Phase Chronic Myeloid Leukemia Patients Research Articles

Correlation of T Regulatory Cells, Cytotoxic T-lymphocyte-associated Antigen 4, and Transforming Growth Factor-β1 with Treatment Response in Patients with Chronic Myeloid Leukemia Receiving Dasatinib Therapy.

Tyrosine kinase inhibitors improve chronic myeloid leukemia (CML) outcomes. Dasatinib inhibits breakpoint cluster region-Abelson 1 proto-oncogene tyrosine kinase better than imatinib in CML. T-regulatory cells prevent autoimmune diseases and aberrant immune responses by reducing oncoprotein antigen reactivity. They also reduce self-antigen-induced immune responses to maintain peripheral tolerance. In this study, T-regulatory cells in peripheral blood of chronic myeloid leukemia-chronic phase patients were measured, together with serum levels of cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and transforming growth factor (TGF)-β1 at diagnosis and 3 months postdasatinib therapy. The Pathology and Clinical Haematology Departments at King George's Medical University, Lucknow, India, conducted this prospective analytical study. Forty CML-chronic patients and 10 healthy controls were analyzed. Flow cytometry was used to determine T-regulatory cell percentage in peripheral blood mononuclear cells of newly diagnosed CML patients before and after 3 months of dasatinib treatment; ELISA was used to measure serum levels of CTLA-4 and TGF-β1. T-regulatory cells, CTLA-4, and TGF-β1 significantly decreased in CML-chronic phase patients after 3 months of dasatinib therapy compared to the initial diagnosis. No significant change in T-regulatory cell, CTLA-4, or TGF-β1 percentages were seen between responders and poor responders. However, responders had a lower percentage of T-regulatory cells than suboptimal responders. The study concluded that dasatinib treatment improved response in CML patients with decreased Treg cells. Dasatinib reduces Treg-mediated immunological suppression, reducing CTLA-4 and TGF-β1 levels.

Choice of Frontline Tyrosine-Kinase Inhibitor and Early Events in Very Elderly Patients With Chronic Myeloid Leukemia in Chronic Phase: A "Campus CML" Study.

The study aimed to evaluate the utilization of frontline TKI therapy in a large cohort of elderly CP-CML patients. A retrospective analysis was conducted on 332 CP-CML patients aged 75 years or older among 1929 diagnosed from January 2012 to December 2019 followed at 36 participating Hematology Centers involved in the "Campus CML" project. Among the patients analyzed, 85.8% received imatinib (IM) while 14.2% received second-generation TKIs (2G-TKI), 59.5% dasatinib, and 40.5% nilotinib. Most patients initiated IM at standard dose (67.3%) while 32.7% at reduced dose. A similar trend was observed with 2G-TKIs. The cumulative incidence of permanent TKI discontinuation at 12 months was 28.4%, primarily due to primary resistance (10.1%) and extra-hematologic toxicity (9.5%), with no significant difference between IM and 2G-TKI groups. Following the introduction of generic IM in Italy in 2018, IM usage increased significantly compared with 2G-TKIs. IM was in our Centers the preferred frontline therapy for older CP-CML patients, with increasing utilization after the introduction of generic formulations. However, 2G-TKIs are still used in a substantial proportion of patients, suggesting individualized physician assessments regarding patient suitability and expectations. Further investigation is needed to assess efficacy and safety of reduced TKI doses in this patient population.

Single-cell proteo-transcriptomic profiling reveals altered characteristics of stem and progenitor cells in patients receiving cytoreductive hydroxyurea in early-phase chronic myeloid leukemia.

Hydroxyurea (HU) is frequently used in the early phase of chronic myeloid leukemia (CML) to achieve cytoreduction prior to tyrosine kinase inhibitor (TKI) therapy. However, its impact on CML stem and progenitor cells (SPC) remains largely unknown. This study utilized targeted proteo-transcriptomic expression data on 596 genes and 51 surface proteins in 60,000 CD14-CD34+ cells from chronic phase CML patients to determine effects of shortterm HU treatment (4-19 days) on CML SPC. Peripheral blood and bone marrow samples were obtained from 17 CML patients eligible for short-term HU treatment (three patients before and after HU; seven patients before HU; and seven patients after HU) and subjected to single-cell CITE-seq and/or flow cytometry analysis. The analysis revealed enhanced frequencies of hemoglobin-expressing (HBA1, HBA2, HBB) erythroid progenitor cells in blood and bone marrow following HU treatment. In addition, there was an accumulation of cell subsets with S/G2/M phase-related gene and protein expression, likely representing cells arrested in, or progressing slowly through, the cell cycle. The increased frequency of cells in S/G2/M phase after HU was observed already among the most immature leukemic stem cells (LSC), and patients with a high fraction of LSC in the S/G2/M phase showed poor responsiveness to TKI treatment. We conclude that short-term HU treatment entails differentiation of erythroid progenitor cells and alters the characteristics of LSC in CML. The results imply that studies of LSC and progenitor populations in CML should take effects of initial HU therapy into account.

