Chronic myeloid leukemia patient manifesting fatal hepatitis B virus reactivation during treatment with imatinib rescued by liver transplantation: case report and literature review

Imatinib mesylate (imatinib) is now a standard treatment for patients with chronic myeloid leukemia (CML). Although imatinib is known to have a potential impact on various infectious organisms by altering the T-cell mediated immune response, only two cases of hepatitis B virus (HBV) reactivation during imatinib treatment have actually been reported. The role of liver transplantation (LT) after fatal HBV reactivation in patients with potentially treatable or curable hematologic malignancy is also unknown. Therefore, this report presents a case of fatal HBV reactivation during imatinib treatment for CML, where the patient is rescued by LT. Following a successful living donor LT, the liver function improves rapidly and the patient remains in complete cytogenetic remission after retreatment with imatinib for 6 months. The present report also covers the role of tyrosine kinase inhibitor in triggering HBV reactivation and a literature review of fulminant hepatic failure in CML patients taking imatinib.     

Hépatotoxicité tardive à l’imatinib chez une patiente de 44 ans

Imatinib mesylate is currently used in the treatment of chronic myeloid leukemia (CML), advanced gastrointestinal stromal tumors, and Philadelphia chromosome-positive acute leukemia. Hepatotoxicity is a rare but potentially serious complication of treatment with imatinib.We report the case of a 44-year-old woman treated by imatinib mesylate (Gleevec®) for CML who was admitted to our institution with severe acute hepatitis two years and nine months after the initiation of treatment. The outcome was favorable after stopping the drug, with normalization of serum aminotransferase activity after 6 months. It is recommended that liver function is regularly monitored during treatment with imatinib. With the ascencion of liver function tests, treatment should be discontinued.     

Imatinib-induced fatal acute liver failure

Imatinib mesylate is a drug that has been approved for treatment of chronic myeloid leukemia (CML) in blast crisis, accelerated or chronic phase, and also for advanced gastrointestinal stromal tumors. Severe hepatic toxicity and three deaths from hepatic failure have been reported. We report the case of a 51-year-old woman who was admitted to our institution with severe acute hepatitis. She was diagnosed with CML and began treatment with imatinib mesylate at a dose of 400 mg/d. Five months after beginning treatment, she developed severe hepatitis associated with coagulopathy, and was admitted to our institution. She had been consuming acetaminophen 500-1000 mg/d after the onset of symptoms. She had a progressive increase in bilirubin level and a marked decrease of clotting factor Ⅴ. Five days after admission, grade Ⅱ encephalopathy developed and she was referred for liver transplantation. Her clinical condition progressively deteriorated, and 48 h after being referred for transplantation she suffered a cardiac arrest and died. This report adds concern about the possibility of imatinib-mesylate-induced hepatotoxicity and liver failure, particularly in the case of concomitant use with acetaminophen. Liver function tests should be carefully monitored during treatment and, with the appearance of any elevation of liver function tests, treatment should be discontinued.     

Imatinib mesylate-sensitive blast crisis immediately after discontinuation of imatinib mesylate therapy in chronic myelogenous leukemia: report of two cases

Although imatinib mesylate has shown encouraging activity in chronic myelogenous leukemia (CML), disease progression during therapy has been observed, manifested by clonal expansion of imatinib mesylate-resistant leukemia cells. On the other hand, myelosuppression related to treatment of imatinib mesylate is often managed with temporary interruption of treatment or dose reduction. We here report two CML patients who had imatinib mesylate-sensitive blast crisis (BC) immediately after discontinuation of imatinib mesylate therapy. The patients discontinued therapy because of neutropenia. Although there was no evidence of blastic phase during therapy, BC occurred 2 weeks after the withdrawal of treatment in both cases. Interestingly, additional chromosomal abnormalities were detected following the withdrawal of imatinib mesylate and disappeared by re-introduction of this agent. The same doses of imatinib mesylate was still effective and remission was sustained with imatinib mesylate alone again. Our report suggests the possibility that withdrawal of imatinib mesylate may lead to proliferation of blast clones even in patients showing good responses to imatinib mesylate without signs of disease progression.     

