Very Elderly Patients with Chronic Phase-Chronic Myeloid Leukemia on Imatinib: No Impact of Concomitant Drugs on Complete Cytogenetic Response

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1582-1582
Author(s):  
Alessandra Iurlo ◽  
Roberto Latagliata ◽  
Cristina Bucelli ◽  
Dario Ferrero ◽  
Fausto Castagnetti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Beta Blockers ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Channel Blockers ◽  
Very Elderly ◽  
Alpha Blockers ◽  
Drug Classes

Abstract Tyrosine-kinase inhibitors (TKIs)have completely changed the expected survival of chronic myeloid leukemia (CML) patients which is now approaching that of the general population: a relevant proportion of CML patients are currently elderly or very elderly. Very elderly patients represent generally a small proportion in published experiences. Older CML patients imatinib treated, as it happens in the general population, receive other drug treatments for associated chronic illnesses. Our aim is to assess if and which classes of concomitant drugs have an impact on cytogenetic response in chronic phase (CP)-CML very elderly (age >75 years) patients. Two hundred and twelve very elderly CP-CML patients, imatinib treated at 33 italian hematological institutions have been retrospectively evaluated. Median age at diagnosis was 78.5 years (range 75.0-93.0); 111 (52.4%) were male. Sixty-two (29.2%) were Sokal high risk. Sixty-seven (31.8%) were treated with reduced dose imatinib (<400 mg/day), and the remaining patients with imatinib >400 mg/day. Concomitant drugs were 1-2 in 73 (34.4%) patients, 3-4 in 59 (27.8%), and >5 in 64 (30.2%); 16 (7.6%) did not assume any concomitant drug. Drugs more frequently used were antiplatelets, assumed by 104 (49.1%) patients, followed by diuretics in 91 (42.9%) patients, proton pump inhibitors (PPIs) in 86 (40.6%), ACE inhibitors in 55 (25.9%), beta blockers in 44 (20.7%), angiotensin II receptors blockers (ARB) in 41 (19.3%), calcium channel blockers in 34 (16%), statins in 25 (11.8%), and alpha blockers in 11 (5.2%). Univariate logistic regression models were computed to assess the association between cytogenetic response after 6 or 12 months of imatinib treatment and number of concomitant drugs or selected drug classes. Statistical analyses were done using JMP 11.1 (SAS Institute Inc., Cary, NC, USA). Complete cytogenetic response (CCyR) was obtained in 124 (58.8%) patients, of whom 70 (33%) within 6 months. Consequently, we focused our study on the impact of number and types of drugs on CCyR rate, which represents the primary therapeutic endpoint in the elderly. Cytogenetic response distribution according to concomitant drugs is reported in table 1. We did not find any significant correlation between number of concomitant drugs, single classes of antihypertensive drugs, antiplatelets, PPIs or statins and CCyR rate at 6 or 12 months. Even though few pharmacokinetic interactions are reported between imatinib and some of medications we considered, this does not seem to have an impact on cytogenetic response rate in our cohort. Indeed, our results confirm the well-known safety and efficacy of imatinib also in very elderly CML patients. Table 1. Cytogenetic response according to concomitant drugs Drug classes Cytogenetic response CCyR <6 months CCyR 7-12 months CCyR >12 months No CCyR Antiplatelets (n=104) 38 (36.5%) 31 (29.8%) 11 (10.6%) 24 (23.1%) Diuretics (n=91) 32 (35.2%) 21 (23.1%) 13 (14.3%) 25 (27.4%) Proton pump inhibitors (n=86) 30 (34.9%) 22 (25.6%) 13 (15.1%) 21 (24.4%) ACE inhibitors (n=55) 19 (34.6%) 11 (20%) 12 (21.8%) 13 (23.6%) Beta blockers (n=44) 18 (40.9%) 11 (25%) 3 (6.8%) 12 (27.3%) Angiotensin II receptor blockers (n=41) 19 (46.3%) 11 (26.8%) 5 (12.3%) 6 (14.6%) Calcium channel blockers (n=34) 10 (29.4%) 7 (20.6%) 6 (17.7%) 11 (32.3%) Statins (n=25) 9 (36%) 7 (28%) 2 (8%) 7 (28%) Alpha blockers (n=11) 4 (36.4%) / 1 (9.1%) 6 (54.5%) Disclosures Castagnetti: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria. Abruzzese:BMS, Novartis, Pfizer, Ariad: Consultancy. Tiribelli:Bristol Myers Squibb: Consultancy, Speakers Bureau; Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis Farma: Consultancy, Speakers Bureau. Rosti:Novartis: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb: Honoraria, Research Funding, Speakers Bureau.

Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3785-3785 ◽  
Author(s):  
H. Jean Khoury ◽  
Carlo Gambacorti-Passerini ◽  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
David Marin ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115     CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110     MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41)     CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119     PFS at 2 yc 70% 81% 79% 38% 75%     OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Acquisition Of Compound BCR-ABL1 Alleles As A Mechanism Of Resistance To Ponatinib In Chronic Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 853-853
Author(s):  
Don L Gibbons ◽  
Sabrina Pricl ◽  
Paola Posocco ◽  
Erik Laurini ◽  
Maurizio Fermeglia ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
In Silico ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
The Impact ◽  
In Cells

Abstract BACKGROUND Ponatinib targets the inactive conformation of the ABL1 kinase and avoids interacting with the side chain of the mutated 315 residue. In vitro, ponatinib inhibits all single-point BCR-ABL1 mutations. Yet, a significant proportion of patients with chronic myeloid leukemia in chronic phase (CML–CP) do not respond to ponatinib and a subset loses their response during the course of treatment. The mechanisms of resistance to ponatinib are currently not well characterized. OBJECTIVE To determine the impact of compound BCR-ABL1 mutations (polymutants) on the activity of ponatinib. METHODS BCR-ABL1 mutational status was determined in 70 pts with CML-CP post imatinib failure and during dasatinib therapy by DNA expansion of specific clones followed by DNA sequencing of ≥10 clones. Free energy of binding (DGbind) for the unmutated and all mutant BCR-ABL1 kinase/inhibitor complexes were obtained using Molecular Mechanics/Poisson-Boltzmann Surface Area (MM-PBSA) methodology. Single and polymutant BCR-ABL1 alleles obtained by direct mutagenesis and their expression was forced into Ba/F3 cells by electroporation by the pMX/eGFP-BCR-ABL1 expression vector using the Amaxa System. RESULTS After imatinib failure, 125 ABL1 kinase domain mutations at 113 amino acid positions were detected in 61/70 (87%) pts, including 38 (54%) with mutations in ≥20% of sequenced clones. Mutations conferring resistance to >1µM imatinib were detected in 30 (43%) pts. Polymutant BCR-ABL1 alleles were detected in 29/70 (41%) pts. These patients received dasatinib for a median of 19 mos (range, 2-52), during which dasatinib-resistant mutations were detected in 10/32 (31%) assessable cases (5 with T315I). Polymutants were present in 16/32 (50%) pts (all of them dead in blast phase). The proportion of clones carrying unmutated BCR-ABL1 was markedly lower in patients who only achieved a minor or no cytogenetic response compared to those achieving a major cytogenetic response (p=0.0001), suggesting exhaustion of unmutated clones and expansion of mutant (and polymutant) clones linked to clinical dasatinib resistance. Then, we performed 3D structural analyses to determine the thermodynamic impact of 21 BCR-ABL1 mutants (11 single and 10 double mutants) in the ability of ponatinib to bind the kinase domain (Table). Most single mutants did not result in high ponatinib resistance (except for E255K, IC50=8.8nM; DGbind=-10.99±0.01). However, the association of any 2 of 3 point mutants (T315I, F317L, V299L) in a dual polymutant produced highly resistant BCR-ABL1 proteins that exhibited fold change values from 19 to 40, compared to the unmutated protein, with T315I/F359V displaying the highest resistance (IC50=61nM; DGbind=-10.23±0.03 kcal/mol), unveiling a mechanism of escape to ponatinib. In Ba/F3-based assays, ponatinib (but not imatinib or dasatinib) was active against Ba/F3-BCR-ABL1T315I cells. Polymutants exhibited very high ponatinib resistance (10-fold higher than that of cells carrying BCR-ABL1T315I). As predicted in silico, BCR-ABL1T315I/F359V was the most resistant polymutant tested. Cell growth inhibition was coupled with CrkL and STAT5 phosphorylation inhibition. Ponatinib, while suppressing STAT5 phosphorylation, could not suppress CrkL phosphorylation in cells expressing the BCR-ABL1T315I/F359V polymutant kinase, even at 100 nM (50-fold the IC50 required to inhibit BCR-ABL1T315I). CONCLUSIONS Polymutants are very frequent in pt samples after TKI failure (particularly after sequential TKI therapy) and tend to induce high ponatinib resistance. Our in silico platform predicted very accurately TKI sensitivity in cells carrying different BCR-ABL1 mutations, which makes it clinically applicable for matching specific mutations to the most effective TKI. Some polymutants require ponatinib concentrations not clinically reachable, thus representing a mechanism of escape to ponatinib therapy through selection and expansion of refractory clones. Disclosures: Talpaz: ariad: Research Funding. Cortes:Ariad: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria, Research Funding. Quintas-Cardama:ariad: Consultancy.

