Dasatanib (D) in patients (pts) with chronic myelogenous leukemia (CML) in lymphoid blast crisis (LB-CML) or Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ALL) who are imatinib (IM)-resistant (IM-R) or intolerant (IM-I): The CA180015 ‘START-L’ study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6528-6528 ◽  
Author(s):  
S. Coutre ◽  
G. Martinelli ◽  
H. Dombret ◽  
A. Hochhaus ◽  
R. Larson ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Poor Response ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Open Label ◽  
Prior Therapy ◽  
Hematologic Response

6528 Background: Dasatinib (D) (BMS-354825) is a multi-targeted kinase inhibitor of BCR-ABL and SRC. Preliminary data from a phase I study suggest high efficacy of D in IM pretreated pts. Methods: START L is an open label phase II study of D in IM-R or IM-I pts with LB-CML and Ph+ALL conducted at 42 centers worldwide. D was given orally, 70 mg twice a day (bid), with escalation to 100 mg bid for poor response or reductions to 50 mg and 40 mg bid for toxicity. Pts had weekly blood counts and monthly bone marrow exams, including cytogenetics. The primary endpoint was confirmed (sustained for at least 4 weeks) major hematologic response (MaHR) rates. Results: From January to June 2005, 101 pts were accrued. Data are available on the first 78 treated pts (42 LB-CML, 36 Ph+ALL). Of the 42 LB-CML pts, 37 were IM-R, 52% were male with median (med) age of 47 years. Prior therapy included IM >600 mg/day in 52% and stem-cell transplant (SCT) in 33% of pts. Med baseline platelet (plt) count was 32.5/nl, med BM blasts were 82%, Bcr-Abl mutations were seen in 48%, and extramedullary disease (EMD) was seen in 29% of pts. The D dose was reduced in 14%, temporarily interrupted in 33%, and escalated in 26% of pts. At 6-months, the MaHR rate was 31% including 26% complete hematologic response (CHR), the MCyR rate was 50%, and 17% of pts remained on study. Of the 36 Ph+ALL pts, 34 were IM-R, 64% were male with med age 46 years. Prior therapy included IM> 600 mg/day in 47% and SCT in 42% of pts. Baseline plt count was 53.5/nl, med BM blasts were 69%, Bcr-Abl mutations were seen in 47% and EMD was seen in 31% of pts. The D dose was reduced in 28%, temporarily interrupted in 39%, and escalated in 47% of the pts. At 6-months, the MaHR rate was 42% including 31% CHR, the MCyR rate was 58%, and 33% pts remained on study. Among all 78 pts, grade 3–4 thrombocytopenia and neutropenia was seen in 82% and 76% of pts, respectively. The most frequent D-related non-hematologic toxicities were diarrhea (30%), nausea (23%), fatigue (19%), rash (17%) and pleural effusion (13%). Conclusions: D is active in IM pretreated LB-CML and Ph+ALL pts. Data on all 101 pts will be presented at the meeting. [Table: see text]

Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): Results of the CA180006 ‘START-B’ study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6529-6529 ◽  
Author(s):  
J. E. Cortes ◽  
D. W. Kim ◽  
G. Rosti ◽  
P. Rousselot ◽  
E. Bleickardt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Initial Response ◽  
Preliminary Evidence ◽  
Marrow Transplant ◽  
Myelogenous Leukemia ◽  
Open Label ◽  
Hematologic Response ◽  
Grade 3

