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1.
Blood ; 132(25): 2639-2642, 2018 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-30266774

RESUMO

The phase 3 AETHERA trial established brentuximab vedotin (BV) as a consolidative treatment option for adult patients with classical Hodgkin lymphoma (cHL) at high risk of relapse or progression after autologous hematopoietic stem-cell transplantation (auto-HSCT). Results showed that BV significantly improved progression-free survival (PFS) vs placebo plus best supportive care alone. At 5-year follow-up, BV continued to provide patients with sustained PFS benefit; 5-year PFS was 59% (95% confidence interval [CI], 51-66) with BV vs 41% (95% CI, 33-49) with placebo (hazard ratio [HR], 0.521; 95% CI, 0.379-0.717). Similarly, patients with ≥2 risk factors in the BV arm experienced significantly higher PFS at 5 years than patients in the placebo arm (HR, 0.424; 95% CI, 0.302-0.596). Upfront consolidation with BV significantly delayed time to second subsequent therapy, an indicator of ongoing disease control, vs placebo. Peripheral neuropathy, the most common adverse event in patients receiving BV, continued to improve and/or resolve in 90% of patients. In summary, consolidation with BV in adult patients with cHL at high risk of relapse or progression after auto-HSCT confers a sustained PFS benefit and is safe and well tolerated. Physicians should consider each patient's HL risk factor profile when making treatment decisions. This trial was registered at www.clinicaltrials.gov as #NCT01100502.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/mortalidade , Doença de Hodgkin/terapia , Imunoconjugados/administração & dosagem , Adolescente , Adulto , Autoenxertos , Brentuximab Vedotin , Criança , Feminino , Seguimentos , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/efeitos adversos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Recidiva , Fatores de Risco , Taxa de Sobrevida
2.
Biol Blood Marrow Transplant ; 25(2): 248-255, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30266677

RESUMO

Mobilization of hematopoietic stem cells for patients with multiple myeloma (MM) may be done using either steady-state granulocyte colony-stimulating factor (G-CSF) or a combination of chemotherapy with G-CSF. The goal of this randomized, open-label, phase 3 trial was to compare the efficacy of chemomobilization using intermediate-dose cytarabine (ID-AraC) plus G-CSF with G-CSF alone in patients with MM referred for tandem autologous stem cell transplantation (autoSCT). The percentage of patients with stem cell yield of at least 5 × 106 CD34+ cells/kg was the primary endpoint. Ninety patients were enrolled, including 44 assigned to the ID-AraC arm and 46 in the G-CSF arm. The threshold number of CD34+ cells was reached in 43 patients (98%) in the ID-AraC arm and in 32 patients (70%) in the G-CSF arm (P = .0003). The median number of collected CD34+ cells was 20.2 × 106 cells/kg in the ID-AraC arm versus 5.9 × 106 cells/kg in the G-CSF arm (P < .000001). A single apheresis was sufficient to achieve the required number of harvested CD34+ cells in 37 patients (86%) in the ID-AraC arm and in 13 patients (41%) in the G-CSF arm (P = .00008). The times to both neutrophil and platelet recovery after autoSCT were significantly shorter in the patients mobilized with ID-AraC. This study provides the first evidence of the advantage of chemomobilization over G-CSF monotherapy in terms of efficacy. ID-AraC with G-CSF should be the preferred chemomobilization protocol for patients with MM scheduled to undergo tandem autoSCT.


Assuntos
Citarabina/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas , Mieloma Múltiplo/terapia , Transplante de Células-Tronco de Sangue Periférico , Adulto , Idoso , Autoenxertos , Citarabina/efeitos adversos , Feminino , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/sangue
3.
Biol Blood Marrow Transplant ; 24(11): 2354-2359, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29859255