Imatinib‐associated neutropenia may not be overcome by filgrastim treatment in patients with blastic phase of chronic myeloid leukaemia

Imatinib mesylate is a very effective treatment in patients with Philadelphia (Ph)‐positive chronic myeloid leukaemia (CML). However, in patients with advanced phase CML, it is still unclear whether, in the presence of myelosuppression, therapy with imatinib should be continued. It has been reported that intermittent filgrastim treatment may overcome imatinib‐associated neutropenia and allow improved delivery of imatinib. Such combined sequential treatment is theoretically attractive as it may lead to better disease response. Here, we report a patient with blastic phase CML who developed severe and prolonged myelosuppression during imatinib treatment. Despite cessation of imatinib and 2 months of filgrastim therapy neither recurrence of Ph‐positive or Ph‐negative cells occurred. We conclude that filgrastim treatment may not always reverse imatinib‐associated neutropenia therefore the decision of continued imatinib therapy in patients with advanced CML should be taken with caution.     

Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation

Imatinib mesylate (STI571) is a promising new treatment for chronic myelogenous leukemia (CML). The effect of imatinib mesylate on primitive malignant progenitors in CML has not been evaluated, and it is not clear whether suppression of progenitor growth represents inhibition of increased proliferation, induction of apoptosis, or both. We demonstrated here that in vitro exposure to concentrations of imatinib mesylate usually achieved in patients (1-2 microM) for 96 hours inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture-initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 microM) did not significantly increase suppression of CML or normal LTCICs but did increase suppression of CML CFCs, and to a lesser extent, normal CFCs. Analysis of cell division using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester indicated that imatinib mesylate (1-2 microM) inhibits cycling of CML primitive (CD34(+)CD38(-)) and committed (CD34(+)CD38(+)) progenitors to a much greater extent than normal cells. Conversely, treatment with 1 to 2 microM imatinib mesylate did not significantly increase the percentage of cells undergoing apoptosis. Although a higher concentration of imatinib mesylate (5 microM) led to an increase in apoptosis of CML cells, apoptosis also increased in normal samples. In summary, at clinically relevant concentrations, imatinib mesylate selectively suppresses CML primitive progenitors by reversing abnormally increased proliferation but does not significantly increase apoptosis. These results suggest that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate restores normal hematopoiesis by removing the proliferative advantage of CML progenitors but that elimination of all CML progenitors may not occur.     

Imatinib-associated neutropenia may not be overcome by filgrastim treatment in patients with blastic phase of chronic myeloid leukaemia

Imatinib mesylate is a very effective treatment in patients with Philadelphia (Ph)-positive chronic myeloid leukaemia (CML). However, in patients with advanced phase CML, it is still unclear whether, in the presence of myelosuppression, therapy with imatinib should be continued. It has been reported that intermittent filgrastim treatment may overcome imatinib-associated neutropenia and allow improved delivery of imatinib. Such combined sequential treatment is theoretically attractive as it may lead to better disease response. Here, we report a patient with blastic phase CML who developed severe and prolonged myelosuppression during imatinib treatment. Despite cessation of imatinib and 2 months of filgrastim therapy neither recurrence of Ph-positive or Ph-negative cells occurred. We conclude that filgrastim treatment may not always reverse imatinib-associated neutropenia therefore the decision of continued imatinib therapy in patients with advanced CML should be taken with caution.     

Nilotinib for the treatment of chronic myeloid leukemia

The introduction of targeted therapy has revolutionized the treatment of chronic myeloid leukemia (CML). The pivotal role of the Philadelphia chromosome, resulting from the breakpoint cluster region-Abelson (BCR-ABL) translocation, led to the development of imatinib mesylate, a tyrosine kinase inhibitor with significant activity against the BCR-ABL oncoprotein. Unprecedented clinical activity in CML led to rapid approval and established first-line therapy with imatinib mesylate as the standard of care in most patients. However, the occurrence of imatinib resistance or intolerance has sparked the development of newer drugs with increased activity or specificity. Nilotinib is a second-generation tyrosine kinase inhibitor that has been rationally designed on the basis of imatinib. An overview is given on clinical results in imatinib-resistant or -intolerant patients that led to its current approval as second-line therapy for the chronic and accelerated phases of CML. Future studies will address the role of nilotinib as first-line therapy, in combination strategies and in the context of specific BCR-ABL mutations.     

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.     

Imatinib mesylate (STI-571) given concurrently with nonmyeloablative stem cell transplantation did not compromise engraftment and resulted in cytogenetic remission in a patient with chronic myeloid leukemia in blast crisis

The main obstacles to successful hematopoietic stem cell transplantation for patients with chronic myeloid leukemia (CML) in blast crisis (BC) are increased post-transplant relapse and high treatment-related mortality. We report a patient with CML in BC who was treated initially with imatinib mesylate and was then concurrently treated with a nonmyeloablative stem cell transplant. Successful engraftment of donor cells followed by complete cytogenetic remission was achieved in the absence of severe therapy-related toxicities. This case demonstrates that imatinib mesylate given through nonmyeloablative transplant is a minimally toxic therapeutic approach, which does not compromise engraftment and may result in a favorable outcome in patients with CML in BC.     

