RESUMEN
OBJECTIVE: Clofarabine is used to treat acute lymphoblastic leukaemia, but evidence of its safety and effectiveness in Japanese patients is limited. We evaluated the safety and effectiveness of clofarabine in patients with relapsed/refractory acute lymphoblastic leukaemia in real-world clinical practice in Japan. METHODS: An observational, multicenter, post-marketing, all-case surveillance was conducted for safety. Effectiveness analyses were conducted in patients aged ≤21 years and those treated with clofarabine monotherapy and combination therapy (clofarabine plus etoposide and cyclophosphamide). RESULTS: In the all-case survey, 260 of 264 registered patients were eligible for safety analysis. Among the 225 patients eligible for effectiveness analysis, 139 were aged ≤21 years. For monotherapy and combination therapy, 20/31 and 34/88 patients were eligible, respectively. In the all-case survey, the median age was 16.0 years, and 47.7% of patients were <15 years old. Adverse drug reaction incidence was 83.5% and the most common were hematologic toxicities. The best overall response rates in the population aged ≤21 years were complete remission, 29.7%; complete remission without platelet recovery, 7.3% and partial remission, 10.9%. The rest (52.2%) were classified as ineffective. The sum of complete remission, complete remission without platelet recovery and partial remission rates (effectiveness rate) was 47.8% (66/138 patients). The effectiveness rates in the monotherapy and combination therapy surveys were 10.0% (2/20 patients) and 58.8% (20/34 patients), respectively. CONCLUSIONS: These post-marketing surveys provide real-world evidence of the safety and effectiveness of clofarabine regimens, including monotherapy and combination therapy in Japanese patients with relapsed/refractory acute lymphoblastic leukaemia. The safety and effectiveness profiles were comparable with those of previous prospective studies.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Clofarabina , Leucemia-Linfoma Linfoblástico de Células Precursoras , Vigilancia de Productos Comercializados , Humanos , Clofarabina/administración & dosificación , Clofarabina/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Masculino , Femenino , Adolescente , Adulto , Adulto Joven , Japón , Niño , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Persona de Mediana Edad , Preescolar , Anciano , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Ciclofosfamida/uso terapéutico , Etopósido/administración & dosificación , Etopósido/efectos adversos , Resultado del Tratamiento , Arabinonucleósidos/efectos adversos , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Pueblos del Este de AsiaRESUMEN
Over 50% of patients with systemic LCH are not cured with front-line therapies, and data to guide salvage options are limited. We describe 58 patients with LCH who were treated with clofarabine. Clofarabine monotherapy was active against LCH in this cohort, including heavily pretreated patients with a systemic objective response rate of 92.6%, higher in children (93.8%) than adults (83.3%). BRAFV600E+ variant allele frequency in peripheral blood is correlated with clinical responses. Prospective multicentre trials are warranted to determine optimal dosing, long-term efficacy, late toxicities, relative cost and patient-reported outcomes of clofarabine compared to alternative LCH salvage therapy strategies.
Asunto(s)
Clofarabina , Histiocitosis de Células de Langerhans , Humanos , Clofarabina/uso terapéutico , Clofarabina/administración & dosificación , Histiocitosis de Células de Langerhans/tratamiento farmacológico , Masculino , Femenino , Adulto , Adolescente , Niño , Persona de Mediana Edad , Preescolar , Adulto Joven , Anciano , Recurrencia , Proteínas Proto-Oncogénicas B-raf/genética , Lactante , Resultado del Tratamiento , Terapia Recuperativa , Nucleótidos de Adenina/uso terapéutico , Nucleótidos de Adenina/administración & dosificación , Nucleótidos de Adenina/efectos adversos , Arabinonucleósidos/uso terapéutico , Arabinonucleósidos/administración & dosificación , Arabinonucleósidos/efectos adversosRESUMEN