RESUMO

The phase III AETHERA trial demonstrated the efficacy of brentuximab vedotin (BV) as consolidation therapy in patients with classical Hodgkin lymphoma (HL) at high risk of relapse or progression after autologous hematopoietic stem cell transplantation (auto-HSCT; hazard ratio, .57; P < .001). The objective of this analysis is to provide further detail on the most common and clinically important treatment-emergent adverse events (AEs) in the AETHERA BV arm including their occurrence and management. AEs of clinical importance occurring in patients who participated in AETHERA (BV + best supportive care [BSC], n = 165; placebo + BSC, n = 164) were evaluated for time to onset, manageability through dose modification, and resolution. As previously reported, peripheral neuropathy (PN; 67%), infections (60%), and neutropenia (35%) were the most common BV-associated treatment-emergent AEs. Neutropenia was managed with dose delays and granulocyte colony-stimulating factor; no dose reductions or discontinuations were required. Most PN cases (57%) were managed with dose delays and reductions. The median time to PN onset was 13.7 weeks (range, .1 to 47.4). After the end of treatment, PN continued to resolve; symptom resolution was similar to that in the placebo arm at 3 years, demonstrating reversibility. BV had no significant impact on pre-existing PN. Patients with PN-related dose modifications had progression-free survival (PFS) comparable with patients without. Other less common but serious AEs, including pulmonary toxicities, hepatotoxicity, and cardiotoxicity, were rare in both arms and were managed with BV dose modifications or discontinuations. Secondary malignancies were rare and reported in patients with comorbidities or other risk factors. Consolidation therapy with BV for patients with HL at high risk of relapse after auto-HSCT is associated with sustained PFS. The most common AEs in the BV arm were manageable and reversible. Awareness of these AEs and management approaches will enable healthcare providers and patients to plan the safest and most effective treatment plan.


Assuntos
Quimioterapia de Consolidação/métodos , Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Brentuximab Vedotin , Feminino , Doença de Hodgkin/patologia , Humanos , Imunoconjugados/farmacologia , Masculino , Resultado do Tratamento
4.
Contemp Oncol (Pozn) ; 22(2): 113-117, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30150889

RESUMO

INTRODUCTION: BEAM (carmustine, etoposide, cytarabine, melphalan) is the most frequently used high-dose chemotherapy regimen for patients with lymphoma referred for autologous haematopoietic cell transplantation (autoHCT). Recently, a novel conditioning protocol containing bendamustine instead of carmustine (BeEAM) has been proposed to potentially increase the efficacy. AIM OF THE STUDY: The aim of this study was to retrospectively compare the safety profile of BEAM and BeEAM based on single-centre experience. MATERIAL AND METHODS: A total of 237 consecutive patients with lymphoma treated with either BEAM (n = 174) or BeEAM (n = 63), between the years 2011 and 2016, were included in the analysis. Clinical characteristics of both groups were comparable. Patients with Hodgkin's lymphoma (HL) constituted 49% of the BEAM group and 40% of the BeEAM group. RESULTS: Median time to neutrophil > 0.5 × 109/l recovery was 10 days in both groups (p = 0.29), while median time to platelet > 50 × 109/l recovery was 13 and 14 days after BEAM and BeEAM, respectively (p = 0.12). The toxicity profile was comparable except for arterial hypertension and severe hypokalaemia, which occurred more frequently after BeEAM compared to BEAM (p = 0.02 and p = 0.004, respectively). The rate of early mortality was 1.7% and 1.6%, respectively. The probabilities of the overall and progression-free survival were comparable for both groups (p = 0.73 and p = 0.55, respectively). CONCLUSIONS: Administration of bendamustine instead of carmustine as part of conditioning does not affect the engraftment or the toxicity profile of the regimen. Therefore, BeEAM may be safely used in patients with lymphoma undergoing autoHCT. Its efficacy requires evaluation in prospective studies.

5.
Am J Hematol ; 92(4): 359-366, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28103640

RESUMO

Intensive induction chemotherapy using anthracycline and cytarabine backbone is considered the most effective upfront therapy in physically fit older patients with acute myeloid leukemia (AML). However, outcomes of the standard induction in elderly AML are inferior to those observed in younger patients, and they are still unsatisfactory. As addition of cladribine to the standard induction therapy is known to improve outcome in younger AML patients. The present randomized phase II study compares efficacy and toxicity of the DAC (daunorubicin plus cytarabine plus cladribine) regimen with the standard DA (daunorubicin plus cytarabine) regimen in the newly diagnosed AML patients over 60 years of age. A total of 171 patients were enrolled in the study (DA, 86; DAC, 85). A trend toward higher complete remission (CR) was observed in the DAC arm compared to the DA arm (44% vs. 34%; P = .19), which did not lead to improved median overall survival, which in the case of the DAC group was 8.6 months compared to in 9.1 months in the DA group (P = .64). However, DAC appeared to be superior in the group of patients aged 60-65 (CR rate: DAC 51% vs. DA 29%; P = .02). What is more, a subgroup of patients, with good and intermediate karyotypes, benefited from addition of cladribine also in terms of overall survival (P = .02). No differences in hematological and nonhematological toxicity between the DA and DAC regimens were observed.


