Dasatinib (SPRYCEL®) 50mg or 70mg BID Versus 100mg or 140mg QD in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Resistant or Intolerant to Imatinib: Results of the CA180-034 Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 166-166 ◽  
Author(s):  
Andreas Hochhaus ◽  
D.W. Kim ◽  
P. Rousselot ◽  
P.E. Dorlhiac-Llacer ◽  
J. Milone ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Hematologic Toxicity ◽  
Inadequate Response ◽  
Previous Response ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Phase II studies of dasatinib (SPRYCEL®, formerly BMS-354825), an oral multi-targeted kinase inhibitor of BCR-ABL and SRC kinases, have demonstrated the efficacy and safety of a 70mg twice daily (BID) dose in CML-CP patients (pts) with resistance or intolerance to imatinib (im). A phase I trial of dasatinib (N Engl J Med 2006;354:2531–41) had shown complete hematologic responses (CHR) and major cytogenetic responses (MCyR) at total daily doses of 100mg and 140mg daily in both BID and once daily (QD) schedule in CML-CP pts. The primary objective of the present study was to compare 6 month (mo) cytogenetic response (CyR) rates among the BID and QD regimens of dasatinib. Secondary objectives included estimating differences in CyR rates between the total daily doses of 100 and 140mg, and safety across the arms to optimize the dose and schedule of the drug. Dasatinib was administered according to one of 4 arms: 50mg BID, 70mg BID, 100mg QD or 140mg QD. Dose escalation to 90mg BID or 180mg QD and reduction to 40mg BID or 80mg QD were allowed for inadequate response or adverse events (AEs), respectively. Evaluation included complete blood counts every 2 weeks x 6 then every 3 mo; bone marrow cytogenetics at mo 3, 6 and then every 6 mo; and qPCR monthly x 3 then every 3 mo. A total of 670 pts were randomized and 663 treated in 139 worldwide sites from July 2005 to March 2006. Median age was 55 years and 47% were male. The median time from CML diagnosis to randomization was 54 mo. All pts received prior im: <1% had <400mg/d, 66% had 400–600mg/d and 34% had >600mg/d. The best previous response to im was CHR in 83% and MCyR in 42%. Prior treatment for CML included interferon alpha in 52%, chemotherapy in 27% and stem cell transplantation in 5% of cases. With a median follow-up of 3 mo, the overall CHR rate for the entire population is 80% and MCyR rate is 37% as of August 2006. 44% of pts required a dose interruption; 25% were due to hematologic toxicity and 14% due to non-hematologic toxicity; 28% required a dose reduction of which 13% were due to hematologic toxicity and 6% due to non-hematologic toxicity; the remainder of dose interruptions and reductions were due to other (including dosing error) or unknown reasons. 3% of pts had a dose escalation typically due to lack of CHR after 3 mo or no decrease in WBC after 1 mo. 601 (90%) pts remain on the trial with the majority of discontinuations for disease progression or study drug toxicity. Grade 3–4 neutropenia and thrombocytopenia occurred in 35% and 30% of pts, respectively. AEs considered drug related by the investigators included headache 24%, diarrhea 20%, nausea 16%, fatigue 12%, rash 11%, edema 10%, dyspnea 7%, pleural effusion 7%, myalgia 7%, arthralgia 5%, anorexia 4%, pneumonia 1%, and gastrointestinal hemorrhage 1%. Rare AEs that were considered drug-related by the investigators included congestive heart failure in 4 pts, and cardiac dysfunction, pulmonary hypertension, pulmonary edema and pericardial effusion in 3 pts each. Other AEs regardless of relationship to study drug included grade 3–4 creatinine elevation in 4%, grade 3–4 transaminase elevation in <1%, and grade 3–4 hypocalcemia in 1% of pts. Updated safety and efficacy data on all treatment groups with a minimum of 6-months of follow-up will be presented at the meeting.