PURPOSE: Despite advances in immunotherapies, the prognosis for adults with Philadelphia chromosome-negative, newly diagnosed (ND) or relapsed/refractory (R/R) acute lymphoblastic leukemia/acute biphenotypic leukemia (ALL/ABL) remains poor. The benzamide derivative entinostat inhibits histone deacetylase and induces histone hyperacetylation. The purine nucleoside analogue clofarabine is FDA-approved for R/R ALL in children 1-21 years of age. Low doses of clofarabine have been reported to induce DNA hypomethylation. We conducted a phase 1 study of low dose clofarabine with escalating doses of entinostat in adults with ND or R/R ALL/ABL. EXPERIMENTAL DESIGN: Adults ≥60 years with ND ALL/ABL or ≥21 years with R/R ALL/ABL received repeated cycles every 3 weeks of entinostat (4 mg, 6 mg or 8 mg orally days 1 and 8) and clofarabine (10 mg/m2/day IV for 5 days, days 3-7) (Arm A). Adults aged 40-59 years with ND ALL/ABL or age ≥21 years in first relapse received entinostat and clofarabine prior to traditional chemotherapy on day 11 (Arm B). Changes in DNA damage, global protein lysine acetylation, myeloid-derived suppressor cells and monocytes were measured in PBMCs before and during therapy. RESULTS: Twenty-eight patients were treated at three entinostat dose levels with the maximum administered dose being entinostat 8 mg. The regimen was well tolerated with infectious and metabolic derangements more common in the older population versus the younger cohort. There was no severe hyperglycemia and no peripheral neuropathy in this small study. There were 2 deaths (1 sepsis, 1 intracranial bleed). Overall response rate was 32 %; it was 50 % for ND ALL/ABL. Entinostat increased global protein acetylation and inhibited immunosuppressive monocyte subpopulations, while clofarabine induced DNA damage in all cell subsets examined. CONCLUSION: Entinostat plus clofarabine appears to be tolerable and active in older adults with ND ALL/ABL, but less active in R/R patients. Further evaluation of this regimen in ND ALL/ABL appears warranted.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linaje de la Célula , Resistencia a Antineoplásicos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adulto , Anciano , Benzamidas/administración & dosificación , Clofarabina/administración & dosificación , Femenino , Estudios de Seguimiento , Inhibidores de Histona Desacetilasas/uso terapéutico , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Piridinas/administración & dosificación , Terapia Recuperativa , Adulto JovenRESUMEN
The therapeutic approach for relapsed/refractory acute lymphoblastic leukemia (ALL) remains to be a challenge. The patient was diagnosed as B-cell ALL at 6 months of age and relapsed for the second time following repeat allogeneic hematopoietic stem cell transplantation (one after first complete remission [CR1] and the other after CR2). During blinatumomab monotherapy, he developed an extramedullary relapse. Finally, the combined therapy with clofarabine, donor lymphocyte infusion, and blinatumomab induced CR of the bone marrow and extramedullary relapse. Unfortunately, the patient developed central nervous system relapse, however, this case showed a promising potential for combination therapy with clofarabine, donor lymphocyte infusion, and blinatumomab in relapsed/refractory B-cell ALL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Transfusión de Linfocitos/métodos , Recurrencia Local de Neoplasia/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Anticuerpos Biespecíficos/administración & dosificación , Donantes de Sangre , Clofarabina/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Etopósido/administración & dosificación , Humanos , Lactante , Masculino , Recurrencia Local de Neoplasia/patología , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Pronóstico , Estudios RetrospectivosRESUMEN
This phase 1/2 study aimed to identify the maximum tolerated dose, the recommended phase 2 dose (RP2D), and efficacy of the clofarabine, etoposide, and cyclophosphamide combination regimen in adult patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients aged ≥ 15 years with relapsed/refractory ALL were enrolled. Escalating doses of clofarabine (20-30 mg/m2/day × 5 days), etoposide (50-100 mg/m2/day × 5 days), and cyclophosphamide (200-440 mg/m2/day × 5 days) were administered. Dose-limiting toxicity was defined as Grade 3 or more non-hematological toxicities and others. A total of 18 patients (B-ALL; n = 13, T-ALL; n = 5) were recruited in phase 1; however, the protocol was amended to close study without proceeding to phase 2. Three patients were enrolled in cohort 1, three in cohort 2, six in cohort 3, and six in cohort 4. The RP2D of clofarabine, etoposide, and cyclophosphamide was 30, 100, and 440 mg/m2 daily, respectively. Complete remission (CR) was achieved in four patients (22%) and CR without platelet recovery in four patients (22%), with an overall response rate of 44%. The RP2D of the combination therapy was successfully determined in this study.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Terapia Recuperativa , Adolescente , Adulto , Aloinjertos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clofarabina/administración & dosificación , Clofarabina/efectos adversos , Terapia Combinada , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Etopósido/administración & dosificación , Etopósido/efectos adversos , Femenino , Estudios de Seguimiento , Trasplante de Células Madre Hematopoyéticas , Humanos , Japón , Linfopenia/inducido químicamente , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/inducido químicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Inducción de Remisión , Trombocitopenia/inducido químicamente , Adulto JovenRESUMEN
Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Acondicionamiento Pretrasplante , Adolescente , Adulto , Anciano , Aloinjertos , Clofarabina/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/mortalidad , Síndromes Mielodisplásicos/terapia , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
Clofarabine is active in refractory/relapsed acute myeloid leukemia (AML). In this phase 2 study, we treated 18- to 65-year-old AML patients refractory to first-line 3 + 7 daunorubicin/cytarabine induction or relapsing after 3 + 7 induction and high-dose cytarabine consolidation, with clofarabine (30 mg/m2 /d, Days 1-5), cytarabine (750 mg/m2 /d, Days 1-5), and mitoxantrone (12 mg/m2 /d, Days 3-5) (CLAM). Patients achieving remission received up to two consolidation cycles of 50% CLAM, with eligible cases bridged to allogeneic hematopoietic stem cell transplantation (allo-HSCT). The mutational profile of a 69-gene panel was evaluated. Twenty-six men and 26 women at a median age of 46 (22-65) years were treated. The overall response rate after the first cycle of CLAM was 90.4% (complete remission, CR: 69.2%; CR with incomplete hematologic recovery, CRi: 21.2%). Twenty-two CR/CRi patients underwent allo-HSCT. The 2-year overall survival (OS), relapse-free survival (RFS), and event-free survival (EFS) were 65.8%, 45.7%, and 40.2%, respectively. Multivariate analyses showed that superior OS was associated with CR after CLAM (P = .005) and allo-HSCT (P = .005), and superior RFS and EFS were associated with allo-HSCT (P < .001). Remarkably, CR after CLAM and allo-HSCT resulted in 2-year OS of 84.3% and 90%, respectively. Karyotypic aberrations and genetic mutations did not influence responses or survivals. Grade 3/4 neutropenia/thrombocytopenia and grade 3 febrile neutropenia occurred in all cases. Other nonhematologic toxicities were mild and uncommon. There was no treatment-related mortality and the performance of allo-HSCT was not compromised. Clofarabine, cytarabine, and mitoxantrone was highly effective and safe in refractory/relapsed AML. This study was registered at ClinicalTrials.gov (NCT02686593).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Neutropenia Febril Inducida por Quimioterapia/epidemiología , Clofarabina/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Femenino , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Mitoxantrona/administración & dosificación , Recurrencia Local de Neoplasia , Tasa de Supervivencia , Trombocitopenia/inducido químicamente , Trombocitopenia/epidemiología , Trasplante Homólogo , Adulto JovenRESUMEN
Relapsed acute myeloid leukemia presenting as an isolated central nervous system myeloid sarcoma (CNS MS) is very rare and generally entails poor outcomes. CNS MS treatment is not well defined and can include systemic chemotherapy, intrathecal chemotherapy, radiation therapy, or hematopoietic stem cell transplant. Thiotepa, vinorelbine, topotecan, and clofarabine (TVTC) has been successful for reinduction therapy in relapsed/refractory leukemia to induce remission before hematopoietic stem cell transplant. There is no published evidence of TVTC being utilized for CNS MS. In this series, we report 2 symptomatic patients with isolated CNS MS at relapse who demonstrated near complete resolution after reinduction with TVTC and additional intrathecal chemotherapy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias del Sistema Nervioso Central , Leucemia Mieloide Aguda , Sarcoma Mieloide , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/tratamiento farmacológico , Preescolar , Clofarabina/administración & dosificación , Femenino , Humanos , Inyecciones Espinales , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/tratamiento farmacológico , Tiotepa/administración & dosificación , Topotecan/administración & dosificación , Vinorelbina/administración & dosificaciónRESUMEN
