Efficacy and Safety of Dasatinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) with Imatinib Resistance or Intolerance

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4444-4444
Author(s):  
Tomoaki Akagi ◽  
Kazunori Murai ◽  
Kenji Shimosegawa ◽  
Kenichi Ishizawa ◽  
Tomohiro Sugawara ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Imatinib Resistance ◽  
Once Daily ◽  
Grade 3 ◽  
Complete Molecular Response

Abstract Abstract 4444 Background: Dasatinib is highly potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with imatinib resistance or intolerance in the Japanese population. Methods: 54 CML- CP patients (median age 63.5 years) with resistance, intolerance or a suboptimal response to imatinib were submitted to dasatinib 100mg once daily. Efficacy and safety were assessed using rates of major molecular response (MMR)/ complete molecular response (CMR) or drug-related adverse events (AEs) respectively. All analyses were based on the intension-treat principle. Results: Until now, the results of 32 patients, who passed more than 12 months, have been analysed. The median time since of prior imatinib therapy was 19.2 months with 57.4 % being imatinib-resistant and 42.6 % imatinib-intolerant. The incidence of MMR (primary endopoint) and complete molecular response at 12 months was 59.3 % (95% confidence interval, 45.0 – 72.4 %), and 24.1 % patients, respectively. Progression to the accelerated or blastic phase had not been observed. All patients with baseline samples tested for mutations, and different mutations were not observed. Non-hematological AEs were mostly grade 1/2. Grade 3/4 non-hematological AEs were infrequent, including increased AST (1.9%), and increased creatinine (1.9%), respectively. Grade 1/2 fluid retention adverse events were shown in 10 patients, including 2 patients with edema, and 9 patients with pleural effusion. Grade 3/4 hematological toxicities including anemia (1.9%), neutropenia (14.8%), and thrombocytopenia (9.3 %) were shown, and 13 patients have permanently discontinued treatment due to adverse effects. Conclusions: Dasatinib treatment results in high rate of molecular response in CML-CP patients with resistance or intolerance to imatinib, and approximately 60% of evaluated patients who switched to dasatinib achieved MMR at 12 months. Importantly, among all patients who achieved molecular response, 24.1 % patients achieved CMR. Dasatinib at a dose of 100 mg once daily was generally well-tolerated, and had better efficacy for patients with CML-CP post imatinib failure. Disclosures: No relevant conflicts of interest to declare.

The Prospective Analysis Of Clinical Efficacy and Adverse Events In Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Patients With Imatinib Resistance Or Intolerance, Evaluated By European Leukemia Net (ELN) 2013 Criteria

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4027-4027
Author(s):  
Kazunori Murai ◽  
Tomoaki Akagi ◽  
Kenji Shimosegawa ◽  
Kenichi Ishizawa ◽  
Tomohiro Sugawara ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
First Line ◽  
Imatinib Resistance ◽  
Grade 3 ◽  
Dasatinib Treatment

