Comparative study of safety and efficacy of imatinib mesylate therapy in pediatric and adult chronic myeloid leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 20016-20016
Author(s):  
N. Raizada ◽  
T. Sagar ◽  
S. Ramanan
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dropout Rate ◽  
The Body ◽  
Imatinib Resistance ◽  
Hematopoietic Stem ◽  
Female Ratio

20016 Background: Chronic Myeloid Leukemia (CML) is one of the rare pediatric cancers. Imatinib is now the standard of care in adult CML (ACML) with newer compounds being investigated to overcome the burden of Imatinib resistance. Pediatric CML (PCML) has been an area little explored and effective strategies are not yet defined. Although, allogenic hematopoietic stem cell transplantation (HSCT) still remains the gold-standard treatment, the choice of drug in the subset in which HSCT is not a suitable option remains to be determined. Methods: This was a single-institution prospective study conducted from April 2004-March 2006, analyzing and comparing 293 Philadelphia chromosome (PH) positive CML patients in pediatric and adolescent subsets (i.e. age =18 years) not eligible for allogenic HSCT with ACML. After obtaining a written informed consent, a starting dose of 400 mg/m2/d Imatinib mesylate was administered in adults, whereas in pediatric and adolescents it was 400 mg/m2/d if the body surface area (BSA) was <1 m2, or 400 mg/d if BSA was >1m2. Results: 27 patients were in the age group =18 years; male to female ratio was 1.07:1. Gender ratio in 266 ACML patients showed a male preponderance (2.5:1). The mean age in ACML was 37.4 years. In pediatric subsets, a trend toward CML in adolescents was observed with mean age 14.85 years. Majority of the patients were in chronic phase (81.5% PCML and 85.7% ACML) with overall 93% patients receiving prior hydroxyurea as a cytoreductive agent. An unusual finding was higher incidence of Hypodiploidy (significance undetermined) and 5 patients had double PH. 80.1% ACML patients achieved complete hematological response, but it was significantly lower (59.3%) in PCML. 39.5% ACML achieved major cytogenetic response which was less than most published western data. Hematologic and non-hematologic toxicities (GI, dermatological etc) were found to be higher in ACML. Low toxicities in PCML were attributed to good tolerance to Imatinib therapy; however a higher dropout rate in pediatric subsets was possibly due to poor social and parental support. Conclusion: We conclude that imatinib mesylate is both safe and efficacious drug for ACML, however further research is warranted in pediatric and adolescent population to establish its efficacy. No significant financial relationships to disclose.

scholarly journals Safety Profile of Imatinib in Indian Chronic Myeloid Leukemia Patients

1970 ◽  
Vol 9 (1) ◽  
pp. 24-30
Author(s):  
R Meena ◽  
NR Biswas ◽  
Lalit Kumar ◽  
T Velpandian ◽  
YK Gupta
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Imatinib Mesylate ◽  
Safety Profile ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Specific Inhibitor ◽  
Chronic Phase ◽  
Symptomatic Treatment ◽  
Weight Changes

Introduction: Imatinib mesylate has become the choice of drug in the treatment of chronic myeloid leukemia. Objective: To study safety profile of Imatinib (specific inhibitor or bcrabl tryosne kinase protein) in Philadelphia chromosome t {(9:22), bcr-abl} positive chronic myeloid leukemia (CML) chronic phase patients. Materials and Methods: After IEC clearance, 36, BCR-ABL positive CML patients in the chronic phase of the disease were recruited. Imatinib mesylate (Gleevec, Novartis), was started (400mg daily) and followed up weekly in first month, two weekly till three months & monthly thereafter. Safety profile data, recorded in pre-designed proforma, were analyzed for time of onset, duration and severity of adverse effects. Causality relationship of recorded adverse events was established with imatinib therapy using WHO-UMC criteria. Results: A total of 222 adverse events were reported in 36 CML-CP patients over 12 months of follow up. Thrombocytopenia was the most commonly reported in 60% of the patients followed by musculoskeletal (17%), dermatological (16%), gastrointestinal disturbances (13%), body weight changes (11%), superficial edema (8%) and liver enzyme rise (4%). More than 80% events reported within months of therapy which persisted for less than 3 months in most of the cases. No treatment was needed in 68% of cases while therapy alteration was not needed in 88% of cases. Most of the reactions (60%) had probable relationship with the therapy. Conclusion: Imatinib was well tolerated, having only mild to moderate grade of toxicities, mostly within 3 months of therapy and most of them persisted for less than 3 months of duration, requiring only symptomatic treatment and drug withhold or dose decrement in only few cases. Keywords: Safety profile; imatinib; causality assessment; adverse events. DOI: 10.3126/hren.v9i1.4358Health Renaissance, 2011: Vol.9 No.1:24-30