Clofarabine is an immunosuppressive purine nucleoside analog that may have better anti-leukemic activity than fludarabine. We performed a prospective phase I/II multisite trial of clofarabine with 2 Gy total body irradiation as non-myeloablative conditioning for allogeneic hematopoietic cell transplantation in adults with acute myeloid leukemia who were unfit for more intense regimens. Our main objective was to improve the 6-month relapse rate following non-myeloablative conditioning, while maintaining historic rates of non-relapse mortality (NRM) and engraftment. Forty-four patients, 53 to 74 (median: 69) years, were treated with clofarabine at 150 to 250 mg/m2 , of whom 36 were treated at the maximum protocol-specified dose. One patient developed multifactorial acute kidney injury and another developed multiorgan failure, but no other grade 3 to 5 non-hematologic toxicities were observed. All patients fully engrafted. The 6-month relapse rate was 16% (95% CI, 5%-27%) among all patients and 14% (95% CI, 3%-26%) among high-risk patients treated at the maximum dose, meeting the pre-specified primary efficacy endpoint. Overall survival was 55% (95% CI, 40%-70%) and leukemia-free survival was 52% (95% CI, 37%-67%) at 2 years. Compared to a historical high-risk cohort treated with the combination of fludarabine at 90 mg/m2 and 2 Gy TBI, protocol patients treated with the clofarabine-TBI regimen had lower rates of overall mortality (HR of 0.50, 95% CI, 0.28-0.91), disease progression or death (HR 0.48, 95% CI, 0.27-0.85), and morphologic relapse (HR 0.30, 95% CI, 0.13-0.69), and comparable NRM (HR 0.85, 95% CI 0.36-2.00). The combination of clofarabine with TBI warrants further investigation in patients with high-risk AML.
Asunto(s)
Clofarabina/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante/métodos , Irradiación Corporal Total/métodos , Anciano , Antimetabolitos Antineoplásicos/administración & dosificación , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia , Análisis de Supervivencia , Resultado del TratamientoAsunto(s)
Clofarabina/efectos adversos , Decoloración de Dientes , Diente/patología , Adulto , Clofarabina/administración & dosificación , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Decoloración de Dientes/inducido químicamente , Decoloración de Dientes/patologíaRESUMEN
PURPOSE: To determine the pharmacokinetics and skin toxicity profile of sorafenib in children with refractory/relapsed malignancies. PATIENTS AND METHODS: Sorafenib was administered concurrently or sequentially with clofarabine and cytarabine to patients with leukemia or with bevacizumab and cyclophosphamide to patients with solid tumor malignancies. The population pharmacokinetics (PPK) of sorafenib and its metabolites and skin toxicities were evaluated. RESULTS: In PPK analysis, older age, bevacizumab and cyclophosphamide regimen, and higher creatinine were associated with decreased sorafenib apparent clearance (CL/f; P < 0.0001 for all), and concurrent clofarabine and cytarabine administration was associated with decreased sorafenib N-oxide CL/f (P = 7e-4). Higher bilirubin was associated with decreased sorafenib N-oxide and glucuronide CL/f (P = 1e-4). Concurrent use of organic anion-transporting polypeptide 1B1 inhibitors was associated with increased sorafenib and decreased sorafenib glucuronide CL/f (P < 0.003). In exposure-toxicity analysis, a shorter time to development of grade 2-3 hand-foot skin reaction (HFSR) was associated with concurrent (P = 0.0015) but not with sequential (P = 0.59) clofarabine and cytarabine administration, compared with bevacizumab and cyclophosphamide, and with higher steady-state concentrations of sorafenib (P = 0.0004) and sorafenib N-oxide (P = 0.0275). In the Bayes information criterion model selection, concurrent clofarabine and cytarabine administration, higher sorafenib steady-state concentrations, larger body surface area, and previous occurrence of rash appeared in the four best two-predictor models of HFSR. Pharmacokinetic simulations showed that once-daily and every-other-day sorafenib schedules would minimize exposure to sorafenib steady-state concentrations associated with HFSR. CONCLUSIONS: Sorafenib skin toxicities can be affected by concurrent medications and sorafenib steady-state concentrations. The described PPK model can be used to refine exposure-response relations for alternative dosing strategies to minimize skin toxicity.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Resistencia a Antineoplásicos/efectos de los fármacos , Leucemia/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias/tratamiento farmacológico , Enfermedades de la Piel/inducido químicamente , Adolescente , Adulto , Bevacizumab/administración & dosificación , Niño , Clofarabina/administración & dosificación , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Humanos , Leucemia/patología , Recurrencia Local de Neoplasia/patología , Neoplasias/patología , Enfermedades de la Piel/patología , Sorafenib/administración & dosificación , Distribución Tisular , Adulto JovenRESUMEN