Discontinuation of Tyrosine Kinase Inhibitor Therapy and Treatment Free Remission (TFR) in Chronic Myeloid Leukemia: Successful Achievement of TFR in More Than Two-Third of Patients in a Real-World Practice

BackgroundDiscontinuation of TKI therapy and treatment-free remission (TFR) have become new goals for chronic-phase chronic myeloid leukemia (CP-CML). The aim of this study was to estimate the TFR post discontinuation of TKI therapy at 3 tertiary-care centers. Patients and MethodsCP-CML patients aged ≥16 years who had an attempt to discontinue TKI therapy till June 2022, were eligible. The collected data included patients’ demographics, prognostic score, type and duration of TKI therapy, response dates, relapse dates, response to re-initiation of TKI therapy, and risk factors for relapse. ResultsFifty-five patients (35, 63.6% females) with a median age of 40 (range 16-74) years at diagnosis discontinued therapy. Forty-eight (87.3%) patients received imatinib as first line therapy. Twenty-nine (52.7%) patients were receiving imatinib at the time of TKI-discontinuation. Median time from diagnosis to TKI discontinuation was 86 months (IQR 60;132) and median duration of TKI therapy after achieving DMR was 66 months (IQR 47;114). After a median follow up of 34 (IQR 12;68) months, 15 (27.3%) patients relapsed. Median time to relapse was 5 months (range 2-38). Most of the relapses occurred during the first 6 months except 3 (20%) patients. All the relapsed patients achieved MMR after a median of 3 (range 2-6) months after restarting TKI therapy. None of the patients progressed to advanced-phase. ConclusionOur experience confirms that discontinuation of TKI therapy in CP-CML patients is feasible and safe in routine clinical practice, and can achieve TFR in more than two-third of carefully selected patients.

Morphology, Morphometry, and Immunohistochemical Profile of Megakaryocytes and Bone Marrow Microenvironment in Disease Progression and Therapy Resistance in Chronic Myeloid Leukemia.

Background Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML) since the beginning of the century. However, resistance to therapy and the progression of disease tend to occur in certain patients. The bone marrow microenvironment may play a role in the disease outcome. Megakaryocytes have multiple roles in the regulation and maintenance of the hematopoietic stem cell microenvironment. In the current study, we evaluated the association of megakaryocyte morphology, morphometry, and microenvironment with disease progression and therapy resistance in CML. Methodology Megakaryocyte morphology and morphometry were analyzed and compared between the different phases (chronic and advanced) at diagnosis in 150 cases of BCR-ABL-positive CML. All CML-CP patients (n = 119) were followed up on tyrosine kinase inhibitor therapy for a minimum of 15 months and classified based on their treatment outcome as a response, resistance to therapy, or progression of disease based on standard criteria. Immunohistochemistry on a bone marrow trephine biopsy was done for vascular endothelial growth factor (VEGF), FOXP3, CD150, CD48, CD44, osteopontin, CXCL12, N-cadherin, PDL-1, and IL-7, and their expression on megakaryocytes and their association with treatment outcome was evaluated. Results The morphology and morphometry of megakaryocytes showed a heterogeneous population in CML. Morphology and morphometric parameters, when compared between the chronic and advanced phases of disease at diagnosis, did not show any statistical difference. Megakaryocytes were variably positive for VEGF, FOXP3, CD150, CD48, osteopontin, N-cadherin, CXCL12, CD44, PDL-1, and IL-7. However, only CD44-positive megakaryocytes were statistically associated with the treatment outcome. The patients with a higher expression of CD44 megakaryocytes progressed to the advanced phase of the disease during therapy compared to those who responded. Conclusion Megakaryocyte morphology and morphometry were heterogeneous in CML; however, they did not show any significant difference with either the phase of the disease or with treatment outcomes. Among the various immunohistochemical markers of the microenvironment, only CD44-positivity on megakaryocytes was associated with poor treatment outcomes.