6529 Background: Dasatinib (D) (BMS-354825) is an oral, multitargeted tyrosine kinase inhibitor of Bcr-Abl and SRC with activity against IM-R cell lines. In a phase I study, there was preliminary evidence that D was active in MBC-CML patients (pts). Methods: START B is an open-label study of D in IM-R or IM-I MBC carried out in 46 sites worldwide. From December 2004 to May 2005, 124 MBC pts were accrued. D was given orally at 70 mg twice a day (BID) with dose escalation to 100 mg BID for poor initial response or dose reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow evaluations, including cytogenetics. The primary endpoint was confirmed (minimum 4 weeks duration) major hematologic response (MaHR). Results: Data are currently available on the first 74 pts (68 IM-R, 6 IM-I). Median age was 55 years, 55% were male. Other prior therapy included interferon in 55% of pts and bone marrow transplant (BMT) in 12%. Prior IM dose was >600 mg/day in 49% of pts and 47% of pts received IM for > 3 years. At baseline, the WBC count was ≥20 × 103/mm3 in 46%, the platelet count was < 100 × 103/mm3 in 72% of pts and 35% of pts had ≥ 50% bone marrow blasts. Mutations in the BCR-ABL domain were found in 27/63 (43%) pts. Median duration of therapy was 3.5 months. D doses were reduced in 35% pts, temporarily interrupted in 58% pts, and escalated in 41% pts. With a minimum of 6-month follow-up, hematologic response was seen in 39 (53%) pts: confirmed MaHR in 24 (32%) pts, Complete in 18 (24%) and No Evidence of Leukemia in 6 (8%). Major cytogenetic responses were documented in 22 (30%) pts and was complete in 20 (27%). The median time to MaHR was 56 days. There was no loss of response in pts with MaHR; the duration of MaHR ranged from 1.2+ to 7.8+ months. The median PFS had not been reached. Severe myelosuppression was very common. Non-hematologic toxicities were usually mild to moderate. Most common Grade 3–4 toxicities included diarrhea in (7%), pleural effusion (9%), nausea (4%). Peripheral edema was reported in 14% of pts (0% Grade 3–4), and rash in 11% of the pts (0% Grade 3–4). Conclusions: Dasatinib was highly effective in IM-R pts with MBC with durable MaHR. Data on all 124 pts will be presented at the meeting. [Table: see text]

Nilotinib Treatment in Pediatric Patients (pts) with Philadelphia Chromosome- Positive (Ph+) Leukemia Refractory to Prior Tyrosine Kinase Inhibitor (TKI) Therapy: Results from Nilotinib Compassionate Use Program

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4264-4264 ◽  
Author(s):  
Alan S. Wayne ◽  
Carla Renata Macedo ◽  
Tomasz Szczudlo ◽  
Richard C. Woodman
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Kinase Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Skin Toxicity ◽  
Myelogenous Leukemia ◽  
Compassionate Use ◽  
Starting Dose