Clofarabine (CLO) and cyclophosphamide (CY) combinations were tested in late stage refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) with disappointing results and high-grade toxicity. We designed a sequential 5-day combination of CLO 40 mg/m2/d plus CY 400 mg/m2/d as first salvage for Philadelphia-negative ALL patients refractory or relapsed until 24 months from complete remission (CR). Primary endpoint was an overall response rate (ORR) ≥ 40%. Among 26 study patients (median age 40.5 years) ORR was 57.6% (CR with complete [n = 8] or incomplete [n = 7] hematologic recovery). Despite severe myelotoxicity, no dose-limiting toxicity suggested de-intensification of CLO schedule. With a median follow-up of 17.0 months, median and 1-year overall and disease-free survival were 6.5 months and 28.6%, and 3.7 months and 28.1%, respectively. This association was tolerable and more effective in patients younger than 40 years with B-precursor ALL, longer first CR, not previously transplanted and achieving CR with full hematological recovery.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Terapia Recuperativa , Adulto , Clofarabina/administración & dosificación , Ciclofosfamida/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Cromosoma Filadelfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Tasa de Supervivencia , Adulto JovenRESUMEN
The treatment of relapsed/refractory (R/R) acute myeloid leukaemia (AML) remains a challenge. Among salvage chemotherapy regimens, the clofarabine and cytarabine (CLARA) combination has been widely evaluated and has a favourable safety/efficacy balance. Predictive factors of efficacy in patients with R/R AML are unclear, particularly the impact of AML-related gene mutations. We report our single-centre experience on 34 R/R AML patients treated with CLARA, with a focus on the genetic characterization of our cohort. CLARA yielded a 47% response rate among this poor-prognosis AML population, while two patients (5·8%) died due to treatment-related toxicity. The two-year progression-free survival and overall survival rates were 29·4% and 35·3%, respectively. Nine patients (26%) had long-term response with a median follow-up of 39·5 months among the responders, of whom six underwent haematopoietic stem cell transplantation. Adverse karyotype did not correlate with response or survival, and secondary AML were more frequent among responders to CLARA, suggesting that this combination may successfully salvage R/R AML patients regardless of adverse prognostic markers. We also observed that a low mutational burden and absence of splice mutations correlated with prolonged survival after CLARA, suggesting that extensive genotyping may have prognostic implications in R/R AML.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Mutación , Adulto , Anciano , Clofarabina/administración & dosificación , Citarabina/administración & dosificación , Esquema de Medicación , Femenino , Estudios de Seguimiento , Genotipo , Trasplante de Células Madre Hematopoyéticas , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Estudios Retrospectivos , Terapia Recuperativa/métodos , Análisis de Supervivencia , Adulto JovenRESUMEN
Clofarabine-based reduced-intensity conditioning (RIC) regimens are well-established schedules for allograft in patients with myeloid malignancies. A retrospective study was conducted including all adults allografted in our department with such a regimen and disease with the aim to assess whether or not the donor type (matched sibling [MSD], matched unrelated [MUD], or haploidentical [haplo]) impacted outcomes. Between October 2009 and February 2018, 118 patients met the inclusion criteria. Thirty-six, 55, and 27 patients received a graft from an MSD, MUD, or haplo donor, respectively. Peripheral blood stem cells (PBSCs) were the source of graft for all patients. The median age of the entire cohort was 62 years (range, 20 to 73), and the median follow-up was 31 months (range, 4.5 to 106). All patients engrafted except 1 haplo recipient. Neutrophils (>.5 × 109/L) and platelets (50 × 109/L) recoveries were significantly delayed in the haplo group (Pâ¯=â¯.0003 and P < .0001) compared with MSD and MUD. Acute grades II to IV or III to IV graft-versus-host disease (GVHD) incidences were similar between the 3 groups as well as the incidence of moderate or severe chronic GVHD. Also, similar 2-year overall survival (OS; 64.7% versus 73.9% versus 60.2%, Pâ¯=â¯.39), disease-free survival (DFS; 57.7% versus 70.9% versus and 53.6%, Pâ¯=â¯.1), and GVHD relapse-free survival (37.9% versus 54.3% versus 38.9%, Pâ¯=â¯.23) were observed between MSD versus MUD versus haplo groups. The same was true when considering only acute myeloid leukemia (AML) cases. In multivariate analysis the type of donor remained independent of outcomes in this series, whereas myelodysplastic syndrome (versus AML), high disease risk index, and older donor (≥50 years) were associated with lower OS and DFS. These data suggest that haplo donors are an acceptable alternative for patients receiving a clofarabine-based RIC PBSC allograft for myeloid malignancies who lack an MSD or a MUD.