Assuntos
Cladribina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Fatores Etários , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cladribina/farmacologia , Citarabina/administração & dosagem , Daunorrubicina/administração & dosagem , Feminino , Humanos , Quimioterapia de Indução/métodos , Cariotipagem , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Polônia , Indução de Remissão
6.
Br J Haematol ; 175(5): 860-867, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27649689

RESUMO

Brentuximab vedotin (BV) significantly improved progression-free survival in a phase 3 study in patients with relapsed or refractory Hodgkin lymphoma (RR-HL) post-autologous-haematopoietic stem cell transplant (auto-HSCT); we report the impact of BV on quality of life (QOL) from this trial. The European Quality of Life five dimensions questionnaire was administered at the beginning of each cycle, end of treatment, and every 3 months during follow-up; index value scores were calculated using the time trade-off (TTO) method for UK-weighted value sets. Questionnaire adherence during the trial was 87·5% (N = 329). In an intent-to-treat analysis, compared with placebo, TTO scores in the BV arm did not exceed the minimally important difference (MID) of 0·08 except at month 15 (-0·084; 95% confidence interval, -0·143 to -0·025). On-treatment index scores were similar between arms and did not reach the MID at any time point; mixed-effect modelling showed that BV treatment effect was not significant (P = 0·2127). BV-associated peripheral neuropathy did not meaningfully impact QOL. Utility scores for patients who progressed declined compared with those who did not; TTO scores between these patients exceeded the MID beginning at month 15. In conclusion, QOL decreased modestly with BV consolidation treatment in patients with RR-HL at high risk of relapse after auto-HSCT.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Doença de Hodgkin/terapia , Imunoconjugados/uso terapêutico , Qualidade de Vida , Inquéritos e Questionários , Autoenxertos , Brentuximab Vedotin , Quimioterapia de Consolidação , Transplante de Células-Tronco Hematopoéticas/psicologia , Doença de Hodgkin/psicologia , Humanos , Terapia de Salvação/métodos
7.
Lancet ; 385(9980): 1853-62, 2015 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-25796459

RESUMO

BACKGROUND: High-dose therapy followed by autologous stem-cell transplantation is standard of care for patients with relapsed or primary refractory Hodgkin's lymphoma. Roughly 50% of patients might be cured after autologous stem-cell transplantation; however, most patients with unfavourable risk factors progress after transplantation. We aimed to assess whether brentuximab vedotin improves progression-free survival when given as early consolidation after autologous stem-cell transplantation. METHODS: We did this randomised, double-blind, placebo-controlled, phase 3 trial at 78 sites in North America and Europe. Patients with unfavourable-risk relapsed or primary refractory classic Hodgkin's lymphoma who had undergone autologous stem-cell transplantation were randomly assigned, by fixed-block randomisation with a computer-generated random number sequence, to receive 16 cycles of 1·8 mg/kg brentuximab vedotin or placebo intravenously every 3 weeks, starting 30-45 days after transplantation. Randomisation was stratified by best clinical response after completion of salvage chemotherapy (complete response vs partial response vs stable disease) and primary refractory Hodgkin's lymphoma versus relapsed disease less than 12 months after completion of frontline therapy versus relapse 12 months or more after treatment completion. Patients and study investigators were masked to treatment assignment. The primary endpoint was progression-free survival by independent review, defined as the time from randomisation to the first documentation of tumour progression or death. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01100502. FINDINGS: Between April 6, 2010, and Sept 21, 2012, we randomly assigned 329 patients to the brentuximab vedotin group (n=165) or the placebo group (n=164). Progression-free survival by independent review was significantly improved in patients in the brentuximab vedotin group compared with those in the placebo group (hazard ratio [HR] 0·57, 95% CI 0·40-0·81; p=0·0013). Median progression-free survival by independent review was 42·9 months (95% CI 30·4-42·9) for patients in the brentuximab vedotin group compared with 24·1 months (11·5-not estimable) for those in the placebo group. We recorded consistent benefit (HR <1) of brentuximab vedotin consolidation across subgroups. The most frequent adverse events in the brentuximab vedotin group were peripheral sensory neuropathy (94 [56%] of 167 patients vs 25 [16%] of 160 patients in the placebo group) and neutropenia (58 [35%] vs 19 [12%] patients). At time of analysis, 28 (17%) of 167 patients had died in the brentuximab vedotin group compared with 25 (16%) of 160 patients in the placebo group. INTERPRETATION: Early consolidation with brentuximab vedotin after autologous stem-cell transplantation improved progression-free survival in patients with Hodgkin's lymphoma with risk factors for relapse or progression after transplantation. This treatment provides an important therapeutic option for patients undergoing autologous stem-cell transplantation. FUNDING: Seattle Genetics and Takeda Pharmaceuticals International.


