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.

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.

The development of imatinib as a therapeutic agent for chronic myeloid leukemia

Blood ◽  
2005 ◽  
Vol 105 (7) ◽  
pp. 2640-2653 ◽  
Author(s):  
Michael Deininger ◽  
Elisabeth Buchdunger ◽  
Brian J. Druker
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Chronic Phase ◽  
Initial Response ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Interferon Α ◽  
Disease Mutations ◽  
Risk Of Disease

AbstractImatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-α (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription–polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.

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 Characteristics and outcome of chronic myeloid leukemia patients with F317L BCR-ABL kinase domain mutation after therapy with tyrosine kinase inhibitors

Blood ◽  
2008 ◽  
Vol 112 (13) ◽  
pp. 4839-4842 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Neeli Reddy ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Disease Stage ◽  
Kinase Domain Mutation

Abstract Mutations in codon 317 after treatment with imatinib and dasatinib have been reported. We reviewed patients with chronic myeloid leukemia and mutations after tyrosine kinase inhibitor (TKI) therapy. F317L was detected in 20, including 12/99 (12%) with mutation after imatinib failure, and 8/16 (50%) after dasatinib (P = .001). Median follow-up from mutation detection was 25 months. At the time of F317L, 8 patients were in chronic phase (CP), 6 in accelerated phase, and 6 in blast phase. There was no difference in characteristics between patients with or without F317L mutations, or with no mutations. A complete cytogenetic response was acheived in 3 of 6 patients treated with nilotinib, 2 of 2 with imatinib, and 0 of 3 with dasatinib. Survival of patients with F317L was similar to those with other mutations (P = .45). Patients in CP had better outcome, with a 2-year survival of 75%. F317L mutation is resistant to dasatinib but sensitive to other TKIs. The prognosis is dependent mostly on the disease stage.

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.

scholarly journals Late Emergence of an Imatinib-Resistant ABL1 Kinase Domain Mutation in a Patient with Chronic Myeloid Leukemia

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Mireille Crampe ◽  
Claire Andrews ◽  
Anne Fortune ◽  
Stephen E. Langabeer
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Significant Proportion ◽  
Chronic Phase ◽  
Kinase Domain ◽  
Molecular Response ◽  
Late Emergence ◽  
Kinase Domain Mutation

The introduction of the tyrosine kinase inhibitor (TKI) imatinib has revolutionised the outlook of chronic myeloid leukemia (CML); however, a significant proportion of patients develop resistance through several mechanisms, of which acquisition of ABL1 kinase domain mutations is prevalent. In chronic-phase patients, these mutations become evident early in the disease course. A case is described of a chronic-phase CML patient who achieved a sustained, deep molecular response but who developed an Y253H ABL1 kinase domain mutation nearly nine years after commencing imatinib. Switching therapy to bosutinib resulted in a rapid reachievement of a major molecular response. Long-term TKI treatment impacts on quality of life and late losses of responses are usually due to lack of adherence. This case highlights the requirement for ABL1 kinase domain mutation analysis in those CML patients on long-term imatinib who lost their molecular response, regardless of whether nonadherence is suspected.

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.

Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis

2008 ◽  
Vol 26 (20) ◽  
pp. 3358-3363 ◽  
Author(s):  
Hugues de Lavallade ◽  
Jane F. Apperley ◽  
Jamshid S. Khorashad ◽  
Dragana Milojkovic ◽  
Alistair G. Reid ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Newly Diagnosed

Purpose Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded. Patients and Methods A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated. Results At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR. Conclusion Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.

scholarly journals Exploratory study on the impact of switching to nilotinib in 18 patients with chronic myeloid leukemia in chronic phase with suboptimal response to imatinib

2016 ◽  
Vol 8 (1) ◽  
pp. 3-12 ◽  
Author(s):  
Sikander Ailawadhi ◽  
Luke P. Akard ◽  
Carole B. Miller ◽  
Anand Jillella ◽  
Daniel J. DeAngelo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Primary Endpoint ◽  
Exploratory Study ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Open Label ◽  
The Impact

Background: The phase II, exploratory, open-label Exploring Nilotinib BCR-ABL Effects (ENABL) study [ ClinicalTrials.gov identifier: NCT00644878] assessed the impact of switching to nilotinib therapy in patients with chronic myeloid leukemia in chronic phase (CML-CP) who had a suboptimal molecular response with imatinib. Methods: Patients with CML-CP who had previously achieved a complete cytogenetic response (CCyR), but had a suboptimal molecular response, with frontline imatinib therapy ( N = 18) were assigned to receive nilotinib 300 mg twice daily. The primary endpoint was the change in BCR-ABL1 transcript levels from baseline after 12 months; rates of major molecular response (MMR) and safety were also assessed. Results: At 3 months after switching to nilotinib, 10 of 17 (59%) evaluable patients had achieved MMR. At 12 months, 9 of 12 (75%) evaluable patients had achieved MMR, and the median BCR-ABL1 level among all patients remaining in the study was 0.020% on the International Scale (IS), equivalent to a 3.7-log reduction from the standardized IS baseline (primary endpoint). Adverse events (AEs) were typically grade 1/2 and manageable with dose interruptions. A total of three patients experienced serious study drug-related AEs, including pancreatitis, bradycardia, and vertigo. No deaths were reported. Conclusions: Overall, results from this exploratory study suggest that switching to nilotinib due to suboptimal molecular response with imatinib can result in improved molecular response for patients with CML-CP.

Sign in / Sign up

Export Citation Format

Share Document