Two threshold levels of vitamin D and the prevalence of comorbidities in outpatients of a tertiary hospital.

This study evaluated the number of comorbidities between two normal values of 25OHD in outpatients during 1 year of 25OHD measurements. Five hundred twenty-nine outpatients were included, patients with 25OHD ≥ 20 and < 30 ng/mL had the higher number of comorbidities, suggesting that for this specific population, 25OHD ≥ 30 ng/mL would be more appropriate. INTRODUCTION : This study evaluated the comorbidities between two values of 25OHD in outpatients of a tertiary hospital. METHODS: This is a cross-sectional study with measures of 25OHD in 1-year period, excluding 25OHD < 20 and > 50 ng/mL, clinical research participants, and liver disease and chronic renal failure patients. Patients were divided into two groups: group 1 (G1), 25OHD ≥ 20 and < 30 ng/mL; and group 2 (G2), 250HD ≥ 30 and ≤ 50 ng/mL. Medical records were reviewed for demographic, laboratory, and comorbidity data. RESULTS: From 529 outpatients included, 319 were in G1 (53.3 ± 15.8 years, 85% women), mean 25OHD 24.8 ± 2.8 ng/mL; and 210 outpatients in G2 (56.7 ± 16.0 years, 83% women), mean 25OHD was 36.8 ± 4.8 ng/mL. G1 had the higher number of comorbidities, including altered glycemia, dyslipidemia, hypothyroidism, urinary tract diseases, arthropathy, secondary hyperparathyroidism, anemia, and neurological and psychiatric disorders. Osteoporosis and hypothyroidism were more prevalent in G2. After binary logistic regression, the variables age (OR 0.988, CI 0.97-1.00, p = 0.048), osteoporosis (OR 0.54, CI 0.36-0.80, p = 0.003), dyslipidemia (OR 1.61, CI 1.10-2.39, p = 0.015), arthropathy (OR 2.60, CI 1.40-5.10, p = 0.003), anemia (OR 15.41, CI 3.09-280.08, p = 0.008), and neurological and psychiatric diseases (OR 3.78, CI 1.98-7.88, p = 0.001) maintained significance. CONCLUSION: Patients with serum 25OHD ≥ 20 and < 30 ng/mL had higher prevalence of comorbidities compared to ≥ 30 ng/mL.

BCR-ABL1 mutation development during first-line treatment with dasatinib or imatinib for chronic myeloid leukemia in chronic phase.

BCR-ABL1 mutations are a common, well-characterized mechanism of resistance to imatinib as first-line treatment of chronic myeloid leukemia in chronic phase (CML-CP). Less is known about mutation development during first-line treatment with dasatinib and nilotinib, despite increased use because of higher response rates compared with imatinib. Retrospective analyses were conducted to characterize mutation development in patients with newly diagnosed CML-CP treated with dasatinib (n=259) or imatinib (n=260) in DASISION (Dasatinib versus Imatinib Study in Treatment-Naive CML-CP), with 3-year minimum follow-up. Mutation screening, including patients who discontinued treatment and patients who had a clinically relevant on-treatment event (no confirmed complete cytogenetic response (cCCyR) and no major molecular response (MMR) within 12 months; fivefold increase in BCR-ABL1 with loss of MMR; loss of CCyR), yielded a small number of patients with mutations (dasatinib, n=17; imatinib, n=18). Dasatinib patients had a narrower spectrum of mutations (4 vs 12 sites for dasatinib vs imatinib), fewer phosphate-binding loop mutations (1 vs 9 mutations), fewer multiple mutations (1 vs 6 patients) and greater occurrence of T315I (11 vs 0 patients). This trial was registered at www.clinicaltrials.gov as NCT00481247.

Rates of peripheral arterial occlusive disease in patients with chronic myeloid leukemia in the chronic phase treated with imatinib, nilotinib, or non-tyrosine kinase therapy: a retrospective cohort analysis.

Peripheral arterial occlusive disease (PAOD) occurs in patients with chronic phase chronic myeloid leukemia (CML-CP) treated with tyrosine kinase inhibitors (TKIs). The risk of developing PAOD on TKI therapy is unknown and causality has not been established. Patients with CML-CP from three randomized phase III studies (IRIS, TOPS and ENESTnd) were divided into three cohorts: no TKI (cohort 1; n=533), nilotinib (cohort 2; n=556) and imatinib (cohort 3; n=1301). Patients with atherosclerotic risk factors were not excluded. Data were queried for terms indicative of PAOD. Overall, 3, 7 and 2 patients in cohorts 1, 2 and 3, respectively, had PAOD; 11/12 patients had baseline PAOD risk factors. Compared with that of cohort 1, exposure-adjusted risks of PAOD for cohorts 2 and 3 were 0.9 (95% CI, 0.2-3.3) and 0.1 (95% CI, 0.0-0.5), respectively. Multivariate logistic regression revealed that nilotinib had no impact on PAOD rates compared with no TKI, whereas imatinib had decreased rates of PAOD compared with no TKI. Nilotinib was associated with higher rates of PAOD versus imatinib. Baseline assessments, preferably within clinical studies, of PAOD and associated risk factors should occur when initiating TKI therapy in CML; patients should receive monitoring and treatment according to the standard of care for these comorbidities.