Assuntos
Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/tratamento farmacológico , Imunoconjugados/uso terapêutico , Adolescente , Adulto , Idoso , Antineoplásicos/efeitos adversos , Brentuximab Vedotin , Quimioterapia de Consolidação/métodos , Progressão da Doença , Método Duplo-Cego , Feminino , Doença de Hodgkin/terapia , Humanos , Imunoconjugados/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Recidiva , Terapia de Salvação/efeitos adversos , Terapia de Salvação/métodos , Resultado do Tratamento , Adulto Jovem
8.
Ann Hematol ; 95(2): 263-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26611854

RESUMO

Salvage regimens, like DHAP (dexamethasone, cytarabine, and cisplatin) are frequently used for stem cell mobilization in lymphoma. The aim of this study was to compare the efficacy of DHAP + G-CSF with intermediate-dose cytarabine (ID-AraC) + G-CSF, recently proposed as an alternative schedule. Consecutive patients with Hodgkin's or non-Hodgkin lymphoma who had received at least 2 lines of chemotherapy, mobilized with either DHAP (n = 51) or ID-AraC (n = 50) + G-CSF were included in the analysis. AraC was administered at the dose of 400 mg/m [1] bid intravenously for 2 days followed by filgrastim starting from day 5. In the AraC group, 96 % of patients collected at least 2 × 10 [2] CD34(+) cells/kg compared to 71 % in the DHAP group (p = 0.0006). The CD34(+) cell yield was 9.3 (0-30.3) × 10 [2]/kg vs. 5.6 (0-24.8) × 10 [2]/kg, respectively (p = 0.006). A single apheresis was sufficient to achieve the threshold number of CD34(+) cells in 82 % of the cases after AraC compared to 45 % after DHAP (p = 0.001). We conclude that stem cell mobilization using ID-AraC is associated with a significantly higher efficacy than DHAP, allowing for collection of the transplant material in almost all patients with lymphoma. Our observation suggests that ID-AraC + G-CSF may be a preferable mobilization regimen in this setting.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Linfoma/terapia , Adulto , Idoso , Cisplatino/administração & dosagem , Terapia Combinada/métodos , Citarabina/administração & dosagem , Dexametasona/administração & dosagem , Feminino , Humanos , Linfoma/diagnóstico , Linfoma/epidemiologia , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Estudos Retrospectivos , Terapia de Salvação/métodos , Resultado do Tratamento , Adulto Jovem
9.
Blood ; 121(10): 1720-8, 2013 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-23315161

RESUMO

High platelet counts in essential thrombocythemia (ET) can be effectively lowered by treatment with either anagrelide or hydroxyurea. In 259 previously untreated, high-risk patients with ET, diagnosed according to the World Health Organization classification system, the efficacy and tolerability of anagrelide compared with hydroxyurea were investigated in a prospective randomized noninferiority phase 3 study in an a priori-ordered hypothesis. Confirmatory proof of the noninferiority of anagrelide was achieved after 6 months using the primary end point criteria and was further confirmed after an observation time of 12 and 36 months for platelet counts, hemoglobin levels, leukocyte counts (P < .001), and ET-related events (HR, 1.19 [95% CI, 0.61-2.30], 1.03 [95% CI, 0.57-1.81], and 0.92 [95% CI, 0.57-1.46], respectively). During the total observation time of 730 patient-years, there was no significant difference between the anagrelide and hydroxyurea group regarding incidences of major arterial (7 vs 8) and venous (2 vs 6) thrombosis, severe bleeding events (5 vs 2), minor arterial (24 vs 20) and venous (3 vs 3) thrombosis and minor bleeding events (18 vs 15), or rates of discontinuation (adverse events 12 vs 15 or lack of response 5 vs 2). Disease transformation into myelofibrosis or secondary leukemia was not reported. Anagrelide as a selective platelet-lowering agent is not inferior compared with hydroxyurea in the prevention of thrombotic complications in patients with ET diagnosed according to the World Health Organization system. This trial was registered at http://www.clinicaltrials.gov as #NCT01065038.


