scholarly journals Dasatinib induces complete cytogenetic response and loss of F359C in an imatinib resistant chronic myelocytic leukemia patient

2009 ◽  
Vol 84 (6) ◽  
pp. 386-387 ◽  
Author(s):  
Celalettin Ustun ◽  
Anand P. Jillella ◽  
Mohamed E. Salama
Keyword(s):  
Cytogenetic Response ◽  
Chronic Myelocytic Leukemia ◽  
Leukemia Patient ◽  
Complete Cytogenetic Response ◽  
Myelocytic Leukemia ◽  
Imatinib Resistant

scholarly journals Molecular Follow-Up of Disease Progression and Interferon Therapy in Chronic Myelocytic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4918-4923 ◽  
Author(s):  
Dina Ben-Yehuda ◽  
Svetlana Krichevsky ◽  
Eliezer A. Rachmilewitz ◽  
Ayelet Avraham ◽  
Giuseppe A. Palumbo ◽  
...  
Keyword(s):  
De Novo ◽  
Methylation Status ◽  
Pcr Amplification ◽  
Chronic Phase ◽  
Restriction Enzymes ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Chronic Myelocytic Leukemia ◽  
Myelocytic Leukemia

Abstract We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon α (IFNα) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNα-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNα therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNα therapy far better than the cytogenetic response.

A Phase 1/2 Study of SKI-606, a Dual Inhibitor of Src and Abl Kinases, in Adult Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) or Acute Lymphocytic Leukemia (ALL) Relapsed, Refractory or Intolerant of Imatinib.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 168-168 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Tim H. Brummendorf ◽  
Delong Liu ◽  
...  
Keyword(s):  
Safety Profile ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Dual Inhibitor ◽  
Hematologic Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant ◽  
Complete Hematologic Response

Abstract SKI-606 is an orally available, dual Src/Abl kinase inhibitor shown to be 200-fold more potent than imatinib as an inhibitor of Bcr-Abl phosphorylation in biochemical assays. BaF3 cell lines and primary cells from pts expressing different imatinib-resistant Bcr-Abl mutant proteins are sensitive to SKI-606 in vitro. Unlike imatinib and dasatinib, SKI-606 exhibits no significant inhibition of c-kit or PDGFR. This differential selectivity may result in clinical benefit by altering the safety profile. In the phase 1 portion of this phase 1/2 study, pts in chronic phase with imatinib relapsed or refractory disease were eligible for treatment with SKI-606 once-daily dosing. 18 pts [median age: 62 yrs (range 27 – 72); 14 male; 4 female; median CML duration: 5.8 yrs (range 0.9 – 11.1); and median time on imatinib (n=16): 3.9 yrs (range 0.8 – 6.5)] have been enrolled in the following dose cohorts (mg/day): 400 (3 pts), 500 (3 pts) and 600 (12 pts), and have been on treatment for 30 to 192 days. 17/18 pts remain on study; 1 pt discontinued with disease progression. The following SKI-606-related AEs have been reported (n=15, G1/2): diarrhea (87%), nausea (33%), vomiting (20%), abdominal pain (13%), rash (13%), asthenia (13%), and increased AST/ALT levels (7%). 2 pts treated at 600 mg experienced a G3 toxicity: rash and thrombocytopenia. 5 pts (4 pts at 600 mg and 1 pt at 500 mg) had dose reductions for rash, thrombocytopenia, diarrhea, fever and increased AST/ALT levels. No pleural effusion or pulmonary edema has been reported. Of the 7 pts who entered the study in hematologic relapse and have completed 1 month of treatment, all have achieved complete hematologic response. Of the 7 pts on treatment ≥ 12 weeks (time of first cytogenetic assessment), 3 pts have achieved complete cytogenetic response and 1 pt a minimal cytogenetic response. 6/7 pts who have achieved complete hematologic response had pre-treatment imatinib-resistant Bcr-Abl mutations: M351T; F359V; T315I; F359(V,F); and 2 pts with multiple mutations [L248(L,V) and H396(H,R); H396(H,P) and E286(E,G) and M351(T,M)]. The 3 pts with complete cytogenetic response had mutations: M351T; M244V; and H396(H,P), E286(E,G) and M351(T,M). Based on the emergence of 1 DLT of G3 rash, and additional G2 GI and dermatologic toxicities observed at 600 mg, 500 mg has been selected as the dose for the phase 2 portion of the study. Patients in all phases of CML and Ph+ ALL are now being enrolled. SKI-606 is well tolerated in pts with CML, with a primarily GI and dermatologic safety profile, and with encouraging evidence of clinical activity in imatinib-resistant patients with complete hematologic and cytogenetic responses.

