Accurate prediction of the age incidence of chronic myeloid leukemia with an improved two-mutation mathematical model

2016 ◽  
Vol 8 (12) ◽  
pp. 1261-1275 ◽  
Author(s):  
Paola Lecca ◽  
Claudio Sorio
Keyword(s):  
Mathematical Model ◽  
Body Mass Index ◽  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Body Mass ◽  
Myeloid Leukemia ◽  
Accurate Prediction ◽  
Myelogenous Leukemia

A two-step mathematical model integrates haematopoietic turnover parameters and body mass index to predict the age incidence of chronic myelogenous leukemia.

scholarly journals A Novel Methoxybenzyl 5-Nitroacridone Derivative Effectively Triggers G1 Cell Cycle Arrest in Chronic Myelogenous Leukemia K562 Cells by Inhibiting CDK4/6-Mediated Phosphorylation of Rb

2020 ◽  
Vol 21 (14) ◽  
pp. 5077
Author(s):  
Bin Zhang ◽  
Ting Zhang ◽  
Tian-Yi Zhang ◽  
Ning Wang ◽  
Shan He ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Chronic Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
K562 Cells ◽  
Myelogenous Leukemia ◽  
G1 Phase ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest

Chronic myeloid leukemia (CML) is a malignant tumor caused by the abnormal proliferation of hematopoietic stem cells. Among a new series of acridone derivatives previously synthesized, it was found that the methoxybenzyl 5-nitroacridone derivative 8q has nanomolar cytotoxicity in vitro against human chronic myelogenous leukemia K562 cells. In order to further explore the possible anti-leukemia mechanism of action of 8q on K562 cells, a metabolomics and molecular biology study was introduced. It was thus found that most of the metabolic pathways of the G1 phase of K562 cells were affected after 8q treatment. In addition, a concentration-dependent accumulation of cells in the G1 phase was observed by cell cycle analysis. Western blot analysis showed that 8q significantly down-regulated the phosphorylation level of retinoblastoma-associated protein (Rb) in a concentration-dependent manner, upon 48 h treatment. In addition, 8q induced K562 cells apoptosis, through both mitochondria-mediated and exogenous apoptotic pathways. Taken together, these results indicate that 8q effectively triggers G1 cell cycle arrest and induces cell apoptosis in K562 cells, by inhibiting the CDK4/6-mediated phosphorylation of Rb. Furthermore, the possible binding interactions between 8q and CDK4/6 protein were clarified by homology modeling and molecular docking. In order to verify the inhibitory activity of 8q against other chronic myeloid leukemia cells, KCL-22 cells and K562 adriamycin-resistant cells (K562/ADR) were selected for the MTT assay. It is worth noting that 8q showed significant anti-proliferative activity against these cell lines after 48 h/72 h treatment. Therefore, this study provides new mechanistic information and guidance for the development of new acridones for application in the treatment of CML.

Delayed Cytogenetic Response and Reduced Rate of Major Molecular Response Associated to Increased Body Mass Index At Baseline in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2784-2784
Author(s):  
Massimo Breccia ◽  
Giuseppina Loglisci ◽  
Adriano Salaroli ◽  
Alessandra Serrao ◽  
Paola Volpicelli ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Body Mass ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Normal Weight ◽  
First Line ◽  
Reduced Rate ◽  
The Impact

Abstract Abstract 2784 Obesity, measured as body mass index (BMI), has been identified as a possible risk factor for the onset of several solid tumors as well as for chronic myeloid leukemia (CML). To date, no correlations have been reported in this latter disease between BMI at baseline and response to targeted therapies. We refer here on the impact of BMI on clinical response in CML. Three hundred and thirty-nine chronic phase (CP) CML patients treated with imatinib entered the study: 142 patients first received interferon alpha outside clinical trials and were then switched to imatinib for failure. For this group of patients, BMI was collected at the time of start of imatinib. The remaining patients were consecutively treated with imatinib first-line from January 2000 onward. BMI was defined as the individual's body weight divided by the square of his of her height and patients were categorised according to WHO into four categories: underweight (BMI < 18.5), normal weight (BMI 18.5-< 25), overweight (BMI 25-<30) and obese (BMI ≥ 30). All patients were followed according to ELN guidelines. We also analysed 25 CP-CML patients treated frontline with nilotinib. One hundred and fifty-six patients (46%) were categorized as underweight/normalweight, while 183 patients (54%) were classified as overweight/obese. BMI increased with age, with a median age of 29 years in underweight category, 43.4 years in normal weight, 54.9 years in overweight and 62.4 years in obese patients (p=0.001). We did not reveal statistically significant association between BMI and prognostic risk stratification at baseline, even when we used new EUTOS score, or type of BCR/ABL transcript. No statistically significant difference was revealed in terms of overall CCyR rate which was 87% for underweight/normal weight categories compared to 84% for overweight/obese group (p=0.34). If compared to patients with low BMI (< 18.5–25), patients with increased BMI (> 25–40) at diagnosis who received imatinib, showed a significantly longer median time to reach CCyR (6.8 months vs 3.3 months, p=0.01), a reduced rate of MMR (77% vs 58%, p=0.01) which was also achieved in a longer median time (29 months compared to 14 months, p=0.03). At 18 months, molecular kinetics revealed that median BCR-ABL/ABL ratio was 0.6% IS (range 0.001%-2%) in underweight/normal weight group compared to 1.6% IS (range 0.01%-3%) in overweight/obese category (p=0.01). Conversely, no differences were revealed with respect to BMI in patients treated frontline with nilotinib and also patients with increased BMI obtained rapidly CCyR and MMR, with an incidence similar to that of underweight/normal weight patients. These results suggest that CML patients with increased weight at baseline should be followed and carefully monitored if treated with standard dose imatinib frontline for a possible early switch to a second generation TKI or, as an alternative, should preferably be candidate to receive these drugs as a first line therapy. Disclosures: No relevant conflicts of interest to declare.