Assuntos
Hidroxiureia/uso terapêutico , Inibidores da Síntese de Ácido Nucleico/uso terapêutico , Inibidores da Agregação Plaquetária/uso terapêutico , Quinazolinas/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Estudos Retrospectivos , Método Simples-Cego , Trombocitemia Essencial/patologia , Organização Mundial da Saúde , Adulto Jovem
10.
Am J Hematol ; 90(10): 904-9, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26149802

RESUMO

The importance of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for survival outcomes in patients with acute myeloid leukemia (AML) currently remains unclear. The study aimed to compare measures of clinical treatment for patients with AML in CR1 (the first complete remission) with or without being subjected to allo-HSCT. These consisted of leukemia-free survival (LFS), overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality disease (NRM). Subjects were 622 patients, median age of 44, forming part of the prospective, randomized, and multicenter clinical Polish Adult Leukemia Group trials during 1999-2008. The Mantel-Byar approach was used to assess allo-HSCT on survival endpoints, accounting for a changing transplant status. Undergoing allo-HSCT significantly improved the LFS and OS for the entire group of patients with AML in CR1, along with the DAC induction subgroup and for the group with unfavorable cytogenetics aged 41-60. The CIR demonstrated that allo-HSCT reduced the risk of relapse for patients with AML in CR1 and those with an unfavorable cytogenetic risk. In addition, the NRM analysis showed that allo-HSCT significantly reduced the risk of death unrelated to relapse for the entire group of AML patients in CR1 and aged 41-60. The allo-HSCT treatment particularly benefitted survival for the AML in CR1 group having an unfavorable cytogenetic prognosis.


Assuntos
Aberrações Cromossômicas , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Adolescente , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Polônia/epidemiologia , Estudos Retrospectivos , Taxa de Sobrevida
12.
Cryobiology ; 67(3): 327-31, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24125911

RESUMO

Our previous in vitro studies proved a higher clonogenic potential of peripheral blood progenitor cells cryopreserved in 7.5% dimethyl sulfoxide (Me2SO) than in 10% Me2SO containing medium. Based on this findings 7.5% Me2SO cryopreservation medium was introduced to our protocol and both the hematopoietic recovery and infusion-related toxicity were compared with that obtained with standard 10% Me2SO containing solution. Two cohorts of consecutive patients treated with autologous hematopoietic stem cell transplantation were included in the analysis: 56 patients with PBPCs cryopreserved in 7.5% Me2SO solution and 52 patients who obtained cells cryopreserved in 10% Me2SO. Both study groups did not differ significantly with regard to age, diagnosis, and the number of transplanted CD34(+) cells. The time to leukocyte recovery was shorter for patients in the 7.5% Me2SO treated group than in the 10% one. Reconstitution of platelets and the frequency of adverse events did not differ in both groups. Reduction of Me2SO concentration from 10% to 7.5% in cryoprotective mixture has a beneficial impact on leukocyte recovery. These findings require verification in a prospective, randomized trial.


Assuntos
Criopreservação/métodos , Crioprotetores/metabolismo , Dimetil Sulfóxido/metabolismo , Hematopoese , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/citologia , Adulto , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , Adulto Jovem
13.
Cancers (Basel) ; 15(22)2023 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-38001691

RESUMO

Adult acute lymphoblastic leukemia (ALL) is associated with poor outcomes. ALL is initiated by primary aberrations, but secondary genetic lesions are necessary for overt ALL. In this study, we reassessed the value of primary and secondary aberrations in intensively treated ALL patients in relation to mutator enzyme expression. RT-PCR, genomic PCR, and sequencing were applied to evaluate primary aberrations, while qPCR was used to measure the expression of RAG and AID mutator enzymes in 166 adult ALL patients. Secondary copy number alterations (CNA) were studied in 94 cases by MLPA assay. Primary aberrations alone stratified 30% of the patients (27% high-risk, 3% low-risk cases). The remaining 70% intermediate-risk patients included BCR::ABL1pos subgroup and ALL lacking identified genetic markers (NEG ALL). We identified three CNA profiles: high-risk bad-CNA (CNAhigh/IKZF1pos), low-risk good-CNA (all other CNAs), and intermediate-risk CNAneg. Furthermore, based on RAG/AID expression, we report possible mechanisms underlying the CNA profiles associated with poor outcome: AID stratified outcome in CNAneg, which accompanied most likely a particular profile of single nucleotide variations, while RAG in CNApos increased the odds for CNAhigh/IKZF1pos development. Finally, we integrated primary genetic aberrations with CNA to propose a revised risk stratification code, which allowed us to stratify 75% of BCR::ABL1pos and NEG patients.