The Role of Imatinib Plasma Level in the Achievment of Complete Cytogenetic Response (CCyR) in Chronic Myeloid Leukemia (CML) Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3789-3789
Author(s):  
Sergey Kutsev ◽  
Oxana Oxenjuk ◽  
Sergey Mordanov ◽  
Yuri Shatokhin ◽  
Tatiana Pospelova ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Level ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Treatment ◽  
Female Ratio ◽  
Male Female Ratio

Abstract Abstract 3789 Background. The treatment of patients with chronic phase (CP) Ph-positive chronic myeloid leukemia (CML) with imatinib has resulted in high rates of cytogenetic and molecular responses. There are evidences that the achievement of CCyR and MMR to imatinib therapy is related with Imatinib plasma level (IPL) in some studies1,2 but not in others 3. This discrepancy may be possibly explained by the heterogeneity in the analysed cohort patients differing with respect to the phase of the disease and imatinib dose. The Aim of our study was to elucidate the trough role of IPL in the achievement of CCyR in homogeneous cohort of CP CML patients. Methods. IPL were detected in 321 CP CML patients with Imatinib treatment duration more than 12 months (the median – 90,3). Imatinib doses was 400 mg QD. The age of patients was 54,6 (24–76). Male/female ratio was 157/164. All patients gave informed consent before blood sampling. Blood samples were collected in 21–27h after the last Imatinib dose intake. Imatinib concentrations (C trough) were determined by validated LC/MS/MS method. Results. The patients were subdivided in 4 quartiles (Q): Q1 (n=81) with IPL 0 – 670 ng/ml, Q2 (n=80) with IPL 671 – 1042ng/ml, Q3 (n=80) with IPL 1043 – 1362ng/ml, Q4 (n=80) with IPL 1363 – 3826/ml. The results of imatinib treatment in each quartile were estimated according ELN recommendation. The obtained findings have shown that 48,1% CP CML patients in Q1 have achieved CCyR whereas 77,5%, 81,3% and 85% - in Q2,Q3 and Q4 respectively (Fig.1.). Conclusion. Our findings show that the achievement of CCyR in large cohort of CP CML patients (n=321) on imatinib with 400 mg/QD depends on IPL. The low level of IPL may indicate the nonadherence of some CML patients as well as some intrinsic mechanisms of imatinib plasma concentration decrease. Disclosures: Kutsev: Novartis: Research Funding, Speakers Bureau. Pospelova:Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Speakers Bureau. Khoroshko:Novartis: Speakers Bureau.

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 164-164 ◽  
Author(s):  
Lorenzo Falchi ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Susan O'Brien ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Molecular Responses ◽  
Free Survival