Once-Daily Dasatinib for Treatment of Patients with Chronic Myeloid Leukemia

2009 ◽  
Vol 43 (5) ◽  
pp. 920-927 ◽  
Author(s):  
Timothy Tyler
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Once Daily ◽  
Number Of Patients ◽  
Significant Difference ◽  
American Society

Objective To discuss the new dasatinib dosing regimen for the treatment of chronic phase chronic myelogenous leukemia (CP CML) in patients who failed or were intolerant to imatinib therapy. Data Sources Literature published between July 2008 and December 2008 was accessed via MEDLINE, the Proceedings of the American Society of Hematology, and the Proceedings of the American Society of Clinical Oncology using the key words chronic myelogenous leukemia, chronic myeloid leukemia, dasatinib, imatinib, nilotinib, pharmacokinetics, and regimen. Study Selection And Data Extraction Meeting abstracts and reports of major Phase 1–3 studies published in English are included. Data Synthesis Imatinib is the standard first-line therapy for CML; however, some patients develop resistance or are intolerant to the drug. Dasatinib was approved for the treatment of imatinib-resistant/intolerant patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia at the dosage of 70 mg twice daily. A Phase 3 dose-optimization study was performed to compare this regimen with others, including dasatinib 100 mg once daily, in patients with CP CML. Results of this study showed that there was no significant difference in efficacy between these 2 regimens. The safety profile was improved in the 100-mg once-daily dasatinib arm with significantly reduced frequencies of grade 3–4 thrombocytopenia and all-grade pleural effusions. The number of patients who had to discontinue, reduce, or interrupt their dosage was also less among patients taking dasatinib 100 mg once daily. Conclusions Dasatinib 100 mg once daily has a more favorable risk to benefit assessment compared with the previous 70 mg twice-daily regimen and is now the recommended schedule for patients with CP CML.

scholarly journals Management of Patient Primigravida 36-37 Weeks with Chronic Myeloid Leukemia, Anemia, and Thrombocytopenia: A Case Report

2021 ◽  
Vol 1 (2) ◽  
pp. 58
Author(s):  
Muhammad Farlyzhar Yusuf ◽  
Ruddi Hartono
Keyword(s):  
Chronic Myeloid Leukemia ◽  
General Anesthesia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Stable Condition ◽  
Pregnant Patient ◽  
Myelogenous Leukemia ◽  
Rapid Sequence Intubation ◽  
Hematopoietic Stem ◽  
Atypical Cml

<p>Chronic myelogenous leukemia (CML) is a type of cancer caused by a disturbance in the hematopoietic stem cells. CML itself rarely occur on women who are in labor and an advanced procedure in this event has become a special challenge for medics, especially an anesthesiologist. This limits the development of standard anesthesia guidelines, so in this case we describe the incidence of CML in pregnancies performed by Cesarean section with general anesthesia.</p><p>The first pregnant patient was 36 weeks pregnant; the patient was first diagnosed with Chronic myelogenous leukemia (CML) at the age of 26-28 weeks, at that time the patient complained of frequent dizziness, abdominal pain and weakness, then the patient complained of bleeding gums, and currently the patient complained of nosebleeds. The Bone Marrow shows Conclusion an accelerated phase chronic myeloid leukemia (CML) (suspected atypical CML) with nutritional deficiency. We perform General Anesthesia technique Rapid Sequence Intubation with Regimen Fentanyl 100 mcg, Propofol 80 mg and Rocuronium 50 mg.</p><p>The patient was admitted to the ICU for 2 days before transferring to intensive care and the patient received intravenous paracetamol 1 gram four times, cefazolin 1 gram twice a day, lansoprazole 30 mg once a day, tranexamic acid 1gr three times a day, and 15 mcg per hour fentanyl contionously. Hemodynamic patients in the ICU are in a stable condition. On the second postoperative day of care, the patient was transferred to the High care ward, then at the third postoperative day the patient's hemodynamics was stable and the patient was transferred to a normal room.</p>