Abstract Background Dasatinib is a highly potent BCR-ABL inhibitor, with a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib resistance or intolerance CML. Methods Fifty- five CML-CP patients from 2009 to 2011 with resistance (n=40) or intolerance (n=26) to imatinib were registered to dasatinib administration (100mg once daily). Eleven among 26 patients with intolerance also showed resistance to imatinib at the registration. Imatinib resistance was defined as a lack of partial cytogenetical response at 3 months, a lack of complete cytogenetic response at 6 months or a lack of a major molecular response at 12 months of imatinib treatment. This criteria was identical to the criteria in ELN 2013 recommendation for first line. In another words, the resistance in this study means non-optimal criteria (warning and failure) of definition of the response to TKIs, first line, in ELN 2013 recommendation. Efficacy and safety were assessed using rates of major molecular response (MMR)/ MR4.5 (either (i) detectable disease with<0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) at 12 months and drug-related adverse events (AEs) respectively. All analyses were based on the modified to intension-to treat. Results One patient was withdrawal before dasatinib administration. The median duration of imatinib therapy was 545 days. The overall incidence of MMR (primary endopoint) and MR4.5 at 12 months was 67.2% (95% confidence interval, 53.3-81.1%), and 20.2 % (95% CI, 8.4–32.0 %), respectively. Forty patients with resistance to imatinib, who were warning and failure patients judged by ELN 2013 criteria, were reassessed. Cumulative MMR and MR4.5 rate were 63.4% (95% CI: 46.3-80.6) and 18.0% (95% CI: 4.9-31.1) respectively at 12 months. Eleven patients, who showed more than 1% IS at 3 months of dasatinib treatment, did not reach to MMR at 12 months or discontinued dasatinib due to insufficient efficacy in this resistance cohort. However, progression to the accelerated or blastic phase had not been observed. When imatinib were changed to dasatinib, 5 patients showed the mutations, which were effective in dasatinib therapy. New mutations have not been observed during the treatment of dasatinib. Among 54 patients, most non-hematological AEs were in grade 1/2. including diarrhea (12.7%), rash (7.3%), myalgia (5.5%) and vomiting (3.6%). Grade 3/4 non-hematological AEs were infrequent, including decreased potassium (3.6%), and increased creatinine (3.6%). Grade 1/2 fluid retention AEs were shown in 9.1% of patients, including edema (3.6%). Pleural effusion, which was only in Grade 1/2, was shown in 32.7% of patients. Grade 3/4 hematological toxicities included anemia (7.3%) and thrombocytopenia (3.6 %). Only 3 patients have permanently discontinued dasatinib treatment due to AEs. Conclusions The patients with non-optimal responses (warning and failure) judged by ELN 2013 criteria should have early intervention to dasatinib, which is less toxicity in CML-CP patients. This intervention might induce good prognosis. The BCR-ABL1 IS less than 1% at 3 months of dasatinib administration will be the valuable landmark for outcome. Disclosures: No relevant conflicts of interest to declare.

Efficacy and SAFETY of Dasatinib 50 MG Once Daily DOSE In PATIENTS with CHRONIC PHASE CML WHO Failed IMATINIB

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4440-4440 ◽  
Author(s):  
Mohamed A. Yassin ◽  
Hanadi R. El-Ayoubi ◽  
Rami T Kamzoul
Keyword(s):  
Pleural Effusion ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
X Rays ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily ◽  
Daily Dose ◽  
Grade One

Abstract Abstract 4440 Background: Dasatinib is multi-targeted kinase inhibitor and it is approved therapy for patients with imatinib-resistant or imatinib-intolerant CML or newly diagnosed CML (chronic phase). The recommended dosing regimen is Dasatinib 100 mg once daily (QD), based on results from the CA180-034 dose-optimization study in patients with CML-CP and resistance or intolerance to prior therapy and it is active against the vast majority of BCR/ABL mutations apart from T315I and can overcome emerging resistance. Aims: to assess the efficacy and safety of 50 mg once daily dose of Dasatinib in achieving complete hematological remission (CHR),complete cytogenetic remission(CCYR) and major molecular response (MMR) in patients with CML-CP and resistance or intolerance to prior imatinib therapy. Patients and Methods: nine adult patients (aged ≥18 years) with prior imatinib failure were enrolled in this study after informed consent, between September and November 2009 and followed for 18 months. Received Dasatinib 50 mg once daily as second line therapy and were evaluated at baseline,3,6, 12, and 18 months as per European leukemia net(ELN) guidelines for response CHR, CCYR, MMR mutation analysis was not done because it is not available in our centre. Patients with baseline pleural effusion or ejection fraction less than 50% were excluded. Chest x-rays were performed at baseline and at 6 months, or more frequently if indicated clinically. Pleural effusions were graded according to CTCAE v3.0 criteria: grade 1, asymptomatic; grade 2, symptomatic, ≤ 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, > 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability. Results: All patients achieved complete hematological as well as complete cytogenic response within three months and remains so at 6 and 12 months assessment, 18 months assessment for molecular response showed that 8 out of 9 achieved major molecular response and one patient achieved complete molecular response, grade two or more toxicity were not seen in any patient. Anemia and neutropenia Grade ≥ 2 were not observed in any patient, thrombocytopenia grade one was observed in one patient. Non-hematologic adverse drug reactions like fluid retention; including pleural effusion, nausea vomiting, myalgia, muscle inflammation and rash were not observed in any patient. Conclusion: In patients with chronic phase chronic myeloid leukemia who failed first generation TKI (Imatinib). Dasatinib 50 mg once daily is safe, effective and capable of achieving complete hematological and cytogenetic remissions well as major molecular response‘ with better toxicity profile keeping in consideration the small number of patient’s further studies are needed to confirm this result. Disclosures: No relevant conflicts of interest to declare.

Efficacy of Dasatinib in Patients with Chronic Phase Philadelphia Chromosome-Positive CML Resistant or Intolerant to Imatinib: First Results of the CA180013 ‘START-C’ Phase II Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 41-41 ◽  
Author(s):  
Andreas Hochhaus ◽  
M. Baccarani ◽  
C. Sawyers ◽  
A. Nagler ◽  
T. Facon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
White Blood Cells ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Biomarker Analysis ◽  
Grade 3

Abstract After 3 years of imatinib (IM) therapy, hematologic relapse occurred in 7% of newly diagnosed chronic myeloid leukemia (CML) pts, and 20% of chronic phase (CP)-CML pts after failure to interferon alpha (IFN), which was mostly associated with BCR-ABL mutations and/or clonal evolution. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Dasatinib has been shown to have 325-fold greater potency compared with imatinib in cells transduced with BCR-ABL and is active against 18/19 BCR-ABL mutants tested that confer imatinib resistance. A Phase I dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients in CP-CML, which was followed by ‘START-C’ (CA180013), the first Phase II open-label study in dasatinib in CP IM-R or IM-I CML pts. Between February-May 2005, 186 pts (86 male, median age 60 yrs [range 25–82]) were recruited from 40 institutions. Data from 30 pts accrued prior to March 20, 2005, are available for the initial analysis. The definition of IM-R required a failure of IM doses &gt;600 mg/d or the occurrence of BCR-ABL mutations associated with virtual insensitivity to IM. Dasatinib was administered at 70 mg twice daily (BID), based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in pts lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. In the group of 30 evaluable pts, median age was 59 yrs (range 25–78), 50% were male. Median time from diagnosis of CML was 70.8 months (range 7.9–202.1). Prior therapy included IFN in 77% and stem cell transplantation in 10% of pts. 60% of pts were considered IM-R, with the maximum prior IM dose of &gt;600 mg in 60% of pts. 60% of pts received IM for &gt;3 yrs. Best response to prior IM therapy was a complete hematologic response in 83%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 17% and 13% of pts, respectively. Median (range) baseline hematologic parameters were: white blood cells 16.1/nl (4.3–84.3); platelets 437/nl (173–960). IM-R BCR-ABL mutations were documented in 6/12 pts with currently available data. Within the first 3 months, 2 pts required dose escalations and 6 had a dose reduction, mostly due to thrombocytopenia. Hematologic responses were documented in 21/24 pts with available data. From 16 pts evaluable for 3-month cytogenetic analysis, 7 cytogenetic responses were observed, including CCyR (n=4) and PCyR (n=1). Analysis of molecular response is in progress. Grade 3/4 neutropenia or thrombocytopenia were reported in 6 pts each. Most common non-hematologic toxicities were diarrhea (6 pts, 1 grade 3), rash (5 pts, all grade 1), edema (3 pts, all grade 1) and pleural effusion (1 pt, grade 2). In conclusion, despite the short follow up, major hematologic and cytogenetic responses were seen in a group of pretreated CP-CML pts, which further supports the activity of dasatinib in this disease. An updated analysis based on 186 pts with 6-month follow up will be presented.

scholarly journals First-Line Dasatinib Treatment of CML-CP Leads to Earlier Achievement of MMR and MR4.5 with High Safety

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3102-3102
Author(s):  
Kazunori Murai ◽  
Kohei Yamaguchi ◽  
Shigeki Ito ◽  
Takuto Miyagishima ◽  
Motohiro Shindo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Odds Ratio ◽  
Phase Ii Study ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Dasatinib Treatment

Abstract (INTRODUCTION) Several clinical studies have revealed that dasatinib demonstrated deep and fast responses. We report a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study). (PATIRNTS AND METHODS) Between July 2011 and June 2013, a total of 79 consecutive patients with CML-CP received 100 mg dasatinib daily as a first-line therapy. Treatment was continued until disease progression or until toxicity became unacceptable. The primary end-point was the rate of major molecular response by 12 months. Secondary end-points included the rate of complete cytogenetic response, rate of molecular responses with a 4.5 log reduction (MR4.5) by 12 months, and adverse events. The median age was 62 years, ranging from 27 to 80 years. Patients older than 65 years comprised 41.7% of all patients. Two-thirds of patients (68.4%) were male. Nearly all patients were ECOG performance status 0. Most patients (83.6%) had low and intermediate Sokal scores. The BCR-ABL1 International Scale (BCR-ABL1 IS) in the peripheral blood was measured by the central laboratory center (BML, Tokyo, Japan). (RESULTS) The median BCR-ABL1 IS before therapy was 54.0% (7.8-230.2). Seventy patients (88.6%) received dasatinib therapy for 12 months. The median BCR-ABL1 ISs were 0.25 % at 3 months (range 0.0002-52.2 %, n =77), 0.03 % at 6 months (range not detected-29.2 %, n = 75) and 0.008 % at 12 months (not detected -0.86 %, n = 70). MMR rate was 77.2% (95% CI, 67.9-86.5 %) by 12 months. The rates of CCyR and MR4.5 by 12 months were 88.6% (95% CI; 81.5-95.7 %) and 35.4% (95% CI; 24.8-46.1 %), respectively (Figure 1). Multivariate analysis of MMR or MR4.5 by 12 months showed that female sex (odds ratio 1.1, P = 0.92, odds ratio 1.7, P = 0.35, respectively), low and intermediate Sokal score (odds ratio 0.9, P = 0.90, odds ratio 3.2, P =0.23, respectively), and BCR-ABL1 IS less than 54% at diagnosis (RR =odds ratio 0.8, P = 0.74, odds ratio 0.7, P = 0.55, respectively) were not significantly correlated with MMR by 12 months nor MR4.5 by 12 months (Table 1). However, patients who were more than 62 years old were significantly correlated with MR4.0 and MR4.5 by 12 months (odds ratio 2.8, P =0.04, odds ratio 3.5, P =0.01). Treatment-related all AEs were reported in 98.7% patients (78 of 79). Grade 3/4 non-hematologic AEs were observed in only a few cases. Lymphocytosis (more than 4x 109/L) was observed in 34.1% of patients, which was within grade 2. Only 9 patients withdrew the study because of adverse events (4 patients), ineffectiveness (3 patients), and others (2 patients). (DISCUSSION AND CONCLUSION) The incidence of lymphocyte predominance may depend on a history of previous cytomegalovirus (CMV) infection in CML-CP patients (Leukemia. 2011 25(10): 1587-97). Although the frequency of CMV-positive patients was unknown in this study, that of blood donors in Japan was almost positive in the ages with 60s or older. The median age of CML-CP patients in this study was 62 years. Therefore, we assumed that some immunological effects induced by dasatinib might have improved the clinical efficacy in Japanese CML-CP patients compared to those worldwide. Our phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed CML-CP in Japan revealed that the first-line dasatinib treatment of CML-CP leads to earlier achievement of MMR and MR4.5 with high safety. Elder age patients (>62 years) were significantly associated with achievement of MR4.5. Disclosures Shindo: Sysmex Corporation: Research Funding. Sakamoto:Yakult: Other: Remuneration; Takeda Pharmaceutical: Consultancy.

Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2282-2282 ◽  
Author(s):  
Kimmo Porkka ◽  
Michele Baccarani ◽  
Andreas Hochhaus ◽  
Hagop Kantarjian ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Chronic Phase ◽  
Risk Scores ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Management Interventions ◽  
Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

The Efficacy and Safety of Immunomodulatory Drugs in Multiple Myeloma Maintenance Therapy: Results of a Meta-Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3477-3477
Author(s):  
Yucai Wang ◽  
Fang Yang ◽  
Wenwen Zhang ◽  
Xiaoxiang Guan ◽  
Neil Kothari ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Maintenance Therapy ◽  
Conflicts Of Interest ◽  
Meta Analysis ◽  
Random Effect Model ◽  
Immunomodulatory Drugs ◽  
Efficacy And Safety ◽  
Free Survival ◽  
Grade 3

Abstract Objective: To evaluate the efficacy and safety of immunomodulatory drugs (IMiDs) in maintenance therapy of multiple myeloma through meta-analysis of randomized controlled trials (RCTs). Patients and methods: PubMed, Web of Science, ASCO, ESMO and ASH databases were searched for RCTs that investigated the treatment outcomes (overall survival [OS], progression-free survival [PFS] and/or event-free survival [EFS] and/or time to progression [TTP]) of maintenance therapy with IMiDs in patients with multiple myeloma. Study endpoints included OS, PFS/EFS/TTP, and grade 3 or 4 adverse events. Pooled hazard ratios (HRs) for survival outcomes and risk ratios (RRs) for dichotomous data with 95% confidence interval (CI) were calculated using Comprehensive MetaAnalysis (v2). The random-effect model was utilized in view of clinical heterogeneity in the study population. Results: Eighteen RCTs comprising a total of 6562 patients were included in this meta-analysis. IMiDs used in the RCTs included thalidomide (14 trials) and lenalidomide (4 trials). Overall, IMiD-based maintenance therapy significantly improved OS (HR = 0.91, 95% CI = 0.84 - 0.99, P = 0.027) and PFS (HR = 0.63, 95% CI = 0.60 - 0.68, P < 0.001). Notably, IMiDs maintenance therapy increased OS in the setting of ASCT but showed no OS prolongation without ASCT. On further stratification, thalidomide-based maintenance therapy demonstrated OS benefit only in the setting of ASCT, while lenalidomide-based maintenance therapy did not show OS benefit regardless of transplantation status. For PFS however, both thalidomide- and lenalidomide-based maintenance therapies demonstrated significant survival benefits, regardless of transplantation status (Table 1). IMiD-based maintenance therapy increased the risk of developing grade 3 or 4 neutropenia (RR = 3.04, 95% CI = 2.49 - 3.70, P < 0.001), thrombocytopenia (RR = 2.68, 95% CI = 1.90 - 3.79, P < 0.001), anemia (RR = 1.97, 95% CI = 1.23 - 3.15, P = 0.005), infection (RR = 1.53, 95% CI = 1.22 - 1.92, P < 0.001), fatigue (HR = 1.71, 95% CI = 1.24 - 2.36, P = 0.001), constipation (RR = 2.04, 95% CI = 1.15 - 3.62, P = 0.015), and peripheral neuropathy (RR = 2.02, 95% CI = 1.20 - 3.39, P = 0.008). Conclusions: IMiD-based maintenance therapy results in significant improvement in OS and PFS in multiple myeloma patients but increased the risk of developing some grade 3 or 4 adverse events. While thalidomide-containing maintenance therapy regimens showed OS benefits in the setting of ASCT, lenalidomide-containing maintenance therapy did not prolong OS regardless of transplantation status. Both thalidomide- and lenalidomide-based maintenance therapies increased PFS in multiple myeloma patients independent of transplantation status. When more data on lenalidomide and the newer agent pomalidomide become available, further analysis will be warranted to analyze the efficacy and safety of IMiDs in multiple myeloma maintenance therapy. Table 1. Effects of IMiD-based maintenance therapy on OS and PFS in multiple myeloma patients IMiD ASCT status Survival Number of trials HR 95% CI P value Thalidomide/Lenalidomide combined OS 18 0.91 0.84 - 0.99 0.027 with ASCT OS 10 0.88 0.78 - 0.99 0.036 without ASCT OS 9 0.94 0.83 - 1.06 0.299 Thalidomide combined OS 14 0.92 0.84 - 1.01 0.090 with ASCT OS 8 0.87 0.77 - 1.00 0.049 without ASCT OS 7 0.97 0.85 - 1.10 0.640 Lenalidomide combined OS 4 0.84 0.67 - 1.04 0.102 with ASCT OS 2 0.89 0.66 - 1.20 0.457 without ASCT OS 2 0.78 0.57 - 1.06 0.114 Thalidomide/Lenalidomide combined PFS 17 0.63 0.60 -0.68 < 0.001 with ASCT PFS 9 0.62 0.57 - 0.67 < 0.001 without ASCT PFS 9 0.66 0.60 - 0.73 < 0.001 Thalidomide combined PFS 13 0.67 0.63 - 0.72 < 0.001 with ASCT PFS 7 0.66 0.60 - 0.72 < 0.001 without ASCT PFS 7 0.69 0.62 -0.77 < 0.001 Lenalidomide combined PFS 4 0.50 0.43 - 0.58 < 0.001 with ASCT PFS 2 0.49 0.41 - 0.58 < 0.001 without ASCT PFS 2 0.52 0.40 - 0.67 < 0.001 Disclosures No relevant conflicts of interest to declare.

Velocity of Early BCR-ABL Transcript Elimination As an Optimized Predictor of Deep Molecular Response in Chronic Myeloid Leukemia Patients in Chronic Phase on Treatment with Dasatinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4052-4052
Author(s):  
Kazunori Murai ◽  
Kohei Yamaguchi ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Roc Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Similar Data ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Once Daily ◽  
Deep Molecular Response

Abstract Background: We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study; UMIN000006358). Several groups reported that some of CML patients who achieved stable deep molecular response (DMR) level or deeper could stop Tyrosine Kinase Inhibitor (TKI) and approximately 40% of these patients could keep therapy free survival by cessation of TKI. Discontinuation of TKI has emerged as a new goal of treatment in CML. Achievement of DMR is necessary for discontinuation of TKI. The aim of the present study was to analyze the prognostic significance of (i) BCR-ABL transcript International Scale (BCR-ABL IS) levels, (ii) the halving time and (iii) velocity of BCR-ABL transcript elimination using an optimized cutoff according to receiver operating characteristic (ROC) analysis. Methods: Eighty newly diagnosed CML-CP patients were included in this study. Patients received dasatinib 100mg once daily. Treatment has continued until disease progression or unacceptable toxicity. Clinical efficacy and safety was partially reported in 55th ASH Meeting. We sought to investigate the impacts of above 3 parameters within the initial 1 or 3 months of therapy. Halving time was calculated by the method, described by Branford et al. Velocity of BCR-ABL transcript elimination at 1 or 3 months (V-BCR-ABL1m or 3m respectively) was calculated as BCR-ABL IS at 1 or 3 months (BCR-ABL IS1m or 3m respectively) divided by that at diagnosis. Results: One patient was withdrawal before administration of dasatinib. Seventy-nine patients administered dasatinib 100 mg once daily. The estimated MMR and DMR rates were 92.1 % (95%CI, 76.8-97.3 %) and 60.9% (95%CI; 42.3-73.4 %) by 12 months respectively. The patients who had already achieved DMR at 3 months were excluded from landmark analysis. The cut off values for prediction of DMR at 12 months were obtained by ROC analysis. Those of BCR-ABL IS1m and BCR-ABL IS3m were 11.7% and 0.284% respectively. Those of halving times on 0-1 month and 0-3months (halving time1m and 3m) were 17.8 and 13.6 days respectively. Those of V-BCR-ABL1m and V-BCR-ABL3m were 0.321 and 0.018 respectively. The estimated DMR at 12 months, 95% CI and probability (P), obtained by Kaplan-Myer analysis, were shown in Figure 1. Odd' ratio, obtained by Chi-square test, was shown in Table 1. The patients with less than 0.321 at V-BCR-ABL1m showed the highest DMR at 12 months (80%), the least probability (P=0.009) and the least odd' ratio (0.175). At 3 months, there were similar data in these parameters among BCR-ABL IS3m, halving time3m and V-BCR-ABL3m. Figure 1 showed the cumulative DMR rate according to the cutoff values in V-BCR-ABL1m and V-BCR-ABL3m. V-BCR-ABL1m 0.321 and V-BCR-ABL3m 0.018 separated best. Conclusion: These data strongly suggested that V-BCR-ABL1m,3m would be a significant landmark to predict DMR at 12 months as well as BCR-ABL IS1m,3m, halving time1m,3m. Among them, less than 0.321 in V-BCR-ABL1m was identified as an optimized predictive cutoff value of DMR at 12 months. Disclosures Ishida: Bristol-Myers Squibb: Honoraria.