Abstract Abstract 164 Background: The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives: To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods: Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results: A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was: <MMR in 17% of pts, MMR in 13%, MR4 in 5%, MR4.5 in 19%, UND in 44%. In IM400 pts MR was <MMR in 28% of pts, MMR in 10%, MR4 in 8%, MR4.5 in 14%, UND in 40%. In IM800 pts MR was <MMR in 14% of pts, MMR in 8%, MR4 in 5%, MR4.5 in 19%, UND in 54%. In NILO pts MR was <MMR in 18% of pts, MMR in 20%, MR4 in 7%, MR4.5 in 22%, UND in 33%. In DASA pts MR was <MMR in 18% of pts, MMR in 18%, MR4 in 7%, MR4.5 in 23%, UND in 39%. There was a trend for earlier achievement of MR with NILO: median times to MMR, MR4, MR4.5 and UND were 12, 17.4, 17.9 and 25.1 months, respectively, for IM400 pts; 5.8, 8.7, 11.8 and 23.7 months, respectively, for IM800 pts; 5.7, 7, 8.3 and 16.4 months, respectively, for NILO pts; 5.7, 8.8, 17.4 and 27.2 months, respectively, for DASA pts. To analyze the relationship between the degree of MR and clinical outcome we excluded pts not achieving a CCyR as their best response since the clinical significance of CCyR is well known. For the remaining 438 pts, the depth of molecular remission was inversely correlated with the risk of losing CCyR (19%, 16%, 11%, 7%, 2% in pts with <MMR, MMR, MR4, MR4.5 and UND, respectively) or losing MMR (31%, 42%, 24%, 2%, respectively), as well as the risk of events (22%, 20%, 15%, 12%, 3%, respectively), transformation (3%, 5%, 0%, 1%, 0%, respectively), or death (25%, 11%, 8%, 6%, 4%, respectively). The 6-year OS for pts with <MMR, MMR, MR4, MR4.5 and UND is 74%, 84%, 95%, 96% and 99%, respectively (p<.0001); transformation-free survival (TFS) is 95%, 93%, 100%, 99% and 100%, respectively (p<.014); event-free survival (EFS) is 74%, 74%, 86%, 89% and 99%, respectively (p<.0001). To adjust for the lead-time to achieve deeper responses, we then calculated OS, TFS and EFS rates at 6 years according to the depth of molecular response at 18 or 24 months. Results are summarized in table 1. Conclusion: Most patients treated with TKI as initial therapy for early CP CML achieve a MR during the course of treatment. BCR-ABL transcripts become undetectable in a significant fraction of them. Achieving a MMR or better at 18 months or 24 months is associated with significantly superior 6-years OS, TFS and EFS. These result suggest that deeper molecular responses (MMR and beyond) are associated with clinical benefit, with a particularly good outcome for those achieving undetectable transcript levels. Disclosures: Off Label Use: Imatinib, dasatinib and nilotinib frontline for chronic phase chronic myeloid leukemia on clinical trial. Kantarjian:Bristol-Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Ravandi:Bristol-Myers-Squibb: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

scholarly journals Very Long-Term Follow-up Results of Imatinib Mesylate Therapy in Chronic Phase Chronic Myeloid Leukemia After Failure of Interferon Alpha Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2749-2749
Author(s):  
Mona Lisa Alattar ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Free Survival ◽  
Interferon Alpha Therapy ◽  
Complete Hematologic Response

Abstract Abstract 2749 Background: The long-term outcome of patients with chronic phase chronic myeloid leukemia treated with imatinib after failure of interferon alpha therapy has not been detailed. Patients and Methods: 368 patients were analyzed. Univariate and multivariate analyses for survival were conducted using standard statistical methods. Results: Overall, 247 patients (67%) achieved complete cytogenetic response (CCyR). Of 327 patients studied, 207(63%) achieved major molecular response (MMR), and 99 (30%) had undetectable BCR-ABL levels at some time on therapy. The estimated 10-year survival rate was 68%, progression-free survival rate 67%, and event-free survival rate 51%. By multivariate analysis, age ≥ 60 years, hemoglobin < 10g/dl, marrow basophils ≥ 5%, any peripheral blasts, and clonal evolution were independent adverse factors for survival. The estimated 7-year survival by the presence of none (n=154), 1–2 (n=190), or ≥ 3 factors (n=24) were 93%, 70%, and 25% respectively (p <0.01). Achievement of MMR, CCyR, or partial cytogenetic response at 12 months were associated with significantly better 10-year survival rate by landmark analysis (10-year survival 80–90%) vs. achieving minor cytogenetic response or complete hematologic response (10-year survival 55–65%) vs. other response (10-year survival 10%). Using landmark analysis to include imatinib response at 12 months, achievement of major cytogenetic response or better (hazard ratio 0.12; p< 0.001) and complete hematologic response or minor cytogenetic response (hazard ratio 0.36; p=0.003) were significant favorable prognostic factors. Conclusions: The estimated 10-year survival rate of 68% in patients with chronic myeloid leukemia receiving imatinib after interferon failure has improved. Disclosures: Cortes: Novartis: Consultancy; Novartis: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kantarjian:Novartis: Consultancy; Novartis: Research Funding; Pfizer: Research Funding; BMS: Research Funding.