Predictors of Oral Mucositis in Patients Receiving Hematopoietic Cell Transplants for Chronic Myelogenous Leukemia

2004 ◽  
Vol 22 (7) ◽  
pp. 1268-1275 ◽  
Author(s):  
Kim Robien ◽  
Mark M. Schubert ◽  
Barbara Bruemmer ◽  
Michele E. Lloid ◽  
John D. Potter ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Chronic Myelogenous Leukemia ◽  
Body Mass ◽  
Oral Mucositis ◽  
Methylenetetrahydrofolate Reductase ◽  
Hematopoietic Cell ◽  
Myelogenous Leukemia ◽  
Multivitamin Supplementation ◽  
Supplement Use ◽  
Conditioning Regimens

PurposeOral mucositis is a nearly universal and often severe complication following hematopoietic cell transplantation (HCT). The objective of this study was to evaluate factors predicting oral mucositis severity among 133 patients undergoing allogeneic HCT for chronic myelogenous leukemia.Patients and MethodsAll patients were transplanted between 1992 and 1999, were ≥ 18 years of age, received either cyclophosphamide/total-body irradiation (TBI) or busulfan/cyclophosphamide conditioning regimens, and received four doses of methotrexate for graft-versus-host disease prophylaxis post-transplant. Oral mucositis was measured by a trained examiner every 2 to 3 days using the Oral Mucositis Index (OMI). Multiple linear regression analysis was used to identify predictors of mean OMI during days 6 to 12, 1 to 18, and the maximum OMI score between days 1 to 18.ResultsTBI containing conditioning regimens, body mass index ≥ 25, and methylenetetrahydrofolate reductase 677 TT genotype were found to be predictive of higher mean OMI scores (P < .05). Pretransplant multivitamin supplement use was associated with lower mean OMI scores compared to those who did not use supplements. Smoking status, race, pretransplant treatment with interferon-alfa or hydroxyurea, and patient/donor ABO compatibility were not associated with mean OMI scores.ConclusionPatients who are scheduled to receive conditioning regimens containing TBI, have a pretransplant body mass index ≥ 25, or carry the methylenetetrahydrofolate reductase 677 TT genotype should be considered at greater risk of developing oral mucositis following HCT. Future studies should investigate whether multivitamin supplementation before HCT could reduce mucositis severity.

scholarly journals Summary of the published Indian data on chronic myeloid leukemia

2016 ◽  
Vol 05 (03) ◽  
pp. 162-165 ◽  
Author(s):  
Manish K. Singhal ◽  
Manju Sengar ◽  
Reena Nair
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Service Providers ◽  
Myelogenous Leukemia ◽  
Distinct Entity ◽  
Cancer Service ◽  
Indian Data

AbstractChronic myelogenous leukemia (LML) was recognized as a distinct entity in the mid-1800s. Since Nowell and Hunagerford initiated their research on CML in1960 our understanding in CML has been increasing. Imatinib became the preferred treatment from 2000 onwards as a result of its unprecedented success. The lack of structured Indian data on CML led to the formation of a CML data cansortuim which invited CML data albiet retro spartive form around the country including major cancer service providers both government and private. We provide a summary of published Indian data on CML here.

The effect of body mass index on efficacy and safety of bosutinib or imatinib in patients with newly diagnosed chronic myeloid leukemia.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7037-7037
Author(s):  
Tim H. Brümmendorf ◽  
Jorge E. Cortes ◽  
Lambert Busque ◽  
Carlo Gambacorti-Passerini ◽  
Leif Stenke ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Chronic Myeloid Leukemia ◽  
Body Mass ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety

7037 Background: Bosutinib (BOS) is approved for the treatment (Tx) of Philadelphia chromosome–positive (Ph+) chronic myeloid leukemia (CML) resistant/intolerant to prior therapy and newly diagnosed Ph+ chronic phase (CP) CML. Body mass index (BMI) was shown to influence Tx response with front-line dasatinib vs imatinib (IMA). We report the efficacy and safety of BOS and IMA by BMI in patients (pts) with newly diagnosed CP CML. Methods: In the open-label BFORE trial, pts were randomized to receive 400 mg once daily BOS or IMA. Outcomes were assessed according to baseline BMI ≥25 or = 25 kg/m2. This post hoc analysis was based on the final 5-y analysis (database lock: June 12, 2020). Results: In the BOS and IMA arms, respectively, 149 (56.4%) vs 115 (43.6%) pts and 145 (54.3%) vs 122 (45.7%) pts had BMI ≥25 vs = 25. In both the BOS and IMA arms, median Tx duration and time on study was 55 mo for pts with BMI ≥25 or = 25; respective median dose intensity was 394 vs 393 mg/d and 400 vs 400 mg/d. Molecular response (MR) rates are shown in the table. Cumulative incidence of major MR was similar in pts with ≥25 vs = 25 receiving BOS (HR 0.99; 95% CI 0.74−1.31) or IMA (HR 1.09; 95% CI 0.81−1.47). Event-free survival (EFS) and overall survival (OS) rates at 60 mo are shown in the table. Most common reasons for Tx discontinuation were adverse events (AEs) (BOS 28.2 vs 20.0%; IMA 13.3 vs 10.7%) and lack of efficacy (BOS 5.4 vs 5.2%; IMA 16.1 vs 19.8%). In pts with BMI ≥25 vs = 25, dose reductions and interruptions due to Tx-emergent AEs (TEAEs) occurred in 43.6 % vs 46.2% and 66.4% vs 69.7% of pts with BOS and 24.5% vs 24.6% and 40.6% vs 50.8% with IMA. Any grade TEAEs in ≥30% of pts with BMI ≥25 vs = 25 were diarrhea (73.8 vs 73.1%), nausea (40.9 vs 31.9%), thrombocytopenia (30.9 vs 41.2%), increased alanine (37.6 vs 28.6%) and aspartate aminotransferase (30.2 vs 20.2%) with BOS and diarrhea (49.0 vs 29.5%), nausea (46.2 vs 37.7%), muscle spasms (33.6 vs 26.2%), neutropenia (14.7 vs 32.0%) and thrombocytopenia (10.5% vs 30.3%) with IMA. Conclusions: Efficacy of BOS was consistent in pts with BMI ≥25 or = 25; however, with IMA a low (vs high) BMI appeared to be associated with worse survival outcomes. Differences in certain TEAEs were observed between BMI subgroups in both treatment arms. Clinical trial information: NCT02130557. [Table: see text]

scholarly journals Philadelphia chromosome-negative chronic myelogenous leukemia without breakpoint cluster region rearrangement: a chronic myeloid leukemia with a distinct clinical course

Blood ◽  
1990 ◽  
Vol 75 (2) ◽  
pp. 445-452 ◽  
Author(s):  
R Kurzrock ◽  
HM Kantarjian ◽  
M Shtalrid ◽  
JU Gutterman ◽  
M Talpaz
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Chronic Myelogenous Leukemia ◽  
Myeloid Leukemia ◽  
Clinical Course ◽  
Bone Marrow Failure ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Cell Counts

Abstract The hallmarks of chronic myelogenous leukemia (CML) include the Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and consistent molecular genetic aberrations: a break within a restricted 5.8 kb DNA segment, bcr, on chromosome 22q11; transposition of the c- abl protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented tyrosine kinase enzymatic activity. These molecular phenomena may occur even in the absence of cytogenetic evidence of the Ph translocation. They are highly specific and sensitive markers for CML, and are presumed to play a significant role in the pathogenesis of this malignancy. Surprisingly, we have encountered 11 patients who lacked the Ph translocation, bcr rearrangement, and (in the four patients with available mRNA) a bcr-abl message, and yet had a disease phenotype at diagnosis that was a morphologic facsimile of classic chronic phase CML. These patients presented with high white blood cell counts, neutrophilia, occasional basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic hyperplasia and a left shift in myeloid maturation. Despite the striking resemblance between the early stages of bcr-negative and bcr-positive CML, disease progression manifests distinctly in these two disorders. In contrast to the blastic transformation that inevitably complicates bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative CML patients was characterized by increasing leukemia burden with leukocytosis, pronounced organomegaly, extramedullary infiltrates, and eventual bone marrow failure (anemia and thrombocytopenia) without marked increases in blast cells. Our current observations suggest that a chronic myeloid leukemia process can develop without associated changes in the bcr or c- abl genes. Although the initial phase of this disease is indistinguishable from CML, the presence or absence of molecular markers may aid in the prediction of the clinical course of Ph-negative CML.

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