Dasatinib (SPRYCEL®) vs Escalated Dose of Imatinib (im) in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Resistant to Imatinib: Results of the CA180-017 START-R Randomized Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 167-167 ◽  
Author(s):  
Neil Shah ◽  
R. Pasquini ◽  
P. Rousselot ◽  
S. Jootar ◽  
J. Holowiecki ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Dose Escalation ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Inadequate Response ◽  
Grade 3

Abstract Pts with CML resistant to im have few therapeutic options. A growing body of evidence suggests that treatment outcomes can be improved with increased potency of BCR-ABL inhibition. Escalating the dose of im to 800mg/day (d) can overcome some cases of im-resistance, but tolerability and durability of response are significant issues. Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL, SRC, and other kinases that is approximately 300 times more potent than im in vitro. Dasatinib has been shown to be effective and safe in pts with CML resistant or intolerant to im, leading to recent FDA approval. START-R is an international trial of dasatinib 70mg twice daily (BID) and im 800mg/d in pts with CP-CML resistant to prior im 400–600mg/d. Crossover was allowed upon confirmed progression or intolerance despite dose reduction (grade 3/4 non-hematologic toxicity). Dasatinib dose escalation to 90mg BID was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40mg BID for toxicity. Dose reduction of im to 600mg/d was allowed for patients who had not previously received that dose. Major cytogenetic response (MCyR) rate at 12 weeks was the primary endpoint. From Feb–Nov 2005, 150 pts were randomized (2:1), 101 to dasatinib, 49 to im. MCyR to prior im had been seen in 28% of dasatinib and 29% of im pts. With a minimum follow-up of 10 mo, complete hematologic response (CHR) rate was 92% (93 dasatinib pts) vs 82% (40 im pts), and MCyR rate was 48% dasatinib vs 33% im. Of importance, the primary difference was the complete cytogenetic response (CCyR) rate of 35% (35/101) dasatinib vs 16% (8/49) im, suggesting that dasatinib can achieve deeper responses in this patient population. Of pts with no prior CyR to im, 44% (17/39) achieved a MCyR with dasatinib vs 7% (1/15) with higher dose im. MCyR rates of 40% to dasatinib and 20% to im were achieved in pts with baseline im-resistant BCR-ABL mutations, with 47% of dasatinib pts vs 0 im pts with difficult-to-treat P-loop mutations achieving a MCyR. Pts with no prior CyR to im were able to achieve MCyR with dasatinib, but dose escalation of im was not effective. 23% dasatinib pts vs 80% im pts had treatment failure (TF, defined as progression, lack of response, crossover for intolerance, or off treatment). Median time to TF was not reached for dasatinib, and was 3.5 mo (95% CI: 3.3-3.8) for im. 61 pts discontinued the initially assigned treatment, of whom 50 (12 dasatinib; 38 im) crossed over after progression, no response, or intolerance. Of 45 post-crossover pts (38 dasatinib; 7 im), 17 (45%) dasatinib pts achieved MCyR, but no (0%) im pts with 800mg/d achieved MCyR after crossover following dasatinib. Grade 3/4 non-hematologic toxicity was minimal in both arms. All grades of superficial edema and fluid retention were more common with im than dasatinib (41% im vs 15% dasatinib; and 43% im vs 28% dasatinib respectively), whereas pleural effusion was 13% (3% grade 3/4) dasatinib vs 0 im. Cytopenia was more frequent and severe with dasatinib. This is the first clinical trial in pts with CML to include both im and dasatinib arms. Based on nearly 1 year of follow-up, dasatinib clearly appears to be more effective in achieving MCyR than high-dose im in pts who fail 400–600mg/d im. An update with molecular response data and detailed mutational analysis will be presented.

