Kooperativer Bibliotheksverbund

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 34, No. 23 ( 2016-08-10), p. 2698-2704

Abstract: Cancer cells can exploit the programmed death-1 (PD-1) immune checkpoint pathway to avoid immune surveillance by modulating T-lymphocyte activity. In part, this may occur through overexpression of PD-1 and PD-1 pathway ligands (PD-L1 and PD-L2) in the tumor microenvironment. PD-1 blockade has produced significant antitumor activity in solid tumors, and similar evidence has emerged in hematologic malignancies. Methods In this phase I, open-label, dose-escalation, cohort-expansion study, patients with relapsed or refractory B-cell lymphoma, T-cell lymphoma, and multiple myeloma received the anti–PD-1 monoclonal antibody nivolumab at doses of 1 or 3 mg/kg every 2 weeks. This study aimed to evaluate the safety and efficacy of nivolumab and to assess PD-L1/PD-L2 locus integrity and protein expression. Results Eighty-one patients were treated (follicular lymphoma, n = 10; diffuse large B-cell lymphoma, n = 11; other B-cell lymphomas, n = 10; mycosis fungoides, n = 13; peripheral T-cell lymphoma, n = 5; other T-cell lymphomas, n = 5; multiple myeloma, n = 27). Patients had received a median of three (range, one to 12) prior systemic treatments. Drug-related adverse events occurred in 51 (63%) patients, and most were grade 1 or 2. Objective response rates were 40%, 36%, 15%, and 40% among patients with follicular lymphoma, diffuse large B-cell lymphoma, mycosis fungoides, and peripheral T-cell lymphoma, respectively. Median time of follow-up observation was 66.6 weeks (range, 1.6 to 132.0+ weeks). Durations of response in individual patients ranged from 6.0 to 81.6+ weeks. Conclusion Nivolumab was well tolerated and exhibited antitumor activity in extensively pretreated patients with relapsed or refractory B- and T-cell lymphomas. Additional studies of nivolumab in these diseases are ongoing.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/JCO.2015.65.9789

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2016

detail.hit.zdb_id: 2005181-5

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3226-3226

Abstract: CML-BP has a poor prognosis and is refractory to most therapies. Dasatinib (SPRYCEL®), the most potent BCR-ABL inhibitor, is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL. Dasatinib also inhibits important tyrosine kinases (eg, SRC family kinases) that may play a role in imatinib resistance and disease progression. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with imatinib-resistant or -intolerant CML-BP, leading to its approval in this patient group. CA180-035 is an open-label phase III study comparing dasatinib dosing at 70 mg BID vs 140 mg QD in patients with advanced CML (accelerated phase or BP) or Ph+ ALL who are resistant or intolerant to imatinib. The primary trial objective was to compare major hematologic response (MaHR) rates with QD or BID dosing. The main secondary objectives were to compare major cytogenetic response (MCyR) rates, time to and duration of response, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Preliminary analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, 2-year results from 149 patients with myeloid BP (MBP) CML (75 QD and 74 BID) and 61 patients with lymphoid BP (LBP) CML (33 QD and 28 BID) are reported. Following dasatinib treatment, durable MaHRs and MCyRs were achieved by patients in both the MBP and LBP groups, and extended PFS and OS were observed in a proportion of patients (Table). Excluding patients that were BCR-ABL positive, Ph negative (n=10), rates of MCyR were comparable. Dasatinib was generally well tolerated, and with both schedules, cytopenias were the most commonly reported AEs. Grade 3/4 treatment-related nonhematologic AEs were infrequent with both schedules, with diarrhea, nausea, headache most commonly reported and each occurring in & lt;7% of each group. In the LBP group, fewer drug-related fluid retention AEs of any grade, including pleural effusions, occurred with QD vs BID dosing. Only one grade 4 pleural effusion occurred (MBP QD group). For both patient populations, fewer QD-treated patients required dose reductions for toxicity. In the MBP group, median durations of dasatinib therapy were 3.3 months (QD) and 3.1 months (BID) and in the LBP group, these were 3.4 months (QD) and 3.6 months (BID). Median average daily doses with QD vs BID dosing were 140 mg vs 138 mg (MBP) and 140 mg vs 123 mg (LBP). Overall, extended follow-up from the CA180-035 study supports preliminary findings and demonstrates the equivalent efficacy of dasatinib 140 mg QD and 70 mg BID in patients with imatinib-resistant or -intolerant CML-BP. QD treatment may be associated with improved tolerability, particularly in the LBP group. Durable responses were observed with both schedules in this high-risk population. Table CML-MBP (n=149) CML-LBP (n=61) 140 mg QD (n=75) 70 mg BID (n=74) 140 mg QDm (n=33) 70 mg BID (n=28) MaHR, n (%) 21 (28) 21 (28) 14 (42) 9 (32) Median duration of MaHR (months) 8 9 5 8 MCyR, n (%) 21 (28) 22 (30) 17 (52) 13 (46) MCyR (excluding BCR-ABL+ Ph−, n=10) (%) 25 28 50 40 Median duration of MCyR (months) 7 10 4 8 24-month PFS (%) 11 18 NA NA 24-month OS (%) 24 28 21 16 Grade 3/4 neutropenia (%) 79 74 79 86 Grade 3/4 thrombocytopenia (%) 81 80 85 86 Fluid retention, any grade (%) 34 31 21 39 Pleural effusion, any grade (%) 20 18 21 36 Pleural effusion, grade 3–4 (%) 5 5 6 4 Pericardial effusion, any grade (%) 0 4 0 7 Discontinuation for drug toxicity n (%) 7 (10) 16 (22) 5 (15) 1 (4)