A T315I Gate Keeper Mutation Responding To Pegylated Interferon Alfa-2a (Peg-IFN) Monotherapy With Major Molecular Response (MMR4) At 12 Months In An Imatinib-Resistant Chronic Myeloid Leukemia (CML) Patient

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5179-5179
Author(s):  
Hyacinthe Johnson-Ansah ◽  
Dina Naguib ◽  
Hervé Mittre ◽  
Seyefeddine Kadi ◽  
Xavier Troussard
Keyword(s):  
Weight Loss ◽  
Targeted Therapy ◽  
Mutational Analysis ◽  
Pegylated Interferon ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant ◽  
T315i Mutation

Abstract Since the IRIS Study in 2000, tyrosine kinase inhibitors (TKI) have become a standard therapy for CML patients in lieu of interferon based therapy. Nevertheless, resistance occurs in roughly 30% of imatinib-treated patients. This resistance is attributable to ABL kinase domain mutations in 50% of cases, in which T315I mutation accounts for 10 to 15%. This latter is resistant to all TKIs available except for ponatinib which enables 75% of complete cytogenetic response (CCyR) in this setting (NEJM November 29, 2012). Before Ponatinib, various strategies were proposed to overcome the T315I mutation including more importantly ‘non-targeted' therapy such as Omacetaxine. IFN is also a ‘non-targeted therapy' known to have a well-established immunological effect. There are also clues about its cellular effects: microarray analyses have shown that IFN alfa can upregulate genes that encode for apoptotic proteins (i.e TRAIL, Fas, caspases 4 and 8 and XAF-1…) conferring the anti-growth effect different from ATP competition specific to TKIs. We report here an 80 years-old imatinib-resistant CML patient harboring the T315I mutation who has been successfully treated with Peg-IFN (Pegasys). His past medical history involved hypertension, asthma and chronic obstructive pulmonary disease. He was diagnosed in July 2008 with a chronic phase CML when he presented with weight loss, splenomegaly, leukocytosis (WBC 80G/l), slight anemia (Hemoglobin 112G/l) and normal Platelet count 240G/L. Karyotyping of 26 metaphase cells in the bone marrow showed Philadelphia (Ph1) chromosome without any additional abnormality. The molecular analysis by real time PCR (Light Cycler 480) detected a BCR-ABL p210 transcript. The Sokal score was high (at 1.24) while the Eutos score was low (31). He started Imatinib 400mg daily in July 2008 and achieved 5% IS BCR-ABL ratio at 3 months and complete cytogenetic response (CCyR) at 12 months. But the patient had never reached the major molecular response (MMR) and ended up losing the cytogenetic response in February 2012 (at 40 months) with an increase of 1.5log in the BCR-ABL ratio. Sequencing analysis for ABL mutation was carried out using the applied biosystems 3500 gentic analyzer. It revealed the T315I mutation at 20%. After a request for Ponatinib was dismissed by our health authorities, we decided to treat the patient with Peg-IFN in June 2012 at the dose of 90 µg per week. At this point, the imatinib had been stopped for 3 months, 8 metaphase cells out of 20 showed Ph1 chromosome without additional abnormality, BCR-ABL ratio was 3% IS, the mutational analysis showed 50% of T315I and 20% of another acquired E255K mutation. But the patient was still in complete haematologic response. figure 1 highlights the decline in the BCR-ABL ratio with MMR reached for the first time at 9 months (from Peg-IFN treatment). Of note, the CCyR was obtained again at this landmark. At 12 months from the Peg-IFN the CCyR was confirmed, the BCR-ABL ratio came very close to MMR4 (0.02% IS) while both T315I and E255K mutations disappeared on mutational analysis. Figure 1 Figure 1. No side effect was reported except for weight loss when the dose of Peg-IFN was increased to 180 µg per week which was the dose suggested by J.H. Lipton (Leukemia and Lymphoma, March 2007). The average dose in the past 12 months was 90 µg per week. The latter dose is well tolerated and is still ongoing. This observation shows that, though we are in the ponatinib era, there still is a room for interferon, in the management of CP CML patients even in BCR-ABL domain mutated patients because of its different mechanism of action. In this case the Pegylated Interferon a-2-a at the dose of 90µg per week has allowed clearance of both T315I and E255K mutations with a response close to MMR4. Taking into account the slope of the BCR-ABL decline, deeper molecular response is expected before the ASH meeting in December 2013. Disclosures: No relevant conflicts of interest to declare.

