Posted by rob on June 30, 2004 under Uncategorized | 
Association of HLA Class I and Class II genes with bcr-abl transcripts in leukemia patients with t(9;22) (q34;q11).
BACKGROUND: Based on the site of breakpoint in t(9;22) (q34;q11), bcr-abl fusion in leukemia patients is associated with different types of transcript proteins. In this study we have seen the association of HLA genes with different types of bcr-abl transcripts. The association could predict the bcr-abl peptide presentation by particular HLA molecules. METHODS: The study included a total of 189 patients of mixed ethnicity with chronic myelogenous leukemia and acute lymphocytic leukemia who were being considered for bone marrow transplantation. Typing of bcr-abl transcripts was done by reverse transcriptase PCR method. HLA typing was performed by molecular methods. The bcr-abl and HLA association was studied by calculating the relative risks and chi-square test. RESULTS: Significant negative associations (p < 0.05) were observed with HLA-A*02 (b2a2, e1a2), -A*68 (b2a2, b3a2, e1a2), -B*14 (b2a2, b3a2, e1a2), -B*15 (b2a2, b3a2), -B*40 (b2a2), -DQB1*0303 (b2a2, b3a2), -DQB1*0603 (b2a2), -DRB1*0401 (e1a2), -DRB1*0701 (b3a2), and -DRB1*1101 (b2a2). CONCLUSIONS: The negative associations of a particular bcr-abl transcript with specific HLA alleles suggests that these alleles play a critical role in presenting peptides derived from the chimeric proteins and eliciting a successful T-cell cytotoxic response. Knowledge of differential associations between HLA phenotypes and bcr-abl fusion transcript types would help in developing better strategies for immunization with the bcr-abl peptides against t(9;22) (q34;q11)-positive leukemia.
http://www.hubmed.org/display.cgi?issn=14712407&uids=15202948
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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. Am. J. Hematol. 76:275-278, 2004.
http://www.hubmed.org/display.cgi?issn=03618609&uids=15224366
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Sweet’s syndrome associated with sargramostim (granulocyte-macrophage colony stimulating factor) treatment.
Sweet’s syndrome is an acute febrile neutrophilic dermatosis that is a known complication of the administration of filgrastim, a drug that causes increased neutrophil proliferation and differentiation. This complication has not previously been reported during treatment with sargramostim, a hematopoietic cytokine with activity that overlaps filgrastim. We report a case of Sweet’s syndrome in association with sargramostim treatment following chemotherapy for acute myelogenous leukemia. A suspected second episode occurred after subsequent chemotherapy and sargramostim treatment. Physicians should be aware of this possible association because the signs and symptoms of Sweet’s syndrome are easily mistaken as being due to infection. Am. J. Hematol. 76:283-285, 2004.
http://www.hubmed.org/display.cgi?issn=03618609&uids=15224368
Posted by rob on under Uncategorized |
Eosinophilic folliculitis in a patient after allogeneic bone marrow transplantation: Case report and review of the literature.
We describe a patient with eosinophilic folliculitis (EF) that developed 3 months after allogeneic bone marrow transplantation (BMT) for chronic myelogenous leukemia. Skin biopsy specimen revealed numerous eosinophil infiltrations from the hair follicles to the sebaceous glands. No sign of skin graft-versus-host disease (GVHD) was found. The skin lesions and peripheral eosinophilia subsided within 5 weeks. In the following 8 months, the rash did not recur and GVHD has not developed. Taken together with previous reports, the present case demonstrates that it is important to recognize this distinct skin condition to avoid an inference that it may manifest itself as one of the signs of skin GVHD. Am. J. Hematol. 76:295-296, 2004.
http://www.hubmed.org/display.cgi?issn=03618609&uids=15224372
Posted by rob on under Uncategorized |
Dr. Goldman stated that Gleevec® has become the initial treatment of choice for newly diagnosed patients with CML since the publication of the IRIS study comparing Gleevec® to interferon and cytarabine.1-3 Current data suggests that:
97% of newly diagnosed patients with CML will achieve a complete hematological remission.
