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1.
Br J Haematol ; 204(5): 1888-1893, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38501389

RESUMO

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.


Assuntos
Clofarabina , Histiocitose de Células de Langerhans , Humanos , Clofarabina/uso terapêutico , Clofarabina/administração & dosagem , Histiocitose de Células de Langerhans/tratamento farmacológico , Masculino , Feminino , Adulto , Adolescente , Criança , Pessoa de Meia-Idade , Pré-Escolar , Adulto Jovem , Idoso , Recidiva , Proteínas Proto-Oncogênicas B-raf/genética , Lactente , Resultado do Tratamento , Terapia de Salvação , Nucleotídeos de Adenina/uso terapêutico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Arabinonucleosídeos/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos
2.
Int J Hematol ; 108(3): 348-350, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29542029

RESUMO

Approximately 30-40% of patients with acute myeloid leukemia (AML) experience induction failures. In these patients who do not achieve remission with two cycles of standard induction therapies, the probability of achieving remission with subsequent inductions is very limited. Hematopoietic stem cell transplantation (HSCT) is the only curative option for these patients, but high relapse rate and transplant-related mortality often preclude them to proceed to transplant. Thus, AML not in remission at time of HSCT remains a huge unmet need in current HSCT practice, particularly if the patient does not have an HLA-matched donor identified by the time of two induction failures. We used clofarabine cytoreduction immediately followed by fludarabine (Flu) and busulfan (Bu) × 3 with total-body irradiation (TBI) conditioning (Flu/Bu3/TBI) for haploidentical peripheral blood stem cell transplant with post-transplant cyclophosphamide for two cases of refractory AML with a very high tumor burden at transplant and achieved complete remission by day + 30 in both cases.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Bussulfano/administração & dosagem , Terapia Combinada/métodos , Ciclofosfamida/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Imunossupressores/administração & dosagem , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Transplante Haploidêntico/métodos , Vidarabina/análogos & derivados , Adulto , Clofarabina , Humanos , Masculino , Indução de Remissão , Resultado do Tratamento , Carga Tumoral , Vidarabina/administração & dosagem
3.
J Chemother ; 30(1): 44-48, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29098953

RESUMO

We hereby report our multicentre, retrospective experience with CLARA in patients with fludarabine/cytarabine/G-CSF (FLAG) refractory AML. The study included all consecutive R/R AML patients, who received CLARA salvage during October 2010-October 2015 period. All patients were unresponsive to FLAG salvage chemotherapy regimen and did not undergo previous allo-HCT. A total of 40 patients were included. Following CLARA 5 (12.5%) patients experienced induction mortality and 10 (25%) patients achieved CR. 25 (62.5%) patients were unresponsive to CLARA. 7 (17.5%) out of 10 patients in CR received allo-HCT. Median overall survival of patients who achieved CR after CLARA was 24.5 months (8.5-54.5) and 3 months (2.5-5), in patients who underwent and didn't allo-HCT, respectively. Our results indicate that CLARA may be good alternative even in FLAG refractory AML patients and can be used as a bridge to allo-HCT, who have a suitable donor and able to tolerate the procedure.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação/métodos , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Arabinonucleosídeos/efeitos adversos , Clofarabina , Citarabina/efeitos adversos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Fator Estimulador de Colônias de Granulócitos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Vidarabina/análogos & derivados , Adulto Jovem
4.
Pediatr Hematol Oncol ; 34(4): 187-198, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-29039989

RESUMO

Relapsed/refractory acute myeloid leukemia (AML) has an extremely poor prognosis. We describe 17 children and adolescents with relapsed/refractory AML who received clofarabine, cyclophosphamide, and etoposide. Seven patients (41%) responded: 4 with a complete response (CR); 1 with CR with incomplete platelet recovery; and 2 with a partial response. Additionally, 4 developed hypocellular marrow without evidence of leukemia; 5 patients had resistant disease; and 1 suffered early toxic death. After further therapy including transplantation, 4 patients (24%) are alive without evidence of disease at a median of 60 months. This anthracycline-free regimen may be studied for relapsed or refractory AML, but due to the high risk of marrow aplasia reduced doses of clofarabine and cyclophosphamide should be used.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Criança , Pré-Escolar , Clofarabina , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas , Humanos , Lactente , Masculino , Taxa de Sobrevida
5.
J Am Chem Soc ; 139(40): 14021-14024, 2017 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-28945366

