scholarly journals Phase 2 study of subcutaneous omacetaxine mepesuccinate after TKI failure in patients with chronic-phase CML with T315I mutation

Blood ◽  
2012 ◽  
Vol 120 (13) ◽  
pp. 2573-2580 ◽  
Author(s):  
Jorge Cortes ◽  
Jeff H. Lipton ◽  
Delphine Rea ◽  
Raghunadharao Digumarti ◽  
Charles Chuah ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Confidence Limit ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Lower Confidence Limit ◽  
Hematologic Response ◽  
Lower Confidence ◽  
Omacetaxine Mepesuccinate ◽  
T315i Mutation

Abstract Chronic myeloid leukemia (CML) patients with the BCR-ABL T315I mutation do not benefit from therapy with currently approved tyrosine kinase inhibitors. Omacetaxine mepesuccinate is a protein synthesis inhibitor that has demonstrated activity in cells harboring the T315I mutation. This phase 2 trial assessed the efficacy of omacetaxine in CML patients with T315I and tyrosine kinase inhibitor failure. Patients received subcutaneous omacetaxine 1.25 mg/m2 twice daily, days 1-14, every 28 days until hematologic response or a maximum of 6 cycles, and then days 1-7 every 28 days as maintenance. Results for patients treated in chronic phase are reported here. Patients (n = 62) received a median of 7 (range, 1-41) cycles. Complete hematologic response was achieved in 48 patients (77%; 95% lower confidence limit, 65%); median response duration was 9.1 months. Fourteen patients (23%; 95% lower confidence limit, 13%) achieved major cytogenetic response, including complete cytogenetic response in 10 (16%). Median progression free-survival was 7.7 months. Grade 3/4 hematologic toxicity included thrombocytopenia (76%), neutropenia (44%), and anemia (39%) and was typically manageable by dose reduction. Nonhematologic adverse events were mostly grade 1/2 and included infection (42%), diarrhea (40%), and nausea (34%). Omacetaxine may provide a safe and effective treatment for CML patients with T315I mutation. This study is registered at www.clinicaltrials.gov as NCT00375219.

Safety and Efficacy of Subcutaneous (SC) Omacetaxine Mepesuccinate in Imatinib(IM)-Resistant Chronic Myeloid Leukemia (CML) Patients (pts) with the T315I Mutation – Results of An Ongoing Multicenter Phase II Study.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3239-3239 ◽  
Author(s):  
Jorge Cortes ◽  
H. Jean Khoury ◽  
Sélim Corm ◽  
Franck E Nicolini ◽  
Jeffrey H. Lipton ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Median Duration ◽  
Response Rate ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Safety And Efficacy ◽  
Hematologic Response ◽  
Duration Of Response ◽  
T315i Mutation ◽  
Grade 3