Interim analysis (IA) of OPTIC: A dose-ranging study of three ponatinib (PON) starting doses.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7502-7502 ◽  
Author(s):  
Jorge E. Cortes ◽  
Elza Lomaia ◽  
Anna Turkina ◽  
Beatriz Moiraghi ◽  
Maria Undurraga Sutton ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Final Analysis ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Phase 2 Trial ◽  
Heavily Pretreated ◽  
Long Term Follow Up ◽  
Grade 3 ◽  
Dose Reductions

7502 Background: In PACE (NCT01207440) heavily pretreated patients (pts) with chronic-phase CML (CP-CML) had deep, lasting responses to PON; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). We present IA results from OPTIC (NCT02467270), evaluating the association between PON exposure, efficacy, and safety, and response-based dose reduction in pts with CP-CML. Methods: This ongoing, multicenter, randomized phase 2 trial enrolled pts with CP-CML resistant or intolerant to ≥2 TKIs or with a T315I mutation to receive PON at a starting dose of 45 mg (cohort A), 30 mg (B), and 15 mg (C) qd. Doses were reduced to 15 mg qd on achievement of ≤1% BCR-ABL1IS in A/B. Primary endpoint: 12 mo ≤1% BCR-ABL1IS; secondary endpoints include cytogenetic and molecular response and AOE, VTE, and TEAE rates. Results are descriptive at this IA and will be inferential by adjusting multiplicity across 3 cohorts at final analysis. Results: 283 pts were randomized (A/B/C: n = 94/95/94); median age 48 y (18‒81 y). 26% had hypertension history; 2/43/55% received 1/2/≥3 TKIs; 40% had ≥1 baseline (BL) mutations, with 23% T315I. At IA data cutoff (20 Jul 2019), 162 pts (57%; n = 57/51/54) remained on study treatment. Among 282 pts in the safety population, median duration of exposure was ≈1 y (A/B/C, 12.9/11.2/11.0 mo). At 12 mo, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) in A, B, and C, respectively, achieved ≤1% BCR-ABL1IS. Additional efficacy in Table. Dose reductions due to efficacy (A/B): 35/21%. Most common TEAEs (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. AOEs/serious AOEs were reported by (A, B, C) 5%/2%, 4%/3%, and 1%/0%. Dose reductions due to TEAEs: (A/B/C): 44/31/28%; discontinuations due to TEAEs: 18/15/14%. There were 4 (1.4%) on-study deaths; A, sudden death, n = 2; C, pneumonia, n = 2; no deaths were due to AOEs. Clinical trial information: NCT01207440 . Conclusions: OPTIC IA shows a trend toward dose-dependent efficacy and safety and may provide a refined understanding of the PON benefit:risk profile and its relation to dose. Data from longer follow-up may support an alternate dosing regimen for pts with CP-CML. [Table: see text]

Efficacy and Safety of Bosutinib (SKI-606) in Patients with Chronic Phase (CP) Ph+ Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1098-1098 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M Kantarjian ◽  
Dong- Wook Kim ◽  
H. Jean Khoury ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
Cytogenetic Response ◽  
Fluid Retention ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor demonstrating inhibitory activity against BCR-Abl phosphorylation, and is 200 times more potent than imatinib but with minimal inhibition of platelet-derived growth factor receptor (PDGFR) or c-kit. The phase I portion of this study identified a treatment dose of 500 mg daily and showed evidence of clinical efficacy. The phase II portion of the study to investigate the efficacy and safety of bosutinib in patients (pts) with CP Ph+ CML who have failed imatinib therapy is ongoing. Preliminary data for 283 treated pts, median age 54 yrs (range 18 – 91 yrs) and 52% male are reported. A subset of pts received treatment in addition to imatinib, including interferon (91 pts), dasatinib (71 pts), nilotinib (7 pts) and stem cell transplant (13 pts). Among pts who failed imatinib (and received no other tyrosine kinase inhibitor treatment), 137 were imatinib-resistant (all received imatinib ≥600mg) and 64 pts were imatinib-intolerant; median duration of bosutinib treatment to date is 7.7 mos (range 0.2 – 28.2 mos) and 4.5 mos (range 0.5 – 21.5 mos), respectively. Among 67 imatinibresistant pts evaluable for hematological response, 53 (79%) had complete hematological response (CHR). Of 84 imatinib-resistant pts evaluable for cytogenetic response, 34 (40%), achieved a major cytogenetic response (MCyR), including 24 (29%) with a complete cytogenetic response (CCyR). Of 34 pts with MCyR, 31 have maintained their response to date. Of 60 evaluable imatinib-resistant pts, 20 (33%) achieved major molecular response, 10 (17%) of which were complete. Among imatinib-intolerant pts, 22 of 29 evaluable (76%) achieved CHR, and 13 of 22 evaluable (59%) achieved MCyR, including 11 (50%) with CCyR. Of 25 evaluable imatinib-intolerant pts, 7 (28%) achieved major molecular response, 5 (20%) of which were complete. Of 105 pts with baseline samples tested for mutations, 17 different mutations were found in 45 pts (43%). CHR occurred in 5/6 pts (83%) with P-loop mutations and 13/17 (76%) with non-P-loop mutations; MCyR occurred in 3/6 pts (50%) and 11/24 pts (46%), with P-loop and non-P-loop mutations, respectively. Treatment was generally well tolerated. The most common adverse events among treated pts (n=283) were gastrointestinal (nausea, vomiting, diarrhea), these were usually grade 1 – 2, manageable and transient, diminishing in frequency and severity after the first 3 – 4 weeks of treatment. Grade 3 – 4 non-hematologic toxicity occurring in ≥5% of pts were diarrhea (8%), rash (8%) and increased ALT (5%). 27 pts (10%) reported grade 1/2 fluid retention adverse events, including 21 pts with edema, and 6 pts with effusions: 4 pleural, 1 pericardial, and 1 pleural and pericardial. A single patient experienced grade 3 pleural effusion possibly related to bosutinib with concomitant pneumonia and a pre-treatment history of recurrent pleural effusions. Grade 3 – 4 hematologic laboratory abnormalities included thrombocytopenia in 65 pts (23%), neutropenia in 37 pts (13%) and anemia in 17 pts (6%). 124 pts (44%) had at least 1 temporary treatment interruption and 85 pts (30%) had at least 1 dose reduction due to toxicity. 37 pts (13%) have permanently discontinued treatment due to adverse event. Bosutinib is effective in pts with CP CML with resistance or intolerance to imatinib across a range of mutations. Unlike other tyrosine kinase inhibitors, bosutinib does not significantly inhibit PDGFR or c-kit, and this may be responsible for the relatively favorable toxicity profile with few pts experiencing hematologic toxicity or fluid retention.

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