RESUMO

Tumor-targeted drug delivery with simultaneous cancer imaging is highly desirable for personalized medicine. Herein, we report a supramolecular approach to design a promising class of multifunctional nanoparticles based on molecular recognition of nucleobases, which combine excellent tumor-targeting capability via aptamer, controlled drug release, and efficient fluorescent imaging for cancer-specific therapy. First, an amphiphilic prodrug dioleoyl clofarabine was self-assembled into micellar nanoparticles with hydrophilic nucleoside analogue clofarabine on their surface. Thereafter, two types of single-stranded DNAs that contain the aptamer motif and fluorescent probe Cy5.5, respectively, were introduced onto the surface of the nanoparticles via molecular recognition between the clofarabine and the thymine on DNA. These drug-containing multifunctional nanoparticles exhibit good capabilities of targeted clofarabine delivery to the tumor site and intracellular controlled drug release, leading to a robust and effective antitumor effect in vivo.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Aptâmeros de Nucleotídeos/química , Arabinonucleosídeos/administração & dosagem , Preparações de Ação Retardada/química , Corantes Fluorescentes/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Pró-Fármacos/administração & dosagem , Nucleotídeos de Adenina/química , Nucleotídeos de Adenina/farmacocinética , Nucleotídeos de Adenina/uso terapêutico , Animais , Arabinonucleosídeos/química , Arabinonucleosídeos/farmacocinética , Arabinonucleosídeos/uso terapêutico , Linhagem Celular Tumoral , Clofarabina , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Camundongos , Neoplasias/diagnóstico por imagem , Nucleosídeos/química , Imagem Óptica , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Pró-Fármacos/uso terapêutico
6.
Chemotherapy ; 62(6): 353-356, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28810255

RESUMO

We describe the case of a patient with Philadelphia-positive acute lymphoblastic leukemia treated with dasatinib plus steroids as first-line therapy, who achieved a major molecular response (MMR) before undergoing matched, unrelated donor allogeneic stem cell transplant. Eleven months after the transplant, she experienced molecular relapse. Mutational screening showed negativity for the T315I mutation, The patient underwent a salvage chemotherapy regimen with clofarabine + cyclophosphamide + steroids and ponatinib (clofarabine 70 mg i.v., days 1-5, cyclophosphamide 700 mg i.v., days 1-5, and ponatinib 45 mg p.o., daily starting at day 15). We observed a rapid decrease in minimal residual disease on molecular assessment with an MMR of P190-BCR-ABL/ABL = 0.01% confirmed by bone marrow revaluations at days +23, +59, +108, and +191 after the first day of salvage chemotherapy. After starting ponatinib, the patient experienced skin graft-versus-host disease, suggesting that the efficacy of ponatinib could be related not only to the direct antileukemic effect but also to its ability to promote an indirect graft-versus-leukemia effect. Ponatinib treatment was well tolerated and considered safe with easily manageable side effects.


Assuntos
Doença Enxerto-Hospedeiro/etiologia , Imidazóis/uso terapêutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Inibidores de Proteínas Quinases/uso terapêutico , Piridazinas/uso terapêutico , Nucleotídeos de Adenina/administração & dosagem , Adulto , Arabinonucleosídeos/administração & dosagem , Medula Óssea/patologia , Clofarabina , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Proteínas de Fusão bcr-abl/genética , Humanos , Imidazóis/efeitos adversos , Imunofenotipagem , Mutação , Neoplasia Residual , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Prednisona/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridazinas/efeitos adversos , Recidiva , Terapia de Salvação , Transplante Homólogo
7.
Cancer ; 123(22): 4430-4439, 2017 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-28708931

