A Phase 1/2 Study Of Bosutinib (SKI-606) In Japanese Adults With Philadelphia Chromosome-Positive (Ph+) Chronic Myeloid Leukemia (CML)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2736-2736
Author(s):  
Naoto Takahashi ◽  
Kenichi Ishizawa ◽  
Chiaki Nakaseko ◽  
Yukio Kobayashi ◽  
Kazuteru Ohashi ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Clinical Activity ◽  
Molecular Response ◽  
Multiple Doses ◽  
Starting Dose ◽  
Daily Dose ◽  
Grade 3

Abstract Background Bosutinib (BOS), an oral dual Src/Abl tyrosine kinase inhibitor, has demonstrated efficacy and acceptable safety in patients (pts) with chronic phase (CP)-CML resistant/intolerant to imatinib (IM). This ongoing open-label, 2-part, phase 1/2 study evaluated the safety, pharmacokinetics (PK), and efficacy of BOS in Japanese pts with Ph+ CML. Methods In this study, Part 1 was designed to confirm the safety of BOS up to 600 mg/d (or establish a maximum tolerated dose <600 mg/d) and evaluate PK parameters in IM-resistant/intolerant CP-CML pts. In Part 1, BOS (400 mg, 500 mg, and 600 mg) was administered to successive cohorts of pts aged ≥20 to <75 y as a single daily dose on d 1 and as a continuous once-daily dose from d 3, with each cohort (3-6 pts) evaluated for 28 d before enrolling the next dosing cohort. Part 2 evaluated the efficacy and safety of BOS in CP-CML or advanced (ADV) CML pts after resistance/intolerance to IM (second-line [2L]) or to IM plus dasatinib or nilotinib (third-line [3L]; exploratory cohort). In Part 2, BOS (starting dose: 500 mg/d) was administered to pts aged ≥20 y, with dose escalation to 600 mg/d allowed for lack of efficacy. The primary efficacy endpoint was the cumulative major cytogenetic response (MCyR) rate by wk 24 in CP-CML 2L pts (primary cohort). Results In Part 1, 17 pts received BOS (400 mg, n=7, 500 mg, n=7; 600 mg, n=3); 1 pt each in the 400 mg and 500 mg dose groups was not evaluable for dose limiting toxicities (DLTs) due to early study discontinuation (disease progression and pt request, respectively). DLTs during the first 28 d of treatment occurred in 1/6 pt receiving BOS 400 mg (grade 3 liver injury) and 1/6 pt receiving BOS 500 mg (grade 4 abnormal hepatic function); no DLTs occurred in the 3 BOS 600-mg pts. BOS 500 mg was chosen as starting dose for Part 2 based on DLTs and previous results (Cortes et al. Blood. 