Mutation Analysis of ABL1 Gene and its Relation to the Achievement of Major Molecular Response in Indonesian Chronic Myeloid Leukemia Patients

2020 ◽  
Vol 17 (1) ◽  
pp. 48-54
Author(s):  
Reni Widyastuti ◽  
Melva Louisa ◽  
Ikhwan Rinaldi ◽  
Riki Nova ◽  
Instiaty Instiaty ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Cross Sectional ◽  
Imatinib Resistance

Background: Imatinib mesylate is the first tyrosine kinase inhibitor approved for chronic myeloid leukemia (CML) therapy. Imatinib is an effective drug. However, previous studies have shown that about 20-30% of patients eventually would develop resistance to imatinib. Approximately 40% of imatinib resistance is associated with BCRABL kinase domain mutation. One of the most common and serious variations account for imatinib response is T315I of ABL1 gene. Objective: The study aimed to examine the association of T315I mutation with the ABL1 gene and its relation to major molecular response (MMR) achievement in CML patients. This study also examined other mutations adjacent to T315I, i.e., F311I, F317L, and different possible variations in the ABL1 gene. Methods: This was a cross-sectional study on Indonesian CML patients in chronic phase. We analyzed 120 blood samples from patients in chronic phase who have received imatinib mesylate (IM) for ≥12 months. Results: There were no T315I, F311I, and F317L mutations found in this study. However, we found another variation, which was 36 substitutions from A to G at position 163816 of ABL1 gene (according to NG_012034.1). Conclusions: We found no T315I, F311I, and F317L mutations in this study. Our findings suggest that there might be other factors that influenced the MMR achievement in our study patients. However, there were 36 substitutions from A to G at position 163.816 (according to NG_012034.1) that needed further examination to explore the significance of this mutation in clinical practice.

Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation For Patients With Chronic Myeloid Leukemia In Chronic Phase

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5518-5518
Author(s):  
Liu Xiaoli ◽  
Guanlun Gao ◽  
Xuan Zhou ◽  
Na Xu ◽  
Yajuan Xiao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Hematopoietic Stem Cell ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Hematopoietic Stem ◽  
Risk Patients

Abstract Background and Objective Following the introduction of the tyrosine kinase inhibitor (TKI) imatinib in treatment of chronic myeloid leukemia (CML) patients, the allogeneic hematopoietic stem cell transplantation (allo-HSCT) scene in CML has changed dramatically. This retrospective cohort study was designed to compare medical outcomes of Imatinib mesylate and allo-HSCT for patients with CML in chronic phase. Patients and Methods From February 2002 to February 2012, 198 patients treated consecutively at the Nanfang Hospital,Southern Medical University were assigned to two groups according to treatment with imatinib or allo-HSCT. One hundred fifteen cases of imatinib group were given imatinib at an initial dose of 400mg daily and the dose was then adjusted according to the patient´s blood and therapy response. All the patients were evaluated for hematologic, cytogenetic and molecular response every 1-3months. Eighty-three cases of allo-HSCT group received myeloablative preconditioning regimen, and methotrexate (MTX) and cyclosporine A (CsA) were used for graft-versus-host disease(GVHD), parts combined with mycophenolate mofetil (MMF) and antihuman thymocyte globulin(ATG). The primary end points of the study were complete cytogenetic response (CCyR), relapse rate, overall survival (OS) and progression-free survival (PFS) after therapy. Results In total, 59 (68.9%) patients treated over 12 months achieved a CCyR after 12 months in imatinib group, while 67 (95.7%) patients in allo-HSCT group. The relapse rates were 14.8% (n=17) in imatinib group and 10.8% (n=9) in allo-HSCT group (P=0.456). Ten-year cumulative OS rates were 93.9% in imatinib group and 77.1% in allo-HSCT group(P=0.015) and ten- year cumulative PFS rates of two groups were 86.1% vs.88.0%(P=0.508). For Sokal rating stratified analysis, the ten-year OS rates of two groups were 96.4% vs.68.0% (P = 0.049) for high-risk patients,92.6% vs. 57.1% (P = 0.019) for intermediate-risk patients , while the ten-year PFS rates of two groups were 89.3% vs. 88.0% for high-risk patients (P = 0.942), 70.4% vs. 85.7% for intermediate-risk patients (P = 0.405).The ten-year OS rates and PFS rates were not significant difference for low-risk patients. The cumulative OS rates of two groups were 94.7% vs. 73.5%(P=0.019)for the patients who were not less than 30 years old,and the cumulative PFS rates of two groups were 84.2% vs. 94.1% respectively (P=0.147). Conclusion Imatinib mesylate treatment is superior to allogeneic hematopoietic stem cell transplantation for patients with chronic myeloid leukemia in chronic phase. Disclosures: No relevant conflicts of interest to declare.