Abstract Background: Omacetaxine (homoharringtonine, HHT) shows clinical activity against Ph+ CML, with a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML pts harboring the T315I BCR-ABL mutation. Study Goals: To evaluate the safety and efficacy of omacetaxine in pts with IM-resistant T315I+ Ph+ CML. Methods: Eligible pts include adult CML with confirmed T315I BCR-ABL mutation following imatinib failure after informed consent. Presence of T315I mutation is confirmed at one of 2 central reference labs. Induction schedule consists of 1.25 mg/m2 omacetaxine SC twice daily for 14 days every 28 days until complete hematologic response (CHR) or hematologic improvement (HI). Maintenance schedule may start after at least one induction cycle and after initial hematologic response. Maintenance treatment consists of 1.25 mg/m2 OMA SC twice daily for 7 days every 28 days, for up to 24 months. Study Results: To date, 50 pts have been enrolled, all having failed prior imatinib therapy, and 82% having failed 2 or more prior TKIs. Enrollment includes 26 pts in chronic phase (CP), 13 in accelerated phase (AP) and 11 in myeloid blast phase (BP). Median age: 58 yrs (19–84), 70% male. Mean baseline WBC values (/μl) were 11.51 (range 1.9–23.76) in CP, 18.88 (range 3.6– 78.2) in AP and 16.58 (range 2.4–51.5) in BP patients. Median disease duration is 58 months (range 5–285). Efficacy: Data are available for 30 pts: 15 CP, 10 AP and 6 BP pts. In CP pts, CHR has been achieved in 80% (12/15) with a median duration of response of 8 months (range 2.7 to 13.5+). Of these 12 pts achieving CHR, 11 pts continue on study with the remaining patient achieving complete cytogenetic response (CCyR) and being removed from treatment to receive allograft transplantation. The median time to hematologic response was 1.2 months (range 0.6 to 2.5). Overall cytogenetic response in CP pts is 20% (3/15) with 13% (2/15) achieving CCyR and 1 pt achieving a minimal cytogenetic reponse. Median duration of cytogenetic response is 9.1 months (range 7.1 to 9.2+) with one pt continuing in CCyR and the second patient receiving allograft as described above. In AP pts, overall hematologic response is 60% (6/10) with 5 of these patients remaining active in treatment. Two pts have achieved CHR, 3 returned to chronic phase and 1 showed HI. Median duration of response was 2.2 months (range 1 to 4.4+). Overall cytogenetic response rate in AP patients is 21% (3/14), with 2 pts achieving major cytogenetic response and 1 pt achieving minimal response. In BP patients, overall hematologic response rate is 33% (2/6) with 1 pt achieving CHR and 1 HI. Duration of response was 3.7 and 3.9 months respectively. The T315I mutated clone has been decreased below the limit of detection in 60% of evaluable patients. Safety: Data are available for 32 pts enrolled in all disease phases. The primary toxicity being myelosuppression which is reversible and managed by adjusting the number of dosing days received per cycle. Incidence of treatment emergent grade 3/4 events includes: thrombocytopenia 44%, neutropenia 34%, anemia 28%, febrile neutropenia 16%, and pancytopenia 9.4%. Injection site reactions have been mild with no grade 3–4 events reported. Four pts have died (3 BP, 1 AP) during the study period, all due to disease progression. Conclusions: Omacetaxine therapy in T315I mutated BCRABL+ IM-resistant CML is well tolerated and is producing durable CHRs and cytogenetic responses in these patients.

A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph+) Leukemias Including Patients with T315I Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 601-601 ◽  
Author(s):  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
Hagop M Kantarjian ◽  
Hedy Smith ◽  
Dale Bixby ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Dose Level ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Lower Extremity Weakness ◽  
Hematologic Response ◽  
T315i Mutation ◽  
Dose Levels

