Imatinib Mesylate in the Treatment of Chronic Myelogenous Leukemia

Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase, suppressing the Philadelphia chromosome-positive clone in chronic myelogenous leukemia (CML). Clinical studies of imatinib have yielded impressive results in the treatment of all phases of CML. With the higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease has become mandatory in assessing response and determining prognosis. The practical aspects of the treatment of CML with imatinib are discussed. The emergence of imatinib resistance, albeit in a small percentage of patients, has prompted an evaluation of innovative treatment strategies.     

The Distribution of the Philadelphia Chromosome in Patients with Chronic Myelogenous Leukemia

Thirteen patients with chronic myelogenous leukemia continued to havethe Ph¹ chromosomes in 90-100 per cent dividing marrow cells during drug-induced clinical remissions. The Ph¹ chromosome was present in erythroidas well as granulocytic marrow cells, and possibly in megakaryocytes.

The presence of Ph¹ chromosomes was also studied in cultures of peripheralblood. In six patients in relapse, 40 per cent of metaphases contained the Ph¹chromosome, and the percentage of these cells corresponded roughly to therelative frequency of immature granulocytes in the blood. In contrast, duringremission, few or no Ph¹ chromosomes were found in peripheral blood cultures, presumably because in the absence of immature granulocytes the dividing cells in the cultures originate from lymphocytes, as they do in normalblood.

It is suggested that the Ph¹ chromosome usually arises in a precursor cellcommon to the erythroid, granulocytic, and megakaryocytic, but not thelymphoid series of hemopoietic cells.

Submitted on April 5, 1963 Accepted on June 30, 1963     

Combination of White Blood Cell Count at Presentation With Molecular Response at 3 Months Better Predicts Deep Molecular Responses to Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients

The aim of this study was to evaluate the impact of white blood cell (WBC) counts at presentation on the achievement of deep molecular response.A total of 362 newly diagnosed chronic-phase chronic myeloid leukemia patients (CML-CP) receiving 400 mg/day imatinib were serially monitored for a median of 36 months (range 6–115).Patients showing an optimal response at 3, 6, and 12 months as defined by the 2013 European LeukemiaNet recommendations had significantly lower WBC counts at presentation than those showing nonoptimal responses (all P < 0.0001). Among the cutoff values with a similar Youden index, 150 × 10E9/L (abbreviated WBC > 150) was selected to identify the greatest amount of patients with the potential to achieve a sustained molecular response of 4.5 (MR4.5). Regardless of whether the Sokal risk score was included, the BCR-ABL^IS value at 3 months, WBC counts at presentation, hemoglobin levels, and sex were the common independent predictors for an MR4.5, with the former 2 presenting the highest hazard risk. Low Sokal risk scores did not independently predict the achievement of an MR4.5. Patients with concurrent WBC > 150 and BCR-ABL^IS ≤ 10% had a similar incidence of 4-year MR4.5 compared with patients with concurrent WBC ≤ 150 and BCR-ABL^IS > 10% and concurrent WBC > 150 and BCR-ABL^IS > 10% (13.5% vs 13.2% vs 8.8%, P = 0.47), and all of these values were significantly lower than the values for patients with concurrent WBC ≤ 150 and BCR-ABL^IS ≤ 10% (55.0%, all P < 0.0001). Patients with concurrent WBC ≤ 150 and BCR-ABL^IS ≤ 10% had better 4-year event-free survival rates, progression-free survival rates, and overall survival rates compared with patients with WBC > 150 or BCR-ABL^IS > 10%.The combination of WBC count at presentation and BCR-ABL^IS at 3 months provides improved predictions of deep molecular response in imatinib-treated CML-CP patients. Therefore, the WBC count at presentation might be used to differentiate patients at the beginning of imatinib treatment.     

Th1 and Th2 Cytokine Gene Polymorphism in Iranian Patients with Chronic Myelogenous Leukemia

Background:It has been hypothesized that genetic factors other than histocompatibility disparity may play a role in predisposition to developing Chronic Myelogenous Leukemia (CML). In this regard, Th1 and Th2 cytokines and their gene polymorphism seems to be important. Overall expression and secretion of cytokines is dependent, at least in part, on genetic polymorphism (nucleotide variations) within the promoter region or other regulatory sequences of cytokine genes. The majority of polymorphisms described are single nucleotide polymorphism (SNPs). The objective of this study was to analyze the genetic profile of Th1 and Th2 cytokines in 30 Iranian patients with CML and 40 healthy subjects. Methods: In the patients and control subjects, the allelic and genotype frequencies were determined for the cytokine genes. All typing were performed by PCR-SSP assay. Allele and genotype frequencies were calculated and compared with those of normal controls. Results: The results showed that the most frequent alleles in our patients were TGF-b TG/TG, IL-4 T at position -1089, C at position -590, T at position -33 and IL-10 A at position -1082. Whereas the following alleles - TGF-b CG/CG and IL-10 C at position -592 – were seen in much lower frequencies. Conclusion: In conclusion, it could be suggested that the frequency of high producing TGF-b alleles and low producing IL-4 and IL-10 alleles in the CML patients is higher than the normal subjects.     

