Dasatinib Toxicity Research Articles

Dasatinib targets c-Src kinase in cardiotoxicity.

Dasatinib is a multitargeted kinase inhibitor used for treatment of chronic myeloid leukemia and acute lymphoblastic leukemia. Unfortunately, treatment of cancer patients with some kinase inhibitors has been associated with cardiotoxicity. Cancer treatment with dasatinib has been reported to be associated with cardiotoxic side effects such as left ventricular dysfunction, heart failure, pericardial effusion and pulmonary hypertension. Here we aimed to investigate the molecular mechanisms underlying the cardiotoxicity of dasatinib. We found that among the resident cardiac cell types, cardiomyocytes were most sensitive to dasatinib-induced cell death. Exposure of cardiomyocytes to dasatinib attenuated the activity of extracellular signal-regulated kinase (ERK), which is a downstream target of dasatinib target kinase c-Src. Similar to dasatinib, c-Src depletion in cardiomyocytes compromised cardiomyocyte viability. Overexpression of dasatinib-resistant mutant of c-Src rescued the toxicity of dasatinib on cardiomyocytes, whereas forced expression of wild type c-Src did not have protective effect. Collectively, our results show that c-Src is a key target of dasatinib mediating the toxicity of dasatinib to cardiomyocytes. These findings may influence future drug design and suggest closer monitoring of patients treated with agents targeting c-Src for possible adverse cardiac effects.

Dasatinib causes keratinocyte apoptosis via inhibiting high mobility group Box 1-mediated mitophagy

Dasatinib, a second-generation BCR-ABL inhibitor, is currently used as first-line treatment for patients with chronic myeloid leukemia. However, dasatinib treatment increases the risk of severe cutaneous toxicity, which limits its long-term safe use in clinic. The underlying mechanism for dasatinib-induced cutaneous toxicity has not been clarified. In this study, we tested the toxicity of dasatinib on human immortal keratinocyte line (HaCaT) and normal human epidermal keratinocytes (NHEK). We found that dasatinib directly caused cytotoxicity on keratinocytes, which could be the explanation of the clinical characteristic of pathology. Mechanistically, dasatinib impaired mitophagy by downregulating HMGB1 protein level in keratinocytes, which led to the accumulation of dysfunctional mitochondria. Mitochondria-derived ROS caused DNA damage and cell apoptosis. More importantly, we confirmed that overexpression of HMGB1 could reverse dasatinib-induced keratinocyte apoptosis, and preliminarily explored the intervention effect of saikosaponin A, which could increase HMGB1 expression, on cutaneous toxicity caused by dasatinib. Collectively, our study revealed that dasatinib induced keratinocyte apoptosis via inhibiting HMGB1-mediated mitophagy and saikosaponin A could be a viable strategy for prevention of dasatinib-induced cutaneous toxicity.

Dasatinib and PD-L1 inhibitors provoke toxicity and inhibit angiogenesis in the embryo

Dasatinib is a targeted cancer therapy, while programmed death ligand 1 (PD-L1) inhibitors are a form of immune checkpoint therapy used to treat various types of cancers. Several studies showed the potential efficacy of these drugs in the management of triple-negative breast cancer- an aggressive subtype of breast cancer, which can develop during pregnancy. Nevertheless, side effects of Dasatinib (DA) and PD-L1 drugs during pregnancy, especially in the early stages of embryogenesis are not explored yet. The aim of this study is to assess the individual and combined toxicity of DA and PD-L1 inhibitors during the early stages of embryogenesis and to evaluate their effect(s) on angiogenesis using the chorioallantoic membrane (CAM) model of the embryo. Our results show that embryos die at greater rates after exposure to DA and PD-L1 inhibitors as compared to their matched controls. Moreover, treatment with these drugs significantly inhibits angiogenesis of the CAM. To further elucidate key regulator genes of embryotoxicity induced by the actions of PD-L1 and DA, an RT-PCR analysis was performed for seven target genes that regulate cell proliferation, angiogenesis, and survival (ATF3, FOXA2, MAPRE2, RIPK1, INHBA, SERPINA4, and VEGFC). Our data revealed that these genes are significantly deregulated in the brain, heart, and liver tissues of exposed embryos, compared to matched control tissues. Nevertheless, further studies are necessary to evaluate the effects of these anti breast cancer drugs and elucidate their role during pregnancy.