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.3226.3226

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 123, No. 4 ( 2014-01-23), p. 494-500

Abstract: In a 3-year follow-up of the DASatinib versus Imatinib Study In treatment-Naive CML patients trial, first-line dasatinib resulted in faster and deeper responses compared with imatinib. Deeper responses at 3, 6, and 12 months were associated with better 3-year progression-free survival and overall survival.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2013-06-511592

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 119, No. 5 ( 2012-02-02), p. 1123-1129

Abstract: Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2011-08-376087

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 3224-3224

Abstract: Dasatinib (SPRYCEL®) is the most potent BCR-ABL inhibitor and is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Previous studies have demonstrated the efficacy and safety of dasatinib 70 mg BID for patients with CML-AP who are intolerant or resistant to imatinib. In the phase III CA180-035 study, patients with CML-AP, blast phase CML, or Ph+ ALL were randomized to dasatinib 140 mg QD or 70 mg BID. The primary trial objective was to compare major hematologic response (MaHR) rates between the two schedules. Secondary objectives included a comparison of major cytogenetic response (MCyR) rates, time to and duration of responses, progression-free survival (PFS), overall survival (OS), and safety profiles between the two schedules. Previous analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, 2-year results from the subgroup with CML-AP (n=317) recruited from 97 international sites are reported. Among patients randomized to QD (n=158) or BID (n=159) treatment with dasatinib, rates of MaHR and MCyR were similar (MaHR: 66% vs 68%; MCyR: 39% vs 43%, respectively; Table). Excluding patients that were BCR-ABL positive, Ph negative (n=3), rates of MCyR were nearly identical. Most MaHRs were achieved within 4 months of therapy and most MCyRs were achieved within 6 months. Based on Kaplan-Meier analyses, an estimated 65% vs 60% of patients had maintained a durable MaHR in QD and BID groups, respectively, at 24 months. Estimated PFS rates were 51% vs 55% and OS rates were 63% vs 72%, respectively. Although dasatinib was generally well tolerated with both dose schedules, QD treatment was associated with an improved safety profile compared with BID treatment. Only small increases in AE rates were observed compared with 1-year data. Cytopenias were the most common AEs and for QD vs BID treatment, rates of grade 3/4 events were 59% vs 69% for neutropenia and 64% vs 67% for thrombocytopenia. Fewer drug-related fluid retention events (including pleural effusion, superficial edema, and peripheral edema) were reported in the QD (34%) vs BID (48%) group. In particular, significantly fewer patients experienced a pleural effusion with QD vs BID treatment (p & lt;0.001, all grades). No grade 4 pleural effusions occurred. Pleural effusions were manageable and led to treatment discontinuation in only 5% (QD) and 9% (BID) of patients. Grade 3/4 nonhematologic AEs were reported in less than 7% of all QD and BID patients and included dyspnea (3% vs 7%) and diarrhea (3% in both groups). Median durations of dasatinib therapy were 15 months (QD) and 12 months (BID), and median values of mean daily doses were 138 mg and 110 mg, respectively. Fewer dose reductions (38% vs 50%) and interruptions (64% vs 74%) occurred in the QD group. At the time of analysis, 34% of the QD group and 35% of the BID group remained on study, with a median duration of therapy of 23 months in both groups. Overall, extended follow-up from the CA180-035 study confirms earlier findings and demonstrates that in patients with CML-AP with imatinib resistance or intolerance, dasatinib 140 mg QD has equivalent efficacy to dasatinib 70 mg BID but with an improved safety profile. Similar durable responses were observed with both schedules. Table Patients (%) QD (n=158) BID (n=159) MaHR 66 68 MCyR 39 43 MCyR (excluding BCR-ABL+ Ph−, n=3) 38 43 24-month PFS 51 55 24-month OS 63 72 Neutropenia, grade 3/4 59 69 Thrombocytopenia, grade 3/4 64 67 Pleural effusion (drug-related) All grades 20 39 Grade 3 7 6 Interruption 38 50 Reduction 64 74

