Successful childbirth in a patient with chronic myelogenous leukemia treated with imatinib mesylate during early pregnancy

Aims: To report a case of successful pregnancy in a patient with chronic myelogenous leukemia treated with imatinib mesylate for the first 4 months of pregnancy. Results: Imatinib mesylate is potentially teratogenic and its use during pregnancy in humans can lead to abortion or development of fetal abnormalities in nearly 40% of fully reported cases. We report a case of a 28-year-old woman who delivered a healthy child of normal weight after having been treated with imatinib for Ph1-positive CML during the first four months of her pregnancy. She refused advocated interruption and for the rest of the pregnancy was treated with interferon. The treatment was associated with a rapid 2-log increase in the leukemia clone measured by the real-time polymerase chain reaction. Reintroduction of imatinib after delivery resulted in achievement of the complete cytogenetic response again. Conclusions: We discuss possible strategies for successful management of pregnancy in CML patients treated with imatinib.     

Role of P-glycoprotein in evolution of populations of chronic myeloid leukemia cells treated with imatinib

Imatinib mesylate (imatinib) is a new generation preparation that is now successfully used for treatment of cancer, particularly for chemotherapy of chronic myeloid leukemia (CML). Imatinib inhibits the activity of chimeric kinase BCR-ABL, which is responsible for the development of CML. The goal of this study was to investigate the role of a multidrug resistance protein, P-glycoprotein (Pgp), in the evolution of CML treated with imatinib. We demonstrate here that although imatinib is a substrate for Pgp, cultured CML cells (strain K562/i-S9), overexpressing active Pgp, do not exhibit imatinib resistance. Studies of CML patients in the accelerated phase have shown variations in the number of Pgp-positive cells (Pgp+) among individual patients treated with imatinib. During treatment of patients with imatinib for 6-12 months, the number of Pgp-positive cells significantly increased in most patients. The high number of Pgp+ cells remained in patients at least for 4.5 years and correlated with active Rhodamine 123 (Rh123) efflux. Such correlation was not found in the group of imatinib-resistant patients examined 35-60 months after onset of imatinib therapy: cells from the imatinib-resistant patients exhibited efficient Rh123 efflux irrespectively of Pgp expression. We also compared the mode of Rh123 efflux by cells from CML patients who underwent imatinib treatment for 6-24 months and the responsiveness of patients to this therapy. There were significant differences in survival of patients depending on the absence or the presence of Rh123 efflux. In addition to Pgp, patients' cells expressed other transport proteins of the ABC family. Our data suggest that treatment with imatinib causes selection of leukemic stem cells characterized by expression of Pgp and other ABC transporters.     

Targeting the kinase activity of the BCR-ABL fusion protein in patients with chronic myeloid leukemia

Imatinib mesylate is a major advance in the therapy of patients with chronic myelogenous leukemia (CML). Imatinib mesylate binds to the inactive conformation of BCR-ABL tyrosine kinase suppressing the Philadelphia chromosome positive clone in CML. Clinical studies have yielded impressive results in all phases of CML. With higher rates of complete cytogenetic response with imatinib, molecular monitoring of disease is now advisable in assessing response and determining prognosis. Emergence of resistance to imatinib may be manifest at the hematologic, cytogenetic, or molecular levels in patients who remain in chronic phase, or may be evidenced by the development of more advanced CML phases. Resistance and eventual clinical failure of imatinib occurs in most patients with blastic phase disease. Resistance may occur at the level of Bcr-Abl, with reduction or loss of imatinib effectiveness as a kinase inhibitor, or, despite retention of its inhibitory ability, with changes in the ability to deliver an effective dose at the cellular level, and/or, the leukemia becoming less dependent on Bcr-Abl. The various mechanisms underlying these differing, non-mutually exclusive, mechanisms of resistance must be understood to develop corresponding therapeutic remedies. We review the current data on imatinib in CML, the criteria for diagnosis of imatinib resistance, and the mechanisms that underlie such resistance in CML.     