87% will have a major cytogenetic reduction.
76% will have a complete cytogenetic remission following Gleevec® treatment.
Of the 553 patients entered in this trial, 79% are still receiving first-line therapy with Gleevec®.
Dr. Goldman stated that progression-free survival following Gleevec® treatment depends on the log reduction of BCR-ABL. Those with a 3 log reduction have a 100% PFS at 30 months compared to 93% for a 2 log reduction and 81% for a 1 log reduction….
Over the past 4 years, most transplant centers have seen a 50-75% reduction in the number of transplants for chronic phase CML because patients have opted for Gleevec® rather than a transplant.
http://www.cmlwatch.org/modules.php?op=modload&name=News&file=article&sid=908
Posted by rob on under Uncategorized |
High-affinity interaction of tyrosine kinase inhibitors with the ABCG2 multidrug transporter.
Tyrosine kinase inhibitors (TKIs) are promising new agents for specific inhibition of malignant cell growth and metastasis formation. Because most of the TKIs have to reach an intracellular target, specific membrane transporters may significantly modulate their effectiveness. In addition, the hydrophobic TKIs may interact with so-called multidrug transporters and thus alter the cellular distribution of unrelated pharmacological agents. In the present work, we show that certain TKIs, already in the clinical phase of drug development, directly interact with the ABCG2 multidrug transporter protein with a high affinity. We found that in several in vitro assay systems, STI-571 (Gleevec; imatinib mesylate), ZD1839 (Iressa; gefitinib), and N-[4-[(3-bromophenyl)amino]-6-quinazolinyl]-2-butynamide (EKI-785) interacted with ABCG2 at submicromolar concentrations, whereas other multidrug transporters, human multidrug resistance protein (P-glycoprotein, ABCB1) and human multidrug resistance protein 1 (ABCC1), showed much lower reactivity toward these agents. Low concentrations of the TKIs examined selectively modulated ABCG2-ATPase activity, inhibited ABCG2-dependent active drug extrusion, and significantly affected drug resistance patterns in cells expressing ABCG2. Our results indicate that multidrug resistance protein modulation by TKIs may be an important factor in the clinical treatment of cancer patients. These data also raise the possibility that an extrusion of TKIs by multidrug transporters, e.g., ABCG2, may be involved in tumor cell TKI resistance.
http://www.hubmed.org/display.cgi?issn=0026895X&uids=15155841
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Graft-versus-host disease confined solely to intestine after allogeneic peripheral blood stem cells transplantation in a patient with chronic myelogenous leukemia.
We describe a patient with chronic myelogenous leukemia who developing severe intestinal bleeding after allogeneic peripheral blood stem cells transplantation (allo-PBSCT). PBSC were obtained from an HLA one-locus mismatch sibling donor. On day 26 after PBSCT, although there was no sign of graft-versus-host disease (GVHD) in either the skin or the liver, diarrhea and severe intestinal bleeding occurred. The histopathological examination of the colon revealed complete denudation of the epithelial cells of the mucosa and no obvious apoptosis. Neither red cell fragments nor hemorrhagic diathesis was seen during this episode and the patient was diagnosed as having GVHD. Methylpredonisolone followed by FK506 may be effective in controlling intestinal bleeding and was used in our patient. Acute GVHD involving only the intestine has rarely been described but when using HLA-mismatched PBSCs, acute GVHD may occur severely and atypically.
http://www.hubmed.org/display.cgi?issn=10245332&uids=15203868
Posted by rob on under Uncategorized |
Multicenter prospective study of interferon alpha versus allogeneic stem cell transplantation for patients with new diagnoses of chronic myelogenous leukemia.