2011;118:4567-76). PK analyses indicated relatively slow absorption, with a median Tmax of ∼4 h after single or multiple doses of BOS 400–600 mg. BOS exposure (Cmax and AUC) generally increased with increasing dose after single and multiple doses. In Part 2, 46 additional pts were enrolled (2L, n=35 [28 CP-CML, 7 ADV]; 3L, n=11 [10 CP-CML, 1 accelerated-phase (AP)]); 63 pts were treated with BOS (median [range] age: 55 [20-78] y; 62% male; entry diagnosis: CP-CML, n=58; AP-CML, n=3; blast phase [BP]-CML, n=2). Median follow-up was 132 wk for 2L pts and 37 wk for 3L pts. In the CP-CML 2L cohort in Part 2 (n=28), the MCyR rate by wk 24 was 36% (10/28 pts; complete [CCyR], n=8; partial [PCyR], n=2) (primary endpoint); maintained MCyR at wk 24 was 64% (18/28 pts; CCyR, n=16; PCyR, n=2); median time to MCyR was 12.3 wk. Only 1 of 13 CP-CML 2L pts who attained MCyR at any point during the study lost it. Cumulative major molecular response (MMR) rate through the study was 43% (12/28 pts). AP/BP transformation occurred in 1 CP-CML 2L pt; at wks 48 and 96, progression-free survival (PFS) rates were 100% and 94%, respectively, and overall survival (OS) rate was 96% (both). Of 7 ADV 2L pts, 1 had confirmed complete hematologic response (cCHR) at wk 84 with duration of 95 wk (cCHR lost). AP/BP transformation occurred in 1 ADV 2L pt; at wks 48 and 96, PFS rate was 21% (both), and OS rate was 43% (both). In the 3L cohort, the cumulative MCyR rate by wk 24 and maintained MCyR rate at wk 24 were 18% (2/11 pts) and 64% (7/11 pts [CCyR, n=6; PCyR, n=1]); cumulative MMR rate through the study was 18% (2/11 pts). The only 3L pt with AP-CML attained cCHR at 12 wk with a duration of 24 wk as of the date of this analysis (censored due to data cutoff). No AP/BP transformation occurred in the 3L cohort; treatment duration was inadequate for assessment of PFS and OS. Overall, the most common treatment-emergent AEs (TEAEs) were diarrhea (95%), rash (57%), nasopharyngitis (51%), nausea (38%), vomiting (38%), increased alanine aminotransferase (ALT; 38%), lymphopenia (35%), thrombocytopenia (30%), and increased aspartate aminotransferase (30%). Grade 3/4 TEAEs were reported in 54 (86%) pts, most commonly lymphopenia (21%), increased lipase (19%), neutropenia (18%), thrombocytopenia (18%), and increased ALT (18%). 16 (25%) pts discontinued treatment due to AEs. No deaths occurred within 30 d of last BOS dose. Conclusions The safety and PK profiles of BOS up to 600 mg/d was confirmed in Japanese pts with Ph+ CML resistant/intolerant to IM. BOS 500 mg/d demonstrated clinical activity and an acceptable safety profile in this population. Disclosures: Kobayashi: Ariad: Research Funding; Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Ohtsuka: Research Funding; Onconova: Research Funding. Shibata:Pfizer Japan Inc: Employment. Fujii:Pfizer Japan Inc: Employment. Ono:Pfizer Japan Inc: Employment.

