Efficacy of imatinib mesylate (STI571) in chronic neutrophilic leukemia with t(15;19): Case report
In Keun ChoiByung‐Soo KimKyung‐A LeeSook-Won RyuHee Yun SeoHyeryoung SulJong Gwon ChoiHwa Jung SungKyong Hwa ParkSo Young YoonSang Cheul OhJae Hong SeoChul Won ChoiSang Won ShinSoo‐Young YoonYunjung ChoYoung‐Kee KimYeul Hong KimJun Suk Kim
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Abstract Chronic neutrophilic leukemia (CNL) is a rare hematologic disorder, for which there is no standard therapy. Recently, STI (imatinib mesylate) has been shown to be effective in treating patients with chronic myeloproliferative disorder (CMPD) displaying the translocation of the PDGFβR gene. Here, we present a case of a patient with CNL carrying t(15;19)(q13;p13.3) who achieved a cytogenetic remission following treatment with imatinib, 400 mg daily. After failure of alpha interferon and hydroxyurea therapy, a durable and complete clinical and cytogenic remission was induced by imatinib. To our knowledge, this is the first case with CNL who showed complete response with cytogenic remission after treatment of imatinib. The mechanism of response to this molecule is unknown in our case (other oncogenes than c‐kit, tyrosine kinase, or PDGFR may be involved). The patient remains in complete remission with an excellent performance status after 7 months of therapy. We demonstrate here that imatinib can induce a clinical and cytogenetic response in a case of CNL associated with a novel translocation other than a 5q33 rearrangement. Further studies including the molecular cloning of the t(15;19)(q13;p13.3) will be important in understanding the pathophysiology of CNL with a heterogeneous clinical course and the exploitation of the basic mechanisms of imatinib treatment. Am. J. Hematol. 77:366–369, 2004. © 2004 Wiley‐Liss, Inc.Keywords:
Imatinib Mesylate
Philadelphia chromosome
breakpoint cluster region
The BCR-ABL fusion gene product is a constitutively activated tyrosine kinase, which is fundamental in the pathogenesis of chronic myeloid leukemia (CML). Imatinib mesylate (imatinib, Glivec® or Gleevec®), a small molecule inhibitor of the BCR-ABL tyrosine kinase, is now the first-line treatment for all newly diagnosed chronic phase CML patients. Imatinib treatment results in a high frequency of complete cytogenetic response (CCgR). Patients in CCgR can be further stratified by the degree of minimal residual disease, measured by quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR). The present thesis deals with different aspects on molecular monitoring of imatinib treated CML patients. By serially analyzing peripheral blood and bone marrow BCR-ABL transcript levels using qRT-PCR in CML patients commencing imatinib therapy, we found that the major decline in BCR-ABL transcripts occurred within 6 months after start of imatinib treatment. An apparent plateau in BCR-ABL transcript level seems to have been reached after 12-15 months of imatinib treatment, which indicates a stable number of remaining BCR-ABL positive cells. To search for markers associated with molecular response in CML patients treated with imatinib, we studied the mRNA expression of apoptosis-related genes in peripheral blood nucleated cells from chronic phase CML patients commencing imatinib treatment. We found that a lower BAD expression at diagnosis correlates with a better molecular response at 12 months of imatinib therapy. Studies of BCR-ABL kinase domain mutations in imatinib treated CML patients revealed that point mutations were mainly associated with acquired resistance, but not with cytogenetic or molecular disease persistence in CML patients without signs of increasing leukemia burden. Finally we studied “off-target” effects of imatinib on peripheral blood on T-lymphocytes. We found that therapeutic doses of imatinib alter the expression of apoptosis related genes in CD3+ lymphocytes and change the phenotype of CD4+CD28+ T-helper cells.