Abstract Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of adults with Ph+ chronic myelogenous leukemia (CML) in chronic (CP) or accelerated phase (AP) resistant to prior therapy including imatinib. Pts &lt;18 years were not included in the pivotal nilotinib phase I/II registration study. The mechanisms of BCR-ABL resistance to imatinib are reported to be similar in pediatric and adult pts. We describe the use of nilotinib in pediatric pts (≤18 years) with advanced refractory Ph+ leukemia through a global compassionate use program. These represent the first reported results of nilotinib in pediatric pts. Methods : Between June 2006 and April 2008, pts were evaluated for compassionate use of nilotinib for the treatment of Ph+ CML or Ph+ acute lymphoblastic leukemia (ALL) resistant or intolerant to other therapies including imatinib alone or sequential imatinib and dasatinib. Resistance and intolerance were defined using the same criteria as those previously reported in the nilotinib phase II study. Pediatric pts with body weight ≥40 kg received nilotinib at a starting dose of 400 mg twice daily (BID) while pediatric pts &lt; 40 kg started at 300 mg BID. Dose modifications were performed based on tolerance and response. Results : A total of 36 pts were evaluated for compassionate use of nilotinib, of which 16 received treatment with nilotinib. Mean age was 15 yrs (range 10–18). There were 9 males. 8 pts had Ph+ CML: 3 CP; 3 AP; 2 blast crisis (BC) and 8 pts had Ph+ ALL. 15/16 pts were resistant to imatinib, 1 pt was intolerant to imatinib, 7 pts (6 Ph+ ALL; 1 BC) had also received dasatinib and 6 pts had undergone SCT prior to receiving nilotinib. Starting dose was 400 mg BID in 12 pts and 300 mg BID in 4 pts. Two pts had dose reductions (1, 200 mg BID; 1, 400 mg with 200 mg QD) while 3 pts had dose escalation (2, 400 mg BID; 1, 600 mg BID). At the time of data analysis 9/16 pts remained on nilotinib therapy with clinical benefit. Mean duration of nilotinib treatment was 3.3 mos (range 1–9). Seven pts had disease progression while on nilotinib and discontinued therapy at a mean of 2.1 mos (1–5) duration of therapy. Six of these pts had received 2 prior TKIs, 1 of whom (18 yrs, Ph+ ALL) had a T315I mutation at the time of progression. Nilotinib serum levels were obtained from 1 pt (10 yrs, 29 kg female with Ph+ ALL) who received a dose of 300 mg BID. The trough (prior to morning dose) concentrations were determined to be 2,430 ng/mL on Day 10 and 1,890 ng/mL on Day 24, similar to that observed for adults in the phase I study with nilotinib dosing of 400 mg BID. AEs reported during treatment include thrombocytopenia (unknown grade), grade 1 skin toxicity, and grade 1 chest and bone pain. 3 SAEs were reported: grade 4 neutropenia (Ph+ ALL); relapsed disease with hepatomegaly and grade 3 increased liver transaminases (Ph+ ALL); 1 death due to disease progression (11 yrs, Ph+ ALL). Conclusions : Nilotinib safety profile in this group of pediatric pts appears to be similar to that reported in adult pts. Similar to adults, these results suggest that nilotinib has activity in pediatric pts with Ph+ leukemias and that heavily treated pts with advanced Ph+ leukemia resistant to 2 TKIs have a poor prognosis. A phase I/II study with nilotinib in pediatric pts with imatinibresistant or intolerant Ph+ leukemia is planned.

scholarly journals A Rare Case of Chronic Myelogenous Leukemia Presenting as T-Cell Lymphoblastic Crisis

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
Parikshit Padhi ◽  
Margarita Topalovski ◽  
Radwa El Behery ◽  
Eduardo S. Cantu ◽  
Ramadevi Medavarapu
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Chronic Myelogenous Leukemia ◽  
Stem Cell Transplant ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Myelogenous Leukemia ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant

Chronic Myelogenous Leukemia in blast crisis can manifest as either myeloid (more common) or lymphoid blast crisis. Most lymphoblastic crises are of B-cell lineage. T-cell blast crisis is extremely rare, with only a few reported cases. We present a case of a middle-aged man who was diagnosed with CML on peripheral blood and bone marrow biopsy. Because of a generalized lymphadenopathy noted at the time of diagnosis, a lymph node biopsy was also performed, which revealed a T-cell lymphoblastic leukemia/lymphoma, BCR/ABL1 positive, with clonal evolution. This is a very rare manifestation of CML in blast crisis with no standard treatment and with poor outcomes despite chemotherapy or allogeneic stem cell transplant. Given its rarity, it would be difficult to develop standard chemotherapy protocols. We believe the treatment for this condition should be similar to any lymphoid blast crisis. The patient was treated with induction chemotherapy (hyper-CVAD regimen) plus dasatinib for 3 cycles followed by sibling-donor allogeneic stem cell transplant and is currently on maintenance dasatinib and has minimal residual disease at this time.

Nilotinib: A Review of its Use in Chronic Myelogenous Leukemia

2010 ◽  
Vol 2 ◽  
pp. CMT.S24
Author(s):  
Ting-Wei Lu ◽  
Ronan Swords ◽  
Francis J. Giles ◽  
Kevin Kelly
Keyword(s):  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chromosomal Translocation ◽  
Standard Of Care ◽  
Kinase Domain ◽  
Myelogenous Leukemia ◽  
Large Randomized Control Trial ◽  
Prior Therapy ◽  
Frontline Treatment ◽  
Favourable Safety Profile

Chronic myeloid leukemia (CML) is characterized by the reciprocal chromosomal translocation, t(9;22), forming the BCR-ABL oncogene known as the Philadelphia chromosome. The development of imatinib, a small-molecule kinase inhibitor targeted against BCR-ABL, has revolutionized the management of CML and significantly improved the prognosis and outcome and until very recently was the standard of care in patients presenting with newly diagnosed CML. Nilotinib (Tasigna®) is an orally administered kinase inhibitor made by the Novartis Pharmaceuticals Corporation that was rationally designed to bind to the ABL kinase domain of BCR-ABL resulting in enhanced BCR-ABL inhibition. It is well tolerated and has a favourable safety profile. Nilotinib has been shown to be effective in patients who have failed prior therapy with imatinib. Recently a large randomized control trial comparing imatinib and nilotinib has demonstrated that niloitinb is superior to imatinib in the frontline treatment of CML. This review summarizes the preclinical and clinical data supporting the use of nilotinib in the frontline and secondline treatment of CML.

A Pilot Study Evaluating the Safety and Efficacy of Imatinib Given Early after Transplant for High-Risk Philadelphia Chromosome-Postive Leukemias.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1095-1095
Author(s):  
Paul A. Carpenter ◽  
David S. Snyder ◽  
Mary E. Flowers ◽  
Jean E. Sanders ◽  
Paul J. Martin ◽  
...  
Keyword(s):  
Pilot Study ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Antigen Expression ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Cell Transplant ◽  
Hematopoietic Cell Transplant

Abstract Patients with Ph+ acute lymphoblastic leukemia (ALL) or chronic myelogenous leukemia (CML) in stages other than first chronic phase (CP1) frequently have recurrent malignancy after allogeneic hematopoietic cell transplant (HCT). Imatinib given after HCT for the treatment of hematological relapse has been of limited success in Ph+ALL but may induce more durable remissions in CML. Hypothesis: We postulated that imatinib might be most effective for preventing hematological relapse after myeloablative HCT if given immediately after engraftment to patients without detectable leukemia, or with leukemia that can be detected only at the molecular level. Study design: A pilot study is ongoing to evaluate the safety and preliminary efficacy of imatinib begun early after myeloablative HCT and continued until post-transplant day 365 (D+365). Study participants became eligible to start imatinib (adults 400 mg/day, children 260 mg/m2/day) if the residual marrow leukemia burden at the time of initial engraftment (ANC&gt;500 on 2 consecutive days) did not exceed &gt;1/20 Ph+ metaphases, &gt;1% aberrant antigen expression on blasts by multidimensional flow, or presence of bcr/abl in &gt;5% interphase nuclei by FISH. The primary endpoint of safety was defined by ability to tolerate imatinib (adults ≥200 mg/day, children ≥100 mg/day) for ≥ 6 days/week until D+90. An attempt was made to administer higher daily doses of imatinib after D+90. Patient characteristics: Ten patients with Ph+ALL (8 CR1, 2 CR2) and 6 patients with CML (2 AP, 2 CP2, 2 CP3) have been enrolled; 13/16 had leukemia detected by molecular or cytogenetic methods at the time of transplant. Median age at transplant was 40 y (range 5–62 y). Stem cell sources were cord blood (n=1), marrow (n=4) or G-mobilized peripheral blood (n=11). Donors were unrelated (n=10) or related (n=6). Results: Imatinib therapy began in 15 patients at a median of 29 days (range 24–39 days) after HCT and has been administered for a median of 299 days (range, 33–380 days). The median of average daily doses during this time period was 400 mg/day (range 389 to 510 mg/day) among adults and 304 mg/m2/day for the 2 children. All patients tolerated imatinib at the intended dose intensity within the first 90 days after HCT. Toxicities (NCI CTC v3.0) possibly attributed to imatinib included grade 1–2 nausea (n=3), grade 1 edema (n=3), grade 1–2 anemia (n=2), and grade 3 neutropenia (n=2). Per protocol, one patient with neutropenia received 2 doses of G-CSF at D+75 and continued imatinib without neutropenia. The second patient was not given G-CSF and imatinib was held for 2 weeks from D+160 until the ANC was &gt;2000. All patients are surviving at a median of 333 days after HCT (range, 68–564), and 14/15 patients have no detectable bcr/abl transcripts in the blood or marrow. Seven patients (4 ALL, 3 CML) have completed imatinib therapy and survive at a median of 467 days after HCT (range, 410–564 days) and 6/7 have no detectable bcr/abl transcripts in blood or marrow. One patient (CML-CP3) with cytogenetic relapse at D+118 had a 4th remission after withdrawal of immunosuppression and continued imatinib but developed hematological relapse at D+429. Conclusions: We conclude that imatinib therapy can be safely prescribed early after myeloablative allogeneic HCT at a dose-intensity comparable to that used in general oncology. Preliminary efficacy data are encouraging and worthy of further study.