Asunto(s)
Clofarabina/administración & dosificación , Neoplasias Hematológicas , Leucemia Mieloide Aguda , Hermanos , Acondicionamiento Pretrasplante , Donante no Emparentado , Adulto , Anciano , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Humanos , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HaploidénticoRESUMEN
The primary objective of this work was to characterize the pharmacokinetics (PK) of systemic clofarabine (clo-fara) in pediatric allogeneic hematopoietic cell transplantation (HCT) recipients receiving either nucleoside monotherapy or a dual nucleoside analog preparative regimen. Fifty-one children (median age, 4.9 years; range, .25 to 14.9 years) undergoing allogeneic HCT for a variety of malignant and nonmalignant disorders underwent PK assessment. Plasma samples were collected over the 4 to 5 days of clo-fara treatment and quantified for clo-fara, using a validated liquid chromatography/tandem mass spectrometry assay. Nonlinear mixed-effects modeling was used to develop the population PK model, including identification of covariates that influenced drug disposition. In agreement with previously published models, a 2-compartment PK model with first-order elimination best described the PK of clo-fara. Final parameter estimates for clo-fara were consistent with previous reports and were as follows: clearance (CL), 23 L/h/15 kg; volume of the central compartment, 42 L/15 kg; volume of peripheral compartment, 47 L/15 kg; and intercompartmental CL, 9.8 L/h/15 kg. Unexplained variability was acceptable at 33%, and the additive residual error (reflective of the assay) was estimated to be 0.36 ng/mL. Patient-specific factors significantly impacting clo-fara CL included actual body weight and age. The covariate model was able to estimate clo-fara CL with good precision in children spanning a wide age range from infancy to early adulthood and demonstrates the need for variable dosing in children of different ages. For example, the dose required for a 6-month and 1-year old was approximately 43% and 17% lower, respectively, than the typical 40 mg/m2dose to achieve the median AUC0-24of 1.04 mg·h/L in the study population. Despite the known renal elimination of clo-fara, no significant clinical parameters for renal function were retained in the final model (P> .05). Coadministration of fludarabine with clo-fara did not alter the CL of clo-fara (P> .05). These results will help inform individualized dosing strategies for clo-fara to improve clinical outcomes and limit drug-related adverse events in children undergoing HCT.
Asunto(s)
Clofarabina , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Modelos Biológicos , Adolescente , Aloinjertos , Niño , Preescolar , Clofarabina/administración & dosificación , Clofarabina/farmacocinética , Femenino , Neoplasias Hematológicas/sangre , Neoplasias Hematológicas/terapia , Humanos , Lactante , Masculino , Acondicionamiento PretrasplanteRESUMEN
This open-label, multicentre phase I/II study determined the maximum tolerated dose (MTD), safety and efficacy of clofarabine administered with cytarabine and idarubicin in newly diagnosed acute myeloid leukaemia (AML) patients lacking favourable genetic aberrations. The MTD was 30 mg/m2 clofarabine for patients below and above 60 years. The most frequently reported grade 3-4 non-haematological adverse events were infectious and gastrointestinal toxicities. Complete remission (CR)/CR with incomplete recovery rate was 67%. Allogeneic haematopoietic cell transplantation in first remission was feasible in a high proportion of younger AML patients and probably contributed to the favourable outcome compared to historical controls.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Clofarabina/administración & dosificación , Clofarabina/efectos adversos , Citarabina/administración & dosificación , Citarabina/efectos adversos , Relación Dosis-Respuesta a Droga , Femenino , Trasplante de Células Madre Hematopoyéticas , Humanos , Idarrubicina/administración & dosificación , Idarrubicina/efectos adversos , Quimioterapia de Inducción/métodos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Inducción de RemisiónAsunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Vidarabina/análogos & derivados , Adolescente , Adulto , Clofarabina/administración & dosificación , Citarabina/uso terapéutico , Daunorrubicina/administración & dosificación , Femenino , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Humanos , Idarrubicina/uso terapéutico , Masculino , Persona de Mediana Edad , Reino Unido , Vidarabina/uso terapéutico , Adulto JovenRESUMEN
