BM) failure or blast phase. Allogeneic hematopoietic cell transplantation (HCT) represents a potentially curative therapy for a limited subset of patients with advanced MF, who are eligible, but engraftment in MF vs. AML is delayed which promotes complications. As determinants of engraftment in MF are incompletely characterized, we studied engraftment dynamics at our center.
METHODS
A longitudinal cohort of 71 allogeneic HCT performed 2000-2019 with >50% after 2015 was evaluated.
RESULTS
Median time to neutrophil engraftment ≥0.5x109/l was +20 days post-transplant and associated with BM fibrosis, splenomegaly and infused CD34+ cell number. Engraftment dynamics were similar in primary vs. secondary MF and were independent of MF driver mutations in JAK2, CALR and MPL. Neutrophil engraftment occurred later upon haploidentical HCT with thiotepa-busulfan-fludarabine conditioning, post-transplant cyclophosphamide and G-CSF (TBF-PTCy/G-CSF) administered to 9.9% and 15.6% of patients in 2000-2019 and after 2015, respectively. Engraftment of platelets was similarly delayed, while reconstitution of reticulocytes was not affected.
CONCLUSIONS
Since MF is a rare hematologic malignancy, this data from a large number of HCT for MF is essential to substantiate that later neutrophil and platelet engraftment in MF relates both to host and treatment-related factors. Observations from this longitudinal cohort support that novel conditioning schemes administered also to rare entities such as MF, require detailed evaluation in larger, multi-center cohorts to assess also indicators of long-term graft function and overall outcome in patients with this infrequent hematopoietic neoplasm undergoing allogeneic transplantation.
PubMed: 37637037
DOI: 10.3389/fonc.2023.1205387 -
Materials (Basel, Switzerland) Feb 2024Blast furnace dust waste (BFDW) proved efficient as a photocatalyst for the decolorization of methylene blue (MB) dye in water. Structural analysis unequivocally...
Blast furnace dust waste (BFDW) proved efficient as a photocatalyst for the decolorization of methylene blue (MB) dye in water. Structural analysis unequivocally identified α-FeO as the predominant phase, constituting approximately 92%, with a porous surface showcasing unique 10-30 nm agglomerated nanoparticles. Chemical and thermal analyses indicated surface-bound water and carbonate molecules, with the main phase's thermal stability up to 900 °C. Electrical conductivity analysis revealed charge transfer resistance values of 616.4 Ω and electrode resistance of 47.8 Ω. The Mott-Schottky analysis identified α-FeO as an n-type semiconductor with a flat band potential of 0.181 V vs. Ag/AgCl and a donor density of 1.45 × 10 cm. The 2.2 eV optical bandgap and luminescence stem from α-FeO and weak ferromagnetism arises from structural defects and surface effects. With a 74% photocatalytic efficiency, stable through three photodegradation cycles, BFDW outperforms comparable waste materials in MB degradation mediated by visible light. The elemental trapping experiment exposed hydroxyl radicals (OH•) and superoxide anions (O2-•) as the primary species in the photodegradation process. Consequently, iron oxide-based BFDW emerges as an environmentally friendly alternative for wastewater treatment, underscoring the pivotal role of its unique physical properties in the photocatalytic process.
PubMed: 38399069
DOI: 10.3390/ma17040818 -
International Journal of Molecular... Oct 2023Acute myeloid leukemia (AML) with has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis...