Demonstration of Philadelphia chromosome negative abnormal clones in patients with chronic myelogenous leukemia during major cytogenetic responses induced by imatinib mesylate.

Imatinib mesylate, an Abl-specific kinase inhibitor, produces sustained complete hematologic responses (CHR) and major cytogenetic responses (MCR) in chronic myeloid leukemia (CML) patients, but long-term outcomes in these patients are not yet known. This article reports the identification of clonal abnormalities in cells lacking detectable Philadelphia (Ph) chromosome/BCR-ABL rearrangements from seven patients with chronic- or accelerated-phase CML, who were treated with imatinib. All seven patients were refractory or intolerant to interferon therapy. Six of seven patients demonstrated MCR and one patient, who had a cryptic translocation, achieved low-level positivity (2.5%) for BCR-ABL by fluorescence in situ hybridization. The median duration of imatinib treatment before the identification of cytogenetic abnormalities in BCR-ABL-negative cells was 13 months. The most common cytogenetic abnormality was trisomy 8, documented in three patients. All patients had varying degrees of dysplastic morphologic abnormalities. One patient exhibited increased numbers of marrow blasts, yet consistently demonstrated no Ph-positive metaphases and the absence of morphologic features of CML. The presence of clonal abnormalities in Ph-negative cells of imatinib-treated CML patients with MCR and CHR highlights the importance of routine metaphase cytogenetic testing and long-term follow-up of all imatinib-treated patients.

ST1571, a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia: validating the promise of molecularly targeted therapy.

The deregulated tyrosine kinase activity of the Bcr-Abl fusion protein has been established as the causative molecular event in chronic myelogenous leukemia (CML). Thus the Bcr-Abl tyrosine kinase is an ideal target for pharmacologic inhibition. ST1571 (formerly CGP57148B), is an Abl-specific tyrosine kinase inhibitor that in preclinical studies selectively kills Bcr-Abl-containing cells in vitro and in vivo. The results of clinical studies have demonstrated the potential of molecularly targeted therapies, and ST1571 is emerging as a new therapeutic agent for CML.

STI571: targeting BCR-ABL as therapy for CML.

Therapeutic agent STI571 (signal transduction inhibitor number 571) is a rationally developed, potent, and selective inhibitor for abl tyrosine kinases, including bcr-abl, as well c-kit and the platelet-derived growth factor receptor tyrosine kinases. Results of clinical trials to date have demonstrated the crucial role of the bcr-abl tyrosine kinase in chronic myelogenous leukemia (CML) pathogenesis and the potential of anticancer agents designed to target specific molecular abnormalities in human cancer. An initial phase I study of STI571 included 83 Ph(+) CML patients who had failed interferon-based therapy. Patients were required to be in chronic phase, defined liberally as less than 15% blasts in blood or bone marrow. Patients were treated with once-daily oral doses of STI571 in 14 successive dose cohorts ranging from 25-1,000 mg. In this phase I study, no dose-limiting toxicity was encountered and toxicity at all dose levels was minimal. The threshold for a maximally effective dose was found at 300 mg; for patients treated at or above this level, complete hematologic response was seen in 98% of patients, with complete cytogenetic responses in 13% and major cytogenetic responses in 31%. With a median duration of follow-up of 310 days, ongoing responses are evident in 96% of patients. In the phase II study of the accelerated phase of CML, 233 patients were treated with either 400 or 600 mg of STI571. With similar follow-up to the chronic phase trial, 91% of patients showed a hematological response; 63% of patients achieved a complete hematological response but not all patients had recovery of peripheral blood counts. In addition to the phase II clinical trials with STI571, a phase III trial randomizing newly diagnosed patients to either interferon with low-dose s.c. cytosine arabinoside versus STI571 is ongoing; this trial accrued rapidly and data collection is ongoing. Integration of STI571 into CML treatment algorithms will require long-term follow-up data from the ongoing phase II and III clinical studies.

STI571: a gene product-targeted therapy for leukemia.

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem-cell disorder characterized by the (9:22) translocation and resultant production of the constitutively activated bcr-abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem-cell transplantation, with stem-cell transplantation being the only curative therapy. Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product-targeted therapy, offering new hope for expanded treatment options for patients with CML.

Chronic myelogenous leukemia.

Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem cell disorder characterized by the (9:22) translocation and resultant production of the constitutively activated bcr-abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Interferon-based regimens and stem cell transplantations are the standard therapeutic options, with stem cell transplantation being the only curative therapy. As therapy for CML improves, molecular methods of monitoring response will become integrated in patient treatment. Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as targeted therapy that offers new hope for expanded treatment options for patients with CML.