RESUMO

BACKGROUND: Fludarabine and clofarabine are purine nucleoside analogues with established clinical activity in patients with acute myeloid leukemia (AML). METHODS: Herein, the authors evaluated the efficacy and safety of idarubicin and cytarabine with either clofarabine (CIA) or fludarabine (FIA) in adults with newly diagnosed AML. Adults with newly diagnosed AML who were deemed suitable for intensive chemotherapy were randomized using a Bayesian adaptive design to receive CIA (106 patients) or FIA (76 patients). Patients received induction with idarubicin and cytarabine, plus either clofarabine or fludarabine. Responding patients could receive up to 6 cycles of consolidation therapy. Outcomes were compared with a historical cohort of patients who received idarubicin and cytarabine. RESULTS: The complete remission/complete remission without platelet recovery rate was similar among patients in the CIA and FIA arms (80% and 82%, respectively). The median event-free survival was 13 months and 12 months, respectively (P = .91), and the median overall survival was 24 months and not reached, respectively (P = .23), in the 2 treatment arms. CIA was associated with more adverse events, particularly transaminase elevation, hyperbilirubinemia, and rash. Early mortality was similar in the 2 arms (60-day mortality rate of 4% for CIA vs 1% for FIA; P = .32). In an exploratory analysis of patients aged <50 years, FIA was found to be associated with improved survival compared with idarubicin and cytarabine (2-year event-free survival rate: 58% vs 30% [P = .05] and 2-year overall survival rate: 72% vs 36% [P = .009]). CONCLUSIONS: CIA and FIA have similar efficacy in younger patients with newly diagnosed AML, although FIA is associated with a better toxicity profile. Cancer 2017;123:4430-9. © 2017 American Cancer Society.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Arabinonucleosídeos/administração & dosagem , Citarabina/administração & dosagem , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Vidarabina/análogos & derivados , Nucleotídeos de Adenina/efeitos adversos , Adolescente , Adulto , Idoso , Arabinonucleosídeos/efeitos adversos , Clofarabina , Citarabina/efeitos adversos , Humanos , Idarubicina/efeitos adversos , Leucemia Mieloide Aguda/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Adulto Jovem
8.
J Pediatr Hematol Oncol ; 39(6): 481-484, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28538504

RESUMO

Clofarabine containing chemotherapeutic regimens have demonstrated efficacy in the treatment of relapsed refractory acute myeloid leukemia. Nonetheless, there are limited data on the use of clofarabine in patients with renal failure. The present report describes the use of clofarabine in a patient with renal failure undergoing intermittent dialysis. We describe our rationale for dosing, clofarabine plasma levels obtained, and discuss our findings in the context of other available literature. Consistent with previous findings, intermittent hemodialysis was not found to be a reliable method of removing clofarabine in patients with renal insufficiency.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/sangue , Nucleotídeos de Adenina/farmacocinética , Adulto , Antimetabólitos Antineoplásicos , Arabinonucleosídeos/sangue , Arabinonucleosídeos/farmacocinética , Clofarabina , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Diálise Renal , Adulto Jovem
9.
Biol Blood Marrow Transplant ; 23(7): 1134-1141, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28396162

RESUMO

Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m2. All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m2 in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m2 of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM.


Assuntos
Nucleotídeos de Adenina/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Irradiação Corporal Total/métodos , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/farmacologia , Adolescente , Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacologia , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/farmacologia , Criança , Pré-Escolar , Clofarabina , Feminino , Humanos , Lactente , Masculino , Estudos Prospectivos
11.
J Clin Oncol ; 35(11): 1223-1230, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28221862