Acute myeloid leukemia (AML) with has recently been recognized as a distinct subtype in international classifications. Distinguishing it from myeloid blast crisis chronic myeloid leukemia (BC-CML) without evidence of a chronic phase (CP), remains challenging. We aimed to better characterize this entity by integrating clonal architecture analysis, mutational landscape assessment, and gene expression profiling. We analyzed a large retrospective cohort study including CML and AML patients. Two AML patients harboring a fusion were included in the study. We identified fusion as a primary event in one patient and a secondary one in the other. AML-specific variants were identified in both. Real-time RT-PCR experiments demonstrated that mRNA is overexpressed in advanced-phase CML compared to AML. Unsupervised principal component analysis showed that AML harboring a fusion was clustered within AML. An AML vs. myeloid BC-CML differential expression signature was highlighted, and while (inhibitor of DNA binding 4) mRNA appears undetectable in most myeloid BC-CML samples, low levels are detected in AML samples. Therefore, and mRNA expression might differentiate AML with from BC-CML and assign it to the AML group. A method for identifying this new WHO entity is then proposed. Finally, the hypothesis of AML with arising from driver mutations on a background behaving as a clonal hematopoiesis mutation is discussed. Validation of our data in larger cohorts and basic research are needed to better understand the molecular and cellular aspects of AML with a entity.
Topics: Humans; Blast Crisis; Fusion Proteins, bcr-abl; Retrospective Studies; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; RNA, Messenger
PubMed: 37895120
DOI: 10.3390/ijms242015441 -
Archives of Pathology & Laboratory... Mar 2024BCR::ABL-negative myeloproliferative neoplasm (MPN) has a prolonged clinical course, and some cases eventually undergo transformation to blast phase; its pathogenesis...
Blast Phase of Myeloproliferative Neoplasm Resembles Acute Myeloid Leukemia, Myelodysplasia-Related, in Clinical Presentation, Cytogenetic Pattern, and Genomic Profile, and Often Undergoes Reversion to Second Chronic Phase Status After Induction Chemotherapy.
CONTEXT.—
BCR::ABL-negative myeloproliferative neoplasm (MPN) has a prolonged clinical course, and some cases eventually undergo transformation to blast phase; its pathogenesis remains to be elucidated.
OBJECTIVE.—
To evaluate the clinicopathologic characteristics of MPN in blast phase.
DESIGN.—
The study aimed to retrospectively analyze the clinical and laboratory data of 24 cases.
RESULTS.—
Median latency to blast phase was 48 months (range, 7-384 months). Complex karyotypes were seen in 12 of the 24 cases (50%). Overall, 16 cases (66.7%) exhibited high allele burdens of MPN driver mutations along with increased blasts, consistent with linear clonal evolution, whereas the remainder (8; 33.3%) showed loss or partial loss of the driver mutation suggestive of a parallel evolution. Additional mutations were noted in 23 cases (100%), including TP53 mutations in 10 of 24 cases (41.7%). Following chemotherapy, 15 of the 24 patients (62.5%) reverted to a second chronic phase while retaining or regaining MPN driver mutations and losing blast-related mutations, although 9 of the 15 patients (60%) later died of disease progression. Median overall survival was 10 months (CI, 4.6-15.4), with those harboring complex karyotypes demonstrating decreased survival (6 versus 29 months; P = .004).
CONCLUSIONS.—
MPN-blast phase resembles acute myeloid leukemia, myelodysplasia-related, in cytogenetic pattern, mutation profile, and clinical outcome. Two patterns of clonal evolution are inferred by dynamic analysis of mutation profiles: linear and parallel evolutions. Although overall survival was dismal, 62.5% of our cases achieved second chronic phase, and they showed better survival than those without second chronic phase.
PubMed: 38426696
DOI: 10.5858/arpa.2023-0363-OA -
Genes & Diseases Mar 2024Chronic myeloid leukemia (CML) is a common adult leukemia. Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor...