Ohnishi K,
Ino A,
Kishimoto Y,
Usui N,
Shimazaki C,
Ohtake S,
Taguchi H,
Yagasaki F,
Tomonaga M,
Hotta T,
Ohno R,
We compared interferon alpha (IFN-alpha) therapy with stem cell transplantation (SCT) for patients with chronic-phase chronic myelogenous leukemia in a multicenter prospective study to investigate the optimal indication and timing of SCT, especially from HLA-matched unrelated donors. Of 257 eligible patients, 145 patients who were younger than 50 years were assigned to the IFN-alpha cohort (n = 87) or the SCT cohort (n = 58), according to family donor availability. In the IFN-alpha cohort, 52 patients received IFN-alpha and chemotherapy (the IFN1 group), and 35 patients received an SCT from an unrelated donor (the U-SCT group). In the SCT cohort, 47 patients received an SCT from a related donor (the R-SCT group). In the IFN1 group, 88% of the patients achieved a complete hematologic response, and 33% achieved a complete cytogenetic response. At a median follow-up period of 53 months, the predicted 6-year survival rate was 72% in the IFN1 group, 81% in the R-SCT group, and 81% in the U-SCT group. When overall survival was evaluated for the IFN-alpha and R-SCT cohorts by intention to treat according to family donor availability, the 6-year survival rates were 76% and 84%, respectively. When the outcomes of the U-SCT and IFN1 groups were compared, the survival rate of U-SCT group patients was significantly better than for IFN1 group patients without a major cytogenetic response and seemed better for IFN1 group patients younger than 35 years. Therefore, U-SCT may be recommendable to patients who fail to achieve a major cytogenetic response in IFN-alpha therapy and to younger patients.
http://www.hubmed.org/display.cgi?issn=09255710&uids=15218963
Posted by rob on under Uncategorized |
Imatinib mesylate (STI571) prevents the mutator phenotype of Bcr-Abl in hematopoietic cell lines.
Progression of CML from chronic phase to blast crisis is accompanied by accumulating genetic alterations. To analyze whether this abnormality can be prevented by inhibition of Bcr-Abl, we measured the frequency of spontaneous and irradiation-induced HPRT mutations in cells treated with or without imatinib mesylate (Gleevec, STI571). Imatinib treatment of cells expressing Bcr-Abl reversed the mutation frequency to a value comparable to that of Bcr-Abl negative cells. Experiments with a Bcr-Abl deletion mutant indicate that in addition to the kinase activity, protein-protein interactions are required for induction of the mutator phenotype by Bcr-Abl.
http://www.hubmed.org/display.cgi?issn=01452126&uids=15109541
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Spotlight on imatinib mesylate in chronic myeloid leukemia.
Imatinib mesylate (Gleevec, Glivec) is an orally administered competitive inhibitor of the BCR-ABL tyrosine kinase created by the Philadelphia chromosome (Ph+) in chronic myeloid leukemia (CML). In patients with newly diagnosed and previously untreated (apart from hydroxyurea and/or anagrelide) CML in the chronic phase, imatinib mesylate 400 mg/day, compared with interferon-alpha (IFNalpha) plus cytarabine, resulted in higher hematologic response (HR) and cytogenetic response (CR) rates and fewer patients progressing to the accelerated phase or blast crisis in a large comparative trial. Preliminary results indicate that, compared with IFNalpha plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher health-related quality of life (HR-QOL). Imatinib mesylate was also effective in patients with chronic-phase CML refractory to or intolerant of treatment with IFNalpha (as 400 mg/day) and in those with blast-crisis or accelerated-phase CML (600 mg/day). In the latter groups, HR and CR rates were lower than those in patients with chronic-phase CML. Imatinib mesylate-associated adverse events were common in clinical trials, but were mostly mild to moderate in severity. The most frequently reported adverse events were superficial edema, nausea, muscle cramps, diarrhea, vomiting, and skin rash. Myelosuppression (thrombocytopenia and neutropenia) was also reported, especially in patients with advanced disease. In patients with previously untreated chronic-phase CML, serious adverse events (both hematologic and nonhematologic) were less common with imatinib mesylate than with IFNalpha plus cytarabine treatment. CONCLUSION: Imatinib mesylate is a valuable therapy for patients with newly diagnosed Ph+ chronic-phase CML. It is better tolerated and produces higher HR, CR and freedom from progressive disease rates than conventional therapy with IFNalpha plus cytarabine. Preliminary results indicate that, compared with IFNalpha plus cytarabine, imatinib mesylate treatment was associated with similar total costs, but resulted in a higher HR-QOL. Imatinib mesylate is also effective in patients with accelerated-phase and blast-crisis CML, and patients with chronic-phase CML who have failed IFNalpha therapy. Given its efficacy and generally manageable adverse event profile, imatinib mesylate offers an important early treatment option for patients with CML.