RESUMO

Purpose To evaluate the efficacy and safety of a clofarabine-based combination (CLARA) versus conventional high-dose cytarabine (HDAC) as postremission chemotherapy in younger patients with acute myeloid leukemia (AML). Patients and Methods Patients age 18 to 59 years old with intermediate- or unfavorable-risk AML in first remission and no identified donor for allogeneic stem-cell transplantation (SCT) were eligible. Two hundred twenty-one patients were randomly assigned to receive three CLARA or three HDAC consolidation cycles. The primary end point was relapse-free survival (RFS). To handle the confounding effect of SCT that could occur in patients with late donor identification, hazard ratios (HRs) of events were adjusted on the time-dependent treatment × SCT interaction term. Results At 2 years, RFS was 58.5% (95% CI, 49% to 67%) in the CLARA arm and 46.5% (95% CI, 37% to 55%) in the HDAC arm. Overall, 110 patients (55 in each arm) received SCT in first remission. On the basis of a multivariable Cox-adjusted treatment × SCT interaction, the HR of CLARA over HDAC before or in absence of SCT was 0.65 (95% CI, 0.43 to 0.98; P = .041). In a sensitivity analysis, when patients who received SCT in first remission were censored at SCT time, 2-year RFS was 53.3% (95% CI, 39% to 66%) in the CLARA arm and 31.0% (95% CI, 19% to 43%) in the HDAC arm (HR, 0.63; 95% CI, 0.41 to 0.98; P = .043). Gain in RFS could be related to the lower cumulative incidence of relapse observed in the CLARA arm versus the HDAC arm (33.9% v 46.4% at 2 years, respectively; cause-specific HR, 0.61; 95% CI, 0.40 to 0.94; P = .025). CLARA cycles were associated with higher hematologic and nonhematologic toxicity than HDAC cycles. Conclusion These results suggest that CLARA might be considered as a new chemotherapy option in younger patients with AML in first remission.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Nucleotídeos de Adenina/efeitos adversos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Arabinonucleosídeos/efeitos adversos , Clofarabina , Quimioterapia de Consolidação , Citarabina/administração & dosagem , Intervalo Livre de Doença , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
12.
Int J Hematol ; 105(6): 769-776, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28220349

RESUMO

For refractory or relapsed acute myeloid leukemia patients, allogeneic hematopoietic stem cell transplantation is the only curative treatment option, but the disease must be in remission before this can be attempted. "Salvage" therapy regimens containing high-dose cytarabine plus fludarabine or cladribine with or without anthracyclines or plus mitoxantrone and etoposide fail in 30-50% of cases. We report the outcome of 14 patients treated with a clofarabine-based treatment administered after at least one failed fludarabine-based "salvage" attempt in a "real life" (outside a clinical trial) context. No death related to the clofarabine-based treatment was observed. Four of the 14 patients (29%) reached complete remission and one (7%) achieved a reduction of marrow blasts to fewer than 10%. Three of these five patients were successfully transplanted and have shown a long-term survival. The small number of this group of patients does not permit the identification of clinical features clearly related to a favorable outcome, but we note that all the three long-term survivals were FLT3 wild type. Clofarabine-based "salvage therapy" in patients with very poor expectancy is feasible even after a fludarabine-based salvage attempt, albeit with success only in a small percentage of cases (3/14 = 21%).


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/prevenção & controle , Vidarabina/análogos & derivados , Adolescente , Adulto , Idoso , Aloenxertos , Clofarabina , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Terapia de Salvação/métodos , Vidarabina/administração & dosagem
13.
Int J Hematol ; 105(5): 686-691, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28185203

RESUMO

Haploidentical hematopoietic cell transplantation (HCT) conditioning with clofarabine and target area under the blood concentration-time curve (AUC)-based busulfan adjustment was performed in three patients with refractory pediatric leukemia. The target AUC for two patients who had already received multiple transplantations was 3600 and 4000 µmol min/L, and that for the patient with Down's syndrome was 3000 µmol min/L. Regimen-related toxicity was well tolerated in all cases. All three maintained cytological remission throughout the follow-up period (between 31 and 167 weeks). Thus, haploidentical HCT conditioning with clofarabine and target AUC-based busulfan adjustment may be a preferable option for children with recurrent or refractory pediatric leukemia.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Bussulfano/administração & dosagem , Antígenos HLA/genética , Haploidia , Transplante de Células-Tronco Hematopoéticas , Leucemia/terapia , Condicionamento Pré-Transplante , Criança , Clofarabina , Feminino , Seguimentos , Humanos , Masculino , Recidiva , Indução de Remissão , Fatores de Tempo , Resultado do Tratamento
14.
Biol Blood Marrow Transplant ; 23(2): 285-292, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27816651