Chronic myeloid leukemia (CML) is a common adult leukemia. Both the acute phase of the disease and the adverse effects of anti-cancer treatments can lead to a poor prognosis. The N-methyladenine (mA) modification plays an important regulatory role in various physiological and pathological processes. KIAA1429 is a known mA regulator, but the biological role of KIAA1429 in CML is unclear. In this study, we observed that the mA levels and KIAA1429 expression were significantly up-regulated in patients with blast phase CML. Notably, KIAA1429 regulated the total level of RNA mA modification in the CML cells and promoted the malignant biological behaviors of CML cells, including proliferation, migration, and imatinib resistance. Inhibiting KIAA1429 in CML cells reduced the stability of RAB27B mRNA through the mA/YTHDF1 axis, consequently inhibiting CML proliferation and drug efflux, ultimately increasing the sensitivity of CML cells to imatinib. Moreover, the knockdown of RAB27B also inhibited the proliferation and drug resistance of CML cells and promoted their apoptosis. Rucaparib, a recently developed anti-cancer agent, suppressed the expression of KIAA1429 and CML cell proliferation and promoted cell apoptosis. Rucaparib also inhibited the tumorigenesis of CML cells . The combined use of rucaparib and imatinib enhanced the sensitivity of CML cells to imatinib. Our study provides evidence that elevated KIAA1429 expression in the blast phase of CML enhances the stability of RAB27B mRNA through the mA/YTHDF1 axis to up-regulate RAB27B expression, thereby promoting CML progression. Rucaparib exerts inhibitory effects on KIAA1429 expression and thus reduces CML progression.
PubMed: 37692484
DOI: 10.1016/j.gendis.2023.03.016 -
Frontiers in Medicine 2023Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus causing the coronavirus disease of 2019. The disease has caused millions of deaths since the...
INTRODUCTION
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus causing the coronavirus disease of 2019. The disease has caused millions of deaths since the first pandemic at the end of 2019. Immunocompromised individuals are more likely to develop severe infections. Numerous mutations had developed in SARS-CoV-2, resulting in strains (Alfa Beta Delta Omicron) with varying degrees of virulence disease severity. In CML (chronic myeloid leukemia) patients, there is a lot of controversy regarding the effect of the treatment on the patient outcome. Some reports suggested potential better outcomes among patients with CML, likely due to the use of TKI; other reports showed no significant effects. Additionally, it is unknown how much protection immunization provides for cancer patients.
METHOD
In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards, we conducted a systematic review. Retrospective, prospective studies, reviews, case series, and case reports of chronic myeloid leukemia patients aged above 18 years who had SARS-CoV-2 infection were included. English literature was screened using PubMed, SCOPUS, and Google Scholar. Search terms include chronic myeloid leukemia, chronic myelogenous leukemia, and SARS-CoV-2 and Coronavirus disease 2019 (COVID-19). We searched the reference lists of the included studies for any new articles. The search included all articles published up to April 20, 2023. The review is registered in PROSPERO (registration number CRD42022326674).
RESULTS
We reviewed 33 articles of available published literature up to April 2023 and collected data from a total of 682 CML patients with COVID-19. Most patients were in the chronic phase, seven were in the accelerated phase, and eight were in the blast phase. Disease severity was classified according to WHO criteria. Mortality was seen in 45 patients, and there were no reports of thrombotic events. Two hundred seventy-seven patients were in the era before vaccination; among them, eight were in the intensive care unit (ICU), and mortality was 30 (11%). There were 405 patients after the era of vaccination; among them, death was reported in 15 (4%) patients and ICU in 13 patients.
LIMITATIONS AND CONCLUSION
The major limitation of this review is the lack of details about the use or hold of TKIs during SARS-CoV-2 infection. Additionally, after the appearance of the different variants of the SARS-CoV-2 virus, few studies mentioned the variant of the virus, which makes it difficult to compare the outcome of the other variants of the SARS-CoV-2 virus in patients with CML. Despite the limitations of the study, CML patients with COVID-19 have no significant increase in mortality compared to other hematological malignancy. Hematological cancers are associated with an increased risk of thrombosis, which is expected to increase in patients with COVID-19. However, patient with CML has not been reported to have a significant increase in thrombosis risk. The available data indicates that COVID-19's effect on patients with chronic myeloid leukemia (CML) still needs to be better understood due to the limited data.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/display_record.php? RecordID:326674.