Abstract Abstract 601 Background. DCC-2036 is a novel and potent tyrosine kinase inhibitor (TKI) which binds to a novel region called the switch pocket, thereby preventing BCR-ABL from adopting a conformationally active state. Efficacy against multiple imatinib-resistant BCR-ABL mutants has been demonstrated both in vitro and in vivo (Chan et al., Cancer Cell 2011;19:556). Importantly, DCC-2036 retains full potency against the T315I mutant in preclinical efficacy studies. Methods. This study was designed to find the maximal tolerated dose (MTD) of DCC-2036 when administered daily as a single-agent on a 28-day cycle. Eligible patients included adults with Ph+ CML/ALL who were refractory/intolerant to ≥2 TKI's or were T315I positive. Initially DCC-2036 capsules were administered orally once daily (QD) at increasing dose levels. Only 1 patient was enrolled in each of the lowest dose cohorts of 57mg QD and 114 mg QD. For higher doses, 3– 6 patients were enrolled into each ascending dose cohort with standard dose limiting toxicity (DLT) rules evaluating safety in cycle 1 to determine dose escalation. A transition from unformulated capsules (C) to formulated tablets (T) occurred after the 1200 mg QD dose level. Paired blood samples were obtained for PK and PD assessments. Results. 30 patients (16 males, 14 females; median age 59, range 31 – 80) with CML including 19 in Chronic (CP); 8 in Accelerated (AP) and 3 in Blast (BP) Phase were enrolled. Enrolled patients had received 1–6 prior CML treatments, and 11 patients had the T315I mutation. To date, a total of 212.5 (median 5.6; range 0.2 – 23.4) 28-day cycles were administered over 10 dose levels either as C (7 dose levels) or T (3 dose levels). The 7 C dose levels were studied first and included 57 mg QD through 1200 mg QD. Following transition to T, evaluation continued with 100 mg QD, 100 mg twice daily (BID), and 200 mg BID. Two reversible DLTs (Grade 3 peripheral neuropathy and Grade 4 lower extremity weakness) occurred during the initial treatment cycle at the 200 mg T BID dose level. Evaluation of 6 patients at the 150 mg T BID dose level determined that dose to be the MTD. Preliminary safety data show that other Grade (Gr) 3/4 adverse events (AEs) were Gr 3 slurred speech and Gr 3 eruptive nevi. Gr 1/2 AEs included dry mouth, constipation, diarrhea, paresthesias, and retinal vein occlusion. There was 1 case of Gr 2 pancreatitis that recurred on rechallenge in a patient with previous pancreatitis with nilotinib. Preliminary responses include one major molecular response in a CP patient with T315I mutation who started on capsules and transitioned to 100 mg T QD. There was one complete cytogenetic response in a CP patient at 100 mg T BID, and one partial cytogenetic response in a CP patient who started on capsules and transitioned to 100 mg T BID. One patient with AP CML and T315I mutation had a complete hematologic response at 450 mg C QD. Another patient with AP CML had a partial hematologic response after receiving 200 mg BID for 1 cycle and then downdosing to 100 mg T BID. Four out of 8 patients receiving 100 mg tablets and evaluable for efficacy (completed 3 cycles of treatment) had responses. PK results indicate dose-related, nonlinear increases in both peak plasma concentration (Cmax) and exposure (AUC). PD results reveal both acute and steady state post-treatment reductions in phospho-protein levels on Days 1 and 8. Marked reductions in pSTAT5 and pCRKL have been observed in subjects with both CP and AP and appear to be required for clinical response. Conclusion. The MTD of DCC-2036 tablets is 150 mg BID. Preliminary results suggest that DCC-2036 is well tolerated and has anti-leukemia activity in subjects with refractory CML and T315I positive disease. PD results are consistent with inhibition of BCR-ABL signaling in this first-in-man study of a switch pocket tyrosine kinase inhibitor. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Bixby:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Rafferty:Deciphera Pharmaceuticals: Employment. Berger:Deciphera Pharmaceuticals: Employment. Wise:Deciphera Pharmaceuticals LLC: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment. Smith:Deciphera Pharmaceuticals: Employment. Van Etten:Deciphera Pharmaceuticals: Consultancy, Research Funding.

Efficacy and Safety of Radotinib in Chronic Phase Chronic Myeloid Leukemia Patients with Resistance or Intolerance to BCR-ABL Tyrosine Kinase Inhibitors: Radotinib Phase 2 Clinical Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 695-695 ◽  
Author(s):  
Sung-Hyun Kim ◽  
Hari Menon ◽  
Saengsuree Jootar ◽  
Tapan Saikia ◽  
Jae-Yong Kwak ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Abl Tyrosine Kinase ◽  
Phase 2 Clinical Trial ◽  
Abl Tyrosine Kinase Inhibitor