http://www.hubmed.org/display.cgi?issn=11738804&uids=15161340
Posted by rob on June 29, 2004 under Uncategorized |
Contact: Stephanie Dedeaux
srdedeau@mdanderson.org
713-792-0655
University of Texas M. D. Anderson Cancer Center
Treat the cancer, but take care to protect the heart, cancer cardiologists warn
HOUSTON – Cancer treatments, including the most commonly used chemotherapy agents as well as the newest biologic and targeted therapy drugs, can harm a patient’s heart, sometimes fatally – but many physicians do not adequately monitor their patients for such damage or manage their care to minimize it.
So say cardiologists at The University of Texas M. D. Anderson Cancer Center, who published, in the June 29 issue of the journal Circulation, the first large scale review detailing cardiovascular complications that often occur in cancer therapy, as well as ways to prevent or treat them.
The study draws on 30 years of experience at M. D. Anderson Cancer Center as well as on the current body of research on the cardiotoxicity of various agents.
The findings are important because both patients and doctors may not be aware of the spectrum of heart problems that can arise from cancer treatment, or know that many of these problems can be managed, says the study’s lead author, Edward T. H. Yeh, M.D., professor and chairman of the Department of Cardiology.
“Many cancer survivors will actually be at greater risk from cardiac disease as from recurrent cancer,” says Yeh. “Now that cancer is often being treated as a chronic, manageable disease, it is critical that this treatment doesn’t substantially weaken a patient’s heart.”
In fact, Yeh and a team of nine other cardiologists from M. D. Anderson found in their review of 29 anticancer agents that there is no class of cancer drug that is free of potential damage to the heart, the organ that seems to be most sensitive to toxic effects of anticancer agents.
Generally speaking, patients at most risk for cardiotoxicity are those who are aged and have other illnesses, such as diabetes or existing heart disease, he says. But cardiotoxicity can occur in any patient, either during treatment or months, even years after treatment.
Even the newest targeted therapies, designed to attack only cancer cells, can cause cardiotoxicity, Yeh says. For example, monoclonal antibody drugs such as Avastin, Erbitux, and Rituxin produce a significant amount of hypertension as well as hypotension in patients. “They seem to have more general toxicity than many other agents, but the problems they produce usually involve changes in blood pressure, which can be easily treated if recognized,” Yeh says.
Some agents, however, are clearly more dangerous, especially in large doses. For example, patients using the common class of chemotherapy drugs known as anthracyclines/anthraquinolones that includes adriamycin should be closely monitored because these agents frequently produce irreversible chronic heart failure or left ventricular dysfunction, says Yeh. “This is probably the most problematic class of anticancer drugs, but with experience, cardiotoxicity can be limited,” he says.
Alkylating agents, another class of common chemotherapy drugs, have other toxic effects. Platinol and Cytoxan, the most widely used alkylating agents, can produce heart problems that range from chronic heart failure to hypertension, if the total dose is high.
Chemotherapy drugs known as “antimetabolites,” which include the widely used agent 5-fluorouracil (5-FU), can produce ischemia, which can lead to heart attacks if not treated. However, heart problems are relatively rare in the “antimicrotubules” class of chemotherapy drugs, of which Taxol is a member.