Stem cell transplantation for chronic myeloid leukemia in children

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1224-1231 ◽  
Author(s):  
Kate Cwynarski ◽  
Irene A. G. Roberts ◽  
Simona Iacobelli ◽  
Anja van Biezen ◽  
Ronald Brand ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Disease Stage ◽  
Hematopoietic Stem ◽  
Advanced Phase

Abstract Hematopoietic stem cell transplantation (SCT) is the only proven cure for chronic myeloid leukemia (CML), a rare disease in childhood. We report outcomes of 314 children with Philadelphia-chromosome–positive (Ph+) CML undergoing SCT from HLA-matched siblings (n = 182) or volunteer-unrelated donors (VUD; n = 132). Three-year overall survival (OS) and leukemia-free survival (LFS) rates were 66% and 55% (n = 314). For 156 children in first chronic phase (CP1) who underwent transplantation from HLA-identical siblings, OS and LFS rates were 75% and 63%. For 97 children who underwent SCT in CP1 from VUD, 3-year OS and LFS rates were 65% and 56%, reflecting higher transplantation-related mortality (TRM) after VUD SCT (35% vs 20%; multivariate hazard ratio [HR], 1.9; 95% confidence interval [CI], 1.0-3.5; P = .05). In a multivariate model for OS and LFS, outcomes were superior in CP1 than in advanced phase (AP/CP1) (OS HR, 2.0; 95% CI, 1.3-3; P = .001; LFS HR, 1.8; 95% CI, 1.2-2.6; P = .003). For relapse, donor source (VUD/sibling) (HR, 0.38; 95% CI, 0.19-0.76; P = .006) and disease stage (AP/CP1) (HR, 2.4; 95% CI, 1.36-4.3; P = .003) were significant. This is the first large series to show that SCT confers long-term LFS in most children with CML and helps assess alternative therapy, including tyrosine kinase inhibitors.

Management of Chronic Myeloid Leukemia with BCR/ABL Inhibitors: Current Status and Future Perspectives

2010 ◽  
Vol 2 ◽  
pp. CMT.S2439
Author(s):  
Peter Valent
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Current Status ◽  
Drug Resistant ◽  
Intrinsic Resistance ◽  
Hematopoietic Stem ◽  
Co Morbidity

Chronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by the Philadelphia chromosome (Ph) and the BCR/ABL oncoprotein. In chronic phase (CP) CML, leukemic cells display multilineage differentiation and maturation capacity. The BCR/ABL inhibitor imatinib exerts profound antileukemic effects in these patients and is considered standard frontline therapy. However, not all patients show a long-lasting response to this drug. Rather, resistance to imatinib has been recognized as an emerging clinical problem in CML. While CML stem cells exhibit intrinsic resistance against imatinib and thus survive therapy, one or more stem cell-derived subclones may acquire additional hits over time, so that an overt relapse occurs. A major triggering hit in such subclones are BCR/ABL mutations. For these patients, novel multikinase inhibitors targeting BCR/ABL such as nilotinib, dasatinib, bosutinib, bafetinib, as well as Aurora kinase inhibitors have been developed and shown to exert antileukemic effects in imatinib-resistant CML. In addition, hematopoietic stem cell transplantation (HSCT) remains an important treatment option for drug-resistant patients. The decision concerning second- or third line therapy, selection of drugs, and HSCT, is usually based on the presence and type of BCR/ABL mutation(s), phase of disease, other disease-related factors, and patient-related variables including age and co-morbidity. The current article provides an overview on current diagnostic and therapeutic strategies for patients with drug-naïve and drug-resistant CML.

scholarly journals Molecular, Cytogenetic, and Hematological Analysis of Chronic Myeloid Leukemia Patients and Discovery of Two Novel Translocations

2021 ◽  
Vol 2021 ◽  
pp. 1-19
Author(s):  
Muhammad Asif ◽  
Abrar Hussain ◽  
Abdul Wali ◽  
Nazeer Ahmed ◽  
Irfan Ali ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Real Time ◽  
Imatinib Mesylate ◽  
Real Time Pcr ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Hematopoietic Stem ◽  
Two Samples ◽  
Hematological Analysis ◽  
Variant Translocation

Chronic myeloid leukemia (CML) is a disease of hematopoietic stem cells and is caused by the balanced translocations among the long arms of chromosomes 9 and 22, which are called the Philadelphia (Ph) chromosome. In this study, 131 CML patients were enrolled. Complete blood cell count was performed at the time of diagnosis for all the patients. Cytogenetic (karyotyping) examination using bone marrow samples was conducted on 76 CML patients for the confirmation of Ph-positive (9;22)(q34;q11) standard translocation, complex variant translocation, and additional chromosome abnormalities. FISH was performed on 38 patients for diagnostic purposes and on 39 patients for monitoring purposes. Twenty-two samples of CML patients were evaluated by reverse transcriptase PCR and real-time PCR for the patients who failed to respond against imatinib mesylate. In this study, 72 (54.96%) were males and 59 (45.03%) were females with a median age of 38.5 years. CBC values in the diagnosis process showed that 75 patients had high values of WBC being > 100 × 10 3 / μ l , while 71 (58.01) patients exhibited reduced values of hemoglobin, i.e., <10.00 mg/dl, and high values of PLTs > 100 were observed in 40 (30.53%) patients. Cytogenetic results show that standard translocation was developed in 63 (82.89%), development of complex variant translocations in 4 (5.32%), additional chromosomal abnormalities (ACAs) in 3 (3.94%), and ACAs together with complex variant translocations in 1 (1.31%) patient. At the time of diagnosis, 61 (92.95%) patients were in the chronic phase, 4 (5.63%) were in the accelerated phase, and only 1 (1.40%) was in the blast crisis. Out of twenty-two patients, only 6 CML patients who were shifted from imatinib mesylate to nilotinib showed BCR-ABL-positive amplification. However, only 7 out of twenty-one patients exhibit BCR-ABL gene values ≥ 1 after three months of follow-up when analyzed by the quantitative real-time PCR. In conclusion, we found a novel five-way translocation 46XX,t(1;2;2;17;9;22)(p36.3,q21;q11.2,q21,q34,q11.2) and a novel four-way complex variant translocation 48XY,+8(8;17)(9;22),+der(22)(q11.2;q23)(q34;q11.2) in the accelerated phase.