Dasatinib treatment long-term results among imatinib-resistant/intolerant patients with chronic phase chronic myeloid leukemia are favorable in daily clinical practice

To evaluate long-term real-life results of dasatinib therapy among chronic phase chronic myeloid leukemia patients resistant or intolerant to imatinib, we retrospectively analyzed data of 118 patients treated in centers participating in the database INFINITY. With median follow-up of 37 months, estimated 5-year cumulative incidences of complete cytogenetic and major molecular responses were 78% and 68%, respectively. The estimated 5-year probability of overall survival (OS) and event-free survival (EFS) were 86% and 83%, respectively. Both OS and EFS were significantly improved among patients with BCR-ABL1 transcript level ≤10% at 3 months. Dasatinib toxicity was tolerable however persistent in almost half our patients, even after years of therapy. Pleural effusion occurred in 29% of patients and was responsible for 30% of dasatinib discontinuations. Our results confirmed very good efficacy and acceptable toxicity of dasatinib in second line setting and support the evidence and importance of high-quality real-life CML patient management.

Dasatinib induces gene expression of CYP1A1, CYP1B1, and cardiac hypertrophy markers (BNP, β-MHC) in rat cardiomyocyte H9c2 cells

Dasatinib is a new selective tyrosine kinase inhibitor that targets certain kinases involved in cellular growth and development. This drug belongs to a novel anticancer therapy aiming to increase the survival in patients with imatinib-resistant mutations. However, the dasatinib toxicity was reported as a side effect leading to arrhythmias and/or heart failure. Here, we investigated the possibility of dasatinib-induced toxicity in rat cardiomyocyte H9c2 cells. Our objectives were to investigate the ability of dasatinib to induce expression of cytochrome P450 (CYP1A1, CYP1B1) and cardiac hypertrophy markers (BNP, β-MHC) genes in H9c2 cells. To test this hypothesis, H9c2 cells were incubated with dasatinib at two concentrations (20 and 40 μM). Thereafter, CYP1A1, CYP1B1, BNP, and β-MHC were determined at gene expression level. Our findings showed that dasatinib induces the CYP1A1, CYP1B1, BNP, and β-MHC mRNA. The involvement of AhR/CYP1A1 pathway in dasatinib toxicity was tested by resveratrol (RES), an AhR antagonist. Interestingly, the increase in mRNA of different genes by dasatinib was not affected by RES, which confirms that these effects are not mediated through AhR. In addition, this was accompanied by a significant inhibition of constitutive expression of these genes by RES. The current work provides the first evidence for the ability of dasatinib to induce hypertrophic markers in H9c2 cells through AhR-independent pathway.

Blinatumomab + Tyrosine Kinase Inhibitors in the Treatment of Relapsed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia Patients - Clinical Efficacy and Peripheral Blood Lymphocytes Subpopulations Kinetics

▪Blinatumomab is a bispecific anti-CD3/CD19 monoclonal antibody. It showed efficacy as a single agent in the treatment of relapsed/refractory Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL). T-regulatory (T-reg) and T-helper cells can inhibit effector T-cells used by blinatumomab. Tyrosine-kinase inhibitors (TKI) are the basic treatment of the Ph+ ALL. To improve the long-term results of the relapsed Ph+ ALL treatment we combined blinatumomab with TKIs dasatinib or nilotinib or ponatinib.The aim of this study was to evaluate clinical efficacy of blinatumomab + TKI combination in relapsed Ph+ ALL patients and to study T-cell and NK subpopulations kinetics in R/R-ALL patients during the treatment.From Oct 2015 to June 2016 we treated 6 relapsed Ph+ ALL patients (5 overt hematological relapses and 1 cytogenetic relapse). Blinatumomab was administered in the dose 28 mcg/day by continuous IV infusion 28 days (4 week cycle) with 2 weeks intervals (up to 4 cycles). The dose of blinatumomab in the 1st week of the 1st cycle was 9 mcg/day. Dasatinib 140 mg/day PO started on 1 week and administered daily continuously. Nilotinib 400 mg bid PO was administered in the case of dasatinib toxicity. Ponatinib 45 mg /day PO was administered in the case of T315I ABL kinase domaine mutation. Lymphocytes subpopulations of the peripheral blood (T-helper CD3+/CD4+/CD8-, T-cytotoxic CD3+/CD4-/CD8+, T-reg CD3+/CD4+/CD25+, NK CD3-/CD56+) were studied by flow cytometry on the 1st day of every week during every blinatumomab cycle.Two pts received all 4 cycles of blinatomomab + TKI dasatinib (two MolCR after 2nd cycle). Two pts received 2 cycles of blinatumomab + TKI dasatinib (two MolCR) and are continuing treatment. 1 pt with T315I mutation received 1 cycle of blinatumomab + TKI ponatinib (MolCR). 1 pt progressed during 1st cycle of blinatumomab + dasatinib which were discontinued. AlloBMT was performed in 2 pts in MolCR and 3 pts in MolCR are awaiting alloBMT. All 6 pts are alive. The pt who progressed on the 1-st cycle of blinatumomab + dasatinib was later diagnosed with T315I mutation and CR was obtained on ponatinib + dexamethasone + vincristine. In 1 pt the dasatinib-related pleural effusions and lung infiltration observed which fully regressed after 2 weeks of dasatinib interruption. Dasatinib in that pt was later replaced with nilotinib during 4th cycle and so on. Hypogammaglobulinemia was common and corrected with intravenous human normal immunoglobulin replacement. No neurological toxicity observed. As a result, 5 MolCR were obtained in 6 pts who received blinatumomab + TKI except in 1 pt with T315I mutation who progressed on blinatumomab + dasatinib. In all pts T-helper population was about low limit of normal range or below it (Fig. 1). In 4 of 5 responded pts the restoration of cytotoxic T-cell subpopulation was observed (Fig. 2). In 4 of 5 responded pts the 2nd week T-reg dropping occurred (Fig. 3). In all of responded pts NK population returned to normal range.The blinatumomab + TKI combination is effective in relapsed Ph+ ALL. The MolCR obtaining is possible without glucocorticoid treatment. The combination has acceptable toxicity. The T-reg subpopulation depletion on 2 week and depleted pool of T-helper are correlated with MolCR obtaining during blinatumomab + TKI treatment. The T cell cytotoxic and NK lymphocyte subpopulation restoring possibly reflects normal hemopoiesis establishing in MolCR settings in effectively treated pts. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Abstract 170: Mechanism of Cardiotoxicity of Tyrosine Kinase Inhibitors

Aim: It is becoming evident that many of the signaling elements driving cancer cell division, for which kinase inhibitors (KIs) are targeted, are the same as those necessary for cardiomyocyte viability. Adverse cardiac events have been reported for a number of KIs. Aim of this study was to identify KIs that induce toxicity to cardiomyocytes and to elucidate the central molecular mechanisms mediating the toxicity. Methods: 288 anti-cancer agents (123 are KIs) were screened for their ability to induce cardiotoxicity in cultured primary cardiomyocytes. Cell viability assay was done by measuring the ATP levels in cardiomyocytes after exposure of cells to a 3-log concentration range of each compound for 24 hours. Toxicity data was combined with kinase profiling data to identify protein kinases mediating the toxicity of KIs. In parallel, the molecular mechanism mediating the cardiomyocyte toxicity of dasatinib, a second generation Bcr-Abl and Src family tyrosine kinase inhibitor, was investigated. The role of Src kinase in regulation of cardiomyocyte viability was analyzed by siRNA-mediated Src knockdown. Overexpression of wild type Src and dasatinib- resistant Src in cardiomyocytes was performed to investigate the role of Src in regulating the cardiomyocyte toxicity of dasatinib. Western blotting was used to investigate for downstream signaling targets of Src. Results: Of the KIs, 70 compounds decreased the cardiomyocyte viability by 10-80 %. The kinase profiling data showed that IGF1R, MEK/ERK pathway, PI3K and Src kinases are the key kinases regulating cardiomyocyte viability. Dasatinib treatment dose-dependently increased cardiomyocyte death. Depletion of Src by siRNA also reduced cardiomyocyte viability. Dasatinib treatment attenuated FGF induced ERK phosphorylation. Overexpression of dasatinib-resistant mutant of Src, but not wild type Src, protected the cardiomyocyte from dasatinib toxicity and rescued the FGF-induced ERK phosphorylation. Conclusions: Cardiomyocyte toxicity of KIs can be attributed to inhibition of IGF1R, MEK/ERK pathway, PI3Ks and Src family kinases. Cardiomyocyte toxicity of dasatinib is mediated by Src kinase inhibition which in turn attenuates MEK/ERK pathway signalling.

Propensity Score Matched Comparison of Dasatinib and Nilotinib As a Frontline Therapy in Newly Diagnosed CML with Chronic Phase

Background: Dasatinib (DAS) and nilotinib (NIL) are standard frontline therapy for chronic myeloid leukemia, chronic phase (CML-CP) based on randomized trials compared to imatinib. However, DAS and NIL have not been compared directly. The purpose of this study is to analyze efficacy, long-term outcome and toxicity of DAS and NIL as a front line therapy in newly diagnosed CML-CP. Method: Newly diagnosed patients (pts) with CML-CP, who received front-line therapy by either one of the phase II trials conducted almost in parallel (DAS: NCT00254423, N = 102 and NIL: NCT00129740, N = 104) are matched with caliper matching by the propensity score (PS) to adjust pre-treatment confounding factors. DAS was given orally by either 50mg twice daily (N = 30) or 100mg daily (N = 77). NIL was given 400mg orally twice daily. Toxicity was recorded according to the CTCAE ver. 4.0. Result: PS matching resulted in 87 pts from each trial to be matched for pre-treatment characteristics including age, Sokal score, lab, and organ function (Table). The median observation duration was 50.9 months (95% CI: 40.1-61.7) vs. 43.0 months (95% CI: 35.3-50.7) (DAS vs. NIL, P = 0.56). Response rate at 3, 6, and 12 months as well as cumulative (best) response are shown in Table. There were no significant differences in measures of response throughout the study period except for a higher rate of complete molecular response at 6 months with NIL (NIL vs. DAS, 11% vs. 3%, P = 0.04). However, at 12 months, this difference was not retained; there was also no difference in the rate of optimal response at 3 months. There was no statistical difference in cumulative response between 2 groups. No statistical difference was observed between 2 groups in any of the survival endpoints at 3 years (overall, event-free, failure-free, and transformation-free survival). Treatment discontinuation was observed in 16 (18%) vs. 17 (19%) pts with (DAS vs. NIL, P = 0.82). Reason for the discontinuation was; 1) toxicity (8 vs. 8, P = 1.00), 2) resistance (5 vs. 8, P = 0.39), and 3) financial (4 vs. 1, P = 0.37) (all presented as DAS vs. NIL, respectively). Adverse event (AE) was observed in 40 (46%) vs. 42 (48%) pts (DAS vs. NIL, P = 0.76), whereas grate 3 or more AE was observed in 19 (22%) vs. 15 (17%) pts (DAS vs. NIL, P = 0.44). Conclusion: In PS matched cohort of newly diagnosed CML-CP pts, the outcome observed with both treatment options (DAS and NIL) is excellent with no clear difference in response or long-term survival endpoints. Incidence of clinically significant AEs was similar between DAS and NIL. Disclosures O9Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity9s Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding. Cortes: Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

Dasatinib-induced Chylous Pleural Effusions

Tyrosine kinase inhibitors have revolutionized treatment of chronic myeloid leukemia through their targeted treatment of the BCR-ABL transcript. Imatinib was the first of this class and was found to induce fluid retention and volume overload resulting in pleural effusions. In cases of imatinib-resistant chronic myeloid leukemia, dasatinib provides another treatment option, as a second-generation tyrosine kinase inhibitor, which is 325 times more efficacious in vitro when compared with imatinib. However, a common adverse pulmonary effect is the development of a pleural effusion. Dasatinib-induced toxicity and the development of exudative pleural effusions are dose dependent. Chylous pleural effusions have been described with dasatinib toxicity; however, not all pleural effusions documented with dasatinib are chylous. In our patient, serial chest radiographs show the regression of her effusions with dasatinib discontinuation. Despite the regression of the patient’s effusions, chylomicrons were still present in low concentrations. We suspect the development of chylous pleural effusions from dasatinib exposure is related to lymphatic dysregulation.

Therapeutic Efficacy and Cure Of Sensitive and T315I Pan-Resistant Human Ph+ Leukemia In Mice Using a TCR-Like Antibody To WT1/HLA-A0201 Alone, Or In Combination With Tyrosine Kinase Inhibitors

Acute and chronic leukemias, including CD34+ CML stem cells, overexpress the Wilms tumor gene 1 (WT1) protein, making WT1 an attractive therapeutic target. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201, allowing it to target an undruggable, widely expressed, intracellular oncogene product. BV173 is an HLA-A0201+, human Ph+ ALL cell line that expresses WT1, and tagged by our lab with luciferase. We engineered a tyrosine kinase inhibitor (TKI) resistant BV173-R cell line by transducing BV173 with the resistant T315I Bcr-Abl plasmid. Antibody-dependent cellular cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. Tumor growth in vivo was assessed in NOD/SCID gamma (NSG) mice with bioluminescence imaging (BLI). RT-PCR was used to evaluate minimal residual disease in mice with negative BLI signal at the end of therapy. Imatinib, dasatinib, and ponatinib were used at up to maximally tolerated doses, given IP once daily. ESKM was administered at 100 µg twice weekly IP. ESKM mediated ADCC against both BV173 and BV173-R cell lines in vitro. In a BV173 engrafted human leukemia xenograft model, ESKM was more potent than imatinib, with median tumor growth reduction of 78% vs 52%. Combination of imatinib and ESKM therapy resulted in a 94% reduction in leukemic growth. High dose dasatinib (40 mg/kg daily) was more potent than ESKM, but discontinuation of therapy due to dasatinib toxicity resulted in relapse. Combination with ESKM therapy with dasatinib resulted in cure in 75% of mice, confirmed by bone marrow RT-PCR three weeks after termination of therapy. For mice cytoreduced with dasatinib followed by consolidation therapy with ESKM, delayed relapse was observed, but no cures. ESKM was highly superior to imatinib and dasatinib against the T315I BV173-R leukemia in vivo. Cures were not achieved with combination therapy of ESKM and either first or second generation TKIs against resistant T315I leukemia. Ponatinib at 10 mg/kg had higher efficacy than ESKM alone against BV173-R, but mice treated with combination of ESKM and ponatinib had superior tumor reduction. CONCLUSION: ESKM is an effective therapeutic antibody for sensitive and T315I Ph+ ALL. Resistant T315I Ph+ leukemic growth is inhibited more effectively by ESKM therapy compared to imatinib and dasatinib, and combination therapy with ESKM is superior to ponatinib.Supported by the Leukemia and Lymphoma Society, NIH R01CA55349, P01 23766 and T32CA62948-18. Disclosures:Yan:Eureka Therapeutics: Employment. Liu:Eureka Therapeutics: Employment, Equity Ownership.

Treatment-Related Toxicities in a Phase II Trial of Dasatinib in Patients with Squamous Cell Carcinoma of the Lung

Advanced squamous cell carcinoma (SqCC) of the lung carries a poor prognosis, and new therapeutic targets are needed. Several studies have examined dasatinib in non-small cell lung cancer; these report not only significant toxicities, but also responses in patients found to harbor mutations in discoidin domain receptor tyrosine kinase 2 or BRAF. An open-label phase II trial with dasatinib was carried out to determine the response rates in patients with SqCC who had previously failed standard chemotherapy and to correlate responses with patient genotype. Patients were treated with dasatinib 140 mg daily in 28-day cycles. Patients were included if they had stage IIIb/IV SqCC, Eastern Cooperative Oncology Group performance status of 0 or 1, and for whom treatment with standard chemotherapy had failed. The study was halted after enrolling five patients, all of whom were discontinued from the trial because of excess toxicity of dasatinib administered at 140 mg/day. The patients were treated for 9, 14, 24, 40, and 42 days. Three of five patients (60%) experienced grade 3 or more toxicities (dyspnea, fatigue, elevated level of aspartate transaminase, anorexia, nausea). Intolerable grade 2 pleural effusions were noted in two of five patients. Four of five patients died after 44, 52, 127, and 226 days; one patient remains alive at 279 days. No deaths were associated with the study drug. Similar to other studies, this study too found that dasatinib administered at 140 mg/day for the treatment of advanced SqCC of the lung is associated with excess adverse events, so is not recommended in unselected patients. Further work to identify patients likely to benefit from dasatinib and to manage dasatinib-related toxicities is needed.

Dasatinib After Allogeneic Stem Cell Transplantation in Philadelphia-Positive Leukemias.

Abstract 4304Dasatinib is a second generation tyrosine kinase inhibitor for the treatment of Ph+ chronic myeloid leukemia. However many patients recieving dasatinib are candidates for an allogeneic transplantation and will receive a transplant eventually. The use of dasatinib after an allogeneic transplant is very controversial: First the allogeneic antileukemic immune effect should theoretically obviate the need for further tyrosine kinase inhibition. Second the considerable hematological toxicity of dasatinib might impair the fragile donor hematopoiesis, at least given at full dosage. And third there is evidence that dasatinib inhibits both effector and regulatory T-cells which might hamper the graft-versus-leukemia effect and/or inrease the risk for Graft-versus-host disease.We report our experience with dasatinib in 3 patients with relapsing or persisting Ph+ leukemias after allogeneic stem cell transplantation.Pat. 1 is a 66yr old female patient with an imatinib-resistant lymphoid blast crisis who responded to dasatinib and was transplanted from an unrelated donor. After achieving a complete molecular remission she experienced a molecular relapse and was started on dasatinib 20 mg daily. 3 months later she reached a complete molecular remission without any major changes in blood counts and continued on dasatinib 20 mg.Pat. 2 is a 42yr old male with Ph+ CML and a paraspinal extramedullary lesion who responded to dasatinib after being resistant to imatinib. After an allogeneic transplant from his HLA-compatible brother he was in complete hematologocial and major molecular remission but relapsed 3 months later. Ciclosporin A was stopped and dasatinib introduced at 70 mg once daily. 2 months later he achieved a complete hematological and molecular remission. No hematological toxicity was found.Pat. 3 is a 41yr old female patient with a Ph+ c-ALL with a history of liver cancer and a partial liver transplantation. After achieving a complete remission with chemotherapy with imatinib she reveived an allogeneic stem cell transplantation from her brother who also had donated the liver graft. She lost her remission 9 months after transplant and was retransplanted with the same donor but without immunospuppression. Due to the lack of a complete molecular remission she started dasatinib at 50 mg/d and became bcr-abl negative 3 months later. Blood counts improved during treatment with dasatinib.In summary all patients showed stable responses to dasatinib at low doses without any major hematological toxicity. With a follow up of 8-12 months we did not observe any GvHD during dasatinib treatment. In our hands low dose dasatinib is a feasible treatment option for relapse after allogeneic transplantation in Ph+ leukemias. Disclosures:No relevant conflicts of interest to declare.