Effects of carboxyamidotriazole on in vitro models of imatinib-resistant chronic myeloid leukemia

Although imatinib mesylate (IM) has revolutionized the treatment of chronic myeloid leukemia (CML), some patients develop resistance with progression of leukemia. Alternative or additional targeting of signaling pathways deregulated in bcr-abl-driven CML cells may provide a feasible option for improving clinical response and overcoming resistance. In this study, we show that carboxyamidotriazole (CAI), an orally bioavailable calcium influx and signal transduction inhibitor, is equally effective in inhibiting the proliferation and bcr-abl dependent- and independent-signaling pathways in imatinib-resistant CML cells. CAI inhibits phosphorylation of cellular proteins including STAT5 and CrkL at concentrations that induce apoptosis in IM-resistant CML cells. The combination of imatinib and CAI also down-regulated bcr-abl protein levels. Since CAI is already available for clinical use, these results suggest that it may be an effective addition to the armamentarium of drugs for the treatment of CML.     

The role of interferon-alpha in the treatment of chronic myeloid leukemia

Biological agents have long been used in the treatment of cancer, and interferon-alpha was the first human cytokine to be widely studied in this setting. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder for which interferon-alpha has demonstrated substantial activity. In the 1980s interferon-alpha became first-line therapy for patients with chronic-phase CML, not eligible for allogeneic stem cell transplantation. Following the discovery of the leukemic oncogene BCR/ABL and its causal association with CML, the potent BCR/ABL tyrosine kinase inhibitor imatinib mesylate was developed. Imatinib proved to be superior to interferon-alpha in all outcome measures, making imatinib the new standard of care for patients with CML. There is both clinical and laboratory evidence suggesting imatinib therapy alone is not curative in CML, whereas IFN has induced a low but reproducible curative effect in some patients. This unique activity may be the basis for the reincorporation of IFN into the management of CML. These observations may be best explained by imatinib's negligible activity against the leukemic stem cell (LSC) population. This review discusses the history of interferon-alpha in the treatment of CML, the evolution of molecularly targeted therapies, and some of the lessons we have learned from years of informative research in CML. It also explores the new challenge of managing minimal residual disease in the imatinib era, and addresses the promising role for LSC-directed therapies in the future treatment of CML.     

Identification of differentially expressed proteins in imatinib mesylate-resistant chronic myelogenous cells

Resistance to imatinib mesylate (also known as Gleevec, Glivec, and STI571) often becomes a barrier to the treatment of chronic myelogenous leukemia (CML). In order to identify markers of the action of imatinib mesylate, we used a mass spectrometry approach to compare protein expression profiles in human leukemia cells (K562) and in imatinib mesylate-resistant human leukemia cells (K562-R) in the presence and absence of imatinib mesylate. We identified 118 differentially regulated proteins in these two leukemia cell-lines, with and without a 1 microM imatinib mesylate challenge. Nine proteins of unknown function were discovered. This is the first comprehensive report regarding differential protein expression in imatinib mesylate-treated CML cells.     

Design and synthesis of 3-substituted benzamide derivatives as Bcr-Abl kinase inhibitors

A series of 3-substituted benzamide derivatives structurally related to STI-571 (imatinib mesylate), a Bcr-Abl tyrosine kinase inhibitor used to treat chronic myeloid leukemia (CML), was prepared and evaluated for antiproliferative activity against the Bcr-Abl-positive leukemia cell line K562. About ten 3-halogenated and 3-trifluoromethylated benzamide derivatives were identified as highly potent Bcr-Abl kinase inhibitors. One of these, NS-187 (9b), is a promising new candidate Bcr-Abl inhibitor for the therapy of STI-571-resistant chronic myeloid leukemia.     

Roles of Bim in apoptosis of normal and Bcr-Abl-expressing hematopoietic progenitors

Bcr-Abl kinase is known to reverse apoptosis of cytokine-dependent cells due to cytokine deprivation, although it has been controversial whether chronic myeloid leukemia (CML) progenitors have the potential to survive under conditions in which there are limited amounts of cytokines. Here we demonstrate that early hematopoietic progenitors (Sca-1(+) c-Kit(+) Lin(-)) isolated from normal mice rapidly undergo apoptosis in the absence of cytokines. In these cells, the expression of Bim, a proapoptotic relative of Bcl-2 which plays a key role in the cytokine-mediated survival system, is induced. In contrast, those cells isolated from our previously established CML model mice resist apoptosis in cytokine-free medium without the induction of Bim expression, and these effects are reversed by the Abl-specific kinase inhibitor imatinib mesylate. In addition, the expression levels of Bim are uniformly low in cell lines established from patients in the blast crisis phase of CML, and imatinib induced Bim in these cells. Moreover, small interfering RNA that reduces the expression level of Bim effectively rescues CML cells from apoptosis caused by imatinib. These findings suggest that Bim plays an important role in the apoptosis of early hematopoietic progenitors and that Bcr-Abl supports cell survival in part through downregulation of this cell death activator.     

