Selective Effect of Imatinib on Serum IgM in a Patient with CML

International Journal of Hematology -     

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.     

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.     

Imatinib Mesylate in Combination with Other Chemotherapeutic Agents for Chronic Myelogenous Leukemia

Imatinib therapy is an important contribution to the management of patients with chronic myelogenous leukemia (CML). Despite high rates of hematologic and cytogenetic responses to imatinib therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of CML. Experimental and clinical studies suggest that imatinib as a single drug may not be sufficient to eradicate BCR-ABL-positive stem cells. Therefore, whether combinations of imatinib with other agents can increase the length of molecular remission and whether such combinations can prolong survival should be determined by large-scale clinical studies. In this review, we discuss efficacious combinations for future clinical trials. These regimens combine imatinib with conventional chemotherapeutic agents or with inhibitors of other signal transduction molecules that may be preferentially activated in CML cells.     

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.     

Target Therapy of Unresectable or Metastatic Dermatofibrosarcoma Protuberans With Imatinib Mesylate: An Analysis on 22 Chinese Patients

Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.     

Successful Treatment with Imatinib Mesylate in a Case of Minor BCR-ABL-Positive Acute Myelogenous Leukemia

Philadelphia (Ph) chromosome-positive acute myelogenous leukemia (AML) is a rare disease that is resistant to conventional antitumor chemotherapy and has a poor prognosis. We describe a case of Ph chromosome-positive AML in which imatinib mesylate was used and a favorable outcome was obtained.A 64-year-old man was found to have Ph chromosome-positive, minor BCR-ABL-positive AML. Remission could not be induced by remission induction therapy with antitumor agents. Because the patient had a serious concomitant infectious disease, administration of 600 mg/day of imatinib mesylate, a specific inhibitor of BCR-ABL tyrosine kinase, was started after written informed consent was obtained. Complete cytogenetic response (CCR) was achieved without serious adverse events and persisted for more than 1 year. Our results suggested that imatinib mesylate was very useful for treating Ph chromosome-positive AML.     

Successful Treatment of Idiopathic Hypereosinophilic Syndrome with Imatinib Mesylate: A Case Report

Patients with idiopathic hypereosinophilic syndrome (HES) show persistent hypereosinophilia of unknown etiology that is associated with end-organ damage. Different treatments, including the use of corticosteroids and cytotoxics, have been investigated for HES with modest success. We describe a patient with HES who had significant end-organ damage from hypereosinophilia and remained refractory to conventional therapy. Therapy with imatinib mesylate, a selective tyrosine kinase inhibitor that is highly effective in treating patients with BCR-ABL-positive chronic myeloid leukemia, was tried with the patient. The result was impressive, with hematologic remission achieved after 12 days of administration. Our finding concurs with recent reports that imatinib mesylate may be a promising agent in the treatment of some cases of HES.     

Response to Imatinib Mesylate in a Patient with Idiopathic Hypereosinophilic Syndrome Associated with Cyclic Eosinophil Oscillations

A 26-year-old man with idiopathic hypereosinophilic syndrome (HES) was treated with imatinib mesylate following a 5-year history of prednisolone therapy. The patient had hypereosinophilia (absolute eosinophil counts >1500/microL) occurring in cyclic oscillations as well as histologically diagnosed eosinophilic vasculitis, bursitis, and periodic soft-tissue swellings. Laboratory data revealed high levels of serum tryptase and increased numbers of mast cells in the bone marrow, but serum interleukin 5 levels were within the normal range. The disease initially responded well to 100 mg/day of imatinib mesylate but recurred 8 weeks later. Thereafter, a daily 200-mg dose was temporarily effective. Despite the response to imatinib, the FIP1L1-PDGFRA fusion gene was not detected by fluorescence in situ hybridization analysis. Additional molecular and cytogenetic studies showed neither translocations of platelet-derived growth factor receptor (PDGFR) genes nor mutations in the c-KIT or the PDGFR genes. Although imatinib mesylate is a choice of treatment for patients with HES, its precise molecular mechanism in individual cases remains to be clarified.     

Fluorescence In Situ Hybridization Monitoring of BCR-ABL-Positive Neutrophils in Chronic-Phase Chronic Myeloid Leukemia Patients during the Primary Stage of Imatinib Mesylate Therapy

We describe a method for monitoring chronic myeloid leukemia (CML) patients treated with imatinib that uses fluorescence in situ hybridization (FISH) to detect BCR-ABL in peripheral blood (PB) granulocytes. First, we compared this method, termed Neutrophil-FISH, with interphase FISH (i-FISH) analysis of bone marrow (BM), i-FISH analysis of PB mononuclear cells, and conventional cytogenetic analysis (CCA) of BM in 30 consecutive CML patients. We found the percentage of BCR-ABL-positive neutrophils as determined by Neutrophil-FISH to correlate best with the percentage of Philadelphia chromosome-positive metaphases in the BM determined by CCA (y = 0.8818x + 5.7249; r(2) = 0.968).We then performed a serial Neutrophil-FISH study of 10 chronic-phase CML patients treated with imatinib and found that the technique could clearly separate imatinib responders from nonresponders within 12 weeks of drug administration. There was a significant difference in the percentages of BCR-ABL-positive neutrophils between responder (mean 3 SD, 18.2% 3 11.8%) and nonresponder (82.4% 3 5.1%) groups at 12 weeks (P < .0001, Student t test).Together with real-time quantitative polymerase chain reaction analysis, Neutrophil-FISH represents another useful method for monitoring CML patients during the primary myelosuppressive stage of imatinib therapy because it is a quick, simple, and reliable method for assessing cytogenetic response.     