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.3224.3224

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 2926-2926

Abstract: Patients with ALL who have the Ph chromosome rearrangement and the resulting BCR-ABL oncogene represent 20–40% of cases of adult ALL and have an adverse prognosis. Even with current standard therapies, which comprise aggressive multi-agent chemotherapy, imatinib, and allogeneic stem cell transplant, there is a high risk of relapse. Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor, and has 325-fold greater potency than imatinib against unmutated BCR-ABL in vitro. Dasatinib is also active against SRCfamily kinases, which may have a role in Ph+ ALL pathogenesis. Following a phase II trial, dasatinib was approved for the treatment of imatinib-resistant or -intolerant Ph+ ALL. CA180-035 is a randomized, phase III, open-label trial comparing dasatinib 140 mg QD with 70 mg BID in patients with advanced CML (accelerated or blast phase) or Ph+ ALL. The primary trial objective was to compare the major hematologic response (MaHR) rates of QD and BID dosing schedules. Secondary objectives included comparison of major cytogenetic response (MCyR) rates, time to and duration of response, progressionfree survival (PFS), overall survival (OS), and safety profiles between the two schedules. Preliminary analyses from this study have demonstrated that QD treatment is associated with equivalent efficacy and less frequent key adverse events (AEs) compared with BID treatment. Here, results are reported in 84 patients with Ph+ ALL randomized to QD (n=40) or BID (n=44) schedules with a minimum of 2 years of follow-up. MaHR rates were similar with dasatinib administered QD (38%) or BID (32%), and all MaHRs were achieved within 4 months. Of the 15 patients (QD) and 14 patients (BID) who achieved a MaHR, median durations were 4.6 and 11.5 months, respectively. A MCyR was achieved by 70% (QD) and 52% (BID) of patients, with median durations of 4.1 and 4.4 months, respectively. Excluding patients that were BCR-ABL positive, Ph negative (n=11), rates of MCyR were nearly identical (QD 69% vs BID 51%). Estimated 24-month rates of OS were similar in QD and BID groups (11% vs 20%; hazard ratio 1.26, 95% CI 0.78–2.04). Dasatinib was generally well tolerated. The most common grade 3/4 nonhematologic AEs in both groups included diarrhea (5% in both groups) and nausea (QD 3% vs BID 5%). Fewer patients experienced a pleural effusion when dasatinib was administered QD (all grades, 18%; grade 3–5, 5%) vs BID (all grades, 32%; grade 3–5, 14%). The incidence of grade 3/4 cytopenia was similar in both groups, including neutropenia (QD 67% vs BID 72%) and thrombocytopenia (QD 72% vs BID 61%). Fewer patients required dose reductions for toxicity with QD (10%) vs BID (23%) treatment. Median durations of dasatinib therapy were 3.4 months in the QD group and 2.5 months in the BID group, although these were longer in patients who achieved a MaHR (4.6 and 5.9 months, respectively). Median average daily doses were 140 mg (QD) and 138 mg (BID). At last follow-up, most patients had discontinued therapy, with disease progression (QD 70% vs BID 75%) the most common cause. In conclusion, findings from the CA180-035 trial in patients with Ph+ ALL are consistent with previous data and demonstrate that dasatinib is associated with durable treatment responses in a proportion of patients with a poor prognosis who are resistant or intolerant to imatinib. Compared with the approved BID dosing schedule, dasatinib administered as a once-daily dose has equivalent efficacy, provides greater convenience, and may have improved safety in this patient group.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.2926.2926