Activity of Bosutinib by Baseline and Emergent Mutation Status in Philadelphia Chromosome–Positive Leukemia Patients with Resistance or Intolerance to Other Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 110-110 ◽  
Author(s):  
H. Jean Khoury ◽  
Jorge E Cortes ◽  
Carlo Gambacorti-Passerini ◽  
Dong-Wook Kim ◽  
Andrey Zaritskey ◽  
...  
Keyword(s):  
Research Funding ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Treatment Completion ◽  
Kinase Domain ◽  
Clinical Activity ◽  
New Mutation ◽  
Mutation Status ◽  
Kinase Domain Mutations

Abstract Abstract 110 Bosutinib is an orally active, Src/Abl tyrosine kinase inhibitor (TKI) that has demonstrated clinical activity and an acceptable safety profile in an open-label, phase 1/2 study of patients (pts) with Philadelphia chromosome–positive (Ph+) leukemia following resistance or intolerance to imatinib. Abl kinase domain mutations may affect drug binding and subsequent TKI efficacy. Responses to bosutinib by Bcr-Abl baseline mutation status and the emergence of mutations during bosutinib treatment in this phase 1/2 study are reported here. A total of 570 pts in 3 cohorts received bosutinib: chronic phase chronic myeloid leukemia (CP CML) following prior imatinib only (CP2L cohort; n = 288); CP CML following prior imatinib plus dasatinib and/or nilotinib (CP3L cohort; n = 118); and advanced leukemia (ADV cohort: accelerated and blast phase CML and acute lymphoblastic leukemia; n = 164) following prior treatment with imatinib only or with other TKIs. For the CP2L, CP3L, and ADV cohorts, the respective median times since diagnosis were 3.6 y (range, 0.1–15.1 y), 6.5 y (range, 0.6–18.3 y), and 3.7 y (range, 0.1–22.1y). Per protocol, Bcr-Abl mutational status was evaluated at baseline (pre-dose) and at the end of treatment (EOT). Mutations were assessed at baseline in 412 pts; of these, 79/212 (37%) CP2L pts, 39/83 (47%) CP3L pts, and 65/117 (56%) ADV pts had ≥1 baseline mutation, and 11 (5%), 9 (11%), and 7 (6%) pts, respectively, had ≥2 baseline mutations. The most common mutations were T315I (n = 31; prior to eligibility exclusion), F359C/I/S/V (n = 23), F317L (n = 21), G250E (n = 19), Y253F/H (n = 16), and M351T (n = 15). Rates of confirmed complete hematologic response (CHR) and major cytogenetic response (MCyR) were generally similar among chronic phase pts (CP2L, CP3L) with and without baseline mutations, although the presence of a mutation negatively impacted response rates in ADV pts (CHR, 17% vs 39%; MCyR, 24% vs 37%; see Table). CHR and/or MCyR were observed broadly across mutations, including those associated with dasatinib (F317L) or nilotinib (Y253F/H, E255K/V, and F359C/I/S/V) resistance, with the exception of the T315I mutation in all cohorts and the F317L and Y253H mutations in the ADV cohort (see Table). Of the 140 pts who were assessed for emergent mutations at treatment completion, a new mutation was identified in 39 (28%) pts. Pts with a new mutation were more likely to have discontinued treatment due to PD/unsatisfactory response (UR; n = 34/39 [87%]) than those without a new mutation (n = 47/101 [47%]). The most common emergent mutations were T315I (n = 14) and V299L (n = 12), and nearly all pts who developed these mutations (93% and 100% of pts, respectively) discontinued treatment due to PD/UR. New mutations were more common in pts with ≥1 baseline mutation (n = 26) versus those without a baseline mutation (n = 13); of those pts, 21/26 (81%) and 13/13 (100%), respectively, discontinued treatment due to PD/UR. Eight pts discontinued treatment due to PD/UR within 6 months of starting bosutinib; all but 1 patient had a T315I or V299L mutation present at baseline or identified at treatment completion. In conclusion, clinical activity to bosutinib was observed in CML pts across baseline Bcr-Abl kinase domain mutations, including those associated with resistance to other second-generation TKIs, except typically for T315I. These results support the observed benefit of bosutinib in pts with Ph+ leukemia following prior treatment with TKIs. Pts in whom new mutations were identified at treatment completion were more likely to have pre-existing mutations and to discontinue treatment due to PD/UR. The most common mutations to emerge during bosutinib therapy were T315I and V299L, some of which may have been present but not detected at baseline.Baseline mutation status, n/n evaluablea (%)IC50 fold increaseCP2L cohortCP3L cohortADV cohortCHRMCyRCHRMCyRCHRMCyRNo mutation120/133 (90)65/121 (54)34/44 (77)15/43 (35)19/49 (39)16/43 (37)≥1 mutation65/78 (83)44/78 (56)26/39 (67)11/35 (31)10/59 (17)13/55 (24)    Y253H0.52/22/25/64/61/72/7    F359V0.98/94/90/21/20/20/1    Y253F1.01/10/10000    F317L2.44/43/44/81/70/90/6    F359I2.41/11/12/22/20/21/2    G250E4.35/63/53/60/54/62/7    E255V5.52/21/21/10/10/41/3    E255K9.50/22/30/10/10/41/3    V299L26.1001/20/200    T315I45.42/92/92/70/60/131/13    F359CNA002/21/20/10/1    F359SNA1/11/1001/10/1NA, not available.aTreated pts with adequate baseline response assessment. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria. Kim:Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Research Funding. Hochhaus:Pfizer Inc: Research Funding; BMS: Research Funding; Novartis: Research Funding; Ariad: Research Funding. Leip:Pfizer Inc: Employment. Besson:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment. Brümmendorf:Pfizer Inc: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; BMS: Consultancy, Honoraria.