Effect of imatinib mesylate combined with granulocyte colony-stimulating factor on leukaemic blast cells derived from advanced-stage chronic myelogenous leukaemia patients

Neutropenia is a severe adverse effect that can occur when treating patients with imatinib mesylate for advanced-stage chronic myelogenous leukaemia (CML). Therefore, we evaluated in vitro the combined effect of imatinib and granulocyte colony-stimulating factor (G-CSF) on proliferation and apoptosis of Bcr-Abl-expressing leukaemic cells to infer the safety of G-CSF administration. In KU812 and K562 cell lines, G-CSF neither stimulated their proliferation nor abolished the suppressive effect of imatinib. However, it stimulated the proliferation of blast cells in 2 out of the 5 cases with advanced-stage CML. These in vitro studies appear to provide data for the decision of G-CSF administration in combination with imatinib in the treatment of neutropenic patients with advanced-stage CML.     

Combination of imatinib and anagrelide in treatment of chronic myeloid leukemia in blastic phase

Chronic myeloid leukemia in blast phase (BP) is resistant to chemotherapy and majority of patients die within 6 months. Inhibitor Bcr-Abl tyrosine kinase imatinib mesylate dramatically improved outcome of patients in chronic phase (CP) and is also effective in BP of CML. The prognosis of patients treated with imatinib in BP is worse than in CP. High platelet counts are often observed at diagnosis or in the subsequent course of the CML in about 25% of patients. Thrombohemorrhagic complications associated with the thrombocythemia may be serious. Anagrelide selectively reduces circulating platelets and is used in treatment of thrombocythemia in chronic myeloproliferative disorders. Efficacy and safety of combination imatinib mesylate with anagrelide was demonstrated in chronic and accelerated phase of CML. No study about the use of imatinib with anagrelide in BP has been found. 51-year-old white man with CML presented in blast phase was followed for 4 years. Imatinib mesylate in dose of 600 mg p.o. qd. was administered after the failure of initial chemotherapy. The patient was treated with imatinib for 45 months, 14.5 months in combination with anagrelide. Partial hematologic response in duration of 33 months was induced by imatinib, cytogenetic response was not reached. Imatinib-resistant thrombocythemia was controlled with anagrelide in dose of 0.5-1 mg p.o. qd. No thrombohemorrhagic complications were observed. The patient tolerated the combination of imatinib and anagrelide well and long-term survival gave him the chance of treatment with the new tyrosin kinase inhibitor (dasatinib).     

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.     

Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.     

Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML

The deregulated, oncogenic tyrosine kinase Bcr-Abl causes chronic myeloid leukemia (CML). Imatinib mesylate (Gleevec, STI571), a Bcr-Abl kinase inhibitor, selectively inhibits proliferation and promotes apoptosis of CML cells. Despite the success of imatinib mesylate in the treatment of CML, resistance is observed, particularly in advanced disease. The most common imatinib mesylate resistance mechanism involves Bcr-Abl kinase domain mutations that impart varying degrees of drug insensitivity. AP23464, a potent adenosine 5'-triphosphate (ATP)-based inhibitor of Src and Abl kinases, displays antiproliferative activity against a human CML cell line and Bcr-Abl-transduced Ba/F3 cells (IC(50) = 14 nM; imatinib mesylate IC(50) = 350 nM). AP23464 ablates Bcr-Abl tyrosine phosphorylation, blocks cell cycle progression, and promotes apoptosis of Bcr-Abl-expressing cells. Biochemical assays with purified glutathione S transferase (GST)-Abl kinase domain confirmed that AP23464 directly inhibits Abl activity. Importantly, the low nanomolar cellular and biochemical inhibitory properties of AP23464 extend to frequently observed imatinib mesylate-resistant Bcr-Abl mutants, including nucleotide binding P-loop mutants Q252H, Y253F, E255K, C-terminal loop mutant M351T, and activation loop mutant H396P. AP23464 was ineffective against mutant T315I, an imatinib mesylate contact residue. The potency of AP23464 against imatinib mesylate-refractory Bcr-Abl and its distinct binding mode relative to imatinib mesylate warrant further investigation of AP23464 for the treatment of CML.     