Central Nervous System Blast Crisis in Chronic Myeloid Leukemia on Imatinib Mesylate Therapy: Report of Two Cases

Chronic myeloid leukaemia is a chronic myeloproliferative disorder characterised by a reciprocal translocation between chromosomes 9 and 22 and thereby formation of the Philadelphia chromosome. Imatinib mesylate (STI-571) is a potent and selective inhibitor of BCR-ABL tyrosine kinase and has emerged as a treatment of choice in chronic myeloid leukaemia (CML) patients in chronic phase. It has shown activity in CML patients in the chronic phase or blastic phase. However there is poor penetration of the central nervous system (CNS) by the drug or its active metabolites. Therefore the CNS acts as a sanctuary site for malignant cells for CML patients treated with Imatinib. We report cases of two CML patients on Imatinib therapy, who were in haematological remission but developed CNS disease.     

乳糜腹水247例国内文献分析

目的 分析乳糜腹水的临床特点,探讨其病因及诊断治疗的方法.方法 复习1994～2008年为国内文献104篇,对247例乳糜腹水病例进行回顾性分析.结果 247例乳糜腹水患者男女比例为2.05 1,发病年龄出生2 h~76岁,平均年龄45.6岁.病因主要为肝硬化(23.48%)、肿瘤(16.19%)、结核(11.74%)、手术(14.98%)、肾病综合症(9.72%).合并胸水69例,占27.49%.75.7%经综合保守治疗腹水消退.结论 继发或先天因素引起淋巴管渗漏出现乳糜腹水,通过综合检查可明确病因.通过治疗原发病及综合治疗乳糜腹水大部分腹水可消退.保守治疗效果不佳或有明确淋巴管破裂或阻塞者行手术治疗.预后取决于原发病.     

Complete Response of Myeloid Sarcoma with FIP1L1-PDGFRA -Associated Myeloproliferative Neoplasms to Imatinib Mesylate Monotherapy

Myeloid sarcoma (MS) is a localized, extramedullary tumor of acute myeloid leukemia (AML) that typically presents either de novo or concomitantly with myeloproliferative neoplasms (MPN), AML and myelodysplastic syndrome. Patients who have MS must be treated with intensive chemotherapy, as are patients with AML, because MS usually progresses to a systemic manifestation and leads to dismal outcomes. FIP1L1-PDGFRA-associated MPN, a subtype of myeloid and lymphoid neoplasm, is characterized by eosinophilia and abnormalities in the PDGFRA, PDGFRB or FGFR1 gene. Fusion of the FIP1L1 and PDGFRA genes activates the tyrosine kinase. As a result, imatinib mesylate (IM) is widely used for the treatment of this disorder. The coexistence of FIP1L1-PDGFRA-associated MPN and MS is extremely rare. Patients with this condition fail to achieve durable remission and long-term survival without a combination of intensive chemotherapy and IM. Here, we report a case of MS and FIP1L1-PDGFRA-associated MPN that was successfully treated with IM monotherapy.     

Imatinib improves but may not fully reverse the poor prognosis of patients with CML with derivative chromosome 9 deletions

Deletions of the derivative chromosome 9 occur in a subset of patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) and are associated with a poor prognosis on standard drug therapy. However, it is currently unknown if the presence of deletions influences the response to imatinib, an Abl-specific tyrosine kinase inhibitor, that has recently shown excellent hematologic and cytogenetic responses in patients with CML. We, therefore, compared hematologic and cytogenetic responses with imatinib in 397 patients with CML, and survival and progression in 354 of these patients, according to deletion status and disease phase. We found no difference in survival between patients with and without deletions, contrasting with previous reports in cohorts with a lower proportion of patients treated with imatinib. However, the time to disease progression on imatinib treatment was significantly shorter for patients with deletions, both in chronic phase (P =.02) and advanced phases (P =.02). Moreover, both in chronic phase and more advanced phases of CML, hematologic and cytogenetic responses were uniformly lower in patients with deletions, with significant differences seen for hematologic response (P =.04), for major cytogenetic response (P =.008) in chronic phase, and for hematologic response in advanced phases (P =.007) of CML. This finding suggests that differences in survival may become apparent with longer follow-up.