Similarities of the Erythrocytes in Juvenile Chronic Myelogenous Leukemia to Fetal Erythrocytes

A 4-yr-old boy was studied whoshowed typical findings of juvenilechronic myelogenous leukemia, including massive hepatosplenomegaly,thrombocytopenia, low leukocyte alkaline phosphatase, and absence of aPhiladelphia chromosome. The erythrocytes of the patient exhibited manycharacteristic features of erythrocytesof newborn infants: the fetal hemoglobin concentration was greatly elevated (72%); the oxygen dissociationcurve of the whole blood was displaced to the left of the curve fromnormal adult blood; the hemoglobinA₂ level and the erythrocyte I antigentiter were reduced; and a structuralanalysis of the -chain of the fetalhemoglobin showed the glycine to alanine ratio in -136 to be typical of theneonatal pattern. These findings support the suggestion that juvenilechronic myelogenous leukemia is accompanied by reversion to a fetal pattern of erythropoiesis.

Submitted on November 1, 1971 Revised on December 20, 1971 Accepted on December 22, 1971     

Evaluation of Cytopenias Occurring in Imatinib Treated Chronic Myeloid Leukemia (CML) Patients

Imatinib Mesylate, a Tyrosine Kinase inhibitor, is presently the drug of choice for Chronic myeloid leukemia (CML). During therapy, a few patients develop myelosuppression and present with cytopenias. To study the bone marrow morphology in imatinib treated CML patients presenting with persistent cytopenias. The cases were retrieved from the Hematopathology record files, Department of Pathology; the study period being January 2008–June 2009. Cases of CML on Imatinib presenting with grade 2 or more anemia, neutropenia and/or thrombocytopenias with bone marrow studies, were included in the study. The morphology of all cases was reviewed with cytogenetic studies. Follow-up details were obtained from the Medical Oncology records. During the study period, 683 Imatinib treated CML patients had bone marrow studies as part of their follow-up investigations. Of these, 60 patients (9%) had some form of persistent cytopenia. The patients ranged from 21 to 75 years of age with a median age of 38 years. The male:female ratio was 1:1. There were 46 patients with ≥grade 2 anemia, 25 patients with ≥grade 2 neutropenia and 37 patients with ≥grade 2 thrombocytopenia. Of these, 18 patients had bicytopenia and 13 cases had pancytopenia. The marrow evaluation revealed morphologic response in 30 patients, persistent marrow disease in five patients, marrow hypoplasia in six patients, extensive stromal changes including fibrosis in five patients, megaloblastic erythropoiesis in 11 patients and disease progression to accelerated or blast crisis in three patients. Various degrees of cytopenias may occur in few patients of CML on imatinib therapy. Regular hematologic follow-up is required so that the drug may be stopped or dose modified as per the individual’s needs.     

Efficacy and Safety of Imatinib Mesylate for Patients in the First Chronic Phase of Chronic Myeloid Leukemia: Results of a Japanese Phase II Clinical Study

Imatinib mesylate is a relatively new drug that targets the BCR-ABL chimeric protein, the molecular basis of chronic myeloid leukemia (CML). A phase II clinical trial in 39 Japanese patients in the first chronic phase of CML was conducted with imatinib mesylate at a dose of 400 mg/day. Hematologic complete response was obtained in 92.3% of the patients, complete cytogenetic response (CR) was obtained in 43.6%, and major partial CR was obtained in 20.5% of the patients. Although 29 of 39 patients required an adjustment of dosing because of grade 3 or 4 adverse events, most of the events were reversible, and 25 of the 29 patients were able to resume therapy. Between day 15 and day 35, grade 3 or 4 neutropenia and/or leukocytopenia occurred in 13 patients, and grade 3 thrombocytopenia occurred in 5 patients. Overall, nonhematologic grade 3 adverse events occurred in 28.2% of the patients. These data support the use of imatinib mesylate as the treatment of choice for chronic-phase CML patients.     

Performance of Sokal and Eutos Scores for Predicting Cytogenetic and Molecular Response in Newly Diagnosed Chronic Myeloid Leukemia-Chronic Phase Patients on Imatinib