Other non-chemotherapy drugs noted for their high risk of cardiotoxicity includes Inerleukin-2, which frequently results in hypotension or arrhythmias; Gleevec which can cause heart failure; Trisenox, from which fatal “QT prolongation” can result; and Thalidomide, which can produce a variety of serious heart ailments.
On the other hand, the researchers found that Herceptin is less toxic than generally believed, although it can cause chronic heart failure and left ventricular dysfunction.
“We found a profile of cardiotoxicity for the most often used anticancer drugs, but it is important to know that every patient has different risk factors that will determine how their hearts handle the treatment,” says Yeh. “Monitoring and management is key to surviving cancer with a good and lasting heart.”
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Posted by rob on June 28, 2004 under Uncategorized |
The Medicare lottery is now open and is accepting applications. The application form to get into the lottery is 18 pages long and requires a PDF viewer. The application also has to be filled out and signed by your physician. An article in SeniorJournal today gives more information on the application process. Those who are chosen by lottery will receive Medicare assistance for Gleevec but will still have to pay a $5,298.00 annual co-payment. Low income patients who have exhausted their assets down to or below poverty level who are chosen in the lottery can receive Gleevec for a reduced co-payment ranging from $60.00 to $638.00 per year. Those who are not chosen will have to wait until 2006.
Posted by rob on under Uncategorized |
Molecular markers for the diagnosis of Philadelphia chromosome negative myeloproliferative disorders.
Polycythemia vera, essential thrombocythemia, idiopathic myelofibrosis and chronic myelogenous leukemia have been collectively termed the myeloproliferative disorders due to similarities in their clinical presentation. With the exception of chronic myelogenous leukemia, which is characterized by the presence of the Philadelphia chromosome, the myeloproliferative disorders display no consistent cytogenetic abnormalities. Hence, the diagnosis of Polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis to date relies on clinical criteria. However, several molecular aberrations have been described, which can be used as molecular markers for the diagnosis of these clinical entities. This review outlines the diagnostic assays developed and highlights the advantages and disadvantages of the following markers: (1) Endogenous Erythroid Colonies, (2) Clonality, (3) Reduced c-Mpl protein expression and (4) PRV-1 mRNA over expression.
http://www.pmbrowser.info/pmdisplay.cgi?issn=03698114&uids=15217712
Posted by rob on under Uncategorized |
Imatinib therapy in chronic myelogenous leukemia: strategies to avoid and overcome resistance.
Imatinib is a molecularly targeted therapy that inhibits the oncogenic fusion protein BCR-ABL, the tyrosine kinase involved in the pathogenesis of chronic myelogenous leukemia (CML). Selective inhibition of BCR-ABL activity by imatinib has demonstrated efficacy in the treatment of CML, particularly in chronic phase. Some patients, however, primarily those with advanced disease, are either refractory to imatinib or eventually relapse. Relapse with imatinib frequently depends not only on re-emergence of BCR-ABL kinase activity but may also indicate BCR-ABL-independent disease progression not amenable to imatinib inhibition. Results from phase 2/3 trials suggest that rates of resistance and relapse correlate with the stage of disease and with the monitoring parameters – hematologic, cytogenetic and molecular response. These observations and more recent trials with imatinib, combined with insights provided by an increased understanding of the molecular mechanisms of resistance, have established the rationale for strategies to avoid and overcome imatinib resistance in the management of CML patients. To prevent resistance, early diagnosis and prompt treatment with appropriate initial dosing is essential. Management of resistance may include therapeutic strategies such as dose escalation to achieve individual optimal levels, combination therapy, as well as treatment interruption.Leukemia advance online publication, 24 June 2004; doi:10.1038/sj.leu.2403426
http://www.pmbrowser.info/pmdisplay.cgi?issn=08876924&uids=15215876
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A 2-year-old with atypical CML with a t(5;12)(q33;p13) treated successfully with imatinib mesylate.