Primary results of the phase 4 BYOND study of bosutinib (BOS) for pretreated chronic phase (CP) chronic myeloid leukemia (CML).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7012-7012 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Camille N. Abboud ◽  
Bjorn T. Gjertsen ◽  
Tim H. Brümmendorf ◽  
B. Douglas Smith ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Prior Therapy ◽  
Starting Dose ◽  
Insufficient Response ◽  
Grade 3

7012 Background: The tyrosine kinase inhibitor (TKI) BOS is approved for patients (pts) with Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed pts in CP. Methods: The ongoing phase 4 BYOND study is further evaluating efficacy and safety of BOS (starting dose 500 mg/d) for CML resistant/intolerant to prior TKIs. Primary endpoint (not powered) in Ph+ CP CML cohorts is cumulative confirmed major cytogenetic response (MCyR) by 1 y. Results: Of 163 pts who received BOS, 156 had Ph+ CP CML (46, 61 and 49 after 1, 2 and 3 prior TKIs, respectively). Across Ph+ CP CML cohorts, 51.9% of pts were male; median age was 61 y. As of 1 y after last enrolled pt (median follow-up 30.4 mo), 56.4% remained on BOS. Median BOS duration was 23.7 mo and median dose intensity after adjustment due to adverse events (AEs) 313 mg/d. Of 144 evaluable pts with a valid baseline assessment, cumulative confirmed MCyR by 1 y was 71.5% (95% confidence interval [CI] 63.4–78.7). Cumulative complete cytogenetic response rate anytime on treatment was 81.3% (95% CI 73.9–87.3). Cumulative molecular response (MR) rates were high across lines of therapy (Table). 10 deaths occurred (5 on treatment); 1-y overall survival rate was 98.0%. No pt progressed to accelerated/blast phase on treatment. 25.0% discontinued BOS due to AEs and 5.1% due to insufficient response. Most common treatment-emergent AEs (TEAEs) were diarrhea (87.8%) and nausea (41.0%). Grade 3/4 TEAEs in > 10% of pts were diarrhea (16.7%) and increased alanine aminotransferase (ALT; 14.7%). The only TEAE leading to discontinuation in > 5% of pts was increased ALT (5.1%). Conclusions: Most pretreated pts with Ph+ CP CML had MCyR by 1 y with BOS; a substantial proportion achieved or preserved major MR (MMR) and deep MR in all therapy lines. Results further support BOS use for Ph+ CP CML resistant/intolerant to prior TKIs. Clinical trial information: NCT02228382. [Table: see text]

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

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.

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

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.

Switching To Nilotinib In Patients (pts) With Chronic Myeloid Leukemia In Chronic Phase (CML-CP) With Suboptimal Cytogenetic Response (CyR) On Imatinib: First Results Of The LASOR Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 95-95 ◽  
Author(s):  
Jorge E. Cortes ◽  
Carmino Antonio De Souza ◽  
Jose Luis Lopez ◽  
Manuel Ayala ◽  
Eduardo Bullorsky ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Dose Escalation ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Unmet Need ◽  
Chronic Phase ◽  
Alternate Treatment ◽  
Sensitivity Analyses ◽  
Molecular Response ◽  
Loss Of Response