A Gene Expression Signature of CD34+ Cells to Predict Major Cytogenetic Response in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Imatinib: Potential Involvement of Beta-Catenin in Drug Resistance.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 508-508 ◽  
Author(s):  
Shannon McWeeney ◽  
Gregory Yochum ◽  
Lucy C. Pemberton ◽  
Marc Loriaux ◽  
Kristina Vartanian ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Differential Expression ◽  
Resistance Genes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Beta Catenin ◽  
Cd34 Cells

Abstract Abstract 508 In chronic phase chronic myeloid leukemia (CML) patients the lack of a major cytogenetic response (MCyR, <36% Ph+ metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure we performed gene expression array profiling of CD34+ cells from two independent cohorts of imatinib-naïve chronic phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response (CCyR) or >65% Ph-positive metaphases within 12 months of imatinib therapy. Based on ANOVA p<0.1 and fold difference >I1.5I we identified 885 probe sets with differential expression between responders and non-responders, from which we extracted a 75-probe set minimal signature (classifier) that separated the two groups. Upon application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of non-responders. Bioinformatics analysis and comparison with published studies revealed highly significant overlap of the resistance signature with CML progression signatures. Consistent with this, differential expression of selected resistance genes was confirmed by qPCR on CD34+ cells from an independent set of patients with chronic phase vs. blast crisis. Furthermore, upon analysis of promoter sequences and comparison with a library of physical beta-catenin targets [generated by serial analysis of chromatin occupancy (SACO) in the HCC-116 colon cancer cell line] we find evidence that b-catenin may be a master regulator of resistance genes. Consistent with this, preliminary chromatin immunoprecipitation (ChIP) data on primary cells support physical beta-catenin binding to selected resistance genes, suggesting that Wnt/beta-catenin activation may be involved in primary cytogenetic resistance as well as disease progression. Conclusion: Our data suggest that chronic phase CML patients destined to fail imatinib have more advanced disease than evident by morphological criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit, while sparing good-risk patients from unnecessary toxicity. The potential role of beta-catenin in the regulation of resistance genes suggests that targeting Wnt/beta-catenin signaling may be useful to overcome resistance. Disclosures: Druker: MolecularMD: Equity Ownership; Novartis Pharmaceuticals: ; Bristol-Myers Squibb: . O'Brien:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Wyeth: Research Funding. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Baseline Predictors of Response to Bosutinib in Patients with Chronic Phase Chronic Myeloid Leukemia Following Resistance or Intolerance to Imatinib Plus Dasatinib and/or Nilotinib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2793-2793 ◽  
Author(s):  
Jorge E. Cortes ◽  
H. Jean Khoury ◽  
Jeff H Lipton ◽  
Carlo Gambacorti-Passerini ◽  
Tim H Brümmendorf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Lower Percentage ◽  
P Value ◽  
Kaplan Meier ◽  
Baseline Characteristics