Dasatinib in patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to imatinib: Results of the CA180013 ’START-C’ Study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6508-6508 ◽  
Author(s):  
A. Hochhaus ◽  
H. Kantarjian ◽  
M. Baccarani ◽  
F. Cervantes ◽  
T. Facon ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Response Analysis ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3 ◽  
Dose Reductions

6508 Background: Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with proven preclinical and clinical activity against imatinib resistant BCR-ABL mutations. Methods: CA180013 is an open-label Phase II study of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients (pts) with CP-CML. Between February-August 2005, 424 pts were recruited from 75 centers worldwide. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity. Evaluations were weekly blood counts for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. The primary endpoint was rate of major cytogenetic response (MCyR; ≤35% Philadelphia pos. metaphases) in IM-R pts. Results: Data are currently available from the first 186 pts (127 IM-R, 59 IM-I) accrued prior to May 12, 2005. Median age was 59 yrs (range 24–79); 46% were male. Median time from diagnosis of CML was 64 months. Of the IM-R pts, 72% received IM >3 yrs, and 72% had >600 mg/day of IM. Overall, 70% had received prior interferon alpha. 62 (33%) pts achieved a prior MCyR to IM. With ≥6 months of follow up, 168 (90%) pts had a complete hematologic response (CHR). MCyR were achieved in 83 (45%) pts including 40 (31%) of IM-R pts, and 43 (73%) of IM-I pts. Mutations in the BCR-ABL domain were found in 65/176 (37%) pts; 57 (88%) achieved CHR, and 24 (37%) MCyR. Molecular response analysis is ongoing. 160 (86%) pts remain on study without progression. Grade 3/4 neutropenia or thrombocytopenia was reported in 83 (45%) pts and 85 (46%) pts with onset after 4–8 weeks of therapy in most pts. Temporary dose interruptions occurred in 146 (78%), and dose reductions in 96 (52%) pts with a median daily of 108 (range 19–169) mg. Non-hematologic toxicity consisted mainly of Grade 1/2 diarrhea, headache, superficial edema, and pleural effusion, with ≤2% Grade 3/4. There was no cross-intolerance between dasatinib and IM. Conclusions: Dasatinib demonstrated substantial hematologic and cytogenetic activity in IM-R and IM-I pts with CP-CML. An updated analysis of 424 pts with ≥6 months of follow up will be presented. [Table: see text]