Abstract Introduction The phase 3 LASOR trial is the only randomized trial that compares the effects of imatinib dose escalation with those of switching to nilotinib in pts with Philadelphia chromosome–positive (Ph+) CML-CP who experience suboptimal response to frontline imatinib. Suboptimal response has been associated with inferior long-term outcomes in several landmark analyses and was observed in 13% of pts randomized to the imatinib arm of ENESTnd by 12 mo (vs 4% in each nilotinib arm). Methods Adults (N = 191) with CML-CP with suboptimal CyR to frontline imatinib 400 mg once daily (QD) were randomized 1:1 to nilotinib 400 mg twice daily (BID; n = 96) or imatinib 600 mg QD (n = 95). Suboptimal CyR was defined according to 2009 European LeukemiaNet (ELN) criteria as: no CyR ≥ 3 to < 6 mo (Ph+ > 95%), no partial CyR (PCyR) ≥ 6 to < 12 mo (Ph+ 36%-95%), or no complete CyR (CCyR) ≥ 12 to <18 mo (Ph+ 1%-35%) after starting imatinib. All pts had complete hematologic response at study entry. The primary endpoint was CCyR (Ph+ 0%) at 6 mo after randomization. The key secondary endpoint was major molecular response (MMR; BCR-ABLIS ≤ 0.1%) at 12 mo. Crossover to the alternate treatment arm was allowed for pts who failed to achieve CCyR by 6 mo or had intolerance or loss of response at any time. Results Baseline characteristics were well balanced between arms, with most pts entering study for not having PCyR at 6 mo or CCyR at 12 mo (Table). The primary endpoint, CCyR at 6 mo after randomization, was observed in 47 (49.0%) and 40 (42.1%) pts in the nilotinib and imatinib arms, respectively (P = .3844). Crossover was more common in pts randomized to the imatinib arm. Crossover occurred before the primary endpoint analysis at 6 mo in 6 pts in the nilotinib arm (5 for intolerance; 1 for lack of efficacy) and 15 pts in the imatinib arm (13 for intolerance; 1 for lack of efficacy; 1 for loss of response). Median time to crossover was 3.9 and 3.6 mo in the nilotinib and imatinib arms, respectively. None of the nilotinib pts who crossed over to imatinib vs 6 of the 15 imatinib pts who crossed over to nilotinib achieved CCyR at the primary analysis time point 6 mo after randomization. Ten pts in the nilotinib arm and 7 in the imatinib arm had neither samples evaluable for CyR at 6 mo nor had crossed over to the alternate treatment arm. Excluding these pts (evaluable population) and counting crossed-over pts as non-responders, 47 of 86 pts (54.7%) in the nilotinib arm and 34 of 88 (38.6%) in the imatinib arm achieved CCyR at 6 mo. Analyses of molecular response at 6 mo after randomization suggested higher rates in the nilotinib arm for BCR-ABLIS ≤ 1% (CCyR equivalent) and ≤ 0.1% (MMR) compared with the imatinib arm (52.1% vs 29.5% and 31.3% vs 11.6%, respectively). The safety profile for both drugs was consistent with prior reports of pts who switched therapy after inadequate responses to imatinib. Conclusions Patients with suboptimal CyR to imatinib (today classified by ELN as warning/failure) represent a significant unmet need in the treatment of CML-CP. This important study is the only randomized evaluation of imatinib dose escalation vs switch to the more potent BCR-ABL tyrosine kinase inhibitor nilotinib in this population. Although the primary endpoint was not met, sensitivity analyses accounting for crossover and more sensitive molecular monitoring demonstrated higher rates of response with switch to nilotinib vs imatinib dose escalation in pts with suboptimal response to frontline imatinib. Disclosures: Cortes: Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding; Teva: Consultancy, Research Funding. Bullorsky:Bristol Myers Squibb: Consultancy; Novartis: Consultancy. Sacha:Bristol Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau. Owugah:Novartis Pharmaceuticals Corporation: Employment. Kumar Nidamarthy:NOVARTIS HEALTH CARE Pvt Ltd: Employment. Szczudlo:Novartis: Employment, Equity Ownership. Piccolo:Novartis: Employment. le Coutre:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria.