Abstract Abstract 2793 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated the activity and tolerability of BOS 500 mg/d in Philadelphia chromosome–positive (Ph+) leukemia following prior TKI exposure. The current analysis investigated baseline characteristics as predictors of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR), and 2-year Kaplan- Meier–estimated progression-free survival (PFS) and overall survival (OS). All included patients had chronic phase (CP) chronic myeloid leukemia (CML), had developed resistance/intolerance to prior imatinib, and were also either dasatinib resistant (n = 38), dasatinib intolerant (n = 50), nilotinib resistant (n = 27), nilotinib intolerant (n = 1), or resistant/intolerant to dasatinib and nilotinib (n = 3). Median follow-up was 31.4 mo (range, 0.3–66.0 mo). A summary of results is provided in the Table. Longer time since CML diagnosis versus shorter time (median time 6.61 years) was associated with greater OS (2-y probability, 90% vs 79%; log-rank P= 0.0435); however, no association with MCyR, CCyR, or PFS was observed. A lower percentage of Ph+ cells (<95% Ph+ cells vs ≥95% Ph+ cells) at baseline was significantly associated with a higher rate of MCyR (76% vs 23%; P <0.001) and CCyR (65% vs 14%; P <0.001), as well as PFS (2-y probability, 83% vs 68%; log-rank P = 0.0181); no association with OS was observed. Resistance versus no resistance (ie, only intolerance) to prior TKIs was not significantly associated with response or survival, although a numeric trend toward lower rates of MCyR (39% vs 50%) and CCyR (28% vs 50%), as well as 2-y probabilities of PFS (72% vs 89%) and OS (82% vs 91%) among resistant patients was observed. Prior response of at least a minor cytogenetic response (MiCyR) versus no response to first-line imatinib was associated with a higher rate of MCyR (49% vs 28%; P= 0.0375) and a numeric trend toward a higher rate of CCyR (39% vs 20%) on BOS; no trend for PFS or OS was observed. Prior response of at least MiCyR versus no response to second-line dasatinib/nilotinib was associated with higher rates of MCyR (56% vs 19%; P<0.001) and CCyR (48% vs 7%; P<0.001), as well as PFS (2-y probability, 80% vs 64%; log-rank P= 0.0180) and OS (2-y probability, 89% vs 77%; log-rank P= 0.0285) on BOS. While baseline demographic characteristics showed a numerical trend toward lower response and/or survival rates with age ≥65 y and female gender, no trends were statistically significant. There was also no predictive effect for presence of a Bcr-Abl kinase domain mutation at baseline or CP status at onset of imatinib therapy. In conclusion, most evaluated baseline characteristics appeared not to be predictive of response and/or survival on BOS in patients with CP CML and resistance/intolerance to multiple prior TKIs, although at least MiCyR to prior dasatinib/nilotinib and lower percentage of Ph+ cells at baseline were found to be consistently predictive of better outcomes on BOS. n/n evaluable (%) Kaplan-Meier estimate, % n MCyRa CCyRa PFS at 2 years OS at 2 years Age ≥65 y 26 7/22 (32) 5/22 (23) 70 80 <65 y 93 38/88 (43) 30/88 (34) 76 85 Sex Female 66 23/61 (38) 17/61 (28) 77 83 Male 53 22/49 (45) 18/49 (37) 73 86 Time since CML diagnosis * ≥6.61 y 60 23/57 (40) 17/57 (30) 79 90 <6.61 y 59 22/53 (42) 18/53 (34) 71 79 Status at onset of imatinibb Early CP 44 17/39 (44) 15/39 (39) 71 78 Late CP 75 28/71 (39) 20/71 (28) 77 88 Percentage of Ph+ cells at baseline ** ** * ≥95% Ph+ cells 66 15/66 (23) 9/66 (14) 68 83 <95% Ph+ cells 43 28/37 (76) 24/37 (65) 83 85 Baseline Bcr-Abl mutation No 46 18/45 (40) 15/45 (33) 80 88 Yes 40 14/37 (38) 8/37 (22) 77 80 Prior response to imatinib * No response 44 11/40 (28) 8/40 (20) 76 88 At least MiCyRc 60 28/57 (49) 22/57 (39) 78 87 Prior response to dasatinib/nilotinib ** ** * * No response 33 6/31 (19) 2/31 (7) 64 77 At least MiCyRc 67 35/63 (56) 30/63 (48) 80 89 Resistance to prior TKI No 23 10/20 (50) 10/20 (50) 89 91 Yes 96 35/90 (39) 25/90 (28) 72 82 a Cumulative response rates. b Patients were considered to be in late CP at the moment of starting imatinib if they had commenced imatinib ≥6 mo after diagnosis or had received prior interferon therapy; other patients were considered to be in early CP. c Defined as <15% blasts in bone marrow and blood, <30% blasts + promyelocytes in bone marrow and blood, and <20% basophils in peripheral blood with no extramedullary disease other than spleen and liver. * P value <0.05; ** P value <0.001. Disclosures: Cortes: Novartis, Bristo Myer Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding. Gambacorti-Passerini:Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Kantarjian:Pfizer Inc: Research Funding.

scholarly journals Frontline Treatment with Dasatinib in Very Elderly Patients (> 75 Years) with Chronic Myeloid Leukemia: Is It Feasible?