RESUMO

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged <60 years and 4000 µmol/min for patients aged >59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Aloenxertos , Clofarabina , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Irradiação Corporal Total , Adulto Jovem
15.
Bone Marrow Transplant ; 52(1): 59-65, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27427921

RESUMO

Allogeneic hematopoietic cell transplantation (HCT) may produce long-term survival in AML after relapse or primary induction failure (PIF). However, outcomes of HCT performed for AML not in remission are historically poor given high relapse rates and transplant-related mortality. Preliminary studies suggest conditioning with clofarabine and myeloablative busulfan (CloBu4) may exert significant anti-leukemic effects without excessive toxicity in refractory hematologic malignancies. A prospective multicenter phase II trial was conducted to determine the efficacy of CloBu4 for patients proceeding directly to HCT with AML not in remission. Seventy-one patients (median age: 56 years) received CloBu4. At day 30 after HCT, 90% achieved morphologic remission. The incidence of non-relapse mortality and relapse at 2 years was 25% and 55%, respectively. The 2-year overall survival (OS) and event-free survival (EFS) were 26% and 20%, respectively. Patients entering HCT in PIF had significantly greater EFS than those in relapse (34% vs 8%; P<0.01). Multivariate analysis comparing CloBu4 with a contemporaneous cohort (Center for International Blood and Marrow Transplantation Research) of AML not in remission receiving other myeloablative conditioning (n=105) demonstrated similar OS (HR: 1.33, 95% confidence interval: 0.92-1.92; P=0.12). HCT with myeloablative CloBu4 is associated with high early response rates and may produce durable remissions in select patients with AML not in remission.


Assuntos
Nucleotídeos de Adenina/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Bussulfano/administração & dosagem , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante , Adulto , Idoso , Aloenxertos , Clofarabina , Intervalo Livre de Doença , Feminino , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
16.
Haematologica ; 102(1): 184-191, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27561720

RESUMO

The prognosis of patients with acute myeloid leukemia in whom primary treatment fails remains very poor. In order to improve such patients' outcome, we conducted a phase 2, prospective, multicenter trial to test the feasibility of a new sequential regimen, combining a short course of intensive chemotherapy and a reduced intensity-conditioning regimen, before allogeneic stem-cell transplantation. Twenty-four patients (median age, 47 years) with acute myeloid leukemia in primary treatment failure were included. Cytogenetic risk was poor in 15 patients (62%) and intermediate in nine (38%). The sequential regimen consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a 3-day rest, by reduced-intensity conditioning and allogeneic stem-cell transplantation combining cyclophosphamide (60 mg/kg), intravenous busulfan (3.2 mg/kg/day) for 2 days and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Patients in complete remission at day +120 received prophylactic donor lymphocyte infusion. Eighteen patients (75%) achieved complete remission. With a median follow-up of 24.6 months, the Kaplan-Meier estimate of overall survival was 54% (95% CI: 33-71) at 1 year and 38% (95% CI: 18-46) at 2 years. The Kaplan-Meier estimate of leukemia-free survival was 46% (95% CI: 26-64) at 1 year and 29% (95% CI: 13-48) at 2 years. The cumulative incidence of non-relapse mortality was 8% (95% CI: 1-24) at 1 year and 12% (95% CI: 3-19) at 2 years. Results from this phase 2 prospective multicenter trial endorsed the safety and efficacy of a clofarabine-based sequential reduced-toxicity conditioning regimen, which warrants further investigation. This study was registered at www.clinicaltrials.gov, identifier number: NCT01188174.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante , Nucleotídeos de Adenina/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Clofarabina , Citarabina/administração & dosagem , Resistencia a Medicamentos Antineoplásicos , Feminino , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Retratamento , Análise de Sobrevida , Doadores de Tecidos , Quimeras de Transplante , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Adulto Jovem
17.
Leukemia ; 31(2): 310-317, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27624670