Impact of BCR-ABL mutations on patients with chronic myeloid leukemia

Therapies that target BCR-ABL in chronic myeloid leukemia, including imatinib, dasatinib and nilotinib, have dramatically improved patient outcome. BCR-ABL mutations, however, contribute to treatment resistance by disrupting drug contact sites or causing conformational changes thus making contact sites inaccessible. Clinical data indicate that developing BCR-ABL mutations during imatinib treatment is predictive for shorter progression-free survival, and that outcomes may depend on mutation type or location. In vitro, dasatinib and nilotinib inhibit most imatinib-resistant BCR-ABL mutations, except for T315I. In clinical studies, other mutations associated with treatment resistance include V299L, T315A, and F317I/L for dasatinib and Y253F/H, E255K/V, and F359C/V for nilotinib. Evaluating patients with clinical signs of resistance for BCR-ABL mutations is an important component of disease monitoring, potentially facilitating selection of subsequent therapy. First-line treatment with dasatinib or nilotinib instead of imatinib may reduce emergence of resistance but novel agents are needed to overcome the problematic T315I mutation.     

Clinical outcome in chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation: the experience of the Bone Marrow Transplantation Unit of FUNFARME/BRAZIL using FISH

Investigation of the efficacy of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in chronic myeloid leukemia patients is essential to predict prognosis and survival. In 20 patients treated at the Bone Marrow Transplantation Unit of S?o José do Rio Preto (S?o Paulo, Brazil), we used fluorescence in situ hybridization (FISH) to investigate the frequency of cells with BCR/ABL rearrangement at diagnosis and at distinct intervals after allo-HSCT until complete cytogenetic remission (CCR). We investigated the disease-free survival, overall survival in 3 years and transplant-related mortality rates, too. Bone marrow samples were collected at 1, 2, 3, 4, 6, 12, and 24 months after transplantation and additional intervals as necessary. Success rate of the FISH analyses was 100%. CCR was achieved in 75% of the patients, within on average of 3.9 months; 45% patients showed CCR within 60 days after HSCT. After 3 years of the allo-HSCT, overall survival rate was 60%, disease-free survival was 50% and the transplant-related mortality rate was 40%. The study demonstrated that the BCR-ABL FISH assay is useful for follow-up of chronic myeloid leukemia patients after HSCT and that the clinical outcome parameters in our patient cohort were similar to those described for other bone marrow transplantation units.     

Imatinib impairs CD8+ T lymphocytes specifically directed against the leukemia-associated antigen RHAMM/CD168 in vitro

The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate is highly effective in the front-line treatment of chronic myeloid leukemia (CML) and is increasingly used in patients with residual disease or relapse after allogeneic stem cell transplantation (allo-SCT). Since an impairment of anti-viral CD8+ T-lymphocyte function by imatinib has been described, we question whether imatinib also affects specific anti-leukemic CD8+ T lymphocytes generated from the peripheral blood of healthy donors, and of CML patients after allo-SCT. Here, we assessed CD8+ T-cell expansion and function from healthy donors and patients with CML. The release of IFN-γ and granzyme B by CD8+ T-lymphocytes specific for R3, a recently described T-cell epitope peptide derived from a leukemia-associated antigen designated RHAMM/CD168 (receptor for hyaluronic acid mediated motility), was inhibited by imatinib in a dose-dependent fashion (range: 1–25 μM). These T cells were able to lyse cognate peptide labeled T2 cells and CD34+ CML progenitor cells. This lysis was inhibited by imatinib. The inhibitory effect was not associated with an increased rate of apoptosis of T cells and reversible after removal of imatinib. In the light of these findings, clinical administration of imatinib might result in the reduction of efficacy of the graft-versus-leukemia effect or other T-cell-based immunotherapies.     