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5438-5438
Author(s):  
Roberto Latagliata ◽  
Fabio Stagno ◽  
Mario Annunziata ◽  
Malgorzata Monika Trawinska ◽  
Alessandra Iurlo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Real Life ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Very Elderly ◽  
Blastic Phase ◽  
Median Period

Abstract Dasatinib (DAS) has been licensed for first line treatment of patients (pts) with Chronic Myeloid Leukemia (CML): however, in the current clinical practice, DAS is often considered too toxic for the treatment of elderly CML patient. In particular, no data are available in very elderly CML pts as to toxicity and efficacy. To address this issue, we evaluated a "real-life" cohort of 39 CML pts in chronic phase aged > 75 years and treated with frontline DAS in 20 Italian Centers from 6/2012 to 10/2017. Main clinical features at diagnosis are reported in the Table 1. Overall, 23/39 pts (58.9%) had ≥ 2 comorbidities requiring concomitant therapies: according to ECOG scale, performance status at baseline was 0 - 1 in 34 pts (87.2%) and 2 in 5 pts (12.8%). Median interval from diagnosis to DAS therapy was 0.8 months (IQR 0.5 - 1.4). Daily DAS starting dose was 100 mg in 30 pts (76.9%), 80 mg in 1 pts (2.6%) and 50 mg in 8 pts (20.5%), respectively. All pts were evaluable for toxicity and efficacy; on the whole, grade 3/4 hematological and extra-hematological toxicities were detected in 6 (15.4%) and 11 (28.2%) pts, respectively. DAS therapy was permanently discontinued in 9 pts (23.0%) due to toxicity (3 pts in the first 12-month period of treatment and 6 beyond). Pleural effusions of all WHO grades occurred in 12 pts (30.7%) after a median period of DAS treatment of 16.3 months (IQR 2.2 - 31.8): in 4 of them pleural effusion occurred during the first 6-month period of treatment. Overall, 36/39 patients (92.3%) achieved at any time complete cytogenetic response (CCyR), 30/39 (76.9%) major molecular response (MR 3.0) and 16/39 (41.0%) deep molecular response (MR 4.0/4.5). Only 1 patient (2.6%) evolved in a blastic phase after 13 months from DAS initiation. After a median period of 27.8 months (IQR 19.1 - 37.5), 5 patients died (1 from blastic phase and 4 from unrelated causes): cumulative event-free survival and overall survival at 36 months were 63.2% (95%CI 45.2 - 81.2) and 85.3% (95%CI 73.3 - 97.3), respectively (Figures 1 and 2). In conclusion, these data indicate that DAS therapy may have a role also in the treatment of patients aged > 75 years, being effective as in younger subjects and having an acceptable safety profile. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Incyte: Honoraria. Abruzzese:Ariad: Consultancy; BMS: Consultancy; Novartis: Research Funding; Pfizer: Consultancy. Breccia:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria; Incyte: Honoraria.

scholarly journals Efficacy of Ponatinib after Multiple Lines of Therapy for Chronic Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3013-3013
Author(s):  
Mahesh Swaminathan ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Farhad Ravandi ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Genetics Research ◽  
Line Therapy ◽  
Line Of Therapy