Atypical chronic myelogenous leukemia (aCML) is a myelodysplastic/myeloproliferative disorder that usually occurs in older adults. Here we report a pediatric patient with aCML and a t(5;12)(q33;p13) with a corresponding fusion gene ETV6-PDGFRB. Because the PDGFRB tyrosine kinase is one of the known targets of tyrosine kinase inhibitors, this patient achieved cytogenetic and molecular remission with treatment with imatinib mesylate (formerly STI571; now Gleevec in the United States and Glivec in Europe). This case illustrates one of many myelodysplastic/myeloproliferative disorders that can be treated with this particular tyrosine kinase inhibitor.
http://www.pmbrowser.info/pmdisplay.cgi?issn=01452126&uids=15036944
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Court Upholds Testimony Linking Plutonium Exposure with Leukemia
A reader has passed along news of an April 23 decision by Judge Richard G. Stearns of the District of Massachusetts involving expert testimony on “whether a scientifically reliable hypothesis supports plaintiffâ??s claim that chronic low-level exposure to inhaled or ingested plutonium and americium alpha emitters can cause the onset of chronic myelogenous leukemia (CML) in human beings” (as the opinion puts it). The court’s conclusion:
While I can see a benefit to a rule empowering judges to act as the ultimate arbiters of scientific disputes, at least insofar as they may impact on the conduct of litigation, it would be a difficult rule to reconcile with the constitutional delegation of the fact-finding duty to juries. I cannot dismiss plaintiffâ??s experts as poseurs or witnesses for hire. They are serious scientists with controversial views that are in many respects on the periphery of the mainstream, but views that are not so divorced from a scientific method of investigation that they can be dismissed as quackery or armchair conjecture. Hence, as I understand Daubert, my role is over, and the role of the jury begins.
See Smith v. General Electric Co., No. 91-12912-RGS (D. Mass. Apr. 23, 2004).
http://www.daubertontheweb.com/2004_04_01_archive.html#108319186467859169
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Granulocyte-colony-stimulating factor (filgrastim) may overcome imatinib-induced neutropenia in patients with chronic-phase chronic myelogenous leukemia.
BACKGROUND: Imatinib mesylate administration has become standard treatment for patients with chronic myelogenous leukemia (CML). Although the safety profile of imatinib is favorable, Grade > or = 3 neutropenia (according to the National Cancer Institute Common Toxicity Criteria) occurs in 35-45% of patients with CML in chronic phase who receive standard-dose imatinib. Myelosuppression results in treatment interruptions, which may compromise responses to imatinib. The authors investigated the ability of granulocyte-colony-stimulating factor (filgrastim) to reverse imatinib-associated neutropenia, thereby allowing for more continuous imatinib administration. METHODS: Thirteen patients with chronic-phase CML and Grade > or = 3, imatinib-induced neutropenia were treated with filgrastim. Treatment with filgrastim was initiated after a median of 22 months from the start of imatinib. Eleven patients received filgrastim 5 microg/kg 1-3 times weekly, and 2 patients received filgrastim 5 microg/kg daily; doses were titrated to maintain an absolute neutrophil count (ANC) > or = 10(9)/L. RESULTS: Seven of 11 patients (64%) who began treatment with an ANC < 1.5 x 10(9)/L had responses (i.e., their ANC improved to > or = 2 x 10(9)/L within 21 days); the other 4 patients experienced slower recovery but were able to continue receiving imatinib uninterrupted. Before filgrastim administration was initiated, patients did not receive imatinib (due to neutropenia-related treatment interruptions) for an average of 21% of the total time since the start of imatinib. This figure decreased to 6% after the start of filgrastim treatment (P = 0.0008). Before filgrastim treatment was initiated, only one patient had achieved a major (partial) cytogenetic response. After the start of filgrastim treatment, five patients had major cytogenetic responses (including two complete responses). CONCLUSIONS: The authors concluded that filgrastim may overcome imatinib-associated neutropenia and allow improved delivery of imatinib. Some patients may experience improvements in their responses to therapy as a result.
http://www.pmbrowser.info/pmdisplay.cgi?issn=0008543X&uids=15197801
Posted by rob on under Uncategorized |
Beyond chronic myelogenous leukemia: potential role for imatinib in Philadelphia-negative myeloproliferative disorders.