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 583-583

Abstract: Introduction: The programmed death-1 (PD-1) immune checkpoint pathway regulates T-cell-mediated antitumor immune responses in solid tumors and hematologic malignancies. Nivolumab (Bristol-Myers Squibb, Ono Pharmaceutical) is a fully human IgG4 PD-1-blocking monoclonal antibody with demonstrated efficacy in a range of tumors. Results from an independent cohort of 23 pts with R/R cHL in a phase 1 study (CA209-039) showed that nivolumab was well tolerated and yielded an overall response rate (ORR) of 87% (Ansell et al, N Engl J Med, 2015). This raises important questions including the necessary duration of treatment, the relevance of the depth of response (complete response [CR] vs partial response [PR] ), the duration of response, and the feasibility of retreatment. Here, we present the clinical course and post-treatment outcomes from extended follow-up of these pts to shed some light on these questions. Methods: Pts with R/R cHL received nivolumab 3 mg/kg at weeks (wks) 1 and 4, and then every 2 wks for up to 2 years (yrs). Therapy was stopped earlier in pts with intolerance to treatment or progressive disease (PD) without evidence of clinical benefit. Pts who discontinued treatment due to toxicity were followed for up to 120 days after discontinuation; other pts were followed for 1 yr after discontinuation. Responding pts discontinued after confirmed CR or 16 wks after unconfirmed CR, or continued treatment for up to 2 yrs if they had PR or stable disease (SD). Pts who discontinued treatment with ongoing CR, PR, or SD could be retreated for confirmed PD occurring 〈 1 yr after nivolumab discontinuation. Responses were evaluated using the Revised Response Criteria for Malignant Lymphoma (Cheson et al, J Clin Oncol, 2007). The primary endpoint was safety, and the key secondary endpoint was antitumor activity. Results: A total of 23 pts with R/R cHL were treated. The median follow-up observation time is now 86 wks (range: 32-107 wks). Of 20 responders (14 PR, 6 CR), 10 have had durable responses per protocol assessment; their treatment durations and response characteristics are shown in Table 1. Responses were maintained in 2 pts (#5 and #6) after discontinuing nivolumab for 〉 40 wks and in 1 pt (#7) after stopping due to toxicity. Eight pts with durable responses have received nivolumab for 〉 1 yr, including 7 pts who have been in response for 〉 1.5 yrs. One pt (#2) with an initial CR experienced a relapse 43 wks after treatment was discontinued, and achieved a second response (CR) after retreatment with nivolumab. Of the 10 remaining responders, 4 eventually progressed (time to progression [TTP] range: 21.4-92 wks), 1 discontinued treatment due to toxicity with no PD within the 120-day follow-up period, and 5 discontinued nivolumab to undergo stem cell transplant (SCT; 4 allogeneic, 1 autologous) after achieving remission. Time to CR for all responders ranged from 3-88 wks after starting nivolumab, including 2 pts with initial PRs that converted to CRs with continued treatment. All 5 pts who proceeded to SCT had responded to nivolumab within 16 wks of starting treatment (4 PR, 1 CR). Three pts had a best overall response of SD (1 discontinued due to toxicity without documented PD within the 120-day follow-up period; 2 subsequently discontinued for PD [TTP: 15 and 15.3 wks, respectively] ). Overall, 3 pts discontinued nivolumab due to adverse events (AEs; Grade 2 peripheral neuropathy, Grade 3 myelodysplastic syndrome, Grade 3 pancreatitis). Grade 1 or 2 immune-related AEs (IR-AEs) occurred in 4 of 10 pts and resolved without treatment in 2 pts. The incidence of IR-AEs did not increase with time on treatment. Conclusions: In pts with R/R cHL, nivolumab was well tolerated and produced a high ORR. Responses occurred within 16 wks of nivolumab initiation in 15 of 20 pts. Early responses to nivolumab allowed 5 pts to proceed to SCT and lasted ≥1 yr in 7 of 10 pts who did not pursue SCT. One pt achieved CR again after retreatment with nivolumab when relapse occurred within 1 yr of discontinuing treatment following an initial CR. Table 1. Treatment and Response Parameters for Pts with Durable Ongoing Responses Pt # Best Response Duration of Response, wks Time to First Response, wks Time on Treatment, wks 1 PR 90.7 3.6 96+ 2 CR 82.1 7.1 91+ 3 PR 73.1 7.6 82.4+ 4 PR 71.4 14.9 88+ 5 CR 71.1 3.1 24.9 6 CR 65.1 7.1 22.9 7 PR 55.9 15.3 70.9 8 CR 48.3 39 87 9 CR 45.3 55 82.9 10 PR 41.7 38.7 82.1+ +Still on treatment Disclosures Ansell: Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding. Timmerman:Valor Biotherapeutics: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Bradley Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.583.583