Abstract Background: Ponatinib, a third-generation pan-tyrosine kinase inhibitor (TKI), was found to be effective in heavily pretreated patients (pts) with chronic myeloid leukemia (CML). With the availability of multiple TKI, these agents are used in different sequences, and there is limited information on the value of various TKI in different lines of therapy. Since ponatinib has been effective in 3rd and subsequent lines of therapy, we performed an analysis of a cohort of pts with CML who received ponatinib as a different line of treatment. Method: A total of 80 pts with chronic phase of CML and received ponatinib from 2009 to 2018 were analyzed. Only pts who received ponatinib as a second or subsequent line of therapy of CML were included. Major cytogenetic response (MCyR), complete cytogenetic response (CCyR), major molecular response (MMR), molecular response (MR) 4, and MR 4.5 were assessed. Event-free (EFS), transformation-free (TFS), failure-free (FFS) and overall survival (OS) were also analyzed. Results: Nine pts (11%) received ponatinib as a 2nd line therapy (prior TKI imatinib in 6, dasatinib in 1, and nilotinib in 2 pts); 21 (26%) as a 3rd line, 26 (33%) as a 4th line, and 24 (30%) as a 5th and above line. The median age was over 50 years (Y) in all the groups except for pts who received ponatinib as a 3rd line [38 Y (23-76)]. Among pts who received ponatinib as 2nd line, 9 (100%) achieved CCyR and MR 4.5; the median time to achieve CCyR and MR 4.5 was 3 and 6.8 months (mo), respectively (Table 1). In pts treated in 3rd line CCyR and MR 4.5 were 67% and 57%, respectively and the median time to response was 4.8 and 19.3 mo, respectively. Of the 26 pts treated in 4th line, 13 (50%) achieved CCyR (median time to CCyR 3 mo) and 7 (27%) achieved MR 4.5 (median time 11.6 mo). In 5th line and above 14 (58%) achieved CCyR (median time 6.4 mo) and 8 (33%) achieved MR 4.5 (median time 12.3 mo) (Figure 1). After a median follow-up of 59.8 months (range, 4.7 to 114.3) for all pts, the median OS was not reached in pts treated in 2nd to 4th line and 81.4 mo in ≥5th line. The median FFS was not reached in 2nd line, and was 45.6, 20.2, and 17.8 mo in 3rd, 4th, and ≥5th line, respectively. The median EFS and TFS was not reached in any line of treatment. The TFS was significantly better in pts who received ponatinib as a 2nd-4th line therapy as compared to ≥5th [p=0.0026, HR-55.97 (4.076-768.7)] (Figure 2). Conclusion: Our results suggest that CCyR and MR 4.5 were higher when ponatinib was used in up to 4th line of therapy for resistant CML, and it was particularly effective in 2nd or 3rd line where high rates of MR4.5 can be achieved. These results underscore the efficacy of ponatinib in these settings. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Ravandi:Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Xencor: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Sunesis: Honoraria; Abbvie: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Astellas Pharmaceuticals: Consultancy, Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Macrogenix: Honoraria, Research Funding; Xencor: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau. Kadia:Takeda: Consultancy; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy; Celgene: Research Funding; Takeda: Consultancy; Abbvie: Consultancy; Novartis: Consultancy; Jazz: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; BMS: Research Funding; Amgen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding. DiNardo:Agios: Consultancy; Bayer: Honoraria; Medimmune: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria. Konopleva:Stemline Therapeutics: Research Funding; abbvie: Research Funding; cellectis: Research Funding; Immunogen: Research Funding. Pemmaraju:stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; novartis: Research Funding; samus: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; celgene: Consultancy, Honoraria; Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; abbvie: Research Funding. Daver:ARIAD: Research Funding; BMS: Research Funding; Novartis: Research Funding; Incyte: Consultancy; Incyte: Research Funding; Karyopharm: Research Funding; Kiromic: Research Funding; Pfizer: Research Funding; Daiichi-Sankyo: Research Funding; Sunesis: Research Funding; Alexion: Consultancy; ImmunoGen: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Sunesis: Consultancy. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.

scholarly journals Bosutinib is active in chronic phase chronic myeloid leukemia after imatinib and dasatinib and/or nilotinib therapy failure

Blood ◽  
2012 ◽  
Vol 119 (15) ◽  
pp. 3403-3412 ◽  
Author(s):  
H. Jean Khoury ◽  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Carlo Gambacorti-Passerini ◽  
Michele Baccarani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Abl Tyrosine Kinase ◽  
Kaplan Meier

Bosutinib, a dual Src/Abl tyrosine kinase inhibitor (TKI), has shown potent activity against chronic myeloid leukemia (CML). This phase 1/2 study evaluated the efficacy and safety of once-daily bosutinib 500 mg in leukemia patients after resistance/intolerance to imatinib. The current analysis included 118 patients with chronic-phase CML who had been pretreated with imatinib followed by dasatinib and/or nilotinib, with a median follow-up of 28.5 months. In this subpopulation, major cytogenetic response was attained by 32% of patients; complete cytogenetic response was attained by 24%, including in one of 3 patients treated with 3 prior TKIs. Complete hematologic response was achieved/maintained in 73% of patients. On-treatment transformation to accelerated/blast phase occurred in 5 patients. At 2 years, Kaplan-Meier–estimated progression-free survival was 73% and estimated overall survival was 83%. Responses were seen across Bcr-Abl mutations, including those associated with dasatinib and nilotinib resistance, except T315I. Bosutinib had an acceptable safety profile; treatment-emergent adverse events were primarily manageable grade 1/2 gastrointestinal events and rash. Grade 3/4 nonhematologic adverse events (> 2% of patients) included diarrhea (8%) and rash (4%). Bosutinib may offer a new treatment option for patients with chronic-phase CML after treatment with multiple TKIs. This trial was registered at www.clinicaltrials.gov as NCT00261846.

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