14.
Blood ; 116(1): 122-8, 2010 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-20395416

RESUMO

Human Development Index (HDI) is used by the United Nations Organization to measure socioeconomic achievements of countries. We evaluated the association of HDI with rates and outcomes of hematopoietic stem cell transplantation (HSCT) for patients with acute leukemia. For the analysis of HSCT rates, all adults with acute leukemia (n = 16 403) treated in 30 European countries, between 2001 and 2005, were included. Association of HDI with the outcome was analyzed for 2015 patients with acute myeloid leukemia treated with myeloablative allotransplantation. Countries were classified according to HDI quintiles. Highly significant correlation was found for HDI and the total number of HSCT per population (R = 0.78; P < .001), as well as separately for sibling HSCT (R = 0.84; P < .001), unrelated HSCT (R = 0.66; P < .001), and autologous HSCT (R = 0.43; P = .02). The probabilities of leukemia-free survival for 5 consecutive groups of countries with increasing HDI were: 56%, 59%, 63%, 58%, and 68% (P = .01). In a multivariate analysis, transplantations performed in countries belonging to the upper HDI category were associated with higher leukemia-free survival compared with the remaining ones (HR = 1.36, P = .008), which resulted mainly from reduced risk of relapse (HR = 0.72, P = .04). We conclude that, in Europe, the HDI is associated with both rates and results of HSCT for acute leukemia.


Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/cirurgia , Avaliação de Resultados em Cuidados de Saúde/estatística & dados numéricos , Doença Aguda , Adolescente , Adulto , Idoso , Escolaridade , Humanos , Estimativa de Kaplan-Meier , Leucemia/classificação , Longevidade , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde/métodos , Estudos Retrospectivos , Classe Social , Fatores Socioeconômicos , Transplante Autólogo , Transplante Homólogo , Transplante Isogênico , Adulto Jovem
15.
Haematologica ; 96(9): 1344-50, 2011 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-21659356

RESUMO

BACKGROUND: An alternative reduced-toxicity conditioning regimen for allogeneic transplantation, based on treosulfan and fludarabine, has recently been identified. The rationale for this study was to investigate the efficacy and safety of this regimen prospectively in patients with a primary myelodysplastic syndrome. DESIGN AND METHODS: A total of 45 patients with primary myelodysplastic syndromes were conditioned with 3×14 g/m(2) treosulfan and 5×30 mg/m(2) fludarabine followed by allogeneic hematopoietic stem cell transplantation. Subtypes of myelodysplastic syndromes were refractory anemia with excess blasts-2 (44%), refractory cytopenia with multilineage dysplasia (27%), refractory anemia (9%), refractory anemia with ringed sideroblasts (4%), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (4%), refractory anemia with excess blasts-1 (2%), and myelodysplastic syndrome with isolated del (5q) (2%). The myelodysplastic syndrome was unclassified in 7% of the patients. Forty-seven percent of the patients had a favorable karyotype, 29% an unfavorable one, and 18% an intermediate karyotype. Patients were evaluated for engraftment, adverse events, graft-versus-host disease, non-relapse mortality, relapse incidence, overall survival and disease-free survival. RESULTS: All but one patient showed primary engraftment of neutrophils after a median of 17 days. Non-hematologic adverse events of grade III-IV in severity included mainly infections and gastrointestinal symptoms (80% and 22% of the patients, respectively). Acute graft-versus-host disease grade II-IV developed in 24%, and extensive chronic graft-versus-host disease in 28% of the patients. After a median follow-up of 780 days, the 2-year overall and disease-free survival estimates were 71% and 67%, respectively. The 2-year cumulative incidences of non-relapse mortality and relapse were 17% and 16%, respectively. CONCLUSIONS: Our safety and efficacy data suggest that treosulfan-based conditioning therapy is a promising treatment option for patients with myelodysplastic syndromes. clinicaltrials.gov identifier: NCT01062490.