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Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is a standard of care for chronic myeloid leukemia (CML). There are few publications on responses of patients with CML from the Indian subcontinent. This study analyzed the response rate, progression-free survival (PFS), overall survival (OS), and toxicities in patients with CML given imatinib. Analysis included patients with CML who received imatinib under the GIPAP program at our institution from January 2002 to December 2008. Standard criteria for hematological and cytogenetic responses were used. There were 400 patients, with a median follow-up of 47 months. One hundred and seventy received prior non-imatinib therapy and 230 patients received imatinib upfront. Ninety-five percent of patients achieved complete hematological response. The cumulative best rate of major cytogenetic response was 72%, with 53% complete cytogenetic response and 19% partial cytogenetic response. The estimated PFS and OS at median follow-up for the whole group was 76% and 94%, respectively. Differences in PFS and OS in prior non-imatinib and upfront imatinib groups were not statistically significant. However, better PFS and OS were seen in the upfront imatinib group. Imatinib was well tolerated in our study.
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Imatinib mesylate is a targeted therapy that acts by inhibiting tyrosine kinase of the bcr-abl fusion oncoprotein, which is specific to chronic myeloid leukemia (CML), and the c-transmembrane receptor, which is specific to gastrointestinal stromal tumors. Interstitial pneumonitis is a rare adverse event of imatinib therapy. It is clinically difficult to distinguish from infectious pneumonia, which can frequently occur due to the underlying disease. The standard treatment for imatinib-induced pneumonitis is to discontinue the medication and optionally administer corticosteroids. However, there are a few cases of successful retrial with imatinib. We describe a case of successful rechallenge of imatinib in a patient with imatinib-induced interstitial pneumonitis and CML without a recurrence of the underlying disease after 3 months of follow-up.
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The therapy of chronic myeloid leukemia, characterized by the presence of the Philadelphia chromosome in the clonal hematopoietic stem cells, has changed dramatically in the last years with the development of a specific inhibitor of the BCR-ABL tyrosine kinase: tyrosine kinase inhibitor imatinib mesylate (formerly STI571, [Glivec]). Glivec selectively blocks cellular proliferation and induces apoptosis in Philadelphia chromosome-positive (Ph+) cells harbouring the Bcr-Abl tyrosine kinase. Clinical development of imatinib mesylate began with 3 large, multicenter, phase II trials. The majority (88%) of interferon-alpha-resistant or intolerant patients in chronic-phase CML, achieved a complete hematologic response to imatinib mesylate. More importantly, approximately half of the patients achieved a major cytogenetic response, a result historically associated with improved survival. Furthermore, 21% of patients in accelerated-phase CML and 13.5% of patients in blastic-phase CML (patient populations with typically poor prognosis before the advent of imatinib mesylate) achieved major cytogenetic responses.
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Abstract Chronic neutrophilic leukemia (CNL) is a rare hematologic disorder, for which there is no standard therapy. Recently, STI (imatinib mesylate) has been shown to be effective in treating patients with chronic myeloproliferative disorder (CMPD) displaying the translocation of the PDGFβR gene. Here, we present a case of a patient with CNL carrying t(15;19)(q13;p13.3) who achieved a cytogenetic remission following treatment with imatinib, 400 mg daily. After failure of alpha interferon and hydroxyurea therapy, a durable and complete clinical and cytogenic remission was induced by imatinib. To our knowledge, this is the first case with CNL who showed complete response with cytogenic remission after treatment of imatinib. The mechanism of response to this molecule is unknown in our case (other oncogenes than c‐kit, tyrosine kinase, or PDGFR may be involved). The patient remains in complete remission with an excellent performance status after 7 months of therapy. We demonstrate here that imatinib can induce a clinical and cytogenetic response in a case of CNL associated with a novel translocation other than a 5q33 rearrangement. Further studies including the molecular cloning of the t(15;19)(q13;p13.3) will be important in understanding the pathophysiology of CNL with a heterogeneous clinical course and the exploitation of the basic mechanisms of imatinib treatment. Am. J. Hematol. 77:366–369, 2004. © 2004 Wiley‐Liss, Inc.
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