Sokal index was developed in the pre-imatinib era to predict and prognosticate the outcome of Chronic myeloid leukemia (CML) patients. In the Imatinib era, a new scoring system called EUTOS scoring system has been validated as a predictive marker in CML. The scores have shown variable correlation with complete cytogenetic response (CCyR) and major molecular response (MMR). To assess the performance of Sokal score and EUTOS score as a predictive marker for CCyR and MMR for newly diagnosed CML-CP patients treated with TKIs. 273 patients with newly diagnosed CML were included in the study. They were treated with upfront imatinib. They were followed up for a median period of 3 years. Cytogenetic and Molecular response to the treatment were monitored regularly. Out of 273 patients, 174 patients (63 %) were having low EUTOS score and 99 (37 %) were having high EUTOS score. Patients with low, intermediate and high sokal scores were 237 (86.8 %), 28 (10.3 %) and 8 (2.9 %) respectively. 122 patients with low EUTOS score achieved CCyR within 18 months compared to 42 patients with high EUTOS score (p = 0.000).113 patients with low EUTOS score achieved MMR in 18 months compared to 33 patients with high EUTOS score (p = 0.000). 148, 14, 2 patients with low, intermediate and high Sokal score respectively have achieved CCyR in 18 months (p = 0.054). 133, 11, 2 patients with low intermediate and high sokal score respectively have achieved MMR in 18 months.(p = 0.06). EUTOS is better than Sokal score in predicting the outcome of patients of CML treated with imatinib.     

Total Leukocyte Counts and the Requirement of Dose Reduction due to Cytopenias as Prognostic Indicators Affecting Response to Imatinib in Chronic Myeloid Leukemia

Imatinib is a tyrosine kinase inhibitor and is considered the first line of non stem cell transplantation treatment for patients diagnosed with CML. We evaluated the response rates and adverse reactions to Imatinib in our patients and tried to identify factors which affected the response to Imatinib. Eighty-four patients were diagnosed on the basis of clinical and haematological variables with confirmation by FISH, detecting Philadelphia chromosome or bcr-abl translocation and were then started on oral capsule Imatinib. A complete haematological response was seen in 78.04% patients, while complete cytogenetic response (CCR) was seen in 12.2% of patients and major cytogenetic response (MCR) was seen in 64.63% of patients. It was found that that a greater total leukocyte count (TLC) on presentation had a negative correlation with cytogenetic response. Cytopenias were seen in 36 patients (43.82%). 34.9% of patients having CCR/MCR required dose reduction while 73.6% of patients not achieving CCR/MCR required dose reduction. This was a significant difference, confirmed on statistical analysis (P < 0.05; P = 0.019), establishing the negative prognostic value of dose reduction due to cytopenias.     

Imatinib Mesylate Therapy in Patients of Chronic Myeloid Leukemia with Philadelphia Chromosome Positive: An Experience from Eastern India

Imatinib inhibits constitutively active BCR-ABL tyrosine kinase of chronic myeloid leukemia (CML). In a long term study it was found superior to interferon alfa plus cytarabine for newly diagnosed CML in the chronic phase. However, till date there is no major study to evaluate eastern Indian CML patients treated with imatinib mesylate. The aim of our study was to see the efficacy, tolerability, toxicity and safety of imatinib in eastern Indian subset of CML population. The present study enrolled 831 patients with CML out of which 197 were excluded due to various reasons of noncompliance, death and not being fit to receive the drug. The rest, 634 (76% of total enrolled) were selected for the evaluation. In the beginning of the study, 603 patients were in chronic phase, 27 in accelerated phase and 4 patients in blast crisis phase. Among 634 patients, 280 patients (44%) received previously either interferon alpha or hydroxyurea and other 354 patients (56%) were previously untreated. Complete hematological remission and major cytogenetic response were 91 and 67%, respectively after 1 year of treatment. Complete molecular remission was 35% after 1 year of treatment. Sixty-four patients (10.1%) were resistant to imatinib mesylate in 5 years. The disease free and overall survival at 60 months were 72.2 and 76.1% respectively. After 60 months of follow up, continuous treatment of chronic phase CML with imatinib as initial therapy was found to be safe and able to induce durable responses in a high proportion of patients.     

Use of Imatinib Mesylate for Favorable Control of Hypercalcemia Mediated by Parathyroid Hormone-Related Protein in a Patient with Chronic Myelogenous Leukemia at Blast Phase

The case of a 72-year-old woman with chronic myelogenous leukemia in blast phase (BP) with hypercalcemia is reported. Bone x-ray examination revealed multiple osteolytic lesions throughout the body. The serum level of parathyroid hormone-related protein (PTHrP) was elevated, and PTHrP messenger RNA (mRNA) was detectable in the peripheral blood mononuclear cells (PBMNC) at BP but was not detectable at chronic phase (CP).Treatment with conventional chemotherapy did not completely control either serum calcium level or serum PTHrP level. Treatment with imatinib mesylate (imatinib) alone rapidly normalized these parameters in parallel with a decrease in the number of blast cells. The treatment also maintained the patient in good condition for approximately 3 months, even though the number of blast cells, serum calcium level, serum PTHrP level, and PTHrP mRNA level increased at the terminal stage. Mutations of the p53, K-Ras, and BCR-ABL genes in PBMNC at BP were absent. A noteworthy feature in this patient was that PBMNC at BP but not at CP showed high Lyn mRNA expression. Taken together the findings showed that production of PTHrP by blast cells was favorably controlled by imatinib therapy alone. Imatinib may prolong survival time at BP even though the patients have the complication of PTHrP-mediated hypercalcemia.