Abstract Abstract 695 Background Radotinib is a novel, selective Bcr-Abl tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm, South Korea. Radotinib showed a good efficacy and safety profile to chronic myeloid leukemia (CML) in preclinical and phase 1 clinical studies. To investigate the clinical efficacy and safety of radotinib 400 mg twice daily, data from CML patients treated during phase 2 clinical trial are reported. Methods Philadelphia chromosome (Ph+)-positive chronic phase CML (CP-CML) patients who failed or were intolerable to TKIs (imatinib and/or dasatinib and/or nilotinib) were enrolled between July 2009 and November 2011. Patients were treated with radotinib 400 mg twice daily for 12 cycles (1 cycle=4 weeks). The primary end point was an achievement of major cytogenetic response (MCyR, Ph+£35%) by 12 months. Safety parameters were also analyzed. Results A total of 77 CP CML patients (18 years of age or over) were enrolled from 12 sites in Korea, India, and Thailand. This analysis includes data from last enrolled patient who received at least 3 months of radotinib therapy. The median age of patients was 47 (range; 24–76) years, and 65 (84.4%) were imatinib-resistant and 12 (15.6%) were imatinib-intolerant. Four patients also had intolerance to dasatinib. With a median follow-up of 10.6 months, treatment with radotinib is ongoing in 46 patients (59.7%) and 31 patients (40.3%) discontinued the treatment including two deaths (2.6%). However, there were no CML-related deaths. Median duration of radotinib exposure was 296 (8–798) days. Overall MCyR rate was 63.6%, including 35 patients (45.4%) complete cytogenetic response and 14 patients (18.2%) partial cytogenetic response. The median time to MCyR was 2.8 months (85 days) and the median duration of MCyR was 315 (range; 5–726) days. Of patients achieving complete cytogenetic response, 37% (13/35) achieved major molecular response. Within follow-up durations, 44 patients (57.1%) required dose interruption and 41 patients (53.3%) had dose reduction. Most common grade 3/4 hematologic and laboratory adverse events (AEs) were thrombocytopenia (27.3%), neutropenia (10.4%), anemia (6.5%), and hyperbilirubinemia (31.2%). Common non-hematologic AEs were rash (29.8%), fatigue (14.3%), nausea/vomiting (14.3%), headache (13.0%), and pruritus (11.7%). The majority of AEs were easily manageable with temporal dose interruption and/or reductions. In all patients with CP-CML treated with second-line radotinib, estimated progression-free survival and overall survival rate at 12months was 84.9% (95% CI, 72.7–92.0%) and 97.4% (95% CI, 89.9–99.3% ), respectively. Conclusion Radotinib phase 2 trial confirmed the efficacy and safety of radotinib 400 mg twice daily in patients with CP-CML after failure to TKIs. Most of the AEs occurred in the early treatment period, were tolerable, and were easily controlled by dose interruption or reduction. Disclosures: Off Label Use: Radotinib, new BCR/ABL tyrosine kinase inhibitor, treatment for CML. Lee:IL-YANG Pharm.: Employment. Park:IL-YANG Pharm.: Employment. Woo:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Lee:IL-YANG Pharm.: Employment. Cho:IL-YANG Pharm.: Employment. Shin:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Employment. Kim:IL-YANG Pharm.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1943-1943
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
2Nd Generation ◽  
Hematologic Response ◽  
T315i Mutation

Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.

Imatinib Treatment Experience in a Public Health System, Minority Patient Population with Chronic Myelogenous Leukemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4576-4576
Author(s):  
Sunita Nathan ◽  
Shylendra Sreenivasappa ◽  
Luciano Fochesatto Filho ◽  
Decebal S. Griza ◽  
Tracy Smiley ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Patient Population ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Imatinib Therapy ◽  
Cell Transplant ◽  
Phase 2 ◽  
Minority Patient ◽  
Hematologic Response ◽  
Complete Cytogenetic Response