Imatinib and Type 2 Diabetes

ObjectiveTo characterize the effect, if any, of imatinib mesylate, an inhibitor of abl tyrosine kinase used in the treatment of chronic myeloid leukemia, on type 2 diabetes.MethodsThe centralized pharmacy database was used to identify all patients who had received imatinib at the Mayo Clinic in Rochester, Minnesota, during a 5-year period. The electronic medical records were subsequently reviewed to identify which of these patients had type 2 diabetes. In addition, relevant biochemical data, prior to, during, and after imatinib treatment, were abstracted from the electronic laboratory database and medical records.ResultsAt the Mayo Clinic in Rochester, Minnesota, a total of 164 patients received imatinib during the period of study (1999 to 2004). Of these 164 patients, 7 had preexisting type 2 diabetes, and diabetes developed in 2 patients during treatment with imatinib. Despite 2 previous reports of improvement in glycemic control with use of imatinib in patients with type 2 diabetes, no net effect on glycemic control or diabetes therapy was noted in our study cohort.ConclusionOn the basis of our current study, it seems unlikely that imatinib substantially affects glycemic control in patients with type 2 diabetes. (Endocr Pract. 2007;13:126-130)     

Antitumoral effects of cyclin-dependent kinases inhibitors CR8 and MR4 on chronic myeloid leukemia cell lines

Background

Although Imatinib mesylate has revolutionized the treatment of chronic myeloid leukemia, some patients develop resistance with progression of leukemia. Alternative or additional targeting of signalling pathways deregulated in Bcr-Abl-driven chronic myeloid leukemia may provide a feasible option for improving clinical response and overcoming resistance.

Results

In this study, we investigate ability of CR8 isomers (R-CR8 and S-CR8) and MR4, three derivatives of the cyclin-dependent kinases (CDKs) inhibitor Roscovitine, to exert anti-leukemic activities against chronic myeloid leukemia in vitro and then, we decipher their mechanisms of action. We show that these CDKs inhibitors are potent inducers of growth arrest and apoptosis of both Imatinib-sensitive and –resistant chronic myeloid leukemia cell lines. CR8 and MR4 induce dose-dependent apoptosis through mitochondrial pathway and further caspases 8/10 and 9 activation via down-regulation of short-lived survival and anti-apoptotic factors Mcl-1, XIAP and survivin which are strongly implicated in survival of Bcr-Abl transformed cells.

Conclusions

These results suggest that CDK inhibitors may constitute a complementary approach to treat chronic myeloid leukemia.

Electronic supplementary material

The online version of this article (doi:10.1186/s12929-015-0163-x) contains supplementary material, which is available to authorized users.     

Interferon alfa-2c in chronic myelogenous leukemia (CML): hematologic, cytogenetic and molecular-genetic response of patients with chronic phase CML previously resistant to therapy with interferon gamma

Alpha- and gamma-interferons have been shown to actively suppress hematopoiesis in patients in the chronic phase of chronic myelogenous leukemia in vitro and in vivo. Since both interferons act through different receptors on their hematopoietic target cells, they are expected to be capable of independently inhibiting abnormal blood cell development in patients with chronic myelogenous leukemia. We have utilized recombinant human interferon alfa-2c to treat 11 patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase, who were resistant to previous interferon gamma therapy. Ten of the patients were evaluable for hematologic, cytogenetic and molecular-genetic response following interferon alfa-2c therapy for 6 to 30 months. In 5 patients, IFN alfa-2c treatment failed due to lack of hematologic response. A complete hematologic or partial hematologic response was achieved in the remaining 5 patients. Three of these experienced cytogenetic improvement with reappearence of 100% diploid hematopoietic cells and disappearence of c-abl/bcr rearrangement in one patient. In two patients interferon alfa-2c did not prevent transformation of the disease into an accelerated state or blast crisis, respectively. We conclude that recombinant human interferon alfa-2c may also control hematopoiesis in interferon-gamma resistant chronic myelogenous leukemia patients, although the long-term response will need to be elucidated in further studies.