Survival in children with relapsed/refractory acute myeloid leukemia is unsatisfactory. Treatment consists of one course of fludarabine, cytarabine and liposomal daunorubicin, followed by fludarabine and cytarabine and stem-cell transplantation. Study ITCC 020/I-BFM 2009-02 aimed to identify the recommended phase II dose of clofarabine replacing fludarabine in the abovementioned combination regimen (3+3 design). Escalating dose levels of clofarabine (20-40 mg/m2/day × 5 days) and liposomal daunorubicin (40-80 mg/m2/day) were administered with cytarabine (2 g/m2/day × 5 days). Liposomal DNR was given on day 1, 3 and 5 only. The cohort at the recommended phase II dose was expanded to make a preliminary assessment of anti-leukemic activity. Thirty-four children were enrolled: refractory 1st (n=11), early 1st (n=15), ≥2nd relapse (n=8). Dose level 3 (30 mg/m2clofarabine; 60 mg/m2liposomal daunorubicin) appeared to be safe only in patients without subclinical fungal infections. Infectious complications were dose-limiting. The recommended phase II dose was 40 mg/m2 clofarabine with 60 mg/m2 liposomal daunorubicin. Side-effects mainly consisted of infections. The overall response rate was 68% in 31 response evaluable patients, and 80% at the recommended phase II dose (n=10); 22 patients proceeded to stem cell transplantation. The 2-year probability of event-free survival (pEFS) was 26.5±7.6 and probability of survival (pOS) 32.4±8.0%. In the 21 responding patients, the 2-year pEFS was 42.9±10.8 and pOS 47.6±10.9%. Clofarabine exposure in plasma was not significantly different from that in single-agent studies. In conclusion, clofarabine was well tolerated and showed high response rates in relapsed/refractory pediatric acute myeloid leukemia. Patients with (sub) clinical fungal infections should be treated with caution. Clofarabine has been taken forward in the Berlin-Frankfurt-Münster study for newly diagnosed acute myeloid leukemia. The Study ITCC-020 was registered as EUDRA-CT 2009-009457-13; Dutch Trial Registry number 1880.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Niño , Preescolar , Clofarabina/administración & dosificación , Clofarabina/farmacocinética , Citarabina/administración & dosificación , Citarabina/farmacocinética , Daunorrubicina/administración & dosificación , Daunorrubicina/farmacocinética , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Lactante , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Liposomas , Masculino , Recurrencia , Inducción de Remisión , Retratamiento , Análisis de Supervivencia , Resultado del Tratamiento , Adulto JovenRESUMEN
Recurrent/refractory hematologic malignancies have a poor prognosis, and there is a need for novel treatment regimens that can be tolerated by this heavily pretreated patient group. Clofarabine has antileukemic activity with an acceptable toxicity profile. In a phase I clinical trial (NCT00824135), we substituted clofarabine for fludarabine in a well-established reduced-intensity conditioning regimen for a T cell-depleted, mismatched-related (haploidentical) donor transplant backbone and explored the maximum tolerated dose of clofarabine in this combination in 15 patients undergoing hematopoietic cell transplantation for recurrent/refractory or secondary leukemia. Clofarabine was well tolerated at a dose of 50 mg/m/d for 5 days in this regimen, with minimal treatment-related mortality in a heavily pretreated group of high-risk patients. All patients exhibited quick hematopoietic recovery, with median times to neutrophil and platelet engraftment being 11 and 16 days, respectively. Transient elevation of transaminases was the most common toxicity-observed in 13 patients (86.7%), with 6 (40%) grade III or above. Three patients (20%) developed hepatic veno-occlusive disease. Eleven patients (73.3%) died, with the most common cause of death being disease relapse (in 9 patients [60%]), followed by treatment-related mortality (in 2 patients [13.3%]). Four (26.6%) of the patients are long-term survivors.