Abstract Introduction: Imatinib (STI571/ Gleevec) is a tyrosine kinase inhibitor that functions by blocking the binding of ATP to the bcr-abl tyrosine kinase, inhibiting its activity and preventing myeloid proliferation, a characteristic of CML. We report our experience with imatinib use in a minority patient population. Methods: Data from 67 patients (pts) with CML treated at Cook County Hospital, Chicago, Illinois over a 4 year period were collected. Demographics, presentation, dosage schedule, tolerability and response were analyzed. Continuous data were analyzed via Student’s T test and categorical data via Fisher’s Exact test. Results: 57 pts with complete data [mean age at diagnosis 42.8 yrs, range 19–72 yrs, 46 (80.7%) males and 11 (19.3%) females] were identified and analyzed as a retrospective cohort. 41 pts (71.9%) were between 30 and 60 yrs of age and 17 pts (29.8%) had ≥ 1 major comorbidity at presentation. 28 (49.1%) were African American (AA), 4 (7%) Asian, 5 (8.8%) Eastern European, 17 (29.8%) Hispanic, and 3 (5.3%) Middle Eastern. 50 pts (87.7%) were in chronic phase, 5 (8.8%) in accelerated phase, 2 (3.5%) in blast phase, 2 (3.5%) had granulocytic sarcomas and 5 pts (8.8%) had second malignancies at presentation. 54 pts (94.7%) were started on 400mg of imatinib. 19 pts (33.3%) had imatinib-related toxicities including skin rash, cytopenias and nausea. 17 pts (29.8%) were non-compliant with imatinib therapy. AA pts were as old as the non-AA pts [44.8 ± 12.6 yrs vs 40.9 ± 13.8 yrs, p 0.27]. Non-AA pts were predominantly male. Following imatinib therapy a hematologic response (HR) was noted in 45.7± 54.6 days (d) in AA vs 31.3 ± 23.9 d in non-AA (p= 0.27), a major cytogenetic response (MCR) in 351 ± 342.6 d in AA pts vs 289±132.7 d in non-AA (p=0.58) and a complete cytogenetic response in 664±265.1 d in AA vs 642±292.5 d in non-AA pts (p=0.87). 11 AA pts failed imatinib therapy vs 8 non-AA pts. These pts were then subjected to imatinib dose escalation (600mg or 800mg) with only 4 pts in the AA group attaining MCR and 1 pt in the non-AA group attaining CCR. 4 AA pts then received Dasatanib and 2 went on to Allogeneic Stem Cell Transplant (ASCT) and 3 pts in the non-AA group received Nillotinib or Dasatanib and 2 went on to ASCT. There were 3 deaths in the AA group vs 1 in the non-AA group. Conclusion: In this primarily minority-based cohort there appears to be no significant difference in the age or gender distribution of the AA or non-AA pts although there appeared to be a male preponderance amongst the non-AA pts. The ethnic background does not appear to affect the time to significant hematologic response, major cytogenetic response or complete cytogenetic response to imatinib therapy in the AA or non-AA pts. Since the number of patients is small, definitive conclusions in either cohort cannot be made. Further investigation in minority patients is warranted.

Clinical Characteristics and Outcome of Patients (pts) with T315I Mutation after Imatinib Failure.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2189-2189
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Francis Giles ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Clinical Characteristics ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Abl Kinase ◽  
Hematologic Response ◽  
T315i Mutation

Point mutations of the Bcr-Abl kinase domain are the most frequently identified mechanism of resistance in patients (pts) with CML who failed imatinib. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant to imatinib as well as to the novel tyrosine kinase inhibitors (NTKIs) (eg, dasatinib, nilotinib) both in vitro and in vivo. It has thus been suggested that these pts have a very poor prognosis. To define the clinical characteristics and outcome of these pts, we reviewed all pts with this mutations identified at our institution after failure to imatinib. T315I was detected in 15 of 112 patients (13%) harboring kinase domain mutations. Median age was 49 years (range, 34-66 years). At the time imatinib was started, 12 pts were in chronic (CP) and 3 in accelerated (AP). Ten pts had received prior interferon therapy. The best response to imatinib was major molecular response in 1, major cytogenetic response in 5 (complete in 2), and complete hematologic response in 8. One patient was intolerant to imatinib. The median duration of response was 37 months (range, 10–60 months). T315I was identified after a median of 48 months (range, 10–83 months). At the time the mutation was identified, 9 patients had transformed (7 to AP, 2 to BP). Clonal evolution was observed in only 1 pt. Fourteen patients received subsequent NTKIs; 3 of them received both nilotinib and dasatinib. Among them, 1 patient achieved a partial hematologic response with nilotinib that lasted for 3 months and 1 other had T315I identified while in complete cytogenetic response induced by nilotinib that has been sustained for 16+ months. After a median follow-up of 27 months (range, 3–42 months), 11 pts (73%) are alive: 8 are alive with active disease, and 3 patients are alive with ongoing response: 1 in complete molecular remission following allogeneic stem cell transplantation, 1 in partial cytogenetic response following treatment with aurora kinase inhibtor MK0457, and one in sustained complete cytogenetic response with ongoing treatment with nilotinib. Four patients have died of disease progression. Except for previous treatment with interferon (more frequent in patients harboring the T315I mutation; p=0.024) and the lack of response to the NTKI (p=0.001), there was no difference in patients characteristics and previous response to imatinib compared to patients with other mutations. Similarly, there was no difference in overall survival among patients with T315I mutations or other mutations (p=0.71). In conclusion T315I is a highly resistant mutation to conventional tyrosine kinase inhibitors; however occasional responses can be observed and overall survival may not be as poor as previously reported.

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

Sign in / Sign up

Export Citation Format

Share Document