RESUMO
Natural killer (NK) cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T-cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T-cell numbers in patients treated with IL-15/N-803, compared with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T-cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15. This trial was registered at www.clinicaltrials.gov as #NCT03050216 and #NCT01898793.
Assuntos
Antineoplásicos/administração & dosagem , Linfócitos T CD8-Positivos/imunologia , Transplante de Células-Tronco Hematopoéticas , Imunoterapia Adotiva , Interleucina-15/administração & dosagem , Células Matadoras Naturais/transplante , Leucemia Mieloide Aguda , Proteínas Recombinantes de Fusão/administração & dosagem , Células Alógenas/imunologia , Feminino , Humanos , Interleucina-15/imunologia , Células Matadoras Naturais/imunologia , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/terapia , MasculinoRESUMO
For patients with relapsed or refractory classical Hodgkin lymphoma (cHL), salvage chemotherapy followed by consolidation with autologous stem cell transplant (ASCT) remains the standard of care. Even with this aggressive treatment strategy, 5-year progression-free survival is ≤50%, and there remains interest in maintenance strategies to improve long-term disease-free survival. Lenalidomide is an immunomodulatory agent with demonstrated activity in multiple subtypes of lymphoma including cHL, and has also been shown to improve both progression-free and overall survival as maintenance therapy after ASCT in multiple myeloma. This multicenter study evaluated maintenance lenalidomide after ASCT for patients with cHL. Patients were enrolled 60 to 90 days post-transplant and received oral lenalidomide on days 1 to 28 of 28-day cycles for a maximum of 18 cycles. Lenalidomide was started at 15 mg daily and increased to maximum of 25 mg daily if tolerated. The primary objective of this study was to assess the feasibility of this regimen, with a goal <30% rate of discontinuation at or before cycle 12 for drug-related reasons. Twenty-seven patients were enrolled and 26 received at least 1 dose of lenalidomide. With a median follow-up of 51.3 months (range, 12.2 to 76.2 months), 23 of 26 patients were alive. Median event-free survival was 9.4 months and median progression-free survival had not been reached, with 17 of 26 patients (65.4%) remaining in remission at last follow-up. Excluding 4 patients who discontinued therapy for progression and 2 who discontinued due to noncompliance, the discontinuation rate at or before cycle 12 was 52%. Treatment was complicated by a high frequency of hematologic adverse events, with 15 patients (58%) experiencing grade 3 to 4 hematologic toxicity and 5 (19%) experiencing grade 4 hematologic toxicity. We conclude that the regimen of maintenance lenalidomide explored in this study is not feasible for patients with cHL immediately following ASCT. An alternative lenalidomide dose or schedule may be better tolerated following ASCT for patients with relapsed or refractory cHL.
Assuntos
Doença de Hodgkin , Mieloma Múltiplo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Intervalo Livre de Doença , Doença de Hodgkin/tratamento farmacológico , Humanos , Lenalidomida/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Projetos Piloto , Transplante Autólogo , Resultado do TratamentoRESUMO
BACKGROUND: The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS: We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS: Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS: Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/análogos & derivados , Medula Óssea/patologia , Leucemia Mieloide Aguda/tratamento farmacológico , Mutação , Síndromes Mielodisplásicas/tratamento farmacológico , Proteína Supressora de Tumor p53/genética , 5-Metilcitosina/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/administração & dosagem , Azacitidina/efeitos adversos , Biomarcadores Tumorais/análise , Medula Óssea/química , Decitabina , Exoma , Feminino , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/mortalidade , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
A single subcutaneous (SC) injection of plerixafor results in rapid mobilization of hematopoietic progenitors, but fails to mobilize 33% of normal allogeneic sibling donors in 1 apheresis. We hypothesized that changing the route of administration of plerixafor from SC to IV may overcome the low stem cell yields and allow collection in 1 day. A phase 1 trial followed by a phase 2 efficacy trial was conducted in allogeneic sibling donors. The optimal dose of IV plerixafor was determined to be 0.32 mg/kg. The primary outcome of reducing the failure to collect ≥2 × 106 CD34+/kg recipient weight in 1 apheresis collection to ≤10% was not reached. The failure rate was 34%. Studies evaluating the stem cell phenotype and gene expression revealed a novel plasmacytoid dendritic cell precursor preferentially mobilized by plerixafor with high interferon-α producing ability. The observed cytomegalovirus (CMV) viremia rate for patients at risk was low (15%), as were the rates of acute grade 2-4 graft-versus-host disease (GVHD) (21%). Day 100 treatment related mortality was low (3%). In conclusion, plerixafor results in rapid stem cell mobilization regardless of route of administration and resulted in novel cellular composition of the graft and favorable recipient outcomes. These trials were registered at clinicaltrials.gov as #NCT00241358 and #NCT00914849.
