BCR-ABLT315I transcript disappearance in an imatinib-resistant CML patient treated with homoharringtonine: a new therapeutic challenge?

IntroductionThe BCR-ABL T315I mutation confers in vitro resistance to all tyrosine kinase inhibitors (TKIs) approved for the treatment of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph ϩ ) acute lymphoblastic leukemia (ALL) to date. 1 The survival of patients harboring a T315I mutation discovered by any available methodology, whether associated with other factors or not, is dependent on disease phase at the time of mutation detection, 2 and prognosis remains particularly poor. However, allogeneic stem cell transplantation (SCT) presents a therapeutic alternative for several TKI-resistant patients. [3][4][5] In the present study, we analyzed a series of 64 Ph ϩ leukemic patients (CML in all phases and Ph ϩ ALL patients) harboring a T315I BCR-ABL mutation who underwent allogeneic SCT to evaluate the impact of this procedure on survival. Methods Study populationAdult patients with CML and de novo Ph ϩ ALL whose disease was resistant to TKI according to the European LeukemiaNet guidelines 6,7 or IRIS study (International Randomized Study of Interferon and ST1571) definitions 8 and who harbored a T315I BCR-ABL mutation detected by any validated means between 1999 and 2010 were included in the analysis. Patients were identified from the European Blood and Marrow Transplantation (EBMT) registry and from a previously described updated international database that contained 222 T315I ϩ patients. 2 They, or their legal representative, had provided written consent whenever possible. This retrospective analysis was approved by the institutional review board/ethics review committee in each participating site/country whenever necessary. Data collectionDemographic, clinical, treatment, mutation, transplant, and survival data were collected and previously collected data were updated from each site from the EBMT registry and from the epidemiologic study database. Final data were combined in an ultimate database for analysis. The T315I mutation was detected by different techniques (predominantly direct sequencing, but also PCR-restriction fragment length polymorphisms and denaturing HPLC), including assaying banked material. Unfortunately, For personal use only. on June 7, 2019. by guest www.bloodjournal.org From posttransplantation BCR-ABL data and cytogenetic and chimerism analyses were not available for the large majority of patients in this retrospective international study, and consequently, these data will not be presented. Survival measurementOverall survival (OS) was analyzed since diagnosis, since T315I detection, and since transplantation and was stratified according to disease phase. Progression-free survival could not be analyzed precisely because of missing data and is therefore not reported. Statistical analysisSurvival was analyzed according to the Kaplan-Meier method and by log-rank tests for CML at different phases and for Ph ϩ ALL from the dates of T315I BCR-ABL mutation detection and transplantation. Results and discussionThe 64 patients (who received 67 transplants) who harbored a ...

Section: Resultsmentioning

confidence: 99%

Allogeneic stem cell transplantation for patients harboring T315I BCR-ABL mutated leukemias

Nicolini

Basak

Soverini

et al. 2011

“…Omacetaxine has demonstrated activity against cells with the T315I mutation in preclinical studies, 13 as well as preliminary efficacy in CML patients with this mutation. 14,15 Here, we describe the results of a phase 2 study of omacetaxine in chronic-phase CML patients with a history of the T315I mutation who failed TKI therapy.…”

Section: Introductionmentioning

confidence: 99%

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

Cortes

Lipton

Réa

et al. 2012

127

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/m 2 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. (Blood. 2012;120(13):2573-2580)

“…Giles et al 11 reported 3 patients with T315I ϩ CML or Ph ϩ ALL who achieved clinical responses to the aurora kinase inhibitor MK-0457 without associated adverse events, whereas Legros et al 12 reported that the T315I mutation disappeared in a CML patient treated with homoharringtonine. In addition, it has been reported that some CML patients harboring a T315I mutation may have a transient response to second-generation TKIs in vivo.…”

Section: Introductionmentioning

confidence: 99%

Epidemiologic study on survival of chronic myeloid leukemia and Ph+ acute lymphoblastic leukemia patients with BCR-ABL T315I mutation

Nicolini

Mauro

Martinelli

et al. 2009

117

The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blasticphase (BP) and Philadelphia chromosome-positive (Ph) ؉ acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph ؉ ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-␣ in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph ؉ ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.