Control of aggressive fibromatosis by treatment with imatinib mesylate. A case report and review of the literature

Objective There has been only one report available that focuses on the treatment with imatinib mesylate of two individual persons with aggressive fibromatosis. The authors concluded that after long-term treatment, for 9 and 11 months, with imatinib mesylate, both patients demonstrated radiographic and clinical responses. The novel therapy should be considered as salvage in patients with aggressive fibromatosis expressed platelet-derived growth factor receptor—alfa, beta (PDGFR-alfa, PDGFR-beta), and/or c-kit, whose tumors are uncontrollable by the standard management. On the other hand, the number of kinases blocked by imatinib mesylate is notching up, for instance the tyrosine kinase, which is associated with macrophage-colony stimulating factor receptor (M-CSFR). Methods The patient was suffering from aggressive fibromatosis after prior therapy including surgery (R2), radiotherapy, and systemic treatment with combination of tamoxifen and sulindac. The tumor specimen was immunostained for PDGFR-beta and c-kit (CD117), and PDGFR-alfa and cytokines platelet-derived growth factor-alfa and beta were not assessed. The tests for both assessed molecules revealed negative results. In spite of this, the patient underwent a unique treatment with imatinib mesylate at the dose of 400 mg orally once daily for 3 years and 2 months. Results After three months of the therapy, radiographic (met criteria of SD but small decrease of the tumor was noted) and clinical responses were recorded for the first time. The same was seen after 6 and 13 months of therapy continuation with imatinib mesylate. Currently, the patient is treated with imatinib mesylate (400 mg orally once daily) without any toxicity effects. The last MRI revealed readily a smaller tumor (35 × 20 mm) after such a therapy lasted more than 3 years. Conclusions Treatment with imatinib mesyalte has been a well-accepted therapy for chronic myelagenous leukemia (CML) and gastrointestinal stromal tumors (GIST). There have been established four kinases (p210^bcr/abl, c-kit, PDGFR-alfa, PDGFR-beta) suggested as the target for imatinib mesylate. Other potential targets will be discovered as it has lately been determined that M-CSFR kinase activity was blocked by imatinib mesylate. The salvage therapy for aggressive fibromatosis with imatinib mesylate seems to be an attractive opportunity for patients with the advanced disease, whose prior therapy failed.     

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.     

Malignant gastrointestinal stromal tumor of the small intestine complicated with pulmonary tuberculosis during treatment with imatinib mesylate

We describe a patient who had a metastatic gastrointestinal stromal tumor (GIST) after previous failed extensive therapy, including multiple surgeries and hepatic artery embolization. Within a few months of starting administration of imatinib mesylate, the patient exhibited a clinical response with grade 3 neutropenia, when pulmonary tuberculosis developed. A c-kit mutation in exon 11 was detected only in metastatic liver specimens. It is unclear whether or not pulmonary tuberculosis may be induced by imatinib mesylate treatment, but caution is warranted in immunocompromised GIST patients. This is the first report of tuberculosis associated with neutropenia during imatinib mesylate treatment.     

Imatinib mesylate affects the development and function of dendritic cells generated from CD34+ peripheral blood progenitor cells

Imatinib mesylate (STI571) is a competitive Bcr-Abl tyrosine kinase inhibitor and has yielded encouraging results in treatment of chronic myelogenous leukemia (CML) and gastrointestinal stroma tumors (GISTs). Apart from inhibition of the Abl protein tyrosine kinases, it also shows activity against platelet-derived growth factor receptor (PDGF-R), c-Kit, Abl-related gene (ARG), and their fusion proteins while sparing other kinases. In vitro studies have revealed that imatinib mesylate can inhibit growth of cell lines and primitive malignant progenitor cells in CML expressing Bcr-Abl. However, little is known about the effects of imatinib mesylate on nonmalignant hematopoietic cells. In the current study we demonstrate that in vitro exposure of mobilized human CD34+ progenitors to therapeutic concentrations of imatinib mesylate (1-5 microM) inhibits their differentiation into dendritic cells (DCs). DCs obtained after 10 to 16 days of culture in the presence of imatinib mesylate showed concentration-dependent reduced expression levels of CD1a and costimulatory molecules such as CD80 and CD40. Furthermore, exposure to imatinib mesylate inhibited the induction of primary cytotoxic T-lymphocyte (CTL) responses. The inhibitory effects of imatinib mesylate were accompanied by down-regulation of nuclear localized RelB protein. Our results demonstrate that imatinib mesylate can act on normal hematopoietic cells and inhibits the differentiation and function of DCs, which is in part mediated via the nuclear factor kappaB signal transduction pathway.