Assuntos
Mobilização de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/farmacologia , Células-Tronco de Sangue Periférico/efeitos dos fármacos , Administração Intravenosa , Adulto , Idoso , Antígenos CD34/análise , Benzilaminas , Remoção de Componentes Sanguíneos , Ciclamos , Feminino , Doença Enxerto-Hospedeiro/etiologia , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/farmacologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Compostos Heterocíclicos/administração & dosagem , Compostos Heterocíclicos/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Células-Tronco de Sangue Periférico/citologia , Doadores de Tecidos , Transcriptoma/efeitos dos fármacos , Transplante Homólogo/efeitos adversos , Transplante Homólogo/métodosRESUMO
PURPOSE: Recombinant granulocyte colony-stimulating factors (rG-CSFs), such as filgrastim, are administered to prevent complications in patients receiving chemotherapy. In Europe, a biosimilar to filgrastim, tevagrastim/ratiograstim/biograstim, was approved in 2008. In the USA, the same product was approved as tbo-filgrastim under a 351(a) biologic license application in 2012 with the brand name Granix®. Postmarket surveillance remains a priority for monitoring the safety of biologics and biosimilars to identify rare and immunogenicity-related events. We report the global and US pharmacovigilance data for tevagrastim/ratiograstim/biograstim and tbo-filgrastim, respectively. METHODS: Cumulative exposure and adverse event data from initial approval in Europe to December 31, 2016, were collected globally from spontaneous reports submitted by healthcare professionals and consumers, scientific literature, competent authorities, and solicited case reports from non-interventional studies. A separate search was conducted on the global data set to identify reports originating from the USA and Puerto Rico to describe the US experience. RESULTS: Overall, the global safety profile of tevagrastim/ratiograstim/biograstim in the postmarket, real-world setting was comparable to clinical trial experience. Postmarket safety experience of tbo-filgrastim in the USA was consistent with global data. The most common SAEs were febrile neutropenia and decreased white blood cell count. The most common non-serious event was bone pain. There was no evidence of immunogenicity. CONCLUSIONS: This pharmacovigilance analysis indicates that postmarket experience of tevagrastim/ratiograstim/biograstim and tbo-filgrastim is consistent with clinical trials. Adverse reactions associated with the originator rG-CSF (capillary leak syndrome and glomerulonephritis) have not been observed with tevagrastim/ratiograstim/biograstim or tbo-filgrastim during the postmarket period.
Assuntos
Medicamentos Biossimilares/administração & dosagem , Medicamentos Biossimilares/efeitos adversos , Fator Estimulador de Colônias de Granulócitos/administração & dosagem , Fator Estimulador de Colônias de Granulócitos/efeitos adversos , Europa (Continente) , Filgrastim/administração & dosagem , Filgrastim/efeitos adversos , Humanos , Vigilância de Produtos Comercializados , Porto Rico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/efeitos adversosRESUMO
Chronic myeloid leukemia (CML) is defined by the presence of Philadelphia chromosome (Ph), resulting from a reciprocal translocation between chromosomes 9 and 22 [t(9;22] that gives rise to a BCR-ABL1 fusion gene. CML occurs in 3 different phases (chronic, accelerated, and blast phase) and is usually diagnosed in the chronic phase. Tyrosine kinase inhibitor (TKI) therapy is a highly effective first-line treatment option for all patients with newly diagnosed chronic phase CML (CP-CML). The selection TKI therapy should be based on the risk score, toxicity profile of TKI, patient's age, ability to tolerate therapy, and the presence of comorbid conditions. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CP-CML.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Oncologia/normas , Inibidores de Proteínas Quinases/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/isolamento & purificação , Medula Óssea/patologia , Ensaios Clínicos como Assunto , Progressão da Doença , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/genética , Proteínas de Fusão bcr-abl/isolamento & purificação , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/diagnóstico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Oncologia/métodos , Seleção de Pacientes , Cromossomo Filadélfia , Prognóstico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/normas , Reação em Cadeia da Polimerase em Tempo Real/normas , Medição de Risco/métodos , Medição de Risco/normas , Sociedades Médicas/normas , Estados UnidosRESUMO
CD34+-selected stem cell boost (SCB) without conditioning has recently been utilized for poor graft function (PGF) after allogeneic hematopoietic stem cell transplantation with promising results. Unfortunately, many patients have been unable to receive the boost infusion as their donors were unwilling or unable to undergo an additional stem cell collection. Therefore, we conducted this study utilizing either fresh or cryopreserved peripheral blood stem cell products to create CD34+-selected boost infusions for the treatment of PGF. Additionally, to explore relationship of CD34+ dose and response, we included a cohort of donors mobilized with plerixafor in addition to the standard granulocyte colony-stimulating factor (G-CSF). Twenty-six patients with PGF were included in this study. Seventeen donor-recipient pairs were enrolled onto the prospective study; an additional 9 patients treated off protocol were reviewed retrospectively. Three different donor products were used for CD34+ selection: (1) fresh mobilized product using G-CSF only, (2) fresh mobilized products using G-CSF and plerixafor, and (3) cryopreserved cells mobilized with G-CSF. CD34+ cell selection was performed using a CliniMACS. The infusion was not preceded by administration of any chemotherapy or conditioning regimen. The primary objective was hematologic response rate and secondary objectives included CD34+ yields, incidence and severity of acute and chronic graft-versus-host disease (GVHD), overall survival (OS), and relapse-free survival (RFS). The median post-selection CD34+ counts per kilogram of recipient weight were 3.1 × 106, 10.9 × 106, and 1 × 106 for G-CSF only, G-CSF plus plerixafor, and cryopreserved products, respectively. The median CD34+ yields (defined as the number of CD34+ cells after selection/CD34+ cells before CD34+ selection) were 69%, 66%, and 28% for G-CSF only, G-CSF plus plerixafor, and cryopreserved products, respectively. After SCB, 16 of the 26 recipients (62%) had a complete response, including 5 of 8 (63%) who received cryopreserved products. Five had a partial response (19%), resulting in an overall response rate of 81%. One-year RFS and OS were 50% and 65%, respectively. There was no treatment-related toxicity reported other than GVHD: 6 (23%) developed acute GVHD (2 grade I and 4 grade II) and 8 (31%) developed chronic GVHD (2 limited and 6 extensive). Cryopreserved products are viable alternatives to create SCB for the treatment of PGF. When collecting fresh products is an option, the addition of plerixafor increases CD34+ yield over G-CSF alone; however, it is currently unclear if the CD34+ cell dose impacts the efficacy of the SCB.
