Early results of lower-dose dasatinib, 50 mg daily, in newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18551-e18551 ◽  
Author(s):  
Kiran Naqvi ◽  
Jorge E. Cortes ◽  
Jeffrey A Skinner ◽  
Elias Jabbour ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Schedule ◽  
Treatment Interruption ◽  
Newly Diagnosed ◽  
Pleural Effusions ◽  
Eligibility Criteria ◽  
50Mg Daily ◽  
Early Results

e18551 Background: Dasatinib, a potent BCR-ABL tyrosine kinase inhibitor (TKI), is approved for the treatment of chronic phase CML (CML-CP) in the frontline and salvage settings. The approved dose in chronic phase is 100mg orally daily. Notable side effects include pleural effusions and myelosuppression.We evaluated the efficacy and toxicity profile of dasatinib 50mg orally daily in patients with newly diagnosed CML-CP. Methods: Adults with newly diagnosed CML-CP were eligible. Prior TKI therapy for up to 1 month was allowed. Eligibility criteria were standard. Patients received dasatinib 50mg daily. Responses were defined according to the European LeukemiaNet guidelines (Baccarani et al. Blood 2013 122:872-884). Results: From March 2016 until January 2017, 30 patients were enrolled. Median age was 47 years (22 to 84). Sokal risk was low in 17 patients, intermediate in 10, and high in 3. Response data are shown below. Among 7 patients not in CCyR at 3 months by FISH (% FISH + 3, 3.5, 4.5, 5.5, 7, 9 and 83%), the respective BCR-ABL transcripts (IS) were 0.49, 0.08, 0.1, 0.09, 0.60, 0.69 and 9.2%. Thus, 6/7 patients with FISH + disease at 3 months had BCR-ABL transcripts (IS) < 1%, and 17/18 patients evaluable at 3 months had BCR-ABL transcripts (IS) < 1% (equivalent to CCyR). Significant myelosuppression requiring treatment interruption occurred in only 1 patient. No patients so far had pleural effusions requiring intervention. To date, there have been no dose modifications. Conclusions: Dasatinib 50mg daily is active and well-tolerated in newly diagnosed CML-CP. It should be further explored as a new potential dose-schedule standard-of-care in CML. [Table: see text]

Preliminary Activity of Nilotinib (AMN107), a Novel Selective Potent Oral Bcr-Abl Tyrosine Kinase Inhibitor, in Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Phase Chronic Myelogenous Leukemia (CML-CP).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2172-2172 ◽  
Author(s):  
Elias Jabbour ◽  
Jorge Cortes ◽  
Francis Giles ◽  
Susan O’Brien ◽  
Laurie Letvak ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Patient Choice ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Early Results ◽  
Grade 3

Nilotinib is a novel, highly selective oral Bcr-Abl inhibitor which is approximately 30-fold more potent than imatinib. High response rates with nilotinib were observed in all CML phases post imatinib failure. We evaluated the efficacy of nilotinib in newly diagnosed Ph-positive CML-CP. Thirteen patients with newly diagnosed Ph-positive CML-CP were treated with nilotinib 400 mg orally twice daily. The median age was 49 years (range, 24–72 years). The Sokal risk at pretreatment was low in 10 patients, intermediate in 2, and high in 1. The median follow-up is 8 months (range, 3–12 months). All patients have reached the 6-month evaluation. The rate of complete cytogenetic response [CGCR] (Ph 0%) at 3 and 6 months was 93% and 100%, respectively. This is compared with a CGCR at 3 months of 37% and with imatinib 400 mg/d and 61% with imatinib 800 mg/d (p=0.0002) and 54% and 85% at 6 months, respectively (p<0.0001), in historical data of newly diagnosed patients treated in studies at M. D. Anderson. Six patients were evaluable at 9 months and all were in CGCR. The median QPCR with nilotinib at 3, 6, and 9 months were, respectively, 3.4% (range, 0.02–29.5%), 1.8% (range, 0.004–9.13%), and 0.54% (range, 0.04–1.28%). At 3-month follow-up, major molecular response (BCR-ABL/ABL ratio<0.05%) was observed in 1/13 patients (8%) and in 6/11 (55%) at 6-month. Grade 3–4 myelosuppression was observed in 3 of the 13 patients and other grade 3–4 side effects in 3 patients (increased lipase in 2 and musculo-skeletal pain in 1). Four patients had their dose reduced to 400 mg daily due to extramedullary toxicity. Two patients were taken off after 6 and 8 months (patient choice) and switched to imatinib. In conclusion, early results with nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile.

scholarly journals First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis

2020 ◽  
Vol 4 (12) ◽  
pp. 2723-2735 ◽  
Author(s):  
Claudia Vener ◽  
Rita Banzi ◽  
Federico Ambrogi ◽  
Annalisa Ferrero ◽  
Giuseppe Saglio ◽  
...  
Keyword(s):  
Systematic Review ◽  
Kinase Inhibitor ◽  
Meta Analysis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Third Generation ◽  
Newly Diagnosed ◽  
First Line ◽  
Eligibility Criteria

Abstract Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome–positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.

Preliminary activity of AMN107, a novel potent oral selective Bcr-Abl tyrosine kinase inhibitor, in newly diagnosed Philadelphia chromosome (Ph)-positive chronic phase chronic myelogenous leukemia (CML-CP)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6591-6591 ◽  
Author(s):  
E. Jabbour ◽  
F. Giles ◽  
J. Cortes ◽  
S. O’Brien ◽  
F. Ravandi ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Abl Tyrosine Kinase ◽  
Early Results ◽  
Grade 3 ◽  
Transient Elevation

6591 Background: AMN107 is a novel, highly selective oral Bcr-Abl inhibitor which is 20–50-fold more potent than imatinib. High response rates with AMN107 were observed in all CML phases post imatinib failure. Methods: Study Aims: Evaluate the efficacy of AMN107in newly diagnosed Ph-positive CML-CP. Study Group and Therapy: Patients with newly diagnosed Ph-positive CML-CP were treated with AMN107 400 mg orally twice daily. Results: So far, 13 patients have been treated; median age 49 (range 24 to 72). Sokal risk at pretreatment: low - 10, intermediate - 2, high - 1. Five have reached the 3 month evaluation: all 5 (100%) had a complete cytogenetic response [CGCR] (Ph 0%). This is compared with a CGCR at 3 months of 36% with imatinib 400 mg/d and 55% with imatinib 800 mg/d in historical data of newly diagnosed patients treated at M. D. Anderson. The median QPCR with AMN at 3 months was 0.67% (range 0.3 to 3.0), compared with a median QPCR of 8% with imatinib 800 mg daily. Grade 3–4 myelosuppression was observed in 3/13 and other grade 3–4 side effects in 1/13 requiring temporary AMN107 interruption for < 2 weeks and resumption at same dose level in the 3 patients with myelosuppression, and for 6 weeks+ in the patient with grade 3 elevation of liver enzymes which were reduced to grade 1 on last follow-up. One patient had a transient elevation of total bilirubin > 3 mg/L which was self limited with continued therapy. Conclusions: Early results with AMN107 400 mg orally twice daily are encouraging in newly diagnosed CML. [Table: see text]

Efficacy of Nilotinib (AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 29-29 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Elias Jabbour ◽  
Alexandra Ferrajoli ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is a novel, oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl that is approximately 30-fold more potent than imatinib. High response rates have been reported with nilotinib therapy in CML after imatinib failure. Methods: We evaluated the efficacy of nilotinib as first line therapy in pts with newly diagnosed Ph-positive CML-CP. 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). Results: Thirty-two pts have been treated with nilotinib 400 mg orally twice daily for a median of 5 months (mo) (range, 1 to 31 mo). The median age was 47 years (yrs) (range, 24–73 yrs). The Sokal risk at pretreatment was low in 21 (70%) pts, intermediate in 6 (20%), and high in 3 (10%). The rate of complete cytogenetic response [CCyR] (Ph 0%) at 3, 6 and 12 mo compares favorably to those observed in historical controls treated with imatinib 400 mg or 800 mg daily: The median QPCR with nilotinib at 3, 6, and 12 months were, respectively, 0.52% (range, 0.0–29.5%), 0.03% (range, 0.0–9.13%), and 0.09% (range, 0.0–16.21%). At 3 mo follow-up, major molecular response (MMR; BCR-ABL/ABL ratio ≤0.05%) was observed in 3/22 patients (14%), 7/13 (54%) at 6 mo, and 5/11 (45%) at 12 mo. 12-mo rates of MMR for the historical imatinib groups treated at 400 mg and 800 mg were 24% and 47%, respectively (p=0.02). None of the molecular responses has been lost while on therapy. Grade 3–4 neutropenia was observed in 2 (7%) pts, and thrombocytopenia in 1 (3%). Other grade 3–4 adverse events included elevation of lipase (n=3, 9%), or bilirubin (n=2; 6%), and amylase elevation, back pain, and infection (1 each). Twelve pts had transient treatment interruptions (median 11 days), most frequently due to pain (n=3; musculoskeletal 2, abdominal 1), lipase elevation (n=2). Seven patients had their dose reduced to 400 mg daily, 2 to 200 mg twice daily, and 1 to 200 mg daily due to extramedullary toxicity. Three patients decided to change therapy after 4, 6 and 8 months; 2 switched to imatinib and 1 received SCT. Conclusion: Nilotinib 400 mg orally twice daily suggest significant efficacy manifested by complete cytogenetic responses in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Percent with CCyR (No. evaluable) Months on Therapy Nilotinib Imatinib 400 mg Imatinib 800 mg P value 3mo 95 (22) 37 (49) 62 (202) < 0.0001 6mo 100 (13) 54 (48) 82 (199) <0.0001 12mo 100 (11) 65 (48) 86 (197) 0.0007

Efficacy of Nilotinib (formerly AMN107) in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 446-446 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Alessandra Ferrajoli ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
P Value ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Treatment Interruptions ◽  
Grade 3

Abstract Background: Nilotinib is an oral tyrosine kinase inhibitor with high selectivity towards Bcr-Abl and approximately 30-fold more potent than imatinib, and is effective in patients with 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 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 untreated CML-CP (or with &lt;1 months of therapy with imatinib) were eligible and received nilotinib 400mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Forty-nine pts have been treated for a median of 13 months (mo). The median age was 47 years (yrs) (range, 21 to 81); 69% are Sokal low risk. Eight (16%) had received imatinib for &lt;1 months. Overall, 46/48 (96%) of evaluable CP pts achieved a complete cytogenetic response [CCyR]. The rate of CCyR at 3, 6 and 12 mo for pts in CP compares favorably to those observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Months on therapy Nilotinib Imatinib 400mg Imatinib 800mg P value 3 93 (45) 37 (49) 62 (202) &lt; 0.0001 6 100 (36) 54 (48) 82 (199) &lt; 0.0001 12 96 (27) 65 (48) 86 (197) 0.0003 18 92 (12) 68 (38) 89 (179) 0.0042 24 91 (11) 70 (40) 88 (173) 0.0151 MMR was observed in 45% at 6 mo and 52% at 12 mo. Two of 44 (5%) evaluable pts have achieved confirmed complete molecular response, and 3 others unconfirmed (ie, only achieved on their last assessment). Grade 3–4 hematologic toxicity (transient) included thrombocytopenia in 10%, neutropenia in 12%, and anemia in 2%. Grade 3–4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%. 19 (36%) pts had transient treatment interruptions and 17 (32%) had dose reductions. The actual median dose is 800mg daily. Three pts have come off study: 1 pt’s choice and 2 because of toxicity (1 liver, 1 pericardial effusion). One of them (liver toxicity) transformed to blast phase shortly after coming off study. Estimated 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 95%. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 months after the start of therapy with a favorable toxicity profile. Accrual is ongoing.

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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1101-1101 ◽  
Author(s):  
Carlo Gambacorti- Passerini ◽  
Enrico Maria Pogliani ◽  
Michele Baccarani ◽  
Giovanni Martinelli ◽  
Hagop M Kantarjian ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Growth Factor Receptor ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Molecular Response ◽  
Cell Transplant ◽  
Open Label ◽  
Wide Range ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally available, Src/Abl kinase inhibitor with minimal activity against platelet derived growth factor receptor (PDGFR) and c-kit. An open-label study of patients (pts) with Philadelphia chromosome positive (Ph+) accelerated phase (AP) and blast phase (BP) CML and Ph+ ALL who failed prior imatinib therapy is ongoing. Patients receive 500 mg/day of bosutinib. Preliminary data for 101 subjects, median age 51.5 yrs (range 18 – 84 yrs) and 56% male are reported. 44 pts were in AP, 35 in BP, 21 had Ph+ ALL, and 1 was unclassified. Prior therapy in addition to imatinib included interferon (35 pts), dasatinib (40 pts), nilotinib (15 pts) and stem cell transplant (11 pts). 49 pts failed imatinib (and received no other tyrosine kinase inhibitor [TKI]) and 52 pts failed both imatinib and other TKIs, with median duration of bosutinib treatment to date 4.4 mos (range 0.3 – 21.3 mos) and 2.0 mos (range 0.3 – 18.8), respectively. Among pts with no TKI exposure other than imatinib, complete hematological response (CHR) was obtained in 12/25 evaluable pts (48%), including 7/11 pts (64%) with AP-CML, 4/11 pts (36%) with BP-CML and 1 pt with Ph+ ALL. Major cytogenetic response (MCyR) was achieved in 16/22 evaluable pts (73%) with no TKI exposure other than imatinib, including 9/13 pts (69%) with AP-CML and 6/8 pts (75%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Major molecular response (MMR) was achieved in 9/25 evaluable pts (36%) with no TKI exposure other than imatinib, including 1/7 pts (14%) with AP-CML, 4/10 pts (40%) with BP-CML and 4/8 pts (50%) with Ph+ ALL. Among pts with other TKI exposure in addition to imatinib, CHR was obtained in 3/15 evaluable pts (20%), all with AP-CML; MCyR was achieved in 6/20 evaluable pts (30%), including 3/12 pts (25%) with AP-CML and 2/7 pts (29%) with BP-CML; 1 pt with Ph+ ALL achieved MCyR. Of the 20 pts with other TKI exposure in addition to imatinib who were evaluable for MMR, 1 pt with Ph+ ALL (5%) achieved this response. Of 60 pts with baseline samples tested for mutations, 15 different mutations were found in 32 pts (53%), including 8 instances of T315I. CHR occurred in 2/8 evaluable pts (25%) with non-P-loop mutations; the 1 evaluable pt with a P-loop mutation did not achieve CHR. MCyR occurred in 4/11 evaluable pts (36%) with non-P-loop mutations and in 1/2 evaluable pts (50%) with P-loop mutations. Treatment was generally well tolerated. The most common adverse events among treated pts (n=101) were gastrointestinal (diarrhea [66%], nausea [46%] and vomiting [42%]) 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 non-hematologic toxicities occurring in ≥ 5% of pts were diarrhea (7%), vomiting (6%), pneumonia (6%) and increased ALT (5%). Fluid retention was reported as grade 1 – 2 in 18 pts and grade 3 – 4 in only 3 pts (including 2 pleural effusions, neither related to bosutinib). Grade 3 – 4 hematologic laboratory abnormalities reported include thrombocytopenia (68%), neutropenia (48%) and anemia (37%). 38 pts had at least 1 temporary treatment interruption and 22 pts had at least 1 dose reduction due to toxicity. 11 pts have permanently discontinued treatment due to adverse event. Bosutinib is effective in imatinib-resistant pts with advanced CML. Responses were observed across a wide range of Bcr/Abl mutations.

Dasatinib in Children and Adolescents with Relapsed or Refractory Leukemia: Interim Results of the CA180-018 Phase I Study from the ITCC Consortium.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3241-3241 ◽  
Author(s):  
C. Michel Zwaan ◽  
Carmelo Rizzari ◽  
Vincent H.J. van der Velden ◽  
Berna Beverloo ◽  
M. L. den Boer ◽  
...  
Keyword(s):  
Phase I ◽  
Kinase Inhibitor ◽  
Pediatric Population ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Finding ◽  
Cell Transplant ◽  
Hematological Response ◽  
Advanced Phase ◽  
Grade 3

Abstract Relapsed/refractory leukemia in childhood carries a grave prognosis. Dasatinib (SPRYCEL®) is a potent oral kinase inhibitor of BCR-ABL, KIT, and SRC kinases. Dasatinib is approved for adults with Philadelphia chromosome-positive (Ph(+) CML and ALL, resistant or intolerant to prior imatinib therapy. An investigational phase I dose- finding study of dasatinib treatment of patients aged 1–21 years with various leukemia subtypes is currently being conducted in 12 European centers. The aim of the study is to establish a safe and effective dose for each of the leukemia sub-types. Patients were stratified into three treatment groups - Stratum 1: CML in chronic phase, resistant or intolerant to imatinib; Stratum 2/3: advanced-phase CML resistant or intolerant to imatinib, Ph(+) ALL, relapsed/ refractory after imatinib, or Ph(+) AML, ≥ 2nd relapse; Stratum 4: Ph(−) ALL, or Ph(−) AML in second/subsequent relapse. The starting dose was 60mg/m2 once daily for all strata. Intra-patient dose escalation was allowed for lack of initial response and dose reductions for toxicity. Current data reflect the first 41 patients (median age 11 years, range 1–21) treated from March 2006 through May 2008, including eight in Stratum 1, twelve in Stratum 2/3, and twenty-one in Stratum 4. The patients were heavily pretreated and prior therapy included chemotherapy (n=35), imatinib (n=20), and stem cell transplant (n=24). Dasatinib was well tolerated up to the current 120mg/m2 dose. Treatment-related toxicities were mostly mild to moderate in severity with nausea (34% grade 1/2; 2% grade 3/4) and diarrhea (15% grade 1/2; 0% grade 3/4) occurring most frequently. In Stratum 4, two dose-limiting toxicities were seen: anaphylaxis 5 hours after the first dose (60mg/m2) and upper-GI bleed on Day 6 of dasatinib dosing (120mg/ m2). Only one of the 41 patients experienced a malignant/hemorrhagic pleural effusion at 100mg/m2 dose. A maximum tolerated dose has not been established. PK studies were performed on samples from 32 patients after 60 mg/m2, 80 mg/m2 and 100 mg/m2 dosing. Absorption occurred rapidly (median Tmax 0.75 – 1.0 hour). The area under the curve (AUC) and maximum concentration (Cmax) proportionately increased with higher dose levels, but the difference was much greater between 60 and 80 mg/m2 than between 80 and 100 mg/m2. Complete Hematological Response (CHR) occurred in 75% of patients with CML-CP. Major Hematological Response (MaHR) was achieved in 25% of patients with advanced CML/Ph(+) and Ph(+) ALL/ AML. Major Cytogenetic Response occurred in 88% of CML-CP patients and 50% of patients with advanced Ph(+) CML and Ph(+) ALL/ AML. Stratum 4 observations included a temporary decrease in peripheral blood (PB) blast count in one Ph(−) ALL patient and in PB and bone marrow (BM) blast counts in two Ph(−) AML patients (one with AML7 and one with Down’s syndrome). Additionally, three Ph(+) ALL patients had a CSF response. These interim data demonstrate a favorable safety profile for dasatinib. Clear efficacy was seen in patients with CML-CP, and other Ph(+) leukemias. Further exploration is needed in the Ph(−) leukemias in the pediatric population. Updated data will be presented.

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