Bosutinib (SKI-606) exhibits clinical activity in patients with Philadelphia chromosome positive CML or ALL who failed imatinib

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7006-7006 ◽  
Author(s):  
C. Gambacorti-Passerini ◽  
T. Brummendorf ◽  
H. Kantarjian ◽  
G. Martinelli ◽  
D. Liu ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Clinical Activity ◽  
Low Grade ◽  
Imatinib Resistant ◽  
Philadelphia Chromosome Positive

7006 Background: Bosutinib (SKI-606) is an orally available, dual Src/Abl kinase inhibitor. To assess safety and preliminary clinical activity of bosutinib, we conducted a phase 1/2 study in patients (pts) with Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) or acute lymphocytic leukemia (ALL) who were imatinib resistant/intolerant. Methods: In part 1, 18 pts with imatinib- relapsed/refractory chronic phase (CP) CML received bosutinib 400 mg/day (3 pts), 500 mg/day (3 pts), or 600 mg/day (12 pts). Part 2 was an expanded cohort of 51 pts with all phases of Ph+ CML and ALL dosed at 500 mg daily. Timed blood samples were collected on days 1–3, 15 for PK analysis. Results: Of 69 pts, median age was 59 yrs; 48 were CP; 90% imatinib resistant. Drug-related grade 1/2 adverse events (AEs) occurring in =10% of CP pts: diarrhea (69%), nausea (44%), vomiting (19%), abdominal pain (13%), rash (13%). Grade 3/4 AEs occurring in =5% of CP pts: rash (6%), thrombocytopenia (6%). 17 pts required dose reductions. In evaluable imatinib-resistant CP-CML pts with no prior exposure to other Abl inhibitors, 16/19 (84%) had complete hematologic response (CHR); 4/21 had partial and 7/21 had complete cytogenetic responses for major cytogenetic response (MCyR) rate of 52%. Of 58 pts evaluable for mutations, 13 different imatinib-resistant mutations were found in 32 pts. 12/14 CP pts with non-P-loop mutations and 3/3 with P-loop mutations achieved CHR. 5/11 CP pts with non-P- loop mutations and 1/1 with P-loop mutation achieved MCyR. 4/9 evaluable advanced leukemia pts had CHR, 2 had MCyR. After oral administration, steady state exposure of bosutinib was nearly 2-fold higher than single-dose exposure. Mean elimination half-life was approximately 22–27 hours, supporting a once-daily dosing regimen. Conclusions: Bosutinib was well tolerated in pts with CML, with primarily low-grade gastrointestinal and dermatologic AEs. Bosutinib showed clinical activity in imatinib-resistant pts with cytogenetic responses and CHR across a range of mutations. Durability of response continues to be assessed. [Table: see text]

scholarly journals Preliminary Results from a Phase 1/2 Study of DSP-7888, a Novel WT1 Peptide-Based Vaccine, in Patients with Myelodysplastic Syndrome (MDS)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4335-4335 ◽  
Author(s):  
Shigesaburo Miyakoshi ◽  
Kensuke Usuki ◽  
Itaru Matsumura ◽  
Yasunori Ueda ◽  
Hiromi Iwasaki ◽  
...  
Keyword(s):  
Overall Survival ◽  
Myelodysplastic Syndrome ◽  
Lower Risk ◽  
Research Funding ◽  
Phase 1 ◽  
Peptide Vaccine ◽  
Clinical Activity ◽  
Otsuka Pharmaceutical ◽  
Grade 3 ◽  
Ctl Induction