Assuntos
Antígenos CD34/metabolismo , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco/metabolismo , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long.
Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Leucemia Mieloide Aguda/mortalidade , Linfócitos T/citologia , Doadores de Tecidos/provisão & distribuição , Transplante Haploidêntico/mortalidade , Adulto , Fatores Etários , Idoso , Ciclofosfamida/uso terapêutico , Feminino , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/normas , Histocompatibilidade , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Análise de Sobrevida , Transplante Haploidêntico/métodos , Transplante Haploidêntico/normas , Resultado do Tratamento , Adulto JovemRESUMO
Autologous hematopoietic stem cell transplantation (auto-HSCT) improves survival in patients with multiple myeloma (MM) and non-Hodgkin lymphoma (NHL). Traditionally, filgrastim (Neupogen; recombinant G-CSF) has been used in as a single agent or in combination with plerixafor for stem cell mobilization for auto-HSCT. In Europe, a biosimilar recombinant G-CSF (Tevagrastim) has been approved for various indications similar to those of reference filgrastim, including stem cell mobilization for auto-HSCT; however, in the United States, tbo-filgrastim (Granix) is registered under the original biological application and is not approved for stem cell mobilization. In retrospective studies, stem cell mobilization with tbo-filgrastim has shown similar efficacy and toxicity as filgrastim, but no prospective studies have been published to date. We have conducted the first prospective randomized trial comparing the safety and efficacy of tbo-filgrastim in combination with plerixafor with that of filgrastim in combination with plerixafor for stem cell mobilization in patients with MM and NHL. This is a phase 2 prospective randomized (1:1) open-label single-institution noninferiority study of tbo-filgrastim and filgrastim with plerixafor in patients with MM or NHL undergoing auto-HSCT. Here 10 µg/kg/day of tbo-filgrastim/filgrastim was administered s.c. for 5 days (days 1 to 5). On day 4 at approximately 1800 hours, 0.24 mg/kg of plerixafor was administered s.c. Apheresis was performed on day 5 with a target cumulative collection goal of at least 5.0 × 106 CD34+ cells/kg. The primary objective was to compare day 5 CD34+ cells/kg collected. Secondary objectives included other mobilization endpoints, safety, engraftment outcomes, and hospital readmission rate. A total of 97 evaluable patients were enrolled (tbo-filgrastim, n = 46; filgrastim, n = 51). Tbo-filgrastim was not inferior to filgrastim in terms of day 5 CD34+ cell collection (mean, 11.6 ± 6.7 CD34+ cells/kg versus 10.0 ± 6.8 CD34+ cells/kg. Multivariate analysis revealed a trend toward increased mobilization in the tbo-filgrastim arm, but this was not statistically significant. The tbo-filgrastim and filgrastim arms were similar in all secondary endpoints. Tbo-filgrastim is not inferior in efficacy and has similar safety compared to reference filgrastim when used for stem cell mobilization in patients with MM and NHL. Granix can be safely used instead of Neupogen for stem cell collection in patients undergoing auto-HSCT for MM or NHL. The study is registered at https://clinicaltrials.gov/ct2/show/NCT02098109.
Assuntos
Filgrastim/administração & dosagem , Mobilização de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/administração & dosagem , Linfoma não Hodgkin/terapia , Mieloma Múltiplo/terapia , Idoso , Antígenos CD34/análise , Benzilaminas , Ciclamos , Quimioterapia Combinada , Feminino , Filgrastim/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Compostos Heterocíclicos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Transplante Autólogo , Resultado do TratamentoRESUMO
Cell-of-origin determination has emerged as an important prognostic factor for patients initially diagnosed with diffuse large B cell lymphoma (DLBCL). Specifically, the nongerminal center B cell-like (non-GCB) subtype, composed predominantly of the activated B cell-like (ABