Imatinib-resistant Chronic Myeloid Leukemia Research Articles

A novel small molecule RAD51 inactivator overcomes imatinib‐resistance in chronic myeloid leukaemia

RAD51 recombinase activity plays a critical role for cancer cell proliferation and survival, and often contributes to drug-resistance. Abnormally elevated RAD51 function and hyperactive homologous recombination (HR) rates have been found in a panel of cancers, including breast cancer and chronic myeloid leukaemia (CML). Directly targeting RAD51 and attenuating the deregulated RAD51 activity has therefore been proposed as an alternative and supplementary strategy for cancer treatment. Here we show that a newly identified small molecule, IBR2, disrupts RAD51 multimerization, accelerates proteasome-mediated RAD51 protein degradation, reduces ionizing radiation-induced RAD51 foci formation, impairs HR, inhibits cancer cell growth and induces apoptosis. In a murine imatinib-resistant CML model bearing the T315I Bcr-abl mutation, IBR2, but not imatinib, significantly prolonged animal survival. Moreover, IBR2 effectively inhibits the proliferation of CD34+ progenitor cells from CML patients resistant to known BCR-ABL inhibitors. Therefore, small molecule inhibitors of RAD51 may suggest a novel class of broad-spectrum therapeutics for difficult-to-treat cancers.

5′-OH-5-nitro-Indirubin oxime (AGM130), an Indirubin derivative, induces apoptosis of Imatinib-resistant chronic myeloid leukemia cells

Imatinib is a highly effective drug for the treatment of chronic myeloid leukemia (CML) that targets the BCR–ABL kinase. However, a number of patients have CML that is resistant to Imatinib treatment. In this report, we developed AGM130 as a potential therapeutic drug for Imatinib-resistant CML treatment. The AGM130 compound is derived from Indirubin, which is an ingredient of Danggui Longhui Wan and known as a cyclin-dependent kinase (CDK) inhibitor. The water solubility of AGM130 is more enhanced than that of the original form of Indirubin, which has very poor water solubility. Our data showed that the AGM130 compound efficiently decreased the viability of CML-derived K562 cells. Moreover, this compound also efficiently decreased the viability of Imatinib-resistant K562 cells in in vitro and in vivo systems. In addition, like Indirubin, AGM130 also inhibited phosphorylation of retinoblastoma protein (Rb), which is a major substrate of CDK. Conclusively, our data suggest that AGM130 is a strong candidate for treating Imatinib-resistant CML.

Sustained remission with allogeneic peripheral blood stem cell transplantation and subsequent maintenance therapy with dasatinib in a patient with myeloblastic crisis of imatinib-resistant CML

Sustained remission with allogeneic peripheral blood stem cell transplantation and subsequent maintenance therapy with dasatinib in a patient with myeloblastic crisis of imatinib-resistant CML

Dihydroartemisinin inhibits the Bcr/Abl oncogene at the mRNA level in chronic myeloid leukemia sensitive or resistant to imatinib

Due to the mutations of the Bcr/Abl oncogene that obstacle the binding of the protein with imatinib, the resistance to imatinib has developed in a significant portion of chronic myeloid leukemia (CML) patients. It stimulated the search for novel molecules for treatment of imatinib-resistance CML. Inhibiting the amplification of Bcr/Abl oncogene is believed to be a new effective strategy to override the imatinib resistance on CML cells. In present research, we demonstrated that dihydroartemisinin (DHA), a safe and effective antimalarial analog of artemisinin, could significantly inhibit the Bcr/Abl fusion gene at the mRNA level in CML cells sensitive or resistant to imatinib (including the primary CML cells with T315I mutation) and induce cell death. Moreover, dihydroartemisinin could also lead to the inhibition of the Bcr/Abl protein expression and tyrosine kinase activity, and strongly suppress on the downstream signals of Bcr/Abl, which included inhibition of tyrosine kinase activity of AKT and ERK, promotion of cytochrome c release from the mitochondria and the consequential activation of caspase-9/3 in imatinib-resistant CML cells. These results suggest for the first time that Dihydroartemisinin might be a potential novel drug candidate for treatment of imatinib-resistant CML and worthy of further study.

Multicenter Phase II Clinical Trial of Nilotinib for Patients with Imatinib-Resistant or Intolerant CML From the East Japan CML Study Group (EJCML) Trial: Evaluation of Molecular Responses by the BCR-ABL1 Mutational Status and Plasma Trough Concentration of Nilotinib

AbstractAbstract 1360 Introduction:The tyrosine kinase inhibitor (TKI) imatinib is used as the first-line therapy for newly diagnosed chronic myeloid leukemia (CML). However, some patients fail to respond or become intolerant to imatinib. Nilotinib is a second-generation TKI with higher selectivity and more potent inhibitory effects on BCR-ABL than imatinib. Several studies have shown hematologic and cytogenetic responses to nilotinib in patients with imatinib-resistant or intolerant CML. Purpose:To investigate the safety and efficacy of nilotinib for patients with imatinib-resistant or intolerant, chronic (CP)- or accelerated (AP)-phase CML from the East Japan CML Study Group (EJCML) trial by evaluating molecular responses in terms of the BCR-ABL1 mutational status and plasma trough concentration of nilotinib. Methods:In this multicenter phase II clinical trial, nilotinib (400 mg bid) was administered orally for one year and the molecular responses were monitored by means of the international scale of quantitative PCR (IS-PCR). BCR-ABL1 mutations were analyzed by direct sequencing at the baseline and 12 months or at the time of the event for discontinuation of the treatment (i.e., progressive disease, insufficient effects, or severe adverse events). The plasma trough concentration of nilotinib was measured by high-performance liquid chromatography 3 months after nilotinib administration. Results:From March 2009 through February 2011, 51 patients were registered in this study, and data of 49 patients whose molecular responses were evaluated by the IS-PCR were analyzed (imatinib-resistant CML = 33, imatinib-intolerant CML = 16; CP CML = 46, AP CML = 3). The median follow-up period was 12.0 months (range = 0.1–13.3 months). At 6 and 12 months, the major molecular response (MMR; ≤0.1% IS) rates were 52.5% and 67.6%, respectively, and the complete cytogenetic response (CCyR)-equivalent (≤1.0% IS) rates were 75.0% and 85.3%, respectively. Five types of BCR-ABL1 mutations (M244V, F317L, N358D, F359V, and E459K) were detected in 6 patients (12.2%) at the baseline, but the M244V, N358D, and E459K mutations disappeared after the nilotinib treatment. Acquired BCR-ABL1 mutations (Y253H, I418V, and exon 8/9 35bp insertion) were detected in 3 patients (8.6%) at 12 months or at the time of the event; these patients did not achieve a CCyR or an MMR. No patients showed an acquired mutation of T315I. Most patients except 11 subjects (22.4%) still received the treatment. The reasons for discontinuation were progressive disease in one patient with an F317L mutation, insufficient effects in one patient without any mutation, and adverse events in 9 patients (thrombocytopenia in 5 patients, hyperbilirubinemia in 2 patients, headache in one patient, and heart disease in one patient). Among 30 patients without BCR-ABL1 mutations, the plasma trough concentration of nilotinib was significantly higher in 21 patients with an MMR than in those without an MMR by 12 months (median = 1255.1 ng/mL vs. 372.8 ng/mL, P = 0.0012 by Mann–Whitney U-test; see the figure). The concentration of 761 ng/mL was significantly associated with an MMR by 12 months in a receiver-operating characteristic (ROC) curve analysis of the best sensitivity (76.2%) and specificity (77.8%). Conclusion:The patients with imatinib-resistant or intolerant, CP or AP CML, even those having BCR-ABL1 mutations M244V, N358D, and E459K, achieved an MMR by 12 months of nilotinib treatment. The plasma trough concentration of the drug was related to the MMR by 12 months, and the plasma threshold of nilotinib should be set above 761 ng/mL. These findings suggest that nilotinib shows good efficacy and tolerability in Japanese patients with imatinib-resistant or intolerant, CP or AP CML. (ClicalTrials.gov, UMIN ID 000002201) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Overexpression of the EphB4 Receptor Contributes to Imatinib Resistance in Chronic Myeloid Leukemia Through Regulating Mlcp and VAV1

Abstract 4421 Objective:To study the role of EphB4 in imatinib (IM) resistant chronic myeloid leukemia (CML) and investigate the mechanism. Methods:We derived IM-resistant cells, K562-R cells, from wild K562 cells under gradually increasing IM concentrations. We analysed expression level of EphB4 in CML patients, wild K562 and K562-R cell lines by real-time reverse transcription PCR and Western blot analysis. Then we established stable under-expressing EphB4 cell (K562-R-EphB4-sh) lines. We analysed the sensitive for IM of K562, K562-R, K562-R-EphB4-sh cell lines by CCK8 assay. Microarray analysis was used to screen differential expression genes between K562-R and K562-R-EphB4-sh cell lines. Results:The mRNA and protein of EphB4 were significantly increased in IM resistant CML patients compared to IM sensitive CML patients (p<0.05). The Similar results were observed in K562-R and K562 cells (p<0.01). To analyze the role of EphB4 in IM resistance, EphB4 was knocked down with shRNA expressed by pLL3.7 lentivirus vector. We established stable under-expressing EphB4 cell line K562-R-EphB4-sh. RT-PCR and western blot analysis showed that mRNA and protein expression of EphB4 in K562-R-EphB4-sh cells were reduced (p<0.05). CCK8 assay found K562 cells (IC50 0.1207±0.0234μM), K562-R-EphB4-sh cells (IC50 0.7228±0.04752μM) were sensitive to IM but K562-R (IC50 2.8101±0.04674μM) still showed IM resistance (p<0.05). Those suggested K562-R-EphB4-sh cells resensitize to IM when the expression of EphB4 was down regulated. However, these cells were still less sensitive than K562 cells. Microarray analysis between K562-R and K562-R-EphB4-sh cell lines found 641 differential expression genes, most of them were related to cell adhesion and cell cytoskeleton. We confirmed MLCP and VAV1 were down regulated in K562-R-EphB4-sh cells compared to K562-R cell lines by western blot analysis. Conclusion:Our study suggest EphB4 receptor contributes to IM-resistant in CML through regulating cell adhesion molecular MLCP and VAV1, which may provide new biomarkers and contribute to] developping new drugs for the disease. Disclosures:No relevant conflicts of interest to declare.

Patient Perceived Impact of Diarrhea On Health Related Quality of Life in Imatinib-Resistant or Imatinib-Intolerant Patients with Chronic Myeloid Leukemia Treated with Bosutinib

Abstract 4451 Purpose:Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI) has demonstrated efficacy in a phase I/II study of patients with Imatinib-Resistant or Imatinib-Intolerant Chronic Phase Chronic Myeloid Leukemia (CP CML). Bosutinib was associated with an acceptable safety profile and mild to moderate diarrhea was the most common non-hematologic toxicity. Since diarrhea is a common side effect of TKI therapy, an exploratory objective of the phase I/II trial was to observe how bothersome this side effect was to patient perceived health-related quality of life. Methods:The Functional Assessment of Cancer Therapy- Leukemia (FACT-Leu) was used to evaluate patient reported health-related quality of life (HRQoL) at baseline, prior to treatment, and at weeks 4, 8, 12, every 12-weeks thereafter, and at treatment completion. The modular FACT-Leu uses a 7-day recall period and consists of a core set of general cancer questions and a leukemia specific subscale with 5 domains: Social Well-being (SWB), Emotional Well-being (EWB), Physical Well-being (PWB), Functional Well-being (FWB) and Leukemia Subscale (LeuS). Select questions from the PWB (“I am bothered by side effects of treatment”) and FWB (“I am content with the quality of my life right now”) were used to describe how bothersome diarrhea was to patient HRQoL. To evaluate how bothersome diarrhea was to the patient and how content patients were with their quality of life, a 5-point Likert response format was used (0, not at all; 1, a little bit; 2, somewhat; 3, quite a bit; and 4, very much). Patients’ who experienced diarrhea within the 7-days prior to completion of the HRQoL instrument were classified according to diarrhea grade (CTCAE v3.0) and patients not experiencing diarrhea within the recall period were classified as grade 0 (Table 1). Results:Of the N=288 CP CML patients treated with bosutinib following imatinib failure (second-line TKI) included in the trial, n=237 (82%) completed the bothered by side effects (BSE) question at baseline and n=249 (86%) completed the content with quality of life (CQoL) at baseline. The observed mean scores on the BSE question by diarrhea grade are presented in Figure 1. For each time point, patients not experiencing diarrhea (grade 0) or those experiencing grade 1 diarrhea reported being bothered by the side effects of their treatment “a little bit” (range = 0.6 – 1.3) and patients experiencing grade 2 diarrhea reported being “a little bit” to “somewhat” bothered by the side effects of their treatment (range = 0.5 – 2.0). The mean score on the bothersome side effect between groups for each week was statistically significant at weeks 4, 8, 12, and 24 (p<0.05); these analysis were not adjusted for multiple comparisons. Mean CQoL scores for patients with grade 1 diarrhea were: baseline (2.5), wk4 (2.5), wk8 (2.5), wk12 (2.6), wk24 (2.9), wk36 (2.7), and wk48 (2.7) indicating patients were “somewhat” content with the quality of their life. Similarly, mean CQoL scores for patients with grade 2 diarrhea were: baseline (2.3), wk4 (2.5), wk8 (2.0), wk12 (3.0), wk24 (2.2), wk36 (2.8), and wk48 (2.0) indicating patients were “somewhat” content with the quality of their life. Conclusions:Patients treated with Bosutinib for Imatinib-Resistant or Imatinib-Intolerant CP CML did not report diarrhea to be a bothersome side effect of therapy and patients were content with their quality of life. These results highlight the value of capturing patient perceived HRQoL to better understand the impact of treatment. [Display omitted] Disclosures:Whiteley:Pfizer Inc: Employment, Equity Ownership. Reisman:Pfizer Inc: Employment, Equity Ownership. Kelly:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Cella:Pfizer Inc: Honoraria, Research Funding.

Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis

To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34(+) leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC(50)) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC(50) values were about 10.12-13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xenografts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210(Bcr-Abl) and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210(Bcr-Abl) protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G(1)) arrest in CML cells. Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210(Bcr-Abl) mRNA and β-catenin protein.

Off-Target Effects of BCR-ABL Inhibitors Synergize in Refractory CML

Abstract Danusertib and bosutinib have synergistic activity in imatinib-resistant CML cells.

Quizartinib Induces Terminal Differentiation in AML Blasts

Abstract Danusertib and bosutinib have synergistic activity in imatinib-resistant CML cells.

Impact of BCR-ABL mutations on response to dasatinib after imatinib failure in elderly patients with chronic-phase chronic myeloid leukemia

To assess the impact of BCR-ABL kinase domain mutations on dasatinib response in elderly chronic myeloid leukemia (CML) patients, we analyzed the outcome of 76 individuals aged >60 affected by imatinib-resistant chronic-phase CML. We found that 36 cases (47%) displayed mutations before dasatinib. Compared to non-mutated patients, subjects with point mutations had a worse response to dasatinib, with significantly lower rates of complete cytogenetic response (57 vs 32%), higher percentage of primary resistance (16/36 vs 6/40) and a trend towards a shorter median event-free survival. Our data suggest that, in elderly patients, detection of BCR-ABL mutations negatively affects response to dasatinib.

Systems-pharmacology dissection of a drug synergy in imatinib-resistant CML

Occurrence of the BCR-ABL(T315I) gatekeeper mutation is among the most pressing challenges in the therapy of chronic myeloid leukemia (CML). Several BCR-ABL inhibitors have multiple targets and pleiotropic effects that could be exploited for their synergistic potential. Testing combinations of such kinase inhibitors identified a strong synergy between danusertib and bosutinib that exclusively affected CML cells harboring BCR-ABL(T315I). To elucidate the underlying mechanisms, we applied a systems-level approach comprising phosphoproteomics, transcriptomics and chemical proteomics. Data integration revealed that both compounds targeted Mapk pathways downstream of BCR-ABL, resulting in impaired activity of c-Myc. Using pharmacological validation, we assessed that the relative contributions of danusertib and bosutinib could be mimicked individually by Mapk inhibitors and collectively by downregulation of c-Myc through Brd4 inhibition. Thus, integration of genome- and proteome-wide technologies enabled the elucidation of the mechanism by which a new drug synergy targets the dependency of BCR-ABL(T315I) CML cells on c-Myc through nonobvious off targets.

Delayed initiation of front-line imatinib therapy predicts for poor response to nilotinib as second-line treatment of imatinib-resistant or intolerant CML: single center report of the ENACT trial in Lebanon

Delayed initiation of front-line imatinib therapy predicts for poor response to nilotinib as second-line treatment of imatinib-resistant or intolerant CML: single center report of the ENACT trial in Lebanon

Myc induced miR-144/451 contributes to the acquired imatinib resistance in chronic myelogenous leukemia cell K562

Imatinib resistance remains the big hurdle for CML therapy. Previous study reveals that c-myc is important for bcr–abl CML cell proliferation, while its role in imatinib resistance is largely unknown. In this study, we first found that c-myc expression is upregulated in imatinib resistant K562R cells, which in turn enhances the expression of miR-144/451. Knockdown of c-myc or restoration of miR-144/451 in the K562R cells sensitizes K562R cells to imatinib therapy. Our study here reveals an regulatory pathway between myc and miR-144/451 and highlights that targeting either myc or miR-144/451 might be valuable for eliminating the imatinib resistant CML cells.

A retrospective analysis of therapy adherence in imatinib resistant or intolerant patients with chronic myeloid leukemia receiving nilotinib or dasatinib in a real-world setting

Objectives:To compare adherence to second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib in patients with imatinib resistant or intolerant chronic myeloid leukemia (CML) receiving second-line therapies.Methods:Two U.S. administrative claims databases were reviewed (January 1997 to March 2011) for CML patients previously treated with imatinib, who received ≥1 prescription of dasatinib or nilotinib and had continuous enrollment ≥1 month before and after the index date (first dasatinib or nilotinib prescription date). Medication possession ratios (MPRs) and proportion of days covered (PDCs) were evaluated between the treatment initiation date until the end of continuous eligibility, for a maximum of 12 months. Sensitivity analyses were conducted to compare patients initiated on nilotinib to patients who initiated dasatinib 100 mg/day and 140 mg/day separately. This study provides updated results of a previously published study.Results:In total, 878 CML patients who received second-line treatment with either dasatinib (n = 550) or nilotinib (n = 328) were studied. Dasatinib users were less adherent compared to nilotinib users; mean MPR was 0.739 (standard deviation [SD] 0.246) for dasatinib and 0.800 (SD 0.246) for nilotinib (adjusted difference = 0.061; P = 0.002). Subgroup analyses of patients who initiated dasatinib 100 mg/day and 140 mg/day separately presented similar trends; after multivariate adjustment, adherence was 0.039 points lower in the 100 mg/day group (P = 0.034) and 0.120 points lower in the 140 mg/day group (P < 0.001).Conclusions:Among patients treated in the second-line CML setting, those treated with nilotinib had significantly higher adherence compared to patients treated with dasatinib, regardless of dasatinib dose (100 mg/day and 140 mg/day).Limitations:The study was subject to common limitations of claims data, which lack clinical information, may contain inaccuracies in diagnosis and procedure coding, and may not truly reflect actual drug consumption. Moreover, daily doses calculated based on refill records may not reflect accurate dosing regimens.

Dasatinib inhibits proinflammatory functions of mature human neutrophils

AbstractDasatinib is a tyrosine kinase inhibitor used to treat imatinib-resistant chronic myeloid leukemia and Philadelphia chromosome–positive acute lymphoblastic leukemia. At present, little is known about how dasatinib influences nonmalignant cells. In the present study, we tested the effect of dasatinib on functional responses of normal mature human neutrophils. Dasatinib completely blocked integrin- and Fc-receptor–mediated neutrophil functions, with the lowest IC50 values below 10nM under serum-free conditions. Dasatinib caused a partial inhibition of neutrophil responses triggered by G-protein–coupled receptors and had a moderate effect on neutrophil responses triggered by microbial compounds. Whereas dasatinib inhibited neutrophil chemotaxis under static conditions in 2 dimensions, it did not affect migration under flow conditions or in 3-dimensional environments. Dasatinib did not have any major effect on phagocytosis or killing of bacteria by neutrophils. Adhesion of human neutrophils in the presence of whole serum was significantly inhibited by 50-100nM dasatinib, which corresponds to the reported serum concentrations in dasatinib-treated patients. Finally, ex vivo adhesion of mouse peripheral blood neutrophils was strongly reduced after oral administration of 5 mg/kg of dasatinib. Those results suggest that dasatinib treatment may affect the proinflammatory functions of mature neutrophils and raise the possibility that dasatinib-related compounds may provide clinical benefit in neutrophil-mediated inflammatory diseases.

DNA damage response in imatinib resistant chronic myeloid leukemia K562 cells

Resistance to imatinib in patients with chronic myeloid leukemia can lead to advanced disease and blast crisis. Conventional chemotherapy with DNA damaging agents is then used, alone or in combination with other tyrosine kinase inhibitors (TKIs). Our aim was to assess whether imatinib resistant K562 cells were also resistant to DNA damaging agents. After treatment with H2O2 and doxorubicin, but not camptothecin, cell survival was higher in imatinib resistant cells compared to parental cells. DNA damage, measured by comet and γ-H2AX assays, was lower in imatinib resistant cells. mRNA expression levels of 50 genes of the DNA damage response pathway showed increased expression of the base excision repair (BER) genes MBD4 and NTHL1. Knockdown of MBD4 and NTHL1 expression in resistant cells using siRNA decreased cell survival after treatment with H2O2 and doxorubicin. Our results indicate that imatinib resistant cells display cross-resistance to oxidative agents, partly through up-regulation of BER genes. Expression of these genes in imatinib resistant patients was not significantly different compared to sensitive patients. However, the strategy followed in this study could help identify chemotherapeutic agents that are more effective as alternative agents in cases of resistance to TKIs.

Phase I pharmacokinetic study of dasatinib (BMS-354825) in patients with advanced malignancies and varying levels of liver dysfunction: S0711, a SWOG early therapeutics committee study.

3078 Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use in imatinib resistant CML. It is a small molecule targeted therapy hepatically metabolized primarily by CYP3A4. We conducted a phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with advanced solid tumors or lymphoma, Zubrod ≤2, no baseline ascites or pleural effusions, adequate renal and bone marrow function, received PO D daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, moderate, severe, using Child-Pugh classification (CPC). Data also collected for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was escalated in sequential cohorts of pts within each LD category. Blood analysis for D concentrations were determined during cycle 1 using a validated LC-MC/MS assay. Study objectives included characterizing safety, tolerability, PK, identifying the MTD and obtaining preliminary evidence of efficacy. Results: 54 registered pts, 51 pts received 51 cycles of D at doses starting at 100 mg in mild LD (50-140 mg). Median age 60, male 55%, Zubrod 1 70%. CRC 27%. Groups: normal-17, mild-20, moderate-13, severe-1 pt(s). Related AEs include fatigue 35%, diarrhea 27%, anemia 27%, nausea 25%, vomiting 21%, lymphopenia 13%, rash 13%, pleural effusion 8%. 1 DLT of increased CK in a pt in moderate LD with past history of similar episode with previous sorafenib. Previous linear PK disposition, and no accumulation. No apparent PK differences between normal and mild groups. Cycle 1 Day 1 D 140 mg Normal Group: Cmax 129 ng/mL. Mild Group 140mg: Cmax 157 ng/mL. Prolonged disease stabilization (≥4 cycles) in 6 pts, 3 CRC (4,5,8); 1 Pancreas, HCC, Bladder (4,5,6). Conclusions: Recommended dose for Dasatinib given PO QD for pts with mild, moderate, or severe LD using clinical criteria with CPC and no baseline ascites, are 140 mg, 70 mg, insufficient pts, respectively. Dose adjustment not necessary in pts with mild LD.

Dasatinib plus SMO antagonist versus dasatinib alone for treating patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP): Design of CA180-363, a phase II, open-label randomized trial.

TPS6634 Background: Dasatinib 100 mg once daily (QD) is approved as first-line therapy for pts with newly diagnosed Ph+ CML-CP and those who are resistant or intolerant to prior therapy, including imatinib, based on demonstrated efficacy and tolerability. BMS-833923 (SMO antagonist), selectively blocks hedgehog (Hh) pathway signaling by binding to and antagonizing Smoothened (SMO), preventing downstream signaling and activation of target genes. In preclinical studies, SMO loss or inhibition reduces hematopoietic stem cell renewal, induces CML stem cell depletion, and inhibits imatinib-resistant CML cell growth (Dierks, Cancer Cell 2008; Zhao, Nature 2009). In pts with CML, Hh signaling genes (Sonic hedgehog, SMO, and Gli1) are significantly upregulated compared with control pts (Long, J Exp Clin Cancer Res 2011), suggesting that drug resistance and disease recurrence may be overcome by targeting the Hh signaling pathway. Methods: CA180-363 is a phase 2 trial to assess dasatinib activity with or without SMO antagonist in pts with newly diagnosed Ph+ CML-CP. Pts receive dasatinib 100 mg QD for 12 months and are then randomized 1:1 to continuing dasatinib 100 mg QD with or without SMO antagonist up to 24 months, followed by dasatinib 100 mg QD alone until end of study (60 months). Randomization is stratified by Sokal score at diagnosis and major molecular response (MMR) at 12 months (yes/no). Eligible pts are aged ≥18 years, have an Eastern Cooperative Group (ECOG) performance status of 0-2, and previously untreated Ph+ CML-CP diagnosed within 6 months of enrollment. Primary endpoint (evaluated in pts who do not achieve MMR prior to randomization) is comparison of MMR rates for dasatinib alone vs dasatinib plus SMO antagonist. Other endpoints (evaluated in all pts) are complete molecular response, progression-free survival, event-free survival, transformation-free survival, and safety of the combination regimen. Recruitment started in September 2011 (14 pts enrolled to date); estimated primary completion date is November 2014. ClinicalTrials.gov ID: NCT01357655.

Dasatinib, high-dose imatinib and nilotinib for the treatment of imatinib-resistant chronic myeloid leukaemia: a systematic review and economic evaluation.

The present report was commissioned as a supplement to an existing technology assessment report produced by the Peninsula Technology Assessment Group (PenTAG), which evaluated the clinical effectiveness and cost-effectiveness of dasatinib and nilotinib in patients who are either resistant or intolerant to standard-dose imatinib. This report evaluates the clinical effectiveness and cost-effectiveness of dasatinib, nilotinib and high-dose imatinib within their licensed indications for the treatment of people with chronic myeloid leukaemia (CML) who are resistant to standard-dose imatinib. Bibliographic databases were searched from inception to January 2011, including The Cochrane Library, MEDLINE (Ovid), EMBASE (Ovid), and MEDLINE In-Process & Other Non-Indexed Citations. Bibliographies of related papers were screened, key conferences were searched, and experts were contacted to identify additional published and unpublished references. This report includes systematic reviews of clinical effectiveness and cost-effectiveness studies, an independent appraisal of information submitted by drug manufacturers to the National Institute for Health and Clinical Excellence (NICE), an independent appraisal of the PenTAG economic evaluation, and new economic analyses adapting the PenTAG economic model. Standard systematic procedures involving two reviewers to maintain impartiality and transparency, and to minimise bias, were conducted. Eleven studies met the inclusion criteria. Four of these studies included new data published since the PenTAG report; all of these were in chronic-phase CML. No relevant studies on the clinical effectiveness of nilotinib were found. The clinical effectiveness studies on dasatinib [one arm of a randomised controlled trial (RCT)] and high-dose imatinib (one arm of a RCT and three single-arm cohort studies) had major methodological limitations. These limitations precluded a comparison of the different arms within the RCT. Data from the studies are summarised in this report, but caution in interpretation is required. One economic evaluation was identified that compared dasatinib with high-dose imatinib in patients with chronic-phase CML who were CML resistant to standard-dose imatinib. Two industry submissions and the PenTAG economic evaluation were critiqued and differences in the assumptions and results were identified. The PenTAG economic model was adapted and new analyses conducted for the interventions dasatinib, nilotinib and high-dose imatinib and the comparators interferon alfa, standard-dose imatinib, stem cell transplantation and hydroxycarbamide. The results suggest that the three interventions, dasatinib, nilotinib and high-dose imatinib, have similar costs and cost-effectiveness compared with hydroxycarbamide, with a cost-effectiveness of around £30,000 per quality-adjusted life-year gained. However, it is not possible to derive firm conclusions about the relative cost-effectiveness of the three interventions owing to great uncertainty around data inputs. Uncertainty was explored using deterministic sensitivity analyses, threshold analyses and probabilistic sensitivity analyses. The paucity of good-quality evidence should be considered when interpreting this report. This review has identified very limited new information on clinical effectiveness of the interventions over that already shown in the PenTAG report. Limitations in the data exist; however, the results of single-arm studies suggest that the interventions can lead to improvements in haematological and cytogenetic responses in people with imatinib-resistant CML. The economic analyses do not highlight any one of the interventions as being the most cost-effective; however, the analysis results are highly uncertain owing to lack of agreement on appropriate assumptions. Recommendations for future research made by PenTAG, for a good-quality RCT comparing the three treatments remain.