The myeloproliferative disorders (MPDs) are chronic malignant conditions originating from the clonal expansion of a multipotential hematopoietic stem cell. These diseases include polycythemia vera (PV), essential thrombocythenia, atypical chronic myeloid leukemia, idiopathic hypereosinophilic syndrome (HES), agnogenic myeloid metaplasia with myelofibrosis, and others. Receptor tyrosine kinases-the platelet-derived growth factor receptors (PDGFRs) and c-Kit-and their respective ligands have been implicated in the pathogenesis of MPDs. For example, a constitutively activated PDGFR fusion tyrosine kinase (FIP1L1-PDGFRA) was identified in some patients with HES, a disease characterized by sustained overproduction of eosinophils that has been classified by the World Health Organization as a chronic subtype of the MPDs. Imatinib is a selective inhibitor of PDGFRs, c-Kit, Abl and Arg protein-tyrosine kinases, as well as Bcr-Abl, the oncogenic tyrosine kinase that causes chronic myeloid leukemia. The efficacy of imatinib in treating HES, systemic mast cell disease, chronic myelomonocytic leukemia associated with PDGFRbeta fusion genes, and (to a lesser extent) PV and idiopathic myelofibrosis was reviewed from institutional experience and a review of the literature. In 3 studies that involved 11 patients with PV, 10 patients had reductions in phlebotomy with imatinib. Eight studies of 42 patients with HES indicated that 70% achieved complete hematologic remissions with imatinib. Four studies of 6 patients with MPD indicated responses with imatinib in 5 patients. Insight into the molecular pathogenesis of MPDs will improve the definitions of different disease categories and suggests that signal transduction inhibition is likely to be an increasingly important treatment option in the future.
http://www.pmbrowser.info/pmdisplay.cgi?issn=0008543X&uids=15139047
Posted by rob on under Uncategorized |
Novel therapies for patients with chronic myeloid leukemia.
The most immediate issues that will have a major impact on the long-term survival of patients with chronic myeloid leukemia is the optimal use of imatinib mesylate (Gleevec((R)), Novartis) and the development of effective therapies for those patients who are intolerant of, or become resistant to, optimal doses of this agent. Of the multiple new agents that are currently being developed for patients with chronic myeloid leukemia, most are being investigated in patients who have developed resistance to imatinib, which is a confounding factor in itself. The mechanisms of action of novel agents are diverse and they may have a variably synergistic therapeutic relationship with imatinib. The complete blockade of the intracellular pathways that are triggered by Bcr-Abl, combined with successful reversal of apoptotic and/or angiogenic abnormalities in chronic myeloid leukemia, may well lead to a cure for the majority of patients.
http://www.pmbrowser.info/pmdisplay.cgi?issn=14737140&uids=15056057
Posted by rob on under Uncategorized |
Sweet’s syndrome with CML cell infiltration of the skin in a patient with chronic-phase CML while taking Imatinib Mesylate.
Sweet’s syndrome (acute febrile neutrophilic dermatosis) is characterized by an acute onset of erythematous plaques, fever, and leukocytosis. This syndrome has been reported to be associated with leukemia including chronic myelogenous leukemia (CML). Sweet’s syndrome seen in patients with leukemia is usually associated with active and/or refractory disease. Imatinib Mesylate (STI-571, Gleevec) is widely used for therapy of CML. In this case report, CML cell infiltration of the skin was documented by fluorescence in situ hybridization (FISH) analysis in a patient with chronic-phase CML on Imatinib Mesylate (STI-571, Gleevec), who was at the time in molecular remission.
http://www.pmbrowser.info/pmdisplay.cgi?issn=01452126&uids=15036943