Correlation of three methods of measuring cytogenetic response in chronic myelocytic leukemia

2002 ◽  
Vol 137 (2) ◽  
pp. 79-84 ◽  
Author(s):  
Martin L Lesser ◽  
Gordon W Dewald ◽  
Cristina P Sison ◽  
Richard T Silver
Keyword(s):  
Cytogenetic Response ◽  
Chronic Myelocytic Leukemia ◽  
Myelocytic Leukemia

scholarly journals Association between Hasford Scoring System and Hematologic Response in Chronic and Accelerated Phase of Chronic Myelocytic Leukemia Patient with Imatinib for Three Months

2019 ◽  
Vol 3 (2) ◽  
pp. 88
Author(s):  
Andy Purnomo ◽  
Ugroseno Yudho Bintoro ◽  
Made Putra Sedana ◽  
Ami Ashariati
Keyword(s):  
Scoring System ◽  
Fisher Exact Test ◽  
Prognostic Impact ◽  
Chronic Myelocytic Leukemia ◽  
Exact Test ◽  
Leukemia Patient ◽  
Hematologic Response ◽  
Myelocytic Leukemia ◽  
Complete Hematologic Response ◽  
Hasford Score

Background: Hasford score is a scoring system which was made in interferon treatment era to assess chronic myelocytic leukemia (CML) prognosis. Complete hematologic response (CHR) is the milestone of prognosis evaluation. CHR achievement will significantly increase survival. Imatinib is a revolutionized treatment that change the prognosis of CML. With the advent of Imatinib, lessened the prognostic impact of the Hasford score to predict prognosis.Materials and Methods: An observational analytic with prospective cohort study conducted in oncology outward division Dr. Soetomo hospital Surabaya, from July until October 2018. Hasford score determined in 32 patients at the beginning of the study, given imatinib and followed up regularly for 3 months to know the hematologic response. Data were analyzed using Fisher exact test which was considered significant if p<0.05.Results: Median age was 39 years old, male 37.5% and female 62.5%, the median spleen was 18 cm, median hemoglobin was 9.1 g/dL, median leukocyte was 180x109 /L, median thrombocyte was 645x109 /L, median eosinophil was 2.9%, median basophil was 4.6%, median myeloblast was 6%. Hasford score showed 3.1% in low risk, 25% in intermediate risk and 71.9% in high risk. As much as 78.1% complete hematologic response was found in patient, and 21.9% was incomplete.Conclusion: There was no association between Hasford scoring system and hematologic response in chronic and accelerated phase of chronic myelocytic leukemia patient with imatinib for three month. Hasford score had no impact in hematologic response with imatinib.Keywords: Hasford score, hematologic response, CML, imatinib

scholarly journals Molecular Follow-Up of Disease Progression and Interferon Therapy in Chronic Myelocytic Leukemia

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4918-4923 ◽  
Author(s):  
Dina Ben-Yehuda ◽  
Svetlana Krichevsky ◽  
Eliezer A. Rachmilewitz ◽  
Ayelet Avraham ◽  
Giuseppe A. Palumbo ◽  
...  
Keyword(s):  
De Novo ◽  
Methylation Status ◽  
Pcr Amplification ◽  
Chronic Phase ◽  
Restriction Enzymes ◽  
Cytogenetic Response ◽  
Interferon Α ◽  
Chronic Myelocytic Leukemia ◽  
Myelocytic Leukemia

We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon α (IFNα) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNα-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNα therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNα therapy far better than the cytogenetic response.