Abstract Background: Hypomethylating agents (HMA), including azacitidine (AZA) are currently the first-line treatment option for higher-risk myelodysplastic syndrome (MDS). However, the prognosis of patients after AZA failure is poor with a median overall survival of 5.6 months from the treatment failure (J Clin Onclol 2011;29:3322-7 Prébet T et al.), and currently there are no approved therapeutic options for such patients. Suzuki et al. reported that WT4869, one of the HLA-A*24;02-restricted synthetic peptide vaccine derived from Wilms' tumor 1 (WT1) protein, demonstrated the sign of prolongation of overall survival (OS) with a median OS of 13.0 months in AZA failure higher-risk population, in the phase 1/2 study with MDS patients (Blood 126:2868, 2015;Suzuki et al.). DSP-7888 is a novel WT1-based peptide vaccine which induces the CTLs that recognize WT1 antigens in HLA-A*02:01/06 and HLA-A*24:02 restricted manner, and also includes a WT1-derived helper peptide applicable for various subtypes of HLA-DRB1. DSP-7888 is currently being investigated in a phase 1/2 study to evaluate the safety and efficacy in HLA-A*24:02+ and/or HLA-A*02:01/:06+ MDS patients, with some exploratory biomarker analyses. Methods: The objectives of this study were to assess the tolerability of DSP-7888 treatment in MDS patients in the phase 1 portion and to evaluate preliminary clinical activity of DSP-7888 in higher-risk MDS patients after AZA failure in the study. In phase 1 portion, higher-risk or transfusion-dependent lower-risk MDS patients including the AZA failure population were enrolled, and DSP-7888 was administered at doses of 3.5 to 10.5 mg/body by intradermal injections every two to four weeks in dose-escalation cohorts according to the 3 + 3 design until discontinuation criteria were met. Overall survival was evaluated for primarily clinical activity and hematological response and time to AML were also examined. Delayed type hypersensitivity (DTH), WT1-specific CTL induction and expression of WT1 mRNA in peripheral blood and bone marrow cells were also evaluated as exploratory biomarkers. The clinical data in phase 1 portion as of May 25th 2016 was presented in this report. Results: In phase 1 portion, enrollment of patients and dose-limiting toxicities (DLTs) evaluation were completed. Twelve patients including 7 higher- and 5 lower-risk patients were enrolled in 3.5 and 10.5 mg/body cohorts of 6 patients each, and safety profiles were evaluated. DLTs were not observed in either cohorts and the most common adverse drug reaction (ADR) was injection site reaction (ISR). ISR in 6 patients worsened to grade 3 with continuous treatment of DSP-7888 (2 patients at 3.5 mg/body, and 4 patients at 10.5 mg/body). Five serious ADR including 3 ISR, 1 pyrexia and 1 myocarditis were reported and dose-dependent toxicity was not observed except for ISR. All 12 patients were analyzed for preliminary clinical activity. Eight patients remained in stable disease (SD) with 2 hematological improvements (HI), and disease control rate (SD + any HI) was 66.6 %. Seven high risk AZA failure patients were enrolled, and the current survival time in this population is 7.3-10.8 months. Though preliminary, CTL induction was observed in 6 patients, and a trend of higher CTL induction was observed in patients with grade 3 ISR. DTH response was observed in 10 patients. Conclusions: In the phase 1 portion, DSP-7888 was well-tolerated in MDS patients although ISR was observed in all patients. CTL induction was detected with clinically observed reactions that may suggest preliminary signs of clinical activity. Further evaluation is needed to confirm the clinical potential of DSP-7888, and phase 2 portion is currently ongoing to evaluate the efficacy of DSP-7888 in higher-risk MDS patients after AZA failure. Disclosures Usuki: Nippon Shinyaku: Honoraria; MSD: Honoraria; Kyouwa-Kirin: Honoraria; Novartis: Honoraria; Bristol-Myer-Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; SymBio Pharmaceuticals: Research Funding. Matsumura:Bristol-Myers Squibb Company: Honoraria; Novartis Pharma K.K: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Consultancy, Honoraria; Pfizer Japan Inc.: Honoraria. Ueda:Alexion Pharmaceuticals Inc.: Membership on an entity's Board of Directors or advisory committees. Origuchi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Tagashira:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Naoi:Sumitomo Dainippon Pharma Co.,Ltd.: Employment. Naoe:Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Celgene K.K.: Honoraria, Research Funding; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding. Heike:Sumitomo Dainippon Pharma: Consultancy; Chugai Pharma: Consultancy; Otsuka Pharma: Consultancy. Miyazaki:Kyowa Kirin: Honoraria; Nihonshinyaku: Honoraria; Celgene Japan: Honoraria; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria.

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]

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