Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 338-338 ◽  
Author(s):  
Jorge Cortes ◽  
Gautam Borthakur ◽  
Susan O'Brien ◽  
Dan Jones ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Grade 3

Abstract Abstract 338 Dasatinib, a potent inhibitor of ABL and SRC, is approximately 300 times more potent than imatinib in vitro and has significant activity in pts with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP within 6 months from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Sixty-two pts have been enrolled (31 on the QD schedule, 31 BID). Median age was 47 years (yrs) (range 18–76 yrs). Median follow-up is 24 months (mo) (range, 1 to 39 mo). All 45 pts who were not in CHR at the start of therapy achieved CHR. Among 50 pts followed for at least 3 months, 49 (98%) achieved complete cytogenetic response (CCyR). Major molecular response has been achieved in 35 (70%), including 5 (10%) with complete molecular response. The CCyR rate at different timepoints (intention-to-treat) compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Major molecular response was achieved by 45% by 12 mo and 71% by 24 mo (corresponding rates with imatinib 400mg 34% and 55%, and with imatinib 800mg 58% and 66%, respectively). There was a trend for higher MMR rate with the QD schedule: overall 75% vs 65% (p=0.54), and by 12 months 52% and 38% (p=0.54). Grade 3-4 non-hematologic toxicity (regardless of causality) included fatigue (6%), pain (muscle or joint) (6%), dyspnea, neuropathy and memory impairment (5% each). Pleural effusion occurred in 13% evaluable pts (grade 3-4 in 2%). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 10%, neutropenia 21%, and anemia 6%. Thirty (48%) of 62 pts required transient treatment interruptions. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule but there was a trend for less pleural effusion with QD (3%) vs BID (10%; p=0.26). Three pts lost CCyR: 2 because of non-compliance, 1 due to treatment interruption because of pleural effusion. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 88%. All patients are alive. Conclusion: Rapid CCyR occurs in nearly all patients with previously untreated CML-CP treated with frontline dasatinib therapy; the MMR rate at 18 months was 71%, with a favorable toxicity profile. Because of favorable trends in response and toxicity, only QD arm will continue accrual. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of dasatinib as initial therapy for CML, and indication for which dasatinib is not approved.. Borthakur:BMS: Speakers Bureau. O'Brien:BMS: Research Funding. Jabbour:BMS: Speakers Bureau; Novartis: Speakers Bureau. Ravandi:BMS: Consultancy, Honoraria, Research Funding. Kantarjian:Genzyme: Research Funding; BMS: Research Funding; MGI Pharma (Eisai): Research Funding; Novartis: Research Funding.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 182-182 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
Dan Jones ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCRABL and SRC with significant activity in pts with CML-CP resistant to or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45 years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45 (98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Mo on therapy Dasatinib Imatinib 400mg Imatinib 800mg P value 3 78 (45) 37 (49) 62 (202) 0.0003 6 93 (41) 54 (48) 82 (199) <0.0001 12 97 (35) 65 (48) 86 (197) 0.0001 18 88 (33) 68 (38) 89 (179) 0.004 24 80 (25) 70 (40) 88 (173) 0.006 MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last assessment). Grade 3–4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%), neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3–4 in 2%). Grade 3–4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Four pts came off study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 81%. Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.

Results of a Phase II Trial of Dasatinib As Frontline Therapy for Chronic Myeloid Leukemia (CML) In Chronic Phase (CP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1700-1700 ◽  
Author(s):  
Naveen Pemmaraju ◽  
Hagop M. Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Cytogenetic Response ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Grade 3

Abstract Abstract 1700 Background: Dasatinib is approximately 300 times more potent than imatinib (IM) in vitro and has significant activity in patients (pts) with CML-CP resistant to or intolerant of IM. In 2005 we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Objective: To determine the outcome of pts with CML-CP treated with front-line dasatinib. The primary endpoint was attainment of major molecular response (MMR) at 12 months (mos). Methods: Pts with previously untreated CML-CP within 6 mos from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg twice daily (BID) or 100 mg once daily (QD). After 66 pts were accrued, the BID arm was closed and all subsequent pts were treated with 100 mg QD. No prior therapy was allowed except for IM for no more than 1 month, or hydroxyurea. Results: From November 2005 to June 2011, 99 pts have been enrolled (66 on the QD schedule, 33 BID). For the purposes of this analysis, we considered all pts with clonal evolution at baseline (n=6) as accelerated phase and excluded them from the present analysis, therefore leaving 93 pts (62QD, 31 BID) for review. Median age was 48 years (yrs) (range 18–82); 56% were male. Median baseline counts: WBC 22.95 K/uL, PB blasts 0%, BM blasts 3%, BM basophils 2%, and platelets 315; 21 pts (23%) had brief prior exposure to IM. Sokal score by distribution: Low (81%), Intermediate (14%), High (5%). Median follow-up is 29 mos (3–67). Of the 80 evaluable pts who were not in CHR at the start of therapy, 79 (98%) achieved CHR. Of 87 evaluable pts (ie, followed for at least 3 mos), 83 (95%) achieved complete cytogenetic response (CCyR). MMR has been achieved in 75 pts (86%), including 54 pts (67%) with complete molecular response (CMR; ≤0.0032% IS). At 6 mos, 79 (94%) pts had achieved a CCyR and 56 (68%) an MMR; corresponding figures at 12 mos are 95% and 73%, respectively. Grade 3–4 non-hematologic toxicity included fatigue (9%), pain and dyspnea (6% each), memory impairment (5%), headache and sensory neuropathy (4% each), nausea, cardiac arrhythmia, and neurologic (3% each) and diarrhea, visual, and pleural effusion (2% each). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia 13%, neutropenia 24%, and anemia 9%. Fifty-two (56%) of 93 pts required transient treatment interruptions and 36 (39%) have required dose reductions. The actual median daily dose for all pts was 100 mg (20–140). Thirteen pts lost CCyR: (including 3 because of non-compliance and 2 transient losses, regained spontaneously). The 24-mo probability of event-free survival (EFS) is 93%.There have been no transformations or deaths on study. Twelve (13%) pts have discontinued therapy: 3 pt's choice, 1 lost to follow up, 4 toxicity (2 pleural effusion, 1 congestive heart failure, 1 headaches), and 4 for loss of major cytogenetic response (MCyR). Three pts have had mutation assessment upon discontinuation and no mutations were identified. Conclusion: Rapid CCyR occurs in nearly all pts with previously untreated CML-CP treated with frontline dasatinib therapy with a favorable toxicity profile. None of the patients have transformed to AP/BP confirming the efficacy of dasatinib as initial therapy for CML-CP. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Ravandi:BMS: Honoraria, Research Funding. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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.

Bosutinib (SKI-606) Demonstrates Clinical Activity and Is Well Tolerated among Patients with AP and BP CML and Ph+ ALL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 473-473 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
H. Kantarjian ◽  
T. Bruemmendorf ◽  
G. Martinelli ◽  
M. Baccarani ◽  
...  
Keyword(s):  
Philadelphia Chromosome ◽  
Fluid Retention ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Major Molecular Response ◽  
Wide Range ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor. Biochemical assays have shown it to be up to 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation. Unlike imatinib, bosutinib does not exhibit significant inhibition of c-kit or platelet-derived growth factor receptor (PDGFR), which may result in a relatively favorable safety profile. This is an ongoing open-label study in patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase chronic myelogenous leukemia and (Ph+) ALL who failed prior imatinib therapy or other TKIs. Objectives are to assess safety and clinical activity of bosutinib. Pts receive bosutinib 500 mg/day. We report preliminary data for 57 pts, median age 54 yrs (range 22–83 yrs), 54% male. 23 pts (40%) were in AP, 15 (26%) in blast crisis (BC), 14 (25%) had Ph+ALL, and 5 (9%) were unclassified. Prior therapy included interferon (22 pts), imatinib (55 pts; data missing for 2 pts), dasatinib (17 pts), nilotinib (10 pts), stem cell transplant (5 pts). Overall median duration of bosutinib treatment was 2.7 mos (range 0.03–10.8 mos). Complete hematological response (CHR) was obtained in 7/25 evaluable pts (28%), including 4/14 (29%) pts with AP-CML, 2/8 (25%) pts with BC-CML, and 1/3 (33%) pts with Ph+ ALL. Among pts with no other TKI exposure, major cytogenetic responses (MCyR) were observed in 5/14 evaluable pts (36%), including 3/6 (50%) pts with AP-CML, 2/5 (40%) pts with BC-CML. Among pts with prior TKI exposure, 3/10 (30%) had MCyR, including 0/3 AP, 1/4 BP, and 2/3 ALL pts. Median time to MCyR was 8.9 weeks for pts previously exposed and 12 wks for unexposed to other TKIs. Duration of MCyR was 18 wks. 19 previously unexposed patients were evaluable for major molecular response. 4 (21%) had major molecular response, 3 (16%) of which were complete. Of 42 pts with samples tested for mutations, 13 different mutations were found in 20 pts (48%), including 5 cases of T315I. CHR occurred in 2/3 pts with P-loop mutations and 5/17 with non-P-loop mutations; MCyR occurred in 2/2 pts and 4/9 pts, respectively. Treatment was generally well tolerated in this cohort of heavily pretreated patients. The most common adverse events were gastrointestinal (diarrhea [56%], nausea [37%], vomiting [35%]) but these were usually grade 1–2, manageable and transient, reducing in frequency and severity after the first 3–4 weeks of therapy. Grade 3–4 hematologic laboratory abnormalities reported included thrombocytopenia in 31 pts (59%), neutropenia in 20 pts (38%), and anemia in 13 pt (25%). Grade 3–4 non-hematologic toxicities were diarrhea (9%) and vomiting (9%). Fluid retention was reported in 8 pts (14%), including 2 cases (3%) of pleural effusion (grade 2 and 3). Both were considered unrelated to treatment. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations. Bosutinib has a favorable toxicity profile with a small number of pts experiencing hematologic toxicity and fluid retention, possibly due to the lack of c-kit inhibition and PDGFR inhibition, respectively.

Efficacy of Nilotinib in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 341-341 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O'Brien ◽  
Dan Jones ◽  
Elias Jabbour ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Adverse Events ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Line Therapy ◽  
Grade 3

Abstract Abstract 341 Background: Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily: MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.

Dasatinib (Versus Imatinib) In Patients (Pts) with Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase (CML-CP): Analysis of Safety and Efficacy by Use of Baseline Medications In the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2295-2295 ◽  
Author(s):  
Francois Guilhot ◽  
Hagop Kantarjian ◽  
Neil P. Shah ◽  
Andreas Hochhaus ◽  
M. Brigid Bradley-Garelik ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Tumor Lysis Syndrome ◽  
Time Of Day ◽  
Fluid Retention ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Grade 3

Abstract Abstract 2295 Background: During first-line BCR-ABL inhibitor therapy for CML-CP, concomitant medication use is associated with worse adherence to CML therapy, which may detrimentally affect efficacy (St Charles, ASH 2009; Marin, J Clin Oncol 2010). Medications may include adjuvants to anti-CML therapy or treatments for comorbid conditions. Depending on posology, the number of medications may affect BCR-ABL inhibitor efficacy and safety. Dasatinib is a BCR-ABL inhibitor 325-fold more potent than imatinib at inhibiting BCR-ABL in vitro and is taken once daily (QD) at any time of day with or without food. Medications that prolong QTc, or increase or decrease dasatinib levels (CYP3A4 substrates/inhibitors/inducers, PPIs and H2 antagonists) should be avoided. In the phase 3 DASISION trial, first-line dasatinib 100 mg QD had superior efficacy vs imatinib 400 mg QD in pts with newly diagnosed CML-CP, including significantly higher complete cytogenetic response (CCyR) and major molecular response (MMR) rates. Here, efficacy and safety of dasatinib (and imatinib) by number and type of baseline medications were analyzed. Methods: 519 pts with newly diagnosed CML-CP were randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) arms. Exclusion criteria included prior interferon or systemic anti-CML therapy (except anagrelide, hydroxyurea, or ≤28 days of imatinib), and baseline pleural effusion, cardiovascular disease, or bleeding disorder unrelated to CML. Efficacy and safety were assessed using rates of CCyR/MMR or drug-related adverse events (AE), respectively. Baseline medications were defined as any additional medication taken prior to initiating study therapy, as reported by individual investigators. Results: 189/259 pts (73%) in the dasatinib arm and 194/260 pts (75%) in the imatinib arm were receiving ≥1 baseline medication (median 2, range 1–7). Medications taken by ≥5% of pts were prophylactic allopurinol therapy for tumor lysis syndrome (51%); alimentary tract or metabolism therapies, eg, antacids or PPIs (33%: omeprazole 6%, famotidine <1%); nervous system therapies, eg, NSAIDs or other analgesics (22%); cardiovascular therapies, eg, calcium channel blockers, loop diuretics, β blockers, and ACE inhibitors (21%); agents for blood or blood-forming organs, eg, folic acid or statins (15%); systemic antibiotics/antifungals/vaccines (7%); and respiratory system therapies, eg, antihistamines or inhaled steroids (7%). 12-month CCyR and MMR rates were unaffected by the number of baseline medications. Pts in the dasatinib arm receiving 0, 1–3, or ≥4 medications (27%, 56%, and 17%, respectively) had CCyR rates of 79%, 85%, and 87% and MMR rates of 43%, 49%, and 42%, respectively. Pts in the imatinib arm receiving 0, 1–3, or ≥4 medications had CCyR rates of 76%, 70%, and 71% and MMR rates of 35%, 26%, and 23%, respectively. In pts receiving baseline medications, safety was similar irrespective of the number received. Respective grade 3/4 thrombocytopenia rates for pts receiving 0, 1–3, or ≥4 medications were 28%, 17%, and 13% in the dasatinib arm and 9%, 9%, and 17% in the imatinib arm; grade 3/4 neutropenia rates were 29%, 13%, and 31% in the dasatinib arm and 31%, 18%, and 11% in the imatinib arm. Nonhematologic AEs of any grade occurring in ≥10% of pts receiving dasatinib and 0, 1–3, or ≥4 medications, respectively, were diarrhea in 17% vs 19% vs 13% (13% vs 19% vs 17% with imatinib), nausea/vomiting in 12% vs 9% vs 18% (25% vs 23% vs 23% with imatinib), arthralgia/myalgia in 12% vs 10% vs 11% (28% vs 13% vs 14% with imatinib), rash in 6% vs 12% vs 18% (19% vs 16% vs 20% with imatinib), fluid retention in 9% vs 23% vs 24% (41% vs 44% vs 37% with imatinib), pleural effusion in 1% vs 13% vs 13% (0% with imatinib) and superficial edema in 7% vs 8% vs 16% (25% vs 41% vs 31% with imatinib). Efficacy and safety patterns were generally comparable in pts receiving various baseline medication categories. Additional analyses of on-study medication characteristics and effects on efficacy or safety will be presented. Conclusions: Although occurrence of pleural effusion and fluid retention appeared higher in patients receiving ≥1 medication with dasatinib, overall, the number of medications administered at baseline in the DASISION trial did not appear to affect efficacy or safety of dasatinib (or imatinib) in pts with newly diagnosed CML-CP. Disclosures: Guilhot: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: This abstract discusses the use of first-line dasatininb in CML-CP. Kantarjian: Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Wyeth: Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bradley-Garelik: Bristol-Myers Squibb: Employment. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Cortes: Bristol-Myers Squibb: Research Funding.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 30-30 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Charles Koller ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Once Daily ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Based on its high level of activity in pts with CML-CP who are resistant to or intolerant of imatinib (IM), we initiated a phase II trial to study the efficacy and safety of dasatinib in pts with previously untreated CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (BCR-ABL/ABL ratio ≤ 0.05% in our lab) at 12 months (mo). All pts received dasatinib orally 100 mg/day, and were randomized to either a 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD) schedule. Dose escalation to 140 mg/day and 180 mg/day for poor response or dose reduction to 80 mg/day and 40 mg/day for toxicity, maintaining the same schedule, was allowed. Results: Thirty-seven pts have been enrolled between November 2005 and June 2007 (19 on the QD schedule, 18 BID). Median age was 41 years (yrs) (range 18–76 yrs). Nine (24%) of the pts were Sokal intermediate-risk and 3 (8%) were high-risk. Median baseline WBC count was 29.1 x 109/L (range 3.4–300.0). Three pts had clonal evolution at start of therapy. At 3 mo, complete hematologic response (CHR) was achieved in all pts,major cytogenetic response occurred 31/33 (94%), and complete cytogenetic response (CCyR) in 26/33 (79%) evaluable pts. After 6 mo of therapy, 30/32 (94%) evaluable pts had achieved CCyR. This compares favorably with results obtained in historical controls with IM at standard (400 mg) and high-dose (800 mg) at our institution: At 12 mo, 8/25 (32%) evaluable pts had achieved a major molecular response. Responses are similar in both treatment schedule groups. The most common non-hematologic adverse events (AE) included fatigue (n=22), musculoskeletal pain (n=20), headache (n=19), and dizziness (n=14), and were predominantly grade (grade 1–2). Grade 3–4 non-hematologic toxicity (regardless of causality) included headache, pain, rash, neuropathy and memory impairment (1 each). Pleural effusion occurred in 5 (14%) pts (all grade 1–2). Grade 3–4 hematologic toxicity (transient) included neutropenia in 4 (11%) pts, thrombocytopenia in 4 (11) pts, and anemia in (5%). With a median duration of therapy of 10 mo, 18 (49%) pts required transient treatment interruption, 14 due to non-hematologic toxicities, 3 due to hematologic toxicities, and 1 due to both. Sixteen pts (43%) have required dose reductions. The actual median daily dose for all pts was 100 mg; it was 100 mg for pts treated on the QD schedule, and 90 mg for those in the BID schedule. There is no significant difference in grade 3–4 toxicity by treatment schedule. Conclusion: Rapid, complete cytogenetic responses to dasatinib 100 mg/day occur in a high percentage of patients with previously untreated CML-CP. Once daily dosing appears to be associated with less toxicity. Accrual to this trial continues. Percent with CCyR (No. evaluable) Months on Therapy Dasatinib Imatinib 400 mg Imatinib 800 mg P value 3mo 79 (33) 37 (49) 62 (202) 0.0003 6mo 94 (32) 54 (48) 82 (199) <0.0001 12mo 100 (24) 65 (48) 86 (197) 0.0001

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.

Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Myelogenous Leukemia in Accelerated Phase (AP-CML) That Is Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results of the CA180–005 ’START-A’ Phase II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2160-2160 ◽  
Author(s):  
Jorge Cortes ◽  
D.W. Kim ◽  
F. Guilhot ◽  
G. Rosti ◽  
R.T. Silver ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mutational Analysis ◽  
Present Report ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Significant Activity ◽  
Hematologic Response ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity. Evaluation included weekly blood counts and monthly bone marrow including cytogenetics. Molecular evaluation of BCR-ABL transcript levels by real-time qPCR was performed at baseline and upon documentation of complete cytogenetic response. A total of 174 pts (161 im-r and 13 im-i) were enrolled between December 2004 and July 2005 in 39 centers worldwide. There were 96 (55%) males; median age was 57 years (range 22–86); median time from original diagnosis of CML was 82 months. Prior therapy included im in all pts (>600 mg/day in 91 (52%), im for >3 years in 103 (59%) pts, interferon in 126 (72%) pts, stem cell transplantation in 23 (13%) pts. Major cytogenetic response (MCyR) to prior im had been seen in 57 (33%) pts. The average daily dose (median across all pts) was 130 mg/day (range 44–199). Major hematologic response (MaHR) was documented in 110 (63%) pts with complete hematologic response in 75 (43%) and no evidence of leukemia in 35 (20%). At 9 months, 85% of pts have maintained their MaHR. MCyR was documented in 65 (37%) pts, complete in 49 (28%), partial in 16 (9%). Median progression-free survival (PFS) has not been reached; estimated PFS at 9 months is 70%. In the 94 pts with BCR-ABL mutations at baseline the MaHR rate was 69%. Generally, response rates were similar in the im-i and im-r groups. Cytopenias were significant with grade 3–4 thrombocytopenia and neutropenia in 82% and 76% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent (% any grade, % grade 3–4) were diarrhea (51%, 8%), headache (29%, 1%), fatigue (26%, 4%), fever (25%, 3%) and pleural effusion (25%, 3%). Pleural effusions were optimally managed with dose interruption and diuretics and/or pulse steroids. Dasatinib is highly effective in pts with im-r or im-i AP-CML with high rates of durable MaHR and MCyR. An updated analysis with at least 12 months of follow-up, including molecular response data and mutational analysis at time of progression, will be presented.

Clinical Significance of Myelosuppression Associated with the Use of Dasatinib and Nilotinib As Initial Therapy in Chronic Phase (CP) of Chronic Myeloid Leukemia (CML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2761-2761
Author(s):  
Theresa Liu-Dumlao ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Elias Jabbour ◽  
Jan A. Burger ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Clinical Significance ◽  
Research Funding ◽  
Chronic Phase ◽  
Patient Characteristics ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Significant Difference ◽  
Grade 3 ◽  
The Impact

Abstract Abstract 2761 Background: Frontline treatment with tyrosine kinase inhibitors (TKIs) has improved prognosis for patients with chronic myelogenous leukemia (CML). Myelosuppression is the most common adverse event (AE) seen during therapy with frontline second generation TKIs, dasatinib and nilotinib. The impact that grade 3/4 myelosuppression has on future outcome has not been described. Aim: To define the patient characteristics and clinical significance of myelosuppression associated with the use of dasatinib or nilotinib as initial therapy for CML. Methods: From August 2005, 204 patients (pts) diagnosed with CML-CP were treated with dasatinib (n=99) or nilotinib (n=105) in parallel trials. Prior imatinib exposure of less than 4 weeks was allowed. Complete blood counts (CBC) and differentials were done weekly in the first month, every 1–2 months up to the first year, every 3–4 months in the second year, and every 4–6 months thereafter. Results: A total of 44 (42%) pts developed grade 3/4 myelosuppression (MS) defined under CTCAE v4.0 criteria as hemoglobin (Hb)<8g/dL (n=5), absolute neutrophil count (ANC)<1×109/L (n=32), and platelet count (Plt)<50×109/L (n=21); 12 (30%) developed more than one cytopenia. MS occurred in 30 pts on dasatinib (anemia 13%, neutropenia 73%, thrombocytopenia 40%), and 14 pts on nilotinib (7%,71%,64%, respectively). Comparing patient characteristics between those who experienced myelosuppression vs. no myelosuppression, there was no significant difference in age, prior imatinib therapy, percent Ph positivity, or baseline hematologic parameters. There was a trend for more pts in the intermediate Sokal risk category among pts with MS. Of the 44 patients with MS, 39 (89%) experienced the event for the first time within 3 months from initiation of therapy. Five (11%) experienced the event after the first 3 months of treatment: 2 eventually came off study (one for resistance and the other for disease progression, both on nilotinib), and 3 (all on dasatinib) continued on therapy, able to achieve CMR. Complications associated with MS included hospitalization in 2 pts (one for pneumonia, and another for flu and prolonged QTc); 6 (14%) required antibiotics; 2 (5%) required blood transfusions; and 2 (5%) required growth factors (erythropoietin). MS led to TKI dose reduction in 9% of all pts treated (41% of those with MS), including 13% of those on dasatinib, and 5% of those on nilotinib. Dose reduction resolved MS in most instances. Recurrence of MS was seen in 10 pts, 2 of whom had progression of disease to blast phase/AML. The outcome of pts with MS is described in table 1 compared to those without MS. Patients with MS had a significantly lower rate of CCyR, MMR, CMR and EFS compared to those without MS. Conclusion: MS is a common AE among pts receiving therapy with dasatinib or nilotinib as initial therapy for CML that frequently leads to dose reductions, and is associated with an inferior outcome. Whether the worse outcome reflects decreased dose intensity, or whether the outcome and decreased tolerance to therapy reflect an intrinsic difference in disease biology remains to be determined. Disclosures: Kantarjian: BMS: Research Funding; Novartis: Research Funding. Quintas-Cardama:Novartis: Consultancy; BMS: Consultancy. Jabbour:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

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