Update of recent studies in chronic myeloid leukemia

Update of recent studies in chronic myeloid leukemia

Dasatinib pharmacokinetics and exposure-response (E-R): Relationship to safety and efficacy in patients (pts) with chronic myeloid leukemia (CML)

3590 Background: Dasatinib is 325-fold more potent than imatinib and 16-fold more potent than nilotinib against BCR-ABL in vitro. In the randomized, dose optimization Study CA180–034 of pts with chronic phase CML, the 100 mg once daily dose was associated with similar efficacy but less frequent pleural effusion (pl eff), cytopenia, dose reduction, and interruption than the other three dosing schedules. Methods: The clinical study design has been previously described. Here we present population pharmacokinetic (PPK) and E-R analyses. Exposure measures examined included: mean steady-state (ss) concentration (Cavg), ss trough concentration (Cmin), and ss peak concentration (Cmax). E-R was characterized using a Cox proportional-hazards model. Covariates examined included: age, gender, body weight (PPK only), and history of cardiac disease (E-R only). Results: Of the 670 pts randomized, samples from 567 were evaluated for PK. Of these, 94 had a pl eff, 271 required dose reduction and 376 dose interruption. PPK analysis showed that exposure to dasatinib did not depend upon age, gender, or body weight, but was highly dependent on the dosing schedule. E-R analysis showed that the risk of pl eff was greater with increasing Cmin (2.33-fold for each doubling of Cmin, p<0.001) and increasing age (1.93-fold for each decade of life, p<0.001). Cmax and Cavg were not statistically significant predictors of pl eff. Cmin was also correlated with dose reduction and interruption, but not with efficacy. Conclusion: Cmin appears to correlate strongly with dasatinib toxicity but not with efficacy. The lowest Cmin was achieved with the 100 mg once-daily dose regimen, which has been shown to have the optimal therapeutic index among the regimens tested. Mean (CV%) ng/mL 100 mg QD 50 mg BID 140 mg QD 70 mg BID Cmin 2.69 (26) 5.13 (24) 3.86 (28) 6.9 (24) Cmax 66.85 (56) 37.6 (48) 94.09 (55) 53.71 (46) Cavg 14.16 (20) 14.32 (18) 19.96 (18) 20.34 (17) Cmin <2.5 Cmin 2.5-<5.0 Cmin >5.0 Pleural effusion (%) 4 14 25 Dose reduction (%) 26 45 59 Dose interruption (%) 51 64 75 Major cytogenetic response (%) 69 63 62 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Innovive, Merck, Novartis, Wyeth

Chronic Myelogenous Leukemia Guidelines

Chronic myelogenous leukemia (CML) accounts for 15% of adult leukemias. In 2007, an estimated 4500 cases will be diagnosed and 900 patients will die of the disease. The goal of CML therapy is complete remission, which typically progresses from hematologic to cytogenetic remission. These updated 2007 guidelines include changes to several treatment recommendations, including considerations for imatinib dosing, the use of interferon, and management of dasatinib toxicity. Recommendations for hematopoetic stem cell transplantation have also been updated. For the most recent version of the guidelines, please visit NCCN.org