Clinical Validation of the Somatic FANCD2 Mutation (c.2022-5C>T) as a Novel Molecular Biomarker for Early Disease Progression in Chronic Myeloid Leukemia: A Case-Control Study.

Background: Chronic myeloid leukemia (CML) results from chromosomal translocation t(9;22) leading to the formation of the BCR-ABL fusion oncogene. CML has three stages: the chronic phase (CP), the accelerated phase (AP), and the blast crisis (BC). Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML. TKIs work well in CP-CML, and these patients have a survival rate similar to the normal population, but TKIs are less effective in advanced-phase CML. Even with current advances in treatment, BC-CML patients have an average overall survival of less than a year. Early recognition of CML patients at risk of disease progression can help in timely interventions with appropriate TKIs or other therapeutic modalities. Although some markers of disease progression like BCR-ABL kinase domain, ASXL1, and GATA2 mutations are available, no universal and exclusively specific molecular biomarkers exist to early diagnose CML patients at risk of CML progression for timely therapeutic interventions to delay or minimize blast crisis transformation in CML. A recent study found that all BC-CML patients harbored the FANCD2 (c.2022-5C>T) mutation. Therefore, the current study was designed to detect this FANCD2 mutant in AP-CML (early progression phase) and to clinically validate its potential as a novel molecular biomarker of early CML progression from CP to AP. Methods: Our study comprised 123 CP-CML (control group) and 60 AP-CML patients (experimental group) from 2 oncology centers, from January 2020 to July 2023. Mean hemoglobin level, WBC count, platelet count, treatment type, hepatomegaly, splenomegaly, and survival status of AP-CML patients were significantly different from those of CP-CML patients. However, as these clinical parameters cannot help in the early detection of patients at risk of CML progression, there was a need for a clinically validated biomarker of AP-CML. DNA was extracted from the patients' blood samples, and the FANCD2 gene was sequenced using an Illumina NextSeq500 next-generation sequencer (NGS). Results: The NGS analysis revealed a unique splice-site mutation in the FANCD2 gene (c.2022-5C>T). This mutation was detected in the majority (98.3%) of AP-CML patients but in none of the CP-CML patients or healthy control sequences from genomic databases. The mutation was confirmed by Sanger sequencing. FANCD2 is a member of the Fanconi anemia pathway genes involved in DNA repair and genomic stability, and aberrations of this gene are associated with many cancers. Conclusions: In conclusion, our study shows that the somatic FANCD2 (c.2022-5C>T) mutation is a new molecular biomarker for early CML progression. We recommend further clinical validation of this biomarker in prospective clinical trials.

Patched Homolog Gene (PTCHI) as a Reliable Marker for Predicting Imatinib Response in Chronic Phase Chronic Myeloid Leukemia Patients in Correlation with Early Response to First Line of Treatment Imatinib

Abstract Background Chronic myeloid leukaemia BCR-ABL1 + (CML) is a clonal disorder of a pluripotent stem cell. The disease accounts for around 15% of leukaemias and may occur at any age. The diagnosis of CML is rarely difficult and is assisted by the characteristic presence of the Philadelphia (Ph) chromosome. This results from the t (9;22) (q34; q11) translocation between chromosomes 9 and 22, as a result of which part of the oncogene ABL1 is moved to the BCR gene on chromosome 22. and part of chromosome 22 moves to chromosome 9. The abnormal chromosome 22 is the Ph chromosome. Aim of the Work To measure the level of PTCH1 in newly diagnosed CP-CML and to find correlation between the level of PTCH1in those patients and response to first line of treatment; imatinib and other prognostic factors Patients and Methods In our study there are 50 patients newly diagnosed cml recruited from hematology out patients clinic in ain shams university within duration august 2021 –april 2022.We have measured level of PTCH1 protein in newly diagnosed CP-CML and its follow up after 6months Results the studies show that 25% of patients discontinue imatinib due to lack of efficacy. A few years ago, two second-generation tyrosine kinase inhibitors (TKIs), Dasatinib and Nilotinib, were approved for first-line treatment, increasing the options available for patients diagnosed with CP- CML.Currently, the best way to adjust treatment to fit the severity of the disease is by assessing the response at different milestones. One milestone is the BCR-ABL1/ABL1 transcript level at 3 months; a level >10% 3 months after starting treatment has been related to a worse subsequent imatinib response. However, whether a change in therapy is warranted based on this single determination is controversial. Conclusion Patched homolog 1 gene (PTCH1) is marker for predicting first line of treatment imatinib response in chronic myeloid leukemia patients in chronic phase in correlation with response to imatinib. It is detected by PCR and proved to be a reliable marker to detect early imatinib response in chronic myeloid leukemia patients in chronic phase. In our study, we measured level of (PTCH1) in chronic myeloid leukemia patients in chronic phase using ELISA as a cost benefit in comparison to PCR in newly diagnosed cml patients on first line of treatment imatinib then follow up after 6 months. We found that it is a reliable marker, sensitive and specific to detect imatinib response.

Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

A Higher Neutrophil Count Is Associated with Favorable Achievement of Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Who Received Second Generation Tyrosine Kinase Inhibitor as Frontline Treatment.

ABL1 tyrosine kinase inhibitor discontinuation securely became among the therapeutic goal for chronic myeloid leukemia chronic phase patients (CML-CP). To establish successful prognostic factors for treatment-free remission (TFR), it is necessary to diagnose the patients with high-risk molecular relapse, however, a biomarker for the achievement of TFR has not been completely elucidated. Recent investigations have determined that neutrophils function crucially in cancer immunology. The research was a multicenter retrospective observational study to examine the correlation between TFR and neutrophil counts before TKI discontinuation. The investigation included patients having Philadelphia chromosome-positive CML-CP who attempted the discontinuation of TKIs after a durable deep molecular response between January 2012 and July 2021 at four institutions in Japan. 118 CML-CP patients in total discontinued TKIs and an estimated 36-month TFR rate was 65.1%. 52 patients received second-generation TKIs as frontline. Higher neutrophil count (>3210/μL) at TKIs discontinuation was determined as an independent prognostic variable for TFR in patients who received second-generation TKIs as frontline [(HR, 0.235 (95%, confidence interval (CI) 0.078-0.711); p = 0.010]. The neutrophil-mediated immunomodulation can be a significant component for the effective achievement of TFR in CML supported by our clinical observation.

Dasatinib versus high-dose imatinib for chronic-phase chronic myeloid leukemia: A meta-analysis of randomized control trials.

e18523 Background: Chronic Myeloid Leukemia (CML) is one of the few cancers with a unique and identifiable genetic mutation. The issue of imatinib resistance is becoming increasingly significant in patients with chronic phase chronic myeloid leukemia (CP-CML). Methods: We systematically searched Pubmed/MEDLINE, EMBASE, and Cochrane Library from inception through March 2023 to analyze the published literature of randomized control trials (RCT) regarding patients with CP-CML resistant to imatinib. The review was carried out according to the PRISMA guidelines, and the review protocol was registered at PROSPERO (CRD42023422749). The screening was done to include studies with the following criteria: 1) Randomized control trials; (2) comparisons between high-dose imatinib and dasatinib; (3) patients with imatinib-resistant CP-CML; and (4) measurements of Major Molecular Response (MMR) and Complete Cytogenetic Response (CCyR). The quality assessment of the included studies was carried out using JBI's (Joanna Briggs Institute's) RCT checklist. Risk ratios were used to compare the effects of dasatinib vs high dose imatinib with respect to outcomes on MMR and CCyR. Data was analyzed using R version 6.2.1. A p-value of &lt;0.05 was considered statistically significant. Results: We included three studies totaling 929 patients. 585 (62.9%) patients were males. There is a statistically significant improvement in MMR (RR 1.71, 95% CI 1.09 to 2.69, p=0.021, I. = 52%) and an increase in the likelihood of achieving a CCyR (RR 1.24, 95% CI 0.90 to 1.71, p=0.197, I. =74%). Conclusions: Dasatinib shows potential as a management in CP-CML patients with imatinib resistance. However, these results should be interpreted cautiously, and further validation needs to be done with high-quality, large-scale cohort studies or clinical trials to address the safety of dasatinib.

Frequency of comedication of proton pump inhibitors with crystalline dasatinib in chronic myeloid leukemia and effects on TKI-bioavailability.