Dasatinib (SPRYCEL®) in Patients (pts) with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results from the CA180-015 ‘START-L’ Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 286-286 ◽  
Author(s):  
Herve Dombret ◽  
O.G. Ottmann ◽  
G. Rosti ◽  
B. Simonsson ◽  
R.A. Larson ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Median Duration ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
Hematologic Response ◽  
Grade 3 ◽  
Philadelphia Chromosome Positive

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC. Relapsing pts with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) who have been previously treated with chemotherapy including im have a very poor prognosis. START-L is an open label, multi-center, global phase-II study, which treated 46 im-r or im-i pts with Ph(+) ALL from January through June 2005. Dasatinib was given orally, 70 mg twice daily (BID) with escalation to 100 mg BID for poor response or reductions to 50 mg and 40 mg BID for toxicity. Response was assessed on weekly blood counts and monthly bone marrow exams, including cytogenetics. Mutation analysis was conducted at baseline and at end of study. Quantitative PCR was carried out pretreatment and at the time of complete cytogenetic response (CCyR). At the time of this update, all 46 pts had a minimum of 9 months (mo) of follow-up. Of these, 44 (96%) were im-r; due to the small number of im-i pts, data for all pts are presented. 59% of patients were male and median age was 48 years. The median time from initial Ph(+) ALL diagnosis to first dose was 18 mo. All patients had been pretreated with im including 46% with 600 mg per day or more, and 52% whose duration of im treatment was more than 12 mo. 37% of the pts had received a stem cell transplant. At baseline, 67% of pts had WBC <2000/mm3, 74% had platelets <100 × 103/mm3, and 24% had extramedullary disease outside of the spleen. In the 40 pts with baseline mutation data, im-resistant BCR-ABL mutations were observed in 78%, one with T315I. The median duration of therapy was 3.0 mo (range 0.03–16.5) for all pts and was 13.0 mo (9.2–16.5) for pts still on study. The overall complete hematologic response rate was 35%. The major cytogenetic response was 57%, including 54% CCyR. The major hematologic response (MHR) in the 31 pts with baseline mutations was 45%. The median duration of MHR was 11 mo and the median progression-free survival was 3.7 mo (95% CI 1.6–6.1). Grades 3 and 4 thrombocytopenia occurred in 13% and 67%, respectively and grades 3 and 4 neutropenia occurred in 27% and 52% of pts, respectively. Most frequent non-hematologic toxicities included diarrhea in 30% (grade 3–4, 7%), nausea in 22% (no grade 3–4), pyrexia in 22% (grade 3–4, 2%), and pleural effusion in 22% (grade 3–4, 7%) of pts. Dose was reduced in 30% and interrupted in 43% of pts, primarily due to non-hematologic toxicities. Dasatinib has important efficacy in this Ph(+) ALL pt population. Updated efficacy (including molecular response), safety, and mutational analysis data will be presented at the meeting.

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.

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