RESUMO

The study was designed to compare clofarabine plus daunorubicin vs daunorubicin/ara-C in older patients with acute myeloid leukaemia (AML) or high-risk myelodysplastic syndrome (MDS). Eight hundred and six untreated patients in the UK NCRI AML16 trial with AML/high-risk MDS (median age, 67 years; range 56-84) and normal serum creatinine were randomised to two courses of induction chemotherapy with either daunorubicin/ara-C (DA) or daunorubicin/clofarabine (DClo). Patients were also included in additional randomisations; ± one dose of gemtuzumab ozogamicin in course 1; 2v3 courses and ± azacitidine maintenance. The primary end point was overall survival. The overall response rate was 69% (complete remission (CR) 60%; CRi 9%), with no difference between DA (71%) and DClo (66%). There was no difference in 30-/60-day mortality or toxicity: significantly more supportive care was required in the DA arm even though platelet and neutrophil recovery was significantly slower with DClo. There were no differences in cumulative incidence of relapse (74% vs 68%; hazard ratio (HR) 0.93 (0.77-1.14), P=0.5); survival from relapse (7% vs 9%; HR 0.96 (0.77-1.19), P=0.7); relapse-free (31% vs 32%; HR 1.02 (0.83-1.24), P=0.9) or overall survival (23% vs 22%; HR 1.08 (0.93-1.26), P=0.3). Clofarabine 20 mg/m2 given for 5 days with daunorubicin is not superior to ara-C+daunorubicin as induction for older patients with AML/high-risk MDS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Nucleotídeos de Adenina/administração & dosagem , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Arabinonucleosídeos/administração & dosagem , Causas de Morte , Clofarabina , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Recidiva , Análise de Sobrevida , Resultado do Tratamento
18.
Expert Opin Pharmacother ; 17(17): 2319-2330, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27759440

RESUMO

INTRODUCTION: Advances in acute lymphocytic leukemia (ALL) therapy has led to long-term survival rates in children. However, only 30%-40% of adults achieve long-term disease-free survival. After relapse, the outcome of salvage chemotherapy is very disappointing with less than 10% of long survival. Novel agents are therefore desperately required to improve response rates and survival, but also the quality of life of patients. Areas covered: The following review is a comprehensive summary of various novel options reported over the past few years in the therapeutic area of adult ALL. Expert opinion: Identifying key components involved in disease pathogenesis may lead to new approaches. In a near future, the incorporation of monoclonal antibodies and T-cell directed approaches including blinatumomab and chimeric antigen receptor T cells may increase the cure rates and may reduce the need for intensive therapy.


Assuntos
Nucleotídeos de Adenina/uso terapêutico , Antineoplásicos/uso terapêutico , Arabinonucleosídeos/uso terapêutico , Descoberta de Drogas , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Nucleosídeos de Purina/uso terapêutico , Pirimidinonas/uso terapêutico , Terapia de Salvação/métodos , Nucleotídeos de Adenina/administração & dosagem , Adulto , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/administração & dosagem , Arabinonucleosídeos/administração & dosagem , Clofarabina , Intervalo Livre de Doença , Humanos , Terapia de Alvo Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Nucleosídeos de Purina/administração & dosagem , Pirimidinonas/administração & dosagem , Qualidade de Vida , Recidiva
19.
Cancer Med ; 5(11): 3068-3076, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27748046

