Dasatinib In Chronic Myeloid Leukemia Research Articles

CYP Inhibition and Low-Dose Dasatinib for Chronic Myeloid Leukemia: Preliminary Results of a Promising, Cost-Effective Treatment Option

Introduction The standard treatment for newly diagnosed (ND)-CML is tyrosine kinase inhibitors (TKIs) such as dasatinib. However, the cost of treatment with these drugs can be prohibitively high. The CYP inhibition strategy involves intentionally inhibiting a specific enzyme, in this case CYP3A4, to increase plasma concentration of dasatinib and reduce the required dose from 100mg to 25mg daily. Patients and methods Five consecutive patients older than 18 years, with ND-CML in chronic phase and Eastern Cooperative Oncology Group (ECOG) of 0-2.The diagnosis and classification of CML followed the ESMO guidelines. After diagnostic confirmation, patients continuously received half pill of dasatinib (25mg orally daily) and a strong CYP3A4 inhibitor (ketoconazole, 200mg orally twice daily). Patients were monitored weekly during the first month and then monthly after that. The response to treatment was established according to the ESMO guidelines. Statistical analysis We examined the distribution of variables using the Shapiro-Wilk test, and descriptive analyses were conducted for demographic and clinical characteristics. The proportion of hematological and non-hematological side effects and the proportion of hematological response were obtained. To demonstrate the effect of dasatinib on hematological cells, we constructed a line plot showing the values of hemoglobin, leukocytes, and platelets in each visit. We compared basal hemoglobin, leukocytes, and platelets vs. follow-up counts at each visit with the Kruskal-Wallis test Results The median age of the patients was 42 years. All patients had a median ECOG score of 0. Three patients (60%) presented with thrombocytosis, three (60%) with splenomegaly, and two patients (40%) had B symptoms. Basal median (range) hemoglobin, leukocytes, and platelets counts were 9.9 g/dL , 272×10 9/L and 451×10 9/L, respectively. Three patients (60%) had low-risk CML, and two patients (40%) had high-risk disease, with a median EUTOS score of 71 points. Dasatinib treatment was initiated within a median of 9 days from diagnosis. In the first 28 days of treatment, median leukocytes and platelets were significantly reduced compared to baseline, with a reduction in leukocytes of 93.7% (125×10 9/L vs. 7.9×10 9/L, p=0.005) and in platelets of 64.6% (407×10 9/L, vs. 144×10 9/L, p=0.027). Hemoglobin levels significantly increased by the second month of treatment, with an increase of 26.4% from baseline (10.2 g/dL vs. 12.9 g/dL, p=0.023). All patients (100%) achieved major hematological response within a median of 22 days. Patient number 1 achieved the 3-month and 6-month treatment goals with 6.4% and <1% reduction in BCR-ABL transcript levels, respectively. After 3 months of treatment, 60% of patients achieved the BCR/ABL1 transcript level on the IS <10%, which is the optimal response according to guidelines, in the rest of the patients the time of evaluation has not been reached. Mild and self-limited adverse events were reported in 40% of patients at some point in their treatment. Non-hematological toxicity occurred in one patient (20%) with nausea and galactorrhea due to ketoconazole. Hematological toxicity occurred in (20%) of patients; the platelet count returned to normal after suspending ketoconazole for one week. No serious adverse events were reported. Conclusion Apart from this preliminary study, there is currently no evidence supporting the intentional use of CYP inhibition to reduce the dosage and cost of dasatinib for patients with ND-CML. Dasatinib is primarily metabolized using the CYP3A4 isoenzyme, and studies have shown that ketoconazole, an accessible antifungal, can strongly inhibit CYP3A4, increase dasatinib's plasma concentration and AUC by 5-fold and 385%, respectively, and allow for a reduction in dosage while maintaining therapeutic efficacy. The CYP inhibition strategy can decrease the cost of dasatinib to a point where it is cheaper than full-dose imatinib -the cheapest TKI- and represent a treatment option for patients who cannot afford full-dose dasatinib in low income countries. The CYP inhibition strategy can be of added value to the lower effective dose concept and give rise to ultra-low-dose schemes. This strategy could significantly increase dasatinib accessibility in many countries by reducing costs from $1,343.7 to $40.3-$100.8 monthly

Lysozyme-Associated Nephropathy Successfully Treated with Dasatinib in Chronic Myeloid Leukemia

Lysozyme-Associated Nephropathy Successfully Treated with Dasatinib in Chronic Myeloid Leukemia

Despite warnings, co-medication with proton pump inhibitors and dasatinib is common in chronic myeloid leukemia, but XS004, a novel oral dasatinib formulation, provides reduced pH-dependence, minimizing undesirable drug-drug interactions.

Dasatinib and other tyrosine kinase inhibitors (TKI) have revolutionized the treatment of chronic myeloid leukemia (CML). However, as a lipophilic weak base, crystalline monohydrate, dasatinib (Sprycel®) is poorly soluble, rendering a pH-dependent absorption and a highly variable bioavailability. Thus, co-medication with proton pump inhibitors (PPI) profoundly impairs dasatinib uptake and is clearly recommended against. XS004 is a novel oral immediate release and amorphous solid dispersion (ASD) formulation of dasatinib and is bioequivalent to the original crystalline dasatinib at 30% lower dosages. XS004 is designed to mitigate gastric pH dependency, thus optimizing absorption and bioavailability. We investigated the prevalence of dasatinib and PPI co-medication among chronic-phase CML patients in a real-world setting and assessed the plasma pharmacokinetics (PK) of XS004 with and without PPI co-medication (omeprazole) in healthy volunteers. Using the Swedish CML and Prescribed Drug Registers, we identified 676 TKI-treated CML patients; 320 (47%) had been prescribed PPI at some point after CML diagnosis. Among dasatinib-treated patients, the 2-year cumulative PPI co-medication was 24%. Interestingly, the 5-year overall survival was significantly lower for TKI-treated CML patients with versus without PPI co-medication (79% vs. 94%; hazard ratio 3.5; 95% confidence interval, 2.1-5.3; p < .0001). When assessing PK of XS004, neither Cmax nor area under the plasma concentration curve levels in plasma were significantly altered by the PPI co-medication. In conclusion, despite warnings, PPI co-medication is common among dasatinib-treated CML patients in a real-world setting. The new XS004 ASD formulation of dasatinib provided, in contrast to original crystalline dasatinib, superior pH independence with stable bioavailability, thereby minimizing drug-drug interactions. This may improve the long-term efficacy and tolerability of dasatinib in CML.

An Analysis of Dasatinib Treatment Patterns in Patients with Chronic Myeloid Leukemia after Experiencing Pleural Effusion during Dasatinib Therapy

Introduction: Treatment with dasatinib for chronic myeloid leukemia (CML) has been associated with development of pleural effusion; however, data regarding its optimal management are limited. We examined treatment patterns and healthcare resource utilization (HCRU) and costs among patients with CML treated with dasatinib who experienced a subsequent pleural effusion. Methods: Adults with CML and ≥1 pharmacy claim for dasatinib in 2015–2018 who experienced pleural effusion after dasatinib were identified using data from claims databases. Results: Overall, 123 patients were eligible. After 1 year, of the 38.2% of patients with a dose modification, 72.3% did not switch treatment; among these patients, 70.6% continued treatment. Among patients with a stable dose after pleural effusion (61.8%), 57.9% later switched to another TKI. The mean (SD) duration of dasatinib treatment after pleural effusion was 262.0 (124.0) days for patients with a dose modification versus 149.1 (155.2) days for those with a stable dose (p < 0.001). HCRU and costs were similar between groups. Conclusion: Dasatinib dose modification after pleural effusion was not always required; however, patients with dose modifications continued therapy for a longer duration with a lower rate of switching to another TKI versus patients who remained on a stable dose.

Adverse reactions after treatment with dasatinib in chronic myeloid leukemia: Characteristics, potential mechanisms, and clinical management strategies.

Dasatinib, a second-generation tyrosine kinase inhibitor, is recommended as first-line treatment for patients newly diagnosed with chronic myeloid leukemia (CML) and second-line treatment for those who are resistant or intolerant to therapy with imatinib. Dasatinib is superior to imatinib in terms of clinical response; however, the potential pulmonary toxicities associated with dasatinib, such as pulmonary arterial hypertension and pleural effusion, may limit its clinical use. Appropriate management of dasatinib-related severe events is important for improving the quality of life and prognosis of patients with CML. This review summarizes current knowledge regarding the characteristics, potential mechanisms, and clinical management of adverse reactions occurring after treatment of CML with dasatinib.

Differential inhibition of T-cell receptor and STAT5 signaling pathways determines the immunomodulatory effects of dasatinib in chronic phase chronic myeloid leukemia.

Dasatinib is a multi-kinase inhibitor with activity against the SRC kinase LCK, which plays a critical role in T-cell receptor signaling. Dasatinib, initially developed as an immunosuppressive agent, is by contrast, also noted to result in enhanced tumor immunity in a subset of patients. We studied the impact of dasatinib in chronic myeloid leukemia patients and compared it with patients taking other tyrosine kinase inhibitors (TKI) and healthy controls. We found that patients on dasatinib showed inhibition of both T-cell receptor (TCR) and STAT5 signaling pathways, and reduced expression of Teffector pro-inflammatory cytokines. In addition, dasatinib induced selective depletion of regulatory T cells (Tregs) and effector Tregs, particularly in patients with clonal expansion of effector CD8+ T cells, who demonstrated greater and preferential inhibition of Treg TCR intracellular signaling. In addition, we show that dasatinib selectively reduces Treg STAT5 phosphorylation via reduction of IL-2, in relation with the marked reduction of plasma IL-2 levels in patients taking dasatinib. Finally, patients on other TKI had significantly increased TCR signaling in TIM3+ cells compared to patients taking dasatinib, suggesting that chronic SRC kinase inhibition by dasatinib may play a role in preventing TIM-3-mediated T-cell exhaustion and preserve anti-tumor immunity. These data provide further insight into the selective immunomodulatory effects of dasatinib and its potential use for pharmacologic control of immunotherapies.

Comedication of Proton Pump Inhibitors and Dasatinib Is Common in CML but XS004, a Novel Amorphous Solid Dispersion Formulation of Dasatinib, Provides Improved Uptake and Low pH-Dependency, Minimizing Unwanted Drug-Drug Interactions

Dasatinib (Sprycel®), together with other tyrosine kinase inhibitors (TKI), has profoundly improved the prognosis of patients with chronic myeloid leukemia (CML). However, as a lipophilic, poorly soluble, weakly basic, orally applied drug, the bioavailability of dasatinib is highly pH-dependent, with significantly reduced plasma concentrations at higher gastric pH. Comedication with proton pump inhibitors (PPI) such as omeprazole, thus provides a clinical challenge, decreasing dasatinib plasma exposure by more than 40%. Consequently, dasatinib and PPI comedication is cautioned against by the FDA (US). Here we studied TKI-PPI comedication by investigating the prevalence and outcome of such treatments in CML patients in a real-world setting and by assessing the influence of PPI-comedication on the plasma pharmacokinetics of XS004-dasatinib (XS004, Xspray Pharma, Solna, Sweden), a novel immediate release and amorphous solid dispersion (ASD) formulation of dasatinib. Using the Swedish CML- and Prescribed Drug-Registries we identified 722 chronic phase CML-patients, of which 676 (93.6%) had received TKI treatment. We observed that 302 (45%) of these had also been prescribed PPI at some point after CML diagnosis. Among patients given dasatinib, the two-year cumulative prescribed comedication with PPI was 24%. With longer follow-up and given the fact that unprescribed but difficult to quantify over-the-counter usage of PPI is common in Sweden, the proportion of patients with such comedication is likely to be considerably larger. Interestingly, the estimated 5-year survival was lower for TKI-treated CML patients with vs. without PPI comedication (79% vs. 94%; total 5-years survival of TKI-treated CML patients: 88%). This corresponds to a significantly increased crude hazard ratio (HR) of death of 3.5 (95% CI, 2.1-5.3, p<0.0001) and a HR of 3.1 (95% CI, 2.0-4.7, p<0.0001) after adjusting for age, sex, year of diagnosis, and comorbidity index. Further, we assessed the pharmacokinetics of XS004, given alone or together with omeprazole, to sixteen healthy volunteers in a cross-over study design. XS004 is produced with the NyNap™ technology allowing for an ASD-formulation of dasatinib and is designed to increase solubility of the active drug substance in slightly acidic to neutral gastrointestinal pH conditions, thereby reducing gastric pH dependency and promoting optimized absorption and bioavailability of the drug. XS004 has demonstrated improved bioavailability and reduced intra- and inter-individual variability when compared to the original, non-ASD formulated dasatinib (Sprycel®). As shown in Table 1, describing plasma pharmacokinetics of XS004 administered as a single drug or together with omeprazole, neither Cmax nor plasma AUC values of XS004 were significantly altered by the PPI comedication. This contrasts with previous studies describing clear reductions of non-ASD formulated dasatinib plasma AUC after comedication with PPI. We conclude that, despite warnings, co-medication with PPI is common among dasatinib-treated CML patients in a real-world setting. Our data suggest that PPI-comedication to TKI can negatively influence the survival of CML patients, although covariant factors may be present. The plasma pharmacokinetics of XS004 dasatinib was, in contrast to the original non-ASD, pH-sensitive dasatinib formulation, not significantly affected by comedication with omeprazole. In the clinic, with its low pH-dependency and augmented intestinal absorption, XS004 dasatinib can provide an improved option for safely administering the often-needed comedication with PPIs, potentially improving long-term efficacy and tolerability of dasatinib in CML. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of genetic polymorphisms of drug transporters ABCB1 and ABCG2 and regulators of xenobiotic transport and metabolism PXR and CAR on clinical efficacy of dasatinib in chronic myeloid leukemia.

IntroductionFunctional single-nucleotide polymorphisms (SNPs) in genes regulating cellular uptake, elimination, and metabolism of xenobiotics may potentially influence the outcome of chronic myeloid leukemia (CML) patients treated with BCR-ABL1 tyrosine kinase inhibitors (TKI). Dasatinib, a second-generation TKI, is a substrate of the ABC-superfamily xenobiotic transporters ABCB1 (MDR1, Pg-P) and ABCG2 (BCRP). Pregnane X receptor (PXR, NR1I2) and constitutive androstane receptor (CAR, NR1I3) are involved in the control of expression of ABCB1 and ABCG2. Aim of the studyIn this study, we assessed the impact of inherited variants in ABCB1, ABCG2, PXR, and CAR genes on dasatinib efficacy and toxicity in CML.Materials and methodsSixty-one tagging SNPs in ABCB1, ABCG2, PXR, and CAR genes were analyzed by real-time quantitative PCR with specific probes in 86 CML patients who failed imatinib therapy.ResultsWe found the associations between SNPs rs7787082 (ABCB1, OR = 0.2; 95% CI = 0.06-0.66, p = 0.008), rs12505410 (ABCG2, OR = 3.82; 95% CI = 1.38-10.55; p = 0.010), and rs3114018 (ABCG2, OR = 0.24; 95% CI = 0.08-0.71; p = 0.010) and the probability of achieving CCyR. Furthermore, progression-free survival (PFS) was significantly influenced by SNPs rs3732357 (HR = 0.2, 95% CI = 0.26-0.70; p = 0.001), rs3732360 (HR = 0.59; 95% CI = 0.38-0.93; p = 0.020), rs11917714 (HR = 0.58; 95% CI = 0.36-0.92; p = 0.020), and rs3732359 (HR = 0.57; 95% CI = 0.36-0.91; p = 0.024) in PXR; rs2307418 (HR = 2.02; 95% CI = 1.19-3.43; p = 0.048) in CAR; and rs2235023 (HR = 2.49; 95% CI = 1.13-5.50; p = 0.011) and rs22114102 (HR = 1.90; 95% CI = 1.00-3.63; p = 0.028) in ABCB1. Moreover, overall survival (OS) was impacted by rs3842 (HR = 1.84; 95% CI = 1.01-3.33; p = 0.012) and rs2235023 (HR = 2.28; 95% CI = 1.03 = 5.02; p = 0.027) in ABCB1, rs11265571 (HR = 1.59; 95% CI = 0.82-3.08; p = 0.037) and rs2307418 (HR = 73.68; 95% CI = 4.47-1215.31; p = 0.003) in CAR, and rs3732360 (HR = 0.64; 95% CI = 0.40 = 1.04; p = 0.049) in PXR. Taking into account the influence of the tested SNPs on treatment toxicity, we found a significant relationship between allele G of polymorphism in the ABCB1 rs7787082 (OR = 4.46; 95% CI = 1.38-14.39 p = 0.012) and hematological complications assuming the codominant gene inheritance model as well as a significant correlation between the presence of minor allele (G) of SNP rs2725256 in the ABCG2 gene (OR = 4.71; 95% CI = 1.20-18.47; p = 0.026) and the occurrence of non-hematological complications assuming a recessive gene inheritance model.ConclusionOur data suggest that inherited variants in the genes encoding for proteins involved in the transport of xenobiotics may modify the toxicity and efficacy of dasatinib therapy in CML patients.

Low dose of Dasatinib in chronic myeloid leukemia

The oncoprotein BCR-ABL1 helps with the diagnosis and monitoring the therapeutic response in patients with chronic myeloid leukemia. We describe the case of a 70-year-old woman with chronic myeloid leukemia who did not achieve a molecular response after 12 months of treatment. She was then managed with Dasatinib 70 mg orally twice a day until she reached a complete molecular response. She developed pulmonary toxicity probably due to Dasatinib. The dosage was decreased to 70 mg orally once a day. The patient continues with a complete molecular response with less side effects. In chronic myeloid leukemia, as far as we know, there are no previous reports, after a molecular response with Dasatinib 70 mg twice a day, the maintenance of a good molecular control with a single daily dose. This dose may allow a reduction in toxicity with a better quality of life for patients with chronic myeloid leukemia

Dasatinib-Induced Chylothorax in Chronic Myeloid Leukemia

Pulmonary adverse events are common abnormalities associated with the use of dasatinib in chronic myeloid leukemia. We present a case of a 69-year-old man who suddenly developed a rare chylothorax pulmonary adverse event following 10 months of dasatinib treatment.

Retrospektywna analiza skuteczności nilotynibu i dazatynibu w drugiej linii terapii przewlekłej białaczki szpikowej w polskich ośrodkach hematologicznych

Until now, there has been no randomized study directly comparing the activity of second-generation BCR-ABL tyrosine kinase inhibitors (TKI-2G) nilotinib and dasatinib in chronic myeloid leukemia (CML). The aim of our study was to retrospectively analyze efficacy of nilotinib and dasatinib in the real life setting of CML with resistance or intolerance of imatinib. Of 108 included patients treated in polish hematology centers, 75 received dasatinib and 33 patients received nilotinib. Rates of complete cytogenetic response (CCyR) did not differ between the two groups of patients. After six months of therapy, CCyR was achieved in 34.7% of patients treated with dasatinib and 38.7% treated with nilotinib (p=0.86), while after 12 months, the CCyR rates were 60.0% and 77.0% in dasatinib and nilotinib groups, respectively (p=0.11). Moreover, we have not observed any significant difference in the probability of progression-free survival (p=0.89) or overall survival (p=0.99) between patients treated with these two TKI-2G. In conclusion, the results of our analysis indicate that nilotinib and dasatinib have comparable and satisfactory efficacy in the treatment of CML patients refractory or intolerant to imatinib. Our findings support current strategy of choice of IKT-2G according to drug toxicity profile and risk of specific adverse events in an individual patient.

The Effect of Adherence-Encouraging Interventions on Adherence to Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia (TAKE-IT): A Pre-Post Intervention Pilot Study

Introduction: Medication non-adherence (MNA) to tyrosine kinase inhibitors TKIs occurs in around 30% of chronic myeloid leukemia (CML) patients and is associated with adverse outcomes (Noens, 2009; Marin, 2010). Data on adherence-enhancing interventions (AEIs) in CML are scarce and an improvement in dose implementation has yet to be shown.Objective: To evaluate the efficacy of a multilevel AEI in improving MNA to TKIs in CML.Methods: We initiated a prospective multicenter (N=4) pre-post adherence intervention pilot study in CML (NCT01768689). Patients were eligible if they had received at least 3 months of imatinib, nilotinib or dasatinib for CML, irrespective of treatment line or subsequent duration. TKI adherence was assessed for 7.5 months using electronic monitoring (EM) with MEMS (Medical Events Monitoring System 6) and BAASIS. The MEMS bottle cap contains a micro-electronic circuit that registers dates and times of cap opening. The BAASIS is a 4-item patient reported outcome used to assess adherence in solid organ transplants and CML (Cleemput, 2007; Noens, 2009).We designed an investigational AEI to address known barriers to TKI adherence in CML (Figures 1 & 2), using components with proven efficacy in improving MNA in chronic diseases. The key elements were: behavioral change techniques (BCT); motivational interviewing (MI; Figure 2); and multilevel including patient (Figure 1), peer group and health care provider levels (not shown). The BCT taxonomy developed by Michie et al (Ann Behav Med, 2013) was used in Figures 1 & 2 to describe the intervention and to facilitate its reproducibility.During the first 4.5 months of adherence monitoring, MNA was managed as per local practice. The intervention phase was then initiated (Figure 1) and adherence measured for a further 3 months. The pre and post-intervention periods were defined as the 3 months before and after the initiation of the AEI, respectively. The primary outcome measure was EM adherence using MEMS, and primary analysis was the comparison between pre and post-intervention adherence, expressed as the percentage of days with drug taken as prescribed. Generalized Estimating Equation model was used to adjust for correlation between adherence levels pre and post intervention, measured in the same patient. We also explored the association between adherence according to BAASIS (at 3 different time-points during the pre/post intervention periods) and the corresponding 1-month periods of EM adherence.Results: Between 10/2013 and 7/2014, we enrolled 55 CML patients (median age, 60.5 years; median current TKI duration, 34 months) receiving imatinib (59%), nilotinib (18%) or dasatinib (23%).Median pre-intervention EM adherence was 97.5% (min 48%; 10th percentile: 82.6%; 25th: 92.1%; 75th: 99.3%; 90th: 100%; max 100%) and the mean was 93%. Non-membership in a CML patients group (51%), living alone (18%) and 3rd line treatment (9%) were each risk factors for pre-intervention MNA on multivariate analysis, whereby mean adherence was 7% (p<0.01), 10.2% (p=0.03) and 13.9% (p=0.01) lower than patients without each of these risk factors, respectively. The estimated mean adherence was near perfect (99.7%) with none of the above risk factors (N=21; 38%).The AEI affected a 1.45% improvement in adherence for the whole cohort (95% CI: 0.09-2.8%, p=0.04). The AEI led to an improvement of 2.51% in the non-members of a CML patient group (95% CI: 0.2-4.8%, p=0.03) relative to 0.25% (p=0.71) in the members. By extrapolation, this corresponds to an additional 5.3 days of correct intakes over 1 year for the whole cohort, and 9.5 days for non-members of a CML patient group. Using an exploratory cut-off of EM adherence ≥ 95% as adherent, the BAASIS (N=132) correctly classified 75.5% (74/98) as adherent and 73% (25/34) as non-adherent.Conclusion: The effect of the AEI is modest but statistically significant, and higher in non-members of a CML patients group. At the same time, this study shows the futility and potential resource wasting of trying to improve adherence in the large group of near-perfect adherers without risk factors. Our pilot study provides proof of concept that EM adherence may be improved in CML patients by a multilevel AEI, and that the magnitude of improvement is higher in subgroups at risk. These subgroups should be identified, if possible, by combining patient characteristics with the BAASIS. [Display omitted] [Display omitted] DisclosuresLeader:Novartis: Research Funding. Sharf:Pfizer: Honoraria; BMS: Honoraria, Research Funding; Gilead: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria, Research Funding. Tousset:MWV Healthcare: Employment. Ellis:Novartis: Other: Advisory Board; Pfizer: Other: Advisory Board. Raanani:BMS: Other: Advisory Board; Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board, Research Funding; Ariad: Other: Advisory Board.

Reversible skin and hair depigmentation during chemotherapy with dasatinib for chronic myeloid leukemia

Reversible skin and hair depigmentation during chemotherapy with dasatinib for chronic myeloid leukemia

Reversible Pulmonary Arterial Hypertension Associated with Dasatinib for Chronic Myeloid Leukemia

We describe two cases of pulmonary arterial hypertension (PAH) that occurred under dasatinib treatment and were resolved after dasatinib discontinuation. Two patients with chronic phase chronic myeloid leukemia (CML) were switched to dasatinib therapy because of hematological progress while receiving imatinib. These patients had New York Heart Association (NYHA) functional class II dyspnea with elevated right ventricular systolic pressure (RVSP), which progressed under dasatinib treatment. After dasatinib treatment was discontinued, subjective symptoms were improved to NYHA functional class I and the follow-up transthoracic Doppler echocardiography showed improved RVSP. Treatment with an alternate tyrosine kinase inhibitor was initiated and had been continued without development of dyspnea or elevation of RVSP. This report suggests that dasatinib can cause the reversible PAH, therefore, routine cardiopulmonary evaluation before and during treatment with dasatinib may be needed in CML patients with clinical manifestations.

Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity

Treatment with the tyrosine kinase inhibitor (TKI) imatinib for chronic myeloid leukemia in chronic phase (CML-CP) of disease may cause severe hepatotoxicity in rare cases. However, it remains unclear (1) how imatinib-induced hepatotoxicity should be treated; and (2) if and how TKI treatment can be resumed after recovery. We report a 32-year-old woman with CML-CP and histology confirmed imatinib-induced liver toxicity after 6 months of treatment. In this case, the early administration of corticosteroid therapy resulted in rapid and complete hepatic recovery, and treatment for CML-CP with the second generation TKI dasatinib was continued safely after recovery. Thus, dasatinib represents an option for maintaining therapeutic response in patients in whom continuation of imatinib is not possible due to its hepatic toxicity.

Differential effects of dosing regimen on the safety and efficacy of dasatinib: retrospective exposure-response analysis of a Phase III study.

PurposeDasatinib is a prototypic short half-life BCR-ABL1 tyrosine kinase inhibitor. The recommended dose of dasatinib for chronic myeloid leukemia in chronic phase was changed from 70 mg twice daily to 100 mg once daily following a Phase III dose-optimization study. To better understand the superior benefit–risk profile of dasatinib 100 mg once daily, exposure–response was characterized for efficacy (major cytogenetic response) and safety (pleural effusion).Patients and methodsDasatinib exposure in patients with chronic myeloid leukemia in chronic phase was determined by population pharmacokinetic analysis of data from seven dasatinib clinical studies (N = 981), including the Phase III dose-optimization study (n = 567). Data from the Phase III study were then used to characterize exposure–response relationships for the four dasatinib treatment regimens investigated (100 mg once daily, 50 mg twice daily, 140 mg once daily, and 70 mg twice daily).ResultsMajor cytogenetic response was significantly (P < 0.01) associated with weighted average steady-state dasatinib plasma concentrations, and pleural effusion was significantly associated with trough concentration. Major cytogenetic response was also significantly associated with maintenance of uninterrupted dosing. The 100 mg once daily arm had the lowest steady-state trough concentration of the four dose arms investigated in the Phase III study, and although this arm also had the lowest weighted average steady-state dasatinib plasma concentration, it had the highest dose maintenance.ConclusionDasatinib dose optimization to 100 mg once daily from 70 mg twice daily significantly minimizes adverse events while maintaining efficacy by exploiting differences in the measures of exposure associated with efficacy and safety.

Systematic review of dasatinib in chronic myeloid leukemia

Dasatinib is a dual tyrosine kinase inhibitor active against ABL and Src family kinases, and is approved for the treatment of chronic myeloid leukemia (CML) patients in chronic, accelerated, or blast phase with resistance or intolerance to imatinib therapy, for newly diagnosed chronic phase patients, and for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia who have become resistant to or intolerant of other treatments. This review presents clinical data regarding different trials involving CML patients in different phases of the disease. Six-year follow-up of the Phase III dose-optimization study are described, showing overall survival of 71% with the current approved dose of 100 mg once daily. Three-year results of the randomized Phase III DASISION (DASatinib vs Imatinib Study In Treatment-Naïve CML patients) trial confirmed that dasatinib 100 mg once daily was superior to standard-dose imatinib in terms of achieving a faster and deeper molecular response, with similar activity regardless of baseline prognostic score.

BCR/ABL Transcript At 3 Months Predicts Long-Term Outcomes Following Second Generation Tyrosine Kinase Inhibitor Therapy in the Patients with CML in Chronic Phase Who Failed Imatinib.

AbstractAbstract 2777 Background:The BCR/ABL transcript level at 3 months can predict long-term outcomes following frontline therapy with Imatinib or Dasatinib in chronic myeloid leukemia (CML) patients. However, data is lacking with second generation tyrosine kinase inhibitor (2GTKI) therapy after Imatinib failure. Methods:A total of 112 patients with CML in chronic phase (CP) receiving 2GTKI after Imatinib failure were reviewed. Treatment outcomes including complete cytogenetic (CCyR), major molecular (MMR) and molecular response 4.5 (MR4.5), treatment failure, progression-free (PFS) and overall survival (OS) were compared according to BCR/ABL transcript levels at 3 or 6 months, divided into <1%IS, 1–10%IS and °Ã10%IS. Results:Using cut off of 1%IS and 10%IS BCR/ABL transcript level, 70 patients (65%) showed <1%IS of BCR/ABL transcript level at 3 months, 16 patients (15%) between 1 and 10%IS, and 21 patients (20%), °Ã10%IS at 3 months. BCR/ABL transcript level at 3 months showed better correlation with OS (p<0.001) than that at 6 months (p=0.147). Better OS was also observed in the patients achieving <1%IS (100%) and 1–10%IS (100%) than those with °Ã10%IS at 3 months (70.6%, p<0.001). Those with <1%IS exhibited the best CCyR (100% at 12 months), MMR (93.1±3.2% at 18 months) and MR4.5 (80.2±6.3% at 3 years); those with 1–10%IS, intermediate (56.4±15.5% CCyR at 12 months; 22.1±14.1% MMR at 18 months; 10.0±9.5% MR4.5 at 3 years); and those with °Ã10%IS, the lowest CCyR (16.7±11.2% at 12 months), MMR (6.2±6.1% at 18 months) and MR4.5 rates (0%). Especially, in the subgroup of Imatinib resistant patients (n=59), none of them achieved MR4.5 if BCR/ABL transcript level is above 1% at 3 months (i.e. those with 1–10%IS or °Ã10%IS). Multivariate analysis confirmed strong correlation of BCR/ABL transcript level at 3 months with CCyR (HR 0.019), MMR (HR 0.047), MR4.5 (HR 0.057), treatment failure (HR 12.264), PFS (HR 7.754) and OS (HR 15.115). The group with <1%IS at 3 months maintained significantly lower BCR/ABL transcript level compared to other 2 groups. Conclusion:The BCR/ABL transcript level at 3 months is the most relevant surrogate for outcomes following 2GTKI therapy after Imatinib failure. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Analysis of Dasatinib-Induced Molecular Mechanisms of Apoptosis in Hypoxia-Adopted CML Cells Utilizing Quantitative Proteomics Technology.

AbstractAbstract 2773Development of the second-generation ABL tyrosine kinase inhibitor (TKI) dasatinib in CML aimed at overcoming resistance to imatinib, to eliminate persistent residual disease and thus prevent recurrence of active leukemia after TKI discontinuation in chronic myeloid leukemia (CML). Hypoxia has recently been reported as an essential component of the leukemia BM microenvironment that promotes leukemia cell homing, survival and chemoresistance (Benito et al, PlosOne 2011). In this study, we investigated the anti-CML efficacy and molecular mechanisms of action of dasatinib under hypoxic conditions.We developed a hypoxia-adopted subclone of the KBM5 CML cell line (KMB5-HA), which was selected under 1.0% oxygen conditions, and an imatinib-resistant KBM5 subline bearing the T315I mutation (KBM5-T315I). KBM5-HA cells cultured under hypoxia accumulated in G0/G1 and exhibited moderate spontaneous apoptosis compared to KBM5 parental cells in normoxia (sub G1 %: KBM5 3.8±0.8, KBM5-HA 8.7±0.9; p=0.01; proportion of cells in G0/G1: KBM5 36.5±1.1%, KBM5-HA 52.4±6.6%; p=0.02, PI analysis). These cells displayed higher sensitivity to dasatinib than parental KBM cells (IC50; 1.3 nM for KBM5, 0.3 nM for KBM5-HA, at 48hrs by MTT). Low-dose dasatinib (0.5nM) which failed to cause inhibition of proliferation in parental KBM5 cells, caused significant apoptosis induction with cell cycle arrest in KBM-HA cells (sub G1 %: control 8.7±0.9, datatinib 49.1±16.9; p=0.02, G0/G1 %: control 52.4±6.4%, dasatinib 74.1±3.5%; p=0.01). In KBM5-T315I cells, dasatinib induced more prominent cell growth inhibition under hypoxia compared to normoxia (IC50 at 48hrs: normoxia 16.2 nM, hypoxia 3.7 nM). Treatment with 5nM dasatinib, which did not affect KBM5-T315I cell growth under normoxia, induced significant apoptotic effects under hypoxia (sub G1 %: control 6.9±0.9, dasatinib 20.3±3.3; p=0.05, G0/G1 %: control 57.3±5.8, dasatinib 67.4±8.9; p=0.41).We next investigated dasatinib-induced changes of Stat-5 and ERK activation in CML cells by immunoblotting Treatment with 0.5 nM dasatinib resulted in marked down-regulation of phosphorylated (p-) Stat-5 and p-ERK in both, KBM5 and KBM5-T315I cells. In KBM5-HA cells, however, no baseline expression of p-Stat-5 or p-ERK was detected. These results suggest that in KBM5-HA cells dasatinib induces apoptosis and cell cycle arrest via Stat-5 or ERK-independent pathways. To investigate the candidate signaling factors responsible for dasatinib effects on KBM-HA, we performed the proteomic analysis utilizing proteomic technology of isobaric tags for relative and absolute quantitation (iTRAQ, Applied Biosystems) coupled with two-dimensional-liquid chromatography-tandem mass spectrometry. A total of 1,234 proteins were detected, and 296 proteins were found to be significantly up-regulated in response to dasatinib treatment in KBM5-HA cells. Among the up-regulated proteins, we found 39 proteins involved in apoptosis induction including Cytochrome C and Cytochrome C oxydase subunits (p<0.001). Mass spectrometry further revealed the up-regulation of apoptosis related mitochondrial chaperones HSP10 and HSP60 (p<0.001), suggesting a role of HSP60/HSP10 in mitochondrial membrane permeabilization.In summary, these findings unravel novel mechanisms of action of dasatinib under conditions mimicking the hypoxic BM microenvironment via induction of Cytochrome C oxydase and mitochondrial chaperones HSP10 and HSP60, which lead to loss of mitochondrial transmembrane potential and release of apoptogenic Cytochrome C in CML cells. Disclosures:Tabe:Bristol-Myers Squibb: Research Funding.

The quantitative level of T315I mutated BCR-ABL predicts for major molecular response to second-line nilotinib or dasatinib treatment in patients with chronic myeloid leukemia

The BCR-ABL T315I mutation causes resistance to imatinib, nilotinib and dasatinib in chronic myeloid leukemia. Forty BCR-ABL positive patients with imatinib resistance were analyzed for T315I mutated clones after six months on nilotinib or dasatinib treatment by quantitative allele-specific ligation polymerase chain reaction with a sensitivity of 0.05%. Ligation polymerase chain reaction revealed 10 patients with more than 10(-5) BCR-ABL(T315I%)/GUS (high levels), none of whom achieved major molecular response after 12 months, and a further 8 patients with 10(-5) or below BCR-ABL(T315I%)/GUS (low levels) who all achieved major molecular response (P<0.001). A second independent group showed molecular response in one of 12 patients with high levels and 5 of 8 patients with low levels (P=0.018). Combining the groups resulted in a sensitivity and specificity of 92.9% and 87.5%, respectively. We conclude that the quantitative level of mutant T315I allele is predictive of major molecular response at 12 months on second-line nilotinib or dasatinib treatment. www.clinicaltrials.gov: CT00109707, NCT00384228, CA180013, CA180005 CA180006.