Dasatinib or High-Dose Imatinib for Patients with Chronic-Phase Chronic Myeloid Leukemia Resistant to Standard-Dose Imatinib: 2-Year Follow-Up Data from START-R (CA180-017).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 736-736 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Philippe Rousselot ◽  
Ricardo Pasquini ◽  
Nelson Hamerschlak ◽  
Jerzy Holowiecki ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Reduction ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Inadequate Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Resistance to imatinib is a well-recognized problem in chronic-phase chronic myeloid leukemia (CP-CML). Increased potency of BCR-ABL inhibition by escalating imatinib doses to 800 mg/d (‘high-dose imatinib’) can be effective in some cases that are resistant to lower doses, but tolerability and durability of response limit the utility of this approach. Dasatinib (SPRYCEL®) has been shown to be effective in imatinib-resistant CML and its potency against BCR-ABL relative to imatinib (325-fold more potent against BCR-ABL in vitro) as well as its activity against nearly all imatinib-resistant BCR-ABL kinase domain mutations auger its potential in this setting. In this international phase-II study, 150 patients with CP-CML resistant to imatinib 400–600 mg/d were randomized on a 2:1 basis to dasatinib 70 mg BID (n=101) or imatinib 800 mg/d (n=49). Crossover was permitted for confirmed progression, lack of major cytogenetic response (MCyR) at 12 weeks, or intolerance despite dose reduction (grade 3–4 non-hematologic toxicity). Dasatinib dose could be escalated to 90 mg BID for inadequate response at 12 weeks, or reduced to 50 or 40 mg BID for toxicity. Dose reduction of imatinib to 600 mg/d was allowed for patients who had not previously received that dose. Median treatment duration with dasatinib was 13.7 mo and 3.1 mo with imatinib. With a median follow-up of 15 mo, complete hematologic response (CHR) rates were 93% and 82% for patients receiving dasatinib and high-dose imatinib, respectively (p=0.034). Dasatinib was also associated with higher MCyR rates (52% vs 33%, p=0.023); the difference being attributable to complete cytogenetic responses (40% vs 16%, p=0.004). For patients with no prior CyR to imatinib, 49% achieved a MCyR with dasatinib vs 7% with high-dose imatinib. Major molecular responses were also more frequent with dasatinib (16% vs 4%, p=0.038). Responses achieved with dasatinib were highly durable, and superior to historic experience with imatinib. Analyses of progression-free survival (PFS) favored dasatinib (hazard ratio [HR] 0.14, p<0.0001). Results were consistently in favor of dasatinib for PFS irrespective of the prior imatinib dose received (400 mg/d - HR 0.10, p=0.0177; 600 mg/d - HR 0.15, p=0.0005). Grade 3–4 non-hematologic toxicity was minimal for both treatment groups. All-grade superficial edema (15% vs 43%) and fluid retention (30% vs 45%) were less common with dasatinib than imatinib, whereas pleural effusion (17% vs 0%; grade 3–4, 4% vs 0%) was more common. Cytopenia was more frequent and severe with dasatinib. Treatment discontinuation attributable to toxicity occurred in 7% of patients receiving dasatinib and 18% treated with imatinib. The overall benefit-risk assessment favors dasatinib relative to high-dose imatinib in CP-CML patients with resistance to 400–600 mg imatinib. Updated results reflecting a minimum follow-up of 2 years will be presented.

Dasatinib (D) vs high dose imatinib (IM) in patients (pts) with chronic phase chronic myeloid leukemia (CP-CML) resistant to imatinib. Results of CA180017 START-R randomized trial

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6507-6507 ◽  
Author(s):  
N. P. Shah ◽  
P. Rousselot ◽  
R. Pasquini ◽  
N. Hamerschlak ◽  
J. Holowiecki ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Inadequate Response ◽  
The Difference ◽  
Grade 3

6507 Background: High dose imatinib (800 mg/day) has been shown to have efficacy in a subset of CML patients with resistance to IM, although the durability of responses is not well-established. Dasatinib (BMS-354825) is a novel, highly potent, oral multi-targeted kinase inhibitor of BCR-ABL and SRC with activity against 18/19 imatinib resistant BCR-ABL mutants tested in vitro. Methods: START-R is a multicenter randomized (2:1 ratio) trial of D 70 mg twice daily (bid) and IM 800 mg/day in pts with CP-CML resistant to prior IM 400 to 600 mg/day. Cross-over was allowed for lack of response or intolerance (grade 3–4 non hematologic toxicity). D dose escalation to 90 mg bid was allowed for inadequate response at 12 wks, and dose reduction to 50 or 40 mg bid for drug toxicity. IM dose reduction to 600 mg/day was allowed. Evaluations consisted of weekly blood counts for the first 12 wks, bone marrow cytology and cytogenetics every 12 wks. The primary endpoint was major cytogenetic response (MCyR) rate at wk 12. Results: From February 2005 to November 2005, 150 pts were randomized of whom the first 36 pts (D 22, IM 14) are reported. Median age was 57 yrs, with 12 males and 24 females. Treatment groups were balanced with respect to CML characteristics; median time from initial diagnosis was 61 months for D and IM; prior interferon 64% and 79%; no prior CyR on IM 36% and 57%. BCR-ABL mutations were documented in 10 D pts and 1 IM pt. Dose reductions were required in 8 D pts and 1 IM pt. Complete hematologic response was documented in 21 D and 13 IM pts. MCyR rate at 12 wks was 45% for D and 21% for IM (7 complete for D and 1 for IM). With a 95% CI on the difference between D and IM was - 9.9 to +51.2. Two (9%) D and 11 (79%) IM pts crossed over for intolerance (1 D and 6 IM) or no MCyR (1 D and 5 IM). Grade 3–4 neutropenia or thrombopenia occurred in 8 and 9 dasatinib pts and in 8 and 2 IM pts. Most common grade 1–2 non-hematologic toxicities in D and IM groups were diarrhea (7 and 1 pts), nausea (7 and 7 pts), and facial/peripheral edema (8 and 7 pts). Conclusions: Dasatinib was effective in pts with CP-CML resistant to IM 400 to 600 mg/day. Preliminary data suggest that D is more effective and better tolerated than high dose IM. An updated analysis of all randomized pts will be presented. [Table: see text]

Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1047-1047
Author(s):  
Hagop M. Kantarjian ◽  
Brian J. Druker ◽  
Francois Guilhot ◽  
Jorge Cortes ◽  
Stephen G. O’Brien ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Separate Analysis ◽  
Inadequate Response ◽  
Durable Response ◽  
Entire Cohort ◽  
The Impact

Abstract Background: Imatinib mesylate (IM) 400 mg/d is the standard of care for newly diagnosed patients (pts) with CML-CP. Dose escalation to 600 or 800 mg IM has been shown to be beneficial in patients with either an inadequate response or disease progression while on standard therapy (Kantarjian et al Blood 2003). In the International Randomized study of Interferon versus STI571 (IRIS) trial, initiated in 2000, dose escalation was allowed for patients who did not achieve a complete hematologic response (CHR) by 3 months or a minor cytogenetic response (minCyR) by 12 months, lost a major cytogenetic response (MCyR) at any time, or progressed (including increase in WBC); no dose escalation in cases of loss of CCyR were specified. The impact of IM dose escalation for patients on IRIS is presented in this post-hoc analysis. Methods: Patients were evaluated for hematologic and cytogenetic responses, progression (to accelerated or blast phase) free survival (PFS), and overall survival (OS) following dose escalation. Patients were included if their dose was increased within −0.5 to 3 months following the respective landmark evaluation. Instances of dose escalation (to ≥600 mg/d) on the IM arm were reviewed and classified, where possible, based on either criteria established by IRIS protocol or the European LeukemiaNet recommendations Results: Of 551 patients receiving first line IM, 106 pts (19%) had dose escalation to 600–800 mg/d. Median time to dose escalation was 22 months (range:3–74 months; 25th–75th percentile: 13–45 months). After dose escalation the median imatinib dose delivered was 604 mg/d (range: 294–800 mg/d; 25th–75th percentile:600–739 mg/d) and remained on treatment for a median of 19.4 months based on current follow-up. Last recorded dose was ≥600mg/d in 85% of these patients. Dose increases in 39 patients were based on the IRIS protocol criteria. Responses among these patients included: 6 of 7 who had not achieved CHR at 3 months achieved a CHR with dose escalation, 2 of these patients subsequently achieved a CCyR. Of 8 patients who had not achieved a minCyR at 12 months, 4 improved to a CCyR, and of 18 patients who lost their MCyR, 9 subsequently re-achieved an MCyR within 12.5 months after dose escalation, of whom 3 also attained a CCyR by 30-months after dose escalation. The 6 patients who received dose escalations upon progression, had an OS of 83% at 2 years after dose escalation. At 36-months after dose escalation the 39 patients dose escalated per IRIS protocol criteria achieved an estimated PFS and OS of 81%. In a separate analysis of these 106 pts, dose escalations in 48 pts were retrospectively classified according to the ELN recommendations. At 36-months follow-up after dose escalation these 48 patients achieved a 90% PFS and 89% OS. For the entire cohort of 106 patients who were dose escalated, estimated PFS was 89% and OS was 84% at 36 months after dose escalation. Conclusion: Based on these data, IM dose escalation to 600 and/or 800 mg allows poorly responding patients to achieve a clinically important durable response or re-gain responses. These slower responding or progressing patients benefited from IM dose escalation and thus, the data support dose escalation for these patients.

Dasatinib (SPRYCEL®) Efficacy and Safety in Patients (pts) with Chronic Myelogenous Leukemia in Lymphoid (CML-LB) or Myeloid Blast (CML-MB) Phase Who Are Imatinib-Resistant (Im-r) or -Intolerant (Im-i).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 745-745 ◽  
Author(s):  
Giovanni Martinelli ◽  
A. Hochhaus ◽  
S. Coutre ◽  
J.F. Apperley ◽  
N. Shah ◽  
...  
Keyword(s):  
Median Duration ◽  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Blast Phase ◽  
Phase Ii Studies ◽  
Grade 3

Abstract Pts with CML-LB or CML-MB have a poor prognosis with survival from onset of blast crisis of 3–6 months. Dasatinib (SPRYCEL®, formerly BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC, which results in complete hematologic and cytogenetic responses in pts with CML-LB or CML-MB who are Im-i, or who have disease that is Im-r. Between January and June 2005, 48 CML-LB pts were enrolled in the START-L trial, and 109 CML-MB pts in the START-B trial both of which were open label, multi-center, global phase II studies. As previously reported, with a minimum of 6-months follow up in the combined blast-phase pts, the major hematologic response (MHR) rate was 32% including 26% complete hematologic responses (CHR) and the major cytogenic response (MCyR) rate was 38%, including 31% complete cytogenetic responses (CCyR). The median duration of MHR had not been reached and the median progression-free survival (PFS) was 4.3 months (mo). In both studies, dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out at pretreatment and at the time of CCyR. Overall, among all blast-crisis pts in both studies, 90% were Im-r. Due to the small number of Im-i pts, data for all pts is presented. Among the 157 pts, 56% were male, with a median age of 54 years (range 17–81). The median time from diagnosis of CML was 45 mo (range 2–216). Prior therapy included Im &gt;600 mg/d in 50%, with Im for &gt;3 years in 36% and stem cell transplantation in 19% of the pts. At baseline, 57% of pts had WBC &lt;20,000/mm3, 69% had platelets &lt;100,000/mm3, and 17% had extramedullary disease outside of the spleen. In the 149 pts with baseline mutation data, Im-resistant BCR-ABL mutations were observed in 50%. With a minimum of 9 mo follow up on all pts, 19% pts remained on treatment with disease progression as the most common reason for discontinuation. Overall, doses were reduced in 33% of pts and interrupted in 59%, most commonly due to non-hematologic toxicities. Dasatinib dose was escalated in 43% of pts. The median duration of therapy was 3.4 mo (0.03–18) in all pts and was 14 mo (6–18) in pts still on treatment. The MHR rate was 34% including 27% CHR; the MCyR was 38% including 31% CCyR. Of the 73 pts with baseline mutations, the MHR rate was 32%. The median duration of MHR still has not been reached and the median PFS was 4.3 mo. Among all pts, grade 3–4 thrombocytopenia occurred in 17% and 68%, respectively and grade 3–4 neutropenia was observed in 17% and 63%, respectively. Most frequent non-hematologic toxicities included diarrhea in 37% (grade 3–4, 5%), pleural effusion in 27% (grade 3–4, 11%), vomiting in 22% (grade 3–4, 3%), nausea in 20% (grade 3–4, 3%), and fatigue in 21% (grade 3–4, 3%) of pts. Dasatinib has efficacy in pts with blast phase CML including some with substantial duration of response and PFS. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Efficacy and Safety of Nilotinib in Elderly Patients with Imatinib-Resistant or -;Intolerant Chronic Myeloid Leukemia (CML) in Chronic Phase (CP): A Sub-Analysis of the ENACT (Expanding Nilotinib Access in Clinical Trials) Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3286-3286 ◽  
Author(s):  
Philipp D. le Coutre ◽  
Anna Turkina ◽  
Dong-Wook Kim ◽  
Bernadeta Ceglarek ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Abstract 3286 Poster Board III-1 Introduction: Nilotinib, a potent and highly selective BCR-ABL kinase inhibitor, is approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CML-CP) and accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. The ENACT study is a Phase IIIb, open-label, multicenter study that evaluated the efficacy and safety of nilotinib in adult pts with imatinib-resistant or intolerant CML in a clinical practice setting outside of a registration program. It is the largest single source of efficacy and safety information of any available tyrosine kinase inhibitor (TKI) in CML, particularly among the elderly. Methods: The present is a sub-analysis of the ENACT study on the efficacy and safety of 400 mg twice daily nilotinib in elderly (aged =60 years) pts initiating treatment in CML-CP who were resistant and/or intolerant to imatinib. Results: Of the 1,422 CML-CP pts enrolled in the ENACT study between January 2006 and October 2008, 452 (32%) were elderly (=60 years) at study initiation and 165 (37%) of these pts were =70 years [10 (2%) were =80 years]. Countries that enrolled =20 elderly pts include France, Italy, USA, Germany, UK, Spain, Canada, and Brazil. At study initiation, elderly pts had longer median durations of CML (<60: 51.1 months; =60: 69.3; =70: 66.6) and higher proportions with CML duration >5 years (<60: 43%; =60: 56%; =70: 52%). Besides imatinib, prior CML treatments received by elderly pts included dasatinib (=60: 20%; =70: 19%), cytarabine (=60: 23%; =70: 19%), busulfan (=60: 10%; =70: 7%), and interferons (=60: 50%; =70: 42%). Elderly pts were previously treated with imatinib for longer median durations (<60: 27.4 months; =60: 32.7; =70: 29.9), with higher proportions treated for >5 years (<60: 12%; =60: 19%; =70: 18%). The proportion of imatinib-intolerant to resistant elderly pts was about 1:1, which was higher than the proportion among <60 pts at about 0.6:1, such that relatively few elderly pts had prior highest imatinib dose >800 mg (<60: 34%; =60: 26%; =70: 21%). While response rates to prior imatinib were similar, among pts who required therapy after failing imatinib, elderly pts had lower cytogenetic response rates (<60: 22%; =60: 17%; =70: 19%) to prior dasatinib. During ENACT, less than 50% of elderly pts experienced nilotinib dose interruptions (=60: 46%; =70: 41%) and reductions (=60: 7%; =70: 6%) lasting >5 days, which was consistent with the overall ENACT dataset. The median duration of dose interruptions and reductions was 15 (=70: also 15) and 41 (=70: 32) days, respectively. The main reason for dose interruptions and reductions was adverse events (AEs). The median duration of nilotinib exposure was 227 days (=70: 219) and the median dose intensity was 749 mg/day (=70: 775). Efficacy was similar among elderly pts, with 39% (=70: 35%) of pts achieving complete hematologic response (CHR), 41% (=70: 39%) achieving major cytogenetic response (MCyR) and 31% (=70: 33%) achieving complete cytogenetic response (CCyR). MCyR rate was also similar among elderly hematologic responders (=60: 64%; =70: 65%). Among elderly pts requiring nilotinib therapy after both imatinib and dasatinib, and therefore have more resistant CML, CHR rate was 39% (=70: 32%), MCyR rate was 28% (=70: 29%) and CCyR rate was 20% (=70: 16%). Safety was likewise similar among elderly pts, with grade 3/4 study drug-related AEs occurring in 56% of pts (=70: 53%). The most frequent of these AEs were thrombocytopenia (=60: 24%; =70: 21%) and neutropenia (=60: 14%; =70: 11%). The most common method of managing these AEs was brief dose interruptions and/or reductions [thrombocytopenia (=60:86/108 pts; =70: 30/35), neutropenia (=60: 42/62 pts; =70: 9/18)]. Among elderly pts with prior dasatinib, 53% (=70: 58%) experienced grade 3/4 study drug-related AEs, while 7 out of 8 pts with pleural effusion on dasatinib no longer had it on nilotinib. Conclusions: In ENACT, pts aged =60 years at study initiation appear to have longer durations of CML, be more heavily pre-treated and more intolerant to imatinib than the younger cohort. Nonetheless, nilotinib induced comparable clinical responses in CML-CP pts regardless of age. Importantly, the safety profile of nilotinib is maintained in elderly pts. Disclosures: le Coutre: Novartis: Honoraria, Research Funding; BMS: Honoraria. Turkina:Novartis Pharmaceuticals: Honoraria. Kim:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Ceglarek:Novartis Pharmaceuticals: Honoraria. Shen:Novartis Pharmaceuticals: Honoraria. Smith:Novartis Pharmaceuticals: Honoraria. Rizzieri:Novartis Pharma: Honoraria, Research Funding, Speakers Bureau. Szczudlo:Novartis: Employment. Berton:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Employment. Wang:Novartis Pharmaceuticals: Research Funding. Nicolini:Novartis Pharma: Consultancy, Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Chemgenex: Honoraria, Speakers Bureau.