Assuntos
Antineoplásicos/uso terapêutico , Bussulfano/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante , Vidarabina/análogos & derivados , Adulto , Antineoplásicos/efeitos adversos , Bussulfano/efeitos adversos , Bussulfano/uso terapêutico , Quimerismo , Feminino , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Recidiva , Transplante Homólogo , Resultado do Tratamento , Vidarabina/efeitos adversos , Vidarabina/uso terapêutico , Adulto Jovem
16.
Am J Hematol ; 86(5): 437-9, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21465518

RESUMO

The aim of this study was to prospectively evaluate the impact of early bone marrow response on complete remission (CR) rate and long-term outcome in adults with acute myeloid leukemia. Bone marrow cytology was assessed on day 6 of induction treatment in 164 patients, revealing the presence of ≥5% blasts in 61 cases. In this subgroup the CR rate was significantly lower compared to the remaining patients (P < 0.00001) resulting in decrease of the overall survival (P = 0.002). Persistence of ≥5% blasts in bone marrow on day 6 of induction is an easily available surrogate marker to be used for treatment decisions.


Assuntos
Antineoplásicos/uso terapêutico , Células da Medula Óssea/efeitos dos fármacos , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Adolescente , Adulto , Biomarcadores , Células da Medula Óssea/patologia , Contagem de Células , Estudos de Coortes , Humanos , Leucemia Mieloide Aguda/diagnóstico , Pessoa de Meia-Idade , Polônia , Prognóstico , Indução de Remissão , Análise de Sobrevida , Fatores de Tempo , Adulto Jovem
17.
Bone Marrow Transplant ; 56(6): 1297-1304, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33339899

RESUMO

The goal of this phase II trial was to evaluate safety and efficacy of a tandem autologous hematopoietic cell transplantation (auto-HCT) using sequentially total marrow irradiation (TMI) at the dose of 12 Gy (4 Gy on days -3, -2, and -1) and melphalan 200 mg/m2 for patients with multiple myeloma (MM). TMI was performed using helical tomotherapy. Additional "boosts" (total 24 Gy) were applied for patients with active lesions as revealed by PET-FDG. Fifty patients with median age 58 years (41-64 years) were included and received tandem auto-HCT. TMI resulted in absolute neutropenia in all patients. Grade 3 infections were reported in 30% patients. Other toxicities were rare. Proportion of patients who achieved at least very good partial response increased from 46% before the first auto-HCT to 82% after tandem transplantation. Complete remission rates changed from 10% to 42%, respectively. The probabilities of overall and progression-free survival at 5 years were 74% and 55%, respectively. No patient died without progression. We conclude that conditioning with TMI ± PET-guided "boosts" represents personalized treatment approach in MM and is characterized by very good toxicity profile. Tandem auto-HCT using TMI in sequence with high-dose melphalan appears safe with encouraging early efficacy.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo , Adulto , Medula Óssea , Humanos , Melfalan , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Condicionamento Pré-Transplante , Transplante Autólogo , Resultado do Tratamento
18.
Sci Rep ; 11(1): 10017, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976256

RESUMO

Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) genes occur in about 20% patients with acute myeloid leukemia (AML), leading to DNA hypermethylation and epigenetic deregulation. We assessed the prognostic significance of IDH1/2 mutations (IDH1/2+) in 398 AML patients with normal karyotype (NK-AML), treated with daunorubicine + cytarabine (DA), DA + cladribine (DAC), or DA + fludarabine. IDH2 mutation was an independent favorable prognostic factor for 4-year overall survival (OS) in total NK-AML population (p = 0.03, censoring at allotransplant). We next evaluated the effect of addition of cladribine to induction regimen on the patients' outcome according to IDH1/2 mutation status. In DAC group, 4-year OS was increased in IDH2+ patients, compared to IDH-wild type group (54% vs 33%; p = 0.0087, censoring at allotransplant), while no difference was observed for DA-treated subjects. In multivariate analysis, DAC independently improved the survival of IDH2+ patients (HR = 0.6 [0.37-0.93]; p = 0.024; censored at transplant), indicating that this group specifically benefits from cladribine-containing therapy. In AML cells with R140Q or R172K IDH2 mutations, cladribine restrained mutations-related DNA hypermethylation. Altogether, DAC regimen produces better outcomes in IDH2+ NK-AML patients than DA, and this likely results from the hypomethylating activity of cladribine. Our observations warrant further investigations of induction protocols combining cladribine with IDH1/2 inhibitors in IDH2-mutant.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Isocitrato Desidrogenase/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Cladribina/uso terapêutico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Pessoa de Meia-Idade , Variantes Farmacogenômicos , Polônia/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Adulto Jovem
19.
Br J Haematol ; 150(1): 58-71, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20408846