Clonal Chromosomal Abnormalities in Philadelphia Negative Cells during Dasatinib Treatment in Five Patients with Chronic Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4823-4823
Author(s):  
Viviane Dubruille ◽  
Pascaline Talmant ◽  
Herve Avet Loiseau ◽  
Philippe Moreau ◽  
Jean-Luc Harousseau
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Trisomy 8 ◽  
Cytogenetic Abnormalities ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract The emergence of clonal chromosomal abnormalities in Philadelphia negative cells was reported during Imatinib treatment in several patients with chronic myeloid leukemia (CML) in different phases (chronic phase, accelerated phase and blastic crisis). Recently, new tyrosine kinase inhibitors were used in treatment of Imatinib-resistant or Imatinib-intolerant chronic myeloid leukemia. We describe 5 patients with chromosomal abnormalities in Philadelphia negative cells during treatment with Dasatinib. At the beginning of treatment, 4 patients were in chronic phase, 1 patient was in accelerated phase. All patients were in cytogenetic relapse. Additional cytogenetic abnormalities were described in Philadelphia positive cells only in one case (accelerated phase). Clonal cytogenetic abnormalities (4 trisomy 8, 1 monosomy 7) appeared in Philadelphia negative cells during Dasatinib treatment (after 6 months in 1 patient, 9 months in 4 patients).At this time, 4 patients (Imatinib- resistant) received Dasatinib at the dose of 40 mg twice daily (dose reduction due to hematological toxicity); 1 patient (Imatinib cutaneous intolerance in chronic phase) received 140 mg daily. Two patients were in complete cytogenetic response, 2 patients were in partial cytogenetic response (10% and 8.5% Philadelphia positive cells) and obtained a complete cytogenetic response 3 months later, and 1 patient was in minor cytogenetic response. For 2 patients, the presence of trisomy 8 was transient, for 3 patients chromosomal abnormalities were persistent; none showed myelodysplastic changes. At present, all patients are still treated by Dasatinib with the same dosage. Cytogenetic abnormalities occur in Philadelphia negative cells in a fraction of patients with CML treated with Dasatinib. Philadelphia negative abnormal clone can persist despite complete cytogenetic response achievement. Their incidence, etiology and prognosis remain to be clarified and with a short follow-up, no clear clinical consequences can be identified.

A Canadian Expanded Access Trial of Oral Nilotinb in Adult Patients with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia in Blast Crisis, Accelerated Phase or Chronic Phase

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4437-4437
Author(s):  
Robert Delage ◽  
A. Robert Turner ◽  
Brian Leber ◽  
Wanda S. Hasegawa ◽  
Denis-Claude Roy ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Advisory Committees ◽  
Expanded Access ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant

Abstract Abstract 4437 This multi-center, open-label, single-arm study evaluated the safety and efficacy of nilotinib in patients with imatinib resistant/intolerant chronic myeloid leukemia (CML) in blast crisis, accelerated phase and chronic phase. This study provided expanded access to nilotinib prior to commercial availability. Methods: Patients received nilotinib orally at a dose of 400 mg twice daily. Adverse events were monitored throughout the study and assessments of cardiac, hematology and blood chemistry were performed every 3 months at a minimum. The efficacy assessments were performed every 6 months at a minimum and comprised of cytogenetic analysis of bone marrow, evaluation of extramedullary disease, and cancer related symptoms. Results: Sixty-five patients were enrolled in the study. The median age was 56 (range 21–85) years; 50.8% were male, and 89.2% Caucasian. The majority of patients (92.3%) were in chronic phase; 3.1% and 4.6% of the patients were in blast crisis and accelerated phase respectively. Twenty-five (38.5%) patients were imatinib-resistant, thirty-seven (56.9%) imatinib-intolerant and three (4.6%) both imatinib-resistant and -intolerant. The overall median duration of treatment with nilotinib was 27.2 (range 0.3 – 48.8) months. Thirty-six patients (55.4%) were still on treatment at study end. The main reasons for discontinuation were adverse events (16.9%) and unsatisfactory therapeutic effect (12.3%). Treatment related adverse events reported in at least 10% of patients, irrespective of severity, included rash (23.1%), pruritus (20%), fatigue (18.5%), muscle spasms (15.4%), headache (16.9%), alopecia (13.8%), abdominal pain (10.8%) and lipase elevation (10.8%). Grade 3 and 4 adverse events reported in at least 5% of patients, irrespective of study drug relationship, included thrombocytopenia (12.3 %), anemia (6.2%), neutropenia (6.2%) and lipase elevation (6.2%). Three patients (4.6%) discontinued due to cardiac disorders including tachycardia (1), myocardial infarction (1), and palpitations (1). Clinically significant abnormal ECG results were uncommon and mostly transient. There was no evidence of toxicity to a major organ system. One patient died within 28 days after study discontinuation due to progression of recently diagnosed multiple myeloma and chronic obstructive pulmonary disease deterioration not suspected to be related to study drug. Thirty patients received treatment for at least 30 months with nilotinib on study. At month 30, 14 (82.4%) of 17 patients who underwent a bone marrow aspirate achieved a complete cytogenetic response. Seven of these fourteen patients (50%) had never previously achieved complete cytogenetic response with imatinib. Conclusions: This phase IIIB trial provided nilotinib to 65 patients with imatinib-resistant or -intolerant chronic CML in all phases on expanded access for 44 months, allowing evaluation of its safety profile. Nilotinib treatment was reasonably well-tolerated with an overall safety profile similar to that reported in previous studies, without the occurrence of unexpected adverse events. Real-time quantitative RT-PCR of BCR-ABL mRNA levels was not a study endpoint but is used routinely in Canada to monitor patients in complete cytogenetic response instead of cytogenetic assessments which likely explains the low compliance with cytogenetic assessments in this study. Disclosures: Turner: Novartis Pharmaceuticals Canada: Research Funding, Speakers Bureau. Leber:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hasegawa:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Leitch:Novartis Pharmaceuticals: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Bence-Bruckler:Novartis Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees. Sandeep:Novartis Pharmaceuticals: Honoraria. Laneuville:Novartis Pharmaceuticals: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Woo:Novartis Pharmaceuticals Canada Inc.: Employment. Beauparlant:Novartis Pharmaceuticals Canada Inc: Employment. Lipton:Novartis Pharmaceuticals Canada Inc: Honoraria, Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Safety and efficacy of bosutinib (SKI-606) in chronic phase Philadelphia chromosome–positive chronic myeloid leukemia patients with resistance or intolerance to imatinib

Blood ◽  
2011 ◽  
Vol 118 (17) ◽  
pp. 4567-4576 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Complete Cytogenetic Response ◽  
Imatinib Resistant

Abstract Bosutinib, a dual Src/Abl kinase inhibitor, has shown potent activity against chronic myeloid leukemia (CML). In this phase 1/2 study we evaluated bosutinib in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. Part 1 was a dose-escalation study to determine the recommended starting dose for part 2; part 2 evaluated the efficacy and safety of bosutinib 500 mg once-daily dosing. The study enrolled 288 patients with imatinib-resistant (n = 200) or imatinibintolerant (n = 88) CML and no other previous kinase inhibitor exposure. At 24 weeks, 31% of patients achieved major cytogenetic response (primary end point). After a median follow-up of 24.2 months, 86% of patients achieved complete hematologic remission, 53% had a major cytogenetic response (41% had a complete cytogenetic response), and 64% of those achieving complete cytogenetic response had a major molecular response. At 2 years, progression-free survival was 79%; overall survival at 2 years was 92%. Responses were seen across Bcr-Abl mutants, except T315I. Bosutinib exhibited an acceptable safety profile; the most common treatment-emergent adverse event was mild/moderate, typically self-limiting diarrhea. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (9%), rash (9%), and vomiting (3%). These data suggest bosutinib is effective and tolerable in patients with chronic phase imatinib-resistant or imatinib-intolerant CML. This trial was registered at http://www.clinicaltrials.gov as NCT00261846.

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