High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
E. Aoki ◽  
H. Kantarjian ◽  
S. O’Brien ◽  
M. Talpaz ◽  
F. Giles ◽  
...  
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Molecular Responses ◽  
Pre Treatment ◽  
Grade 3

6535 Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated. [Table: see text]

BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) after 30 months of follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6512-6512 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Jeffrey Howard Lipton ◽  
Goh Yeow Tee ◽  
Luis Felipe Casado ◽  
Andrey Zaritskey ◽  
...  
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Geographic Region ◽  
Molecular Response ◽  
Primary Reason ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Grade 3

6512 Background: The BELA study compared the efficacy and safety of BOS (dual Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502 pts with newly diagnosed CP CML were randomized to BOS 500 mg/d (n = 250) or IM 400 mg/d (n = 252) and stratified by Sokal risk group and geographic region. Efficacy analyses included all randomized pts (ITT); safety analyses included all treated pts (BOS, n = 248; IM, n = 251). Data described below are for ≥24 mo of follow-up; updated data for ≥30 mo of follow-up will be presented. Results: Median treatment duration was 27.5 mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving treatment. The primary reason for BOS discontinuation was a treatment-emergent adverse event (TEAE; 24% vs 7% with IM); the primary reason for IM discontinuation was disease progression (13% vs 4% with BOS). Cumulative complete cytogenetic response (CCyR) rates by 24 mo were 79% for BOS and 80% for IM. Cumulative major molecular response (MMR) rates by 24 mo were 59% for BOS and 49% for IM (P = 0.019), including 16% and 12% of pts with complete molecular response (4.0-log sensitivity). On-treatment transformation to accelerated/blast phase occurred in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7 BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML progression); 24-mo Kaplan-Meier overall survival estimates were 97% (BOS) and 95% (IM). BOS was associated with higher incidences of gastrointestinal events than IM (diarrhea [70% vs 25%], vomiting [32% vs 16%]; primarily transient), but lower incidences of edema (13% vs 40%) and musculoskeletal events (cramps [4% vs 22%], bone pain [4% vs 10%]). Grade ≥3 TEAEs in ≥2% of BOS or IM pts were diarrhea (12% vs 1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade ≥3 lab abnormalities (≥15% of pts) with BOS and IM were neutropenia (10% vs 24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase (23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS was effective for newly diagnosed CP CML and had a distinct toxicity profile. With continued follow-up both on-treatment transformation to accelerated/blast phase and overall survival continue to favor BOS versus IM.

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