RESUMO

The purpose of this phase 1-2 study was to investigate the association between the pharmacokinetic properties of ofatumumab, a human monoclonal CD20 antibody, and outcomes in 33 patients with relapsed/refractory chronic lymphocytic leukaemia receiving 4 weekly infusions of ofatumumab. The ofatumumab concentration profiles were fitted well by a two-compartment model with different elimination rate constant at first infusion compared to the remaining infusions in line with the observed rapid and sustained B-cell depletion. Exposure to ofatumumab was linked to clinical outcomes: high exposure was associated with higher probability of overall clinical response and longer progression-free survival. This association still remained statistically significant even when adjusting for relevant baseline covariates including tumour burden.


Assuntos
Anticorpos Monoclonais/sangue , Antineoplásicos/sangue , Leucemia Linfocítica Crônica de Células B/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Antígenos CD20/imunologia , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Humanos , Infusões Intravenosas , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Recidiva , Análise de Sobrevida , Resultado do Tratamento
20.
N Engl J Med ; 356(4): 348-59, 2007 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-17251531

RESUMO

BACKGROUND: Patients with neutropenia resulting from chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome are at high risk for difficult-to-treat and often fatal invasive fungal infections. METHODS: In this randomized, multicenter study involving evaluators who were unaware of treatment assignments, we compared the efficacy and safety of posaconazole with those of fluconazole or itraconazole as prophylaxis for patients with prolonged neutropenia. Patients received prophylaxis with each cycle of chemotherapy until recovery from neutropenia and complete remission, until occurrence of an invasive fungal infection, or for up to 12 weeks, whichever came first. We compared the incidence of proven or probable invasive fungal infections during treatment (the primary end point) between the posaconazole and fluconazole or itraconazole groups; death from any cause and time to death were secondary end points. RESULTS: A total of 304 patients were randomly assigned to receive posaconazole, and 298 patients were randomly assigned to receive fluconazole (240) or itraconazole (58). Proven or probable invasive fungal infections were reported in 7 patients (2%) in the posaconazole group and 25 patients (8%) in the fluconazole or itraconazole group (absolute reduction in the posaconazole group, -6%; 95% confidence interval, -9.7 to -2.5%; P<0.001), fulfilling statistical criteria for superiority. Significantly fewer patients in the posaconazole group had invasive aspergillosis (2 [1%] vs. 20 [7%], P<0.001). Survival was significantly longer among recipients of posaconazole than among recipients of fluconazole or itraconazole (P=0.04). Serious adverse events possibly or probably related to treatment were reported by 19 patients (6%) in the posaconazole group and 6 patients (2%) in the fluconazole or itraconazole group (P=0.01). The most common treatment-related adverse events in both groups were gastrointestinal tract disturbances. CONCLUSIONS: In patients undergoing chemotherapy for acute myelogenous leukemia or the myelodysplastic syndrome, posaconazole prevented invasive fungal infections more effectively than did either fluconazole or itraconazole and improved overall survival. There were more serious adverse events possibly or probably related to treatment in the posaconazole group. (ClinicalTrials.gov number, NCT00044486 [ClinicalTrials.gov].).


Assuntos
Antifúngicos/uso terapêutico , Fluconazol/uso terapêutico , Itraconazol/uso terapêutico , Micoses/prevenção & controle , Neutropenia/tratamento farmacológico , Infecções Oportunistas/prevenção & controle , Triazóis/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antifúngicos/efeitos adversos , Antineoplásicos/efeitos adversos , Feminino , Fluconazol/efeitos adversos , Humanos , Itraconazol/efeitos adversos , Estimativa de Kaplan-Meier , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Micoses/mortalidade , Síndromes Mielodisplásicas/complicações , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/mortalidade , Neutropenia/induzido quimicamente , Neutropenia/mortalidade , Método Simples-Cego , Resultado do Tratamento , Triazóis/efeitos adversos
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