RESUMO

We have retrospectively compared survivals between acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) patients who received either a clofarabine/busulfan (CloB2A2) or a fludarabine/busulfan (FB2A2) RIC regimen for allogeneic stem cell transplantation. Between 2009 and 2014, 355 allotransplanted cases were identified from the SFGM-TC registry as having received either the FB2A2 (n = 316, 56% males, median age: 59.2 years, AML 78.5%, first complete remission [CR1] 72%, median follow-up: 20 months) or the CloB2A2 (n = 39, 62% males, median age: 60.8 years, AML 62%, CR1 69%, median follow-up: 22.4 months) RIC regimen. In multivariate analysis, FB2A2 was associated with significant lower overall survival (OS, HR: 2.14; 95%CI: 1.05-4.35, P = 0.04) and higher relapse incidence (RI, HR: 2.17; 95%CI: 1.02-4.61, P = 0.04) and a trend for lower leukemia-free survival (LFS, HR: 1.75; 95%CI: 0.94-3.26, P = 0.08). These results were confirmed using a propensity score-matching strategy. However, when considering AML and MDS patients separately, the benefit of the CLOB2A2 regimen was restricted to AML patients (2-year OS FB2A2: 38% [14.5-61.6] vs. CloB2A2: 79.2% [62.9-95.4], P = 0.01; 2-year LFS FB2A2: 38% [16-59.9] vs. CloB2A2: 70.8% [52.6-89], P = 0.03). The better survivals were due to the lower risk of relapse in this CloB2A2 AML subgroup (2-year RI FB2A2: 41.2% [19-62.4] vs. CloB2A2: 16.7% [5-34.2], P = 0.05). This retrospective comparison suggests that the CloB2A2 RIC regimen can likely provide longer survival than that awarded by a FB2A2 RIC regimen and may become a new standard of care RIC regimen for allotransplanted AML patients. A prospective phase 3 randomized study is warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante , Nucleotídeos de Adenina/administração & dosagem , Adulto , Idoso , Arabinonucleosídeos/administração & dosagem , Clofarabina , Feminino , Seguimentos , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/diagnóstico , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/análogos & derivados , Adulto Jovem
20.
Lancet Haematol ; 3(7): e330-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27374466

RESUMO

BACKGROUND: The intensive chemotherapy regimens used to treat acute myeloid leukaemia routinely result in serious infections, largely due to prolonged neutropenia. We investigated the use of non-HLA-matched ex-vivo expanded cord blood progenitor cells to accelerate haemopoietic recovery and reduce infections after chemotherapy. METHODS: We enrolled patients with a diagnosis of acute myeloid leukaemia by WHO criteria and aged 18-70 years inclusive at our institution (Fred Hutchinson Cancer Research Center) into this phase 1 trial. The primary endpoint of the study was safety of infusion of non-HLA-matched expanded cord blood progenitor cells after administration of clofarabine, cytarabine, and granulocyte-colony stimulating factor priming. The protocol is closed to accrual and analysis was performed per protocol. The trial is registered with ClinicalTrials.gov, NCT01031368. FINDINGS: Between June 29, 2010, and June 26, 2012, 29 patients with acute myeloid leukaemia (19 newly diagnosed, ten relapsed or refractory) were enrolled. The most common adverse events were fever (27 [93%] of 29 patients) and infections (25 [86%] of 29 patients). We observed one case of acute infusional toxicity (attributed to an allergic reaction to dimethyl sulfoxide) in the 29 patients enrolled, who received 42 infusions of expanded progenitor cells. The following additional serious but expected adverse events were observed (each in one patient): grade 4 atrial fibrillation, grade 4 febrile neutropenia, lung infection with grade 4 absolute neutrophil count, colon infection with grade 4 absolute neutrophil count, grade 4 changed mental status, and one death from liver failure. No unexpected toxicity or graft-versus-host disease was observed. There was no evidence of in-vivo persistence of the expanded progenitor cell product in any patient beyond 14 days or induced alloimmunisation. INTERPRETATION: Infusion of the expanded progenitor cell product seemed safe and might provide a promising treatment method for patients with acute myeloid leukaemia. FUNDING: Biomedical Advanced Research and Development Authority in the US Department of Health and Human Services and Genzyme (Sanofi).


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mieloide Aguda/terapia , Nucleotídeos de Adenina/administração & dosagem , Adolescente , Adulto , Idoso , Arabinonucleosídeos/administração & dosagem , Clofarabina , Estudos de Coortes , Citarabina/administração & dosagem , Feminino , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Adulto Jovem
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