Comparison of Combination Therapy of Imatinib with Trisenox Versus Imatinib Monotherapy for Chronic Myeloid Leukemia Patients in Chronic Phase.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2159-2159 ◽  
Author(s):  
Dongguang Yang ◽  
Ri Zhang ◽  
Yunfeng Shen ◽  
Xuhui Zhang ◽  
De Pei Wu
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Combination Therapy ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Therapy Group ◽  
Combined Therapy ◽  
Chronic Phase ◽  
Monotherapy Group ◽  
Imatinib Resistance

Abstract Targeted therapy with the Bcr-Abl tyrosine kinase inhibitor Imatinib Mesylate can induce high response rates in chronic myelogenous leukemia (CML) patients. However, evidences that discontinuation of imatinib mesylate inevitably exerts rapid loss of response and some patients with imatinib mesylate monotherapy virtually occur potential relapse suggest that the modification of treatment strategy is critical. We have previously demonstrated that the combination of trisenox (arsenic trioxide) with the tyrosine kinase inhibitor imatinib mesylate or genistein appears to induce markedly more cell apoptosis than imatinib mesylate alone through downregulating Bcl-XL and Bcr-Abl in Bcr-Abl gene transfected HL-60 cells. We here report the preliminary results of a pilot study comparing imatinib mesylate plus trisenox with imatinib mesylate alone for frontline treatment of CML patients. Up to date 56 patients were enrolled in this clinical trail. All patients (required to be 18 years or older with Bcr-Abl positive CML in chronic phase within three month of diagnosis) were divided into two groups, i.e., monotherapy group and combined therapy group. 42 patients entering monotherapy received imatinib mesylate 400mg daily and 14 patients entering combined therapy imatinib mesylate 400mg daily plus trisenox 10mg daily for one week and then twice a week. We compared treatment results of both groups including complete hematologic response(CHR), major/complete cytogenetic response(MCR/CCR),--defined as 1–35% Ph+ and 0% Ph+ metaphases respectively and major/complete molecular response(MMR/CMR),--defined as ≥ 3 log reduction and negative expression in Bcr-Abl transcript numbers assayed by RQ-PCR respectively. The median follow-up for patients in both groups lasted 36 months. In the combined therapy group, the median age of patients is 42 years old (range, 22–61), the CHR, MCR, CCR, MMR and CMR is 92.8%, 64.3%, 42.9%, 35.7% and 21.4%, respectively. While in the imatinib mesylate monotherapy group, the median age of patients is 46 years old (range, 23–65), the CHR, MCR, CCR, MMR and CMR is 85.7%, 59.5%, 40.5%, 33.3% and 19%, respectively. Although combination therapy of imatinib with trisenox is not significantly superior to imatinib mesylate monotherapy in efficacy, no resistance case happens in the combination therapy group, in the imatinib mesylate monotherapy group, imatinib resistance occurs in 4 patients. In addition, the safety and tolerability of a combination of imatinib mesylate and trisenox is good. This result indicates that the combination of imatinib and trisenox to treat chronic myeloid leukemia may be promising in avoiding the occur of imatinib resistance.

Reversal of bone marrow angiogenesis in chronic myeloid leukemia following imatinib mesylate (STI571) therapy

Blood ◽  
2004 ◽  
Vol 103 (9) ◽  
pp. 3549-3551 ◽  
Author(s):  
Hans Michael Kvasnicka ◽  
Juergen Thiele ◽  
Peter Staib ◽  
Annette Schmitt-Graeff ◽  
Martin Griesshammer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Fiber Density ◽  
Angiogenic Effect ◽  
Ifn Treatment

Abstract The effect of imatinib mesylate (imatinib) therapy on angiogenesis and myelofibrosis was investigated and compared with interferon (IFN) and hydroxyurea (HU) in 98 patients with newly diagnosed Philadelphia chromosome-positive/BCR-ABL+ (Ph+/BCR-ABL+) chronic myeloid leukemia in first chronic phase and no other pretreatment. By means of immunostaining (CD34) and morphometry, a relationship between microvessel frequency and fiber density was detectable in initial bone marrow (BM) biopsies and sequential examinations after at least 8 months of therapy. First-line monotherapy with imatinib induced a significant reduction (normalization in comparison with controls) of microvessels and reticulin fibers. In most patients, decrease in BM vascularity was associated with a complete cytogenetic response. A significant anti-angiogenic effect was also observed after HU treatment, contrasting with IFN administration or combination regimens (IFN plus HU). In conclusion, our data support the anti-angiogenic capacity of imatinib by normalization of vascularity. In contrast, hematologic response following IFN treatment is independent from BM angiogenesis. (Blood. 2004;103:3549-3551)

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