PubMed: 38327268
DOI: 10.3389/fmed.2023.1280271 -
Oncology 2024Viral infections remain a significant problem for patients with chronic myeloid leukemia (CML) who undergo stem cell transplants (SCTs). These infections often result... (Review)
Review
BACKGROUND
Viral infections remain a significant problem for patients with chronic myeloid leukemia (CML) who undergo stem cell transplants (SCTs). These infections often result from the reactivation of latent viruses. However, our understanding of the risk of viral reactivation in CML patients who have not undergone SCT is limited, and there is a scarcity of data on this topic. Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML as it is highly successful and has transformed the prognosis of patients with CML. However, TKI may be associated with an increased risk of infections.
SUMMARY
We have performed a literature search for publications related to viral infections and their reactivations in patients with CML using PubMed, Scopus, and Google Scholar for the period 2001-2022. The population consisted of patients over 18 years old with a diagnosis of CML and no history of bone marrow transplantation. In an analysis of 41 patients, with 25 males and 16 females, M:F ratio of 1.56:1, and a median age of 50. Age ranged from 22 to 79 years. Most patients with reported viral infections or reactivations were in the chronic phase (CP) of CML, with 22 patients (76%) in the CP, 6 patients (21%) in the accelerated phase, and 1 patient (3%) in the blast phase. Most cases with reported outcomes responded to treatment for CML; only one had refractory disease and 8 cases (32%) had major molecular response. Imatinib was the most used TKI in 31 patients (77%). The most reported viral reactivations were herpes zoster in 17 cases (41%), followed by hepatitis B reactivation in 15 cases (37%).
KEY MESSAGES
This review sheds light on the importance of having a hepatitis B serology checked before starting TKI therapy and close monitoring for viral infections and reactivations in patients with CML.
Topics: Male; Female; Humans; Young Adult; Adult; Middle Aged; Aged; Adolescent; Incidence; Protein Kinase Inhibitors; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Virus Diseases; Hepatitis B
PubMed: 37848004
DOI: 10.1159/000534266 -
Haematologica Jul 2023The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless,...
The BCL-2 inhibitor venetoclax has revolutionized the treatment of acute myeloid leukemia (AML) in patients not benefiting from intensive chemotherapy. Nevertheless, treatment failure remains a challenge, and predictive markers are needed, particularly for relapsed or refractory AML. Ex vivo drug sensitivity testing may correlate with outcomes, but its prospective predictive value remains unexplored. Here we report the results of the first stage of the prospective phase II VenEx trial evaluating the utility and predictiveness of venetoclax sensitivity testing using different cell culture conditions and cell viability assays in patients receiving venetoclax-azacitidine. Participants with de novo AML ineligible for intensive chemotherapy, relapsed or refractory AML, or secondary AML were included. The primary endpoint was the treatment response in participants showing ex vivo sensitivity and the key secondary endpoints were the correlation of sensitivity with responses and survival. Venetoclax sensitivity testing was successful in 38/39 participants. Experimental conditions significantly influenced the predictive accuracy. Blast-specific venetoclax sensitivity measured in conditioned medium most accurately correlated with treatment outcomes; 88% of sensitive participants achieved a treatment response. The median survival was significantly longer for participants who were ex vivo-sensitive to venetoclax (14.6 months for venetoclax-sensitive patients vs. 3.5 for venetoclax-insensitive patients, P<0.001). This analysis illustrates the feasibility of integrating drug-response profiling into clinical practice and demonstrates excellent predictivity. This trial is registered with ClinicalTrials.gov identifier: NCT04267081.
Topics: Humans; Prospective Studies; Leukemia, Myeloid, Acute; Antineoplastic Agents; Bridged Bicyclo Compounds, Heterocyclic; Antineoplastic Combined Chemotherapy Protocols
PubMed: 36519325
DOI: 10.3324/haematol.2022.281692 -
Haematologica Sep 2023
Topics: Humans; Blast Crisis; Myeloproliferative Disorders; Nitriles; Mutation
PubMed: 36794509
DOI: 10.3324/haematol.2022.282627