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. TPS9594-TPS9594

Abstract: TPS9594 Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m 2 twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m 2 (Zwaan, Blood 2010 [abstr 2265]). Further study of dasatinib in pediatric pts is warranted. Methods: To evaluate the safety and efficacy of dasatinib monotherapy in children/adolescents with newly diagnosed CML-CP or Ph+ leukemias resistant/intolerant to imatinib, a phase II nonrandomized, global study of dasatinib in pts birth to 〈 18 y is ongoing (NCT00777036): Cohort 1 (C1), Ph+ CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph+ ALL, accelerated or blast phase CML pts resistant/intolerant to or relapsed after imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph+ CML-CP pts. Treatments are once daily with dasatinib 60 mg/m 2 (C1/C3) or 80 mg/m 2 (C2) for ≥24 months. Primary endpoints are major CyR (C1), complete hematologic response (C2), and complete CyR (C3). Secondary endpoints include safety, tolerability, best response, time to/duration of response, survival, and molecular response rates. BCR-ABL mutations are evaluated. First patient first visit was March 2009; estimated trial completion is September 2016. As of January 2012, 63 pts (n=27 aged 〈 12 y; n=36 aged ≥12 y) have been treated in C1/C2 (n=41) and C3 (n=22). Enrollment is ongoing at 79 sites.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2012.30.15_suppl.tps9594

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2012

detail.hit.zdb_id: 2005181-5

In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 6504-6504

Abstract: 6504 Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P 〈 0.0001; MR 4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR 4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v 〈 1%), death (2% v 〈 1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.

Type of Medium: Online Resource

ISSN: 0732-183X , 1527-7755

URL: Article

DOI: 10.1200/jco.2012.30.15_suppl.6504

Language: English

Publisher: American Society of Clinical Oncology (ASCO)

Publication Date: 2012

detail.hit.zdb_id: 2005181-5

In: Leukemia & Lymphoma, Informa UK Limited, Vol. 55, No. 9 ( 2014-09), p. 2093-2100

Type of Medium: Online Resource

ISSN: 1042-8194 , 1029-2403

URL: Article

DOI: 10.3109/10428194.2013.866663

Language: English

Publisher: Informa UK Limited

Publication Date: 2014

detail.hit.zdb_id: 2030637-4