6561 Background: Tyrosine kinase inhibitors (TKI), including dasatinib, have profoundly improved clinical outcome in chronic myeloid leukemia (CML). However, solubility, bioavailability and systematic exposure of the crystalline formulation of dasatinib (Sprycel) is reduced at higher gastric pH levels. This is problematic for comedication with acid reducing agents as lower bioavailability may reduce clinical response. Methods: We investigated proton pump inhibitor (PPI) and TKI comedication, including dasatinib, in a large real world CML cohort. Furthermore, we assessed the influence of timing of PPI comedication on the absorption and bioavailability of dasatinib. Results: Using the Swedish CML- and Prescribed Drug-Registries, we identified 1,328 chronic phase CML patients, diagnosed 2002-2018. 1,261 (95%) had received specified/known TKI treatment and 685 of those (54%) were prescribed a PPI (ATC-code: “A02BC”) at some point after CML diagnosis. TKIs and PPIs prescribed within 12 months of CML diagnosis were prescribed by different HCPs in 66% of cases (284/432). Of the 388 patients treated with dasatinib, 91 (23.5%) received a concomitant PPI. The PPI prescription rate increased to 53% (204/388) in the dasatinib cohort after dasatinib treatment had ended. Further, we assessed the drug-drug interaction (DDI) in 18 healthy volunteers given crystalline dasatinib (100mg) alone or together with omeprazole (40mg, at steady state) administered 9 hours apart; a time point when a high effect on bioavailability is expected. Compared to dosing with crystalline dasatinib alone, Cmax and AUC0-24 were reduced by 96% and 88% by omeprazole comedication (Table). Conclusions: Despite warnings, comedication with PPI is common among dasatinib treated CML patients. Further, an even larger proportion of patients need PPI co-treatment, which however, cannot fully be administered due to its negative impact on dasatinib pharmacokinetics. Moreover, with an optimized study design, we observed a higher than previously reported negative interaction of PPI comedication on crystalline dasatinib bioavailability. This may compromise clinical efficacy and risk CML disease progression. For patients in need of PPI, selection of a non-crystalline, less pH-sensitive formulation of dasatinib therefore appears more appropriate. Clinical trial information: NCT06145217 . [Table: see text]

The treatment of patients with chronic myeloid leukemia chronic phase combined with myelofibrosis with tyrosine kinase inhibitors: A Chinese population-based study.

e18524 Background: Chronic myeloid leukemia (CML) is a type of hematological malignancy characterized by the excessive proliferation of myeloid cells. Studies have shown that the presence of MF in CML patients has been associated with TFR. Identifying and assessing MF in CML patients at the time of diagnosis can provide valuable information for treatment planning and prognostic evaluation. Methods: The study enrolled 1757 CML-CP patients with pathological results of bone marrow biopsy. Patients with incomplete information from laboratory tests and medical records were excluded. The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhejiang University School of Medicine and conducted in accordance with the Declaration of Helsinki. CML was diagnosed according to National Comprehensive Cancer Network (NCCN) 2023 version. Results: Patients with MF were found to be older (p&lt;0.001) and had higher leukocyte (p&lt;0.001) and platelet counts (p&lt;0.001). They were also more likely to experience anemia (p&lt;0.001), splenomegaly (p&lt;0.001), patients with myelofibrosis had a higher percentage of eosinophils (p&lt;0.001) and basophils (p&lt;0.001) and had a higher proportion of peripheral blood blast cells (p&lt;0.001) compared to patients without myelofibrosis. However, there was no significant difference in the male-to-female ratio between the two groups (p=0.690). Patients with MF were more unlikely to achieve certain treatment milestones, including a 3-month early molecular response (3M-EMR) (p&lt;0.001), 6-month BCR-ABLIS ≤ 1% (p&lt;0.001), and 12-month major molecular response (12M-MMR) (p&lt;0.001). The proportion of medium/high-risk patients, as determined by Sokal score (p&lt;0.001), Hasford score (p&lt;0.001), ELTS score (p&lt;0.001), and EUTOS score (p=0.002), was significantly increased in patients with MF (Table 1). Patients with MF had lower OS and PFS compared to patients without MF, indicating a potentially worse prognosis for those with MF. Patients with MF 10-year cumulative incidences of imatinib-therapy failure (p&lt;0.001). However, there was no statistically significant difference in the treatment failure rate with different second-generation TKIs (p=0.222). CML-CP patients with MF who were treated with different TKIs were found that second-generation TKIs were more likely to achieve a 3-month EMR(p=0.009), 6-month BCR-ABLIS ≤ 1% (p=0.019), and 12-month MMR(p=0.015) compared to imatinib. Conclusions: Based on the available data, the results suggest that MF is indeed a poor prognostic factor for patients with CML. This finding highlights the importance of considering MF as a factor in assessing the outlook for CML patients. These findings indicate that second-generation TKIs are more effective in achieving molecular responses compared to imatinib, particularly in the context of myelofibrosis.

A Real World Analysis of Safety and Efficacy of Nilotinib when Used as First Line and Beyond: Retrospective Single Centre Study Representing Largest Cohort of Indian Patients Treated with Nilotinib

Background: Efficacy and toxicity of TKIs may vary depending on the ethnic background or genetic factors; hence it is important to gather data from individual populations pertaining to each drug. The pivotal registration trial had not enrolled any patient from India and there are very limited published studies on its efficacy as well as safety from Indian patients with CML. Methods: Hospital Electronic Medical Record was screened for adult (age &gt; 18 years) CML patients registered (n = 1290) at our hospital from 1st May 2018 to 31st December 2022. CML-CP or CML-AP patients, those who have received Nilotinib as 1st line (n = 40) or 2nd line (n = 66) or 3rd line TKI (n = 20) for at least 90 days (3 months) and have at least one RQ PCR BCR: ABL value post Nilotinib initiation, were enrolled in this study (n = 126). Results: Eighty (74.1%) patients achieved BCR/ABL of ≤ 1% at 12 months. MMR and MR4 at 12 months was seen in 44 (40.7%) and 19 (17.6%) patients respectively. The most common haematological toxicity was thrombocytopenia of any grade seen in 54 (42.8%) patients. Conclusion: Our study demonstrates that treatment with Nilotinib was well-tolerated in Indian patients and was effective in achieving molecular remission rates in 1st, 2nd or 3rd line therapy in the real-world setting. Safety and efficacy were in line with published western or Asian studies.

Peripheral blood quantitation of CD26 positive leukemic stem cells as a predictor of tyrosine kinase inhibitor response in chronic myeloid leukemia.

Leukemic stem cells (LSCs) are the transcriptionally low/silent cells which are resistant to the tyrosine kinase inhibitor. These have been found to play a pivotal role in disease relapse in chronic myeloid leukemia (CML) cases. The present study evaluated the correlation of absolute CML-LSC count in the peripheral blood (PB) at diagnosis and achievement of major molecular response (MMR) at 12 months in patients of CML-CP. This was a prospective, observational, non-interventional single center study including newly diagnosed adult (>18 yrs) CML-CP patients. Absolute CD26 + CML-LSC quantification was done by multiparametric flow cytometry. Patients were treated with Imatinib treatment and subsequently monitored at 3-month intervals for BCR::ABL transcript levels. MMR was defined as a BCR::ABL1 transcript level of less than 0.1% on international scale. A total of 89 patients were enrolled in the study out of which 40.5% achieved MMR at 12 months. There was a significant difference in the median absolute CML-LSC count of the patients who achieved MMR at 12 months as compared to those who did not (58.5 vs 368.1 cells/μL; p value <0.001). Using a ROC analysis, a count of <165.69 CML LSC/μL was identified to have a sensitivity of 83.8% and specificity of 72.4%, in predicting the MMR at 12 months. Absolute CML-LSC count at diagnosis in the PB predicts the MMR achievement at 12 months. An absolute count of less than 165 cells/μL is highly predictive of achieving MMR at 12 months.

Retraction: Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era.

Retraction: Sensitive Detection of Pre-Existing BCR-ABL Kinase Domain Mutations in CD34+ Cells of Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients Is Associated with Imatinib Resistance: Implications in the Post-Imatinib Era.

The Effect and Safety of Flumatinib in Patients with Chronic Myelogenous Leukemia Failed First-and Second-line Treatment

To analyze the efficacy and safety of flumatinib, a second-generation tyrosine kinase inhibitor (TKI) independently developed in China, in patients with chronic myelogenous leukemia in chronic phase (CML-CP) who falied first-line and second-line treatment. The clinical data of 30 CML-CP patients treated with flumatinib in Lianyungang First People's Hospital from January 2020 to September 2022 were collected retrospectively. Among them, 15 patients who received imatinib first-line treatment but failed treatment were included in the second-line group, and the other 15 patients who failed second-line treatment with nilotinib or dasatinib were included in the third-line group. The hematological and molecular responses of the patients in the two groups at 3, 6 and 12 months of treatment, and the event-free survival (EFS) and adverse reactions of patients at the end of follow-up were statistical analyzed. At 3, 6, and 12 months of treatment, 10, 11, and 12 patients in the second line group achieved major molecular response (MMR), which was higher than that of 3, 4, and 5 patients in the third line group (P =0.010, P =0.011, P =0.010). At 3 months of treatment, 12 and 13 patients achieved complete hematological response (CHR) and early molecular response (EMR) in the second-line group, which was higher than that of 9 and 13 patients in the third-line group, but the difference between the two groups was not statistically significant (P =0.232, P =1.000); At 6 and 12 months of treatment, 6 and 7 patients in the second-line group achieved MR4.5, which were higher than of 3 and 2 cases in the third-line group, but the difference was not statistically significant (P =0.427, P =0.713). The hematological adverse reactions of patients in the second-line group during treatment the period were mainly grade 1-2 thrombocytopenia and anemia, and no grade 3-4 of adverse reactions occurred. In the third-line group, there were 2 cases of grade 1-2 thrombocytopenia, grade 1-2 anemia and white blood cell 3 cases were reduced each, 1 case of grade 3-4 anemia, 2 cases of grade 3-4 neutropenia. The non-hematological adverse reactions in the second-line group were rash (2 cases), headache (1 case), diarrhea (1 case), fatigue (1 case), limb pain (1 case). There were 1 cases of diarrhea, 1 cases of nausea, and 1 cases of edema in the third-line group. There was no statistical significance in hematological and non-hematological adverse reactions between the two groups of patients (P >0.05). At the end of follow-up, the EFS rate of patients in the second-line group was higher than that in the third-line group (100% vs 93.3%), but the difference was not statistically significant (P =0.317). The second-generation TKI flumatinib independently developed in China, has good curative effect and safety for CML-CP patients who failed first-line and second-line treatment.

Treatment status of tyrosine kinase inhibitor for newly-diagnosed chronic myeloid leukemia: a domestic multi-centre retrospective real-world study

Objective: To retrospectively analyze the treatment status of tyrosine kinase inhibitors (TKI) in newly diagnosed patients with chronic myeloid leukemia (CML) in China. Methods: Data of chronic phase (CP) and accelerated phase (AP) CML patients diagnosed from January 2006 to December 2022 from 77 centers, ≥18 years old, and receiving initial imatinib, nilotinib, dasatinib or flumatinib-therapy within 6 months after diagnosis in China with complete data were retrospectively interrogated. The choice of initial TKI, current TKI medications, treatment switch and reasons, treatment responses and outcomes as well as the variables associated with them were analyzed. Results: 6 893 patients in CP (n=6 453, 93.6%) or AP (n=440, 6.4%) receiving initial imatinib (n=4 906, 71.2%), nilotinib (n=1 157, 16.8%), dasatinib (n=298, 4.3%) or flumatinib (n=532, 7.2%) -therapy. With the median follow-up of 43 (IQR 22-75) months, 1 581 (22.9%) patients switched TKI due to resistance (n=1 055, 15.3%), intolerance (n=248, 3.6%), pursuit of better efficacy (n=168, 2.4%), economic or other reasons (n=110, 1.6%). The frequency of switching TKI in AP patients was significantly-higher than that in CP patients (44.1% vs 21.5%, P<0.001), and more AP patients switched TKI due to resistance than CP patients (75.3% vs 66.1%, P=0.011). Multi-variable analyses showed that male, lower HGB concentration and ELTS intermediate/high-risk cohort were associated with lower cytogenetic and molecular responses rate and poor outcomes in CP patients; higher WBC count and initial the second-generation TKI treatment, the higher response rates; Ph(+) ACA at diagnosis, poor PFS. However, Sokal intermediate/high-risk cohort was only significantly-associated with lower CCyR and MMR rates and the poor PFS. Lower HGB concentration and larger spleen size were significantly-associated with the lower cytogenetic and molecular response rates in AP patients; initial the second-generation TKI treatment, the higher treatment response rates; lower PLT count, higher blasts and Ph(+) ACA, poorer TFS; Ph(+) ACA, poorer OS. Conclusion: At present, the vast majority of newly-diagnosed CML-CP or AP patients could benefit from TKI treatment in the long term with the good treatment responses and survival outcomes.

Long-term outcomes after upfront second-generation tyrosine kinase inhibitors for chronic myeloid leukemia: managing intolerance and resistance

Second-generation tyrosine kinase inhibitors (2GTKI) are more effective in inducing rapid molecular responses than imatinib when used first-line in patients with chronic myeloid leukemia in chronic phase (CML-CP). However, failure of first line-2GTKI (1L-2GTKI) still occurs and there is no consensus regarding subsequent management. We retrospectively analyzed the outcome of 106 CML-CP patients treated with 1L-2GTKI and with a median follow-up of 91 months. 45 patients (42.4%) switched to an alternative TKI, 28 for intolerance (26.4%) and 17 (16%) for resistance. Most patients who remained on 1L-2GTKI achieved deep molecular responses (DMR) and 15 (14.1%) are in treatment-free remission (TFR). Intolerant patients also obtained DMR, although most required multiple TKI changes and were slower to respond, particularly if treated with 2L-imatinib. Inferior outcomes were observed in resistant patients, who failed alternative 2L-2GTKI and required 3/4GTKI and/or allogeneic hematopoietic stem cell transplant (alloSCT). 7yr-OS was significantly lower for these individuals (66.1%) than for intolerant patients and those who remained on 1L-2GTKI (100% and 97.9%, respectively; p = 0.001). It is apparent that failure of 1L-2GTKI is a challenging problem in modern CML therapy. Intolerance can be effectively managed by switching to an alternative 2GTKI, but resistance requires early consideration of 3/4GTKI.

Kronik Miyeloid Lösemi Hastalarının Tanı Sırasındaki Hemoglobin, Lökosit ve Trombosit Düzeylerinin Sağkalım Sonuçlarına Etkisi

Background:Since the development of tyrosine kinase inhibitors (TKIs), the prognosis for chronic myeloid leukemia (CML) has significantly improved. Several predicted prognostic scores and indicators at diagnosis have been used to predict the prognosis of chronic phase chronic myeloid leukemia (CML-CP) during the TKI period. When CML patients are first diagnosed, hemogram parameter aberrations are rather prevalent in clinical practice, although it is still unknown how those parameters affect the prognosis. This study aims to evaluate the hemogram parameters at diagnosis on the survival outcomes of CML-CP patients. Materials and Methods:One hundred thirty-seven patients who were diagnosed with CML-CP and received treatment were assessed between the years 2006 and 2020. Results:There were 65 (47.4%) males and 72 (52.6%) females with a median age of 50 (range: 18-78) years at diagnosis. Median hemoglobin level was 12.1 gr/dL (4.3-17.4), leucocyte count was 66.2 ×109 /L (7.5-520.2), and thrombocyte count was 362 ×109 /L (18-3.496) for all patients. The median progression-free survival (PFS) was 16.7 months 16.7 (2.0-106.4) and the median overall survival (OS) was 63.8 months (0.43-166.2) for all patients. Conclusion:This study is valuable in terms of predicting the prognosis of CML patients with hemoglobin, leukocyte, and platelet values at the time of diagnosis. While emphasizing the importance of platelet count at the time of diagnosis, similar to the previously defined risk scores, it showed that leukocyte and hemoglobin values at the time of diagnosis did not have a statistically significant effect on OS and PFS.

Ascites does not accompany pleural effusion developing under dasatinib therapy in patients with CML-CP.

Pleural effusion (PE) is the most frequent pulmonary complication of dasatinib, a tyrosine kinase inhibitor (TKI). Concurrent pericardial effusions have been reported in about one-third of the cases. In this study, we aimed to investigate ascites generation in chronic-phase chronic myeloid leukemia (CML-CP) patients developing PE under dasatinib. We conducted a cross-sectional study to evaluate whether pericardial effusion and ascites accompany PE inCML-CP patients treated with dasatinib. For this purpose, consecutive patients with CML-CP who developed PE underdasatinib therapy have been evaluated with chest X-ray, transthoracic echocardiography, and abdominal ultrasonography. There were seven patients, and the median age was50 years (range, 31-73 years). Most of patients were male(n=5). All patients received imatinib as first-line TKI. Sixpatients received dasatinib following imatinib failure in second line. The median duration from dasatinib initiation to PE generation was 58months (range, 8-135months). Consequently, four patients had grade 1 pericardial effusion, and no patient had ascites. In our small study, dasatinib-related PE was associated with low-grade pericardial effusion but no ascites. There are hypothetical explanations of this phenomenon including the simultaneous activation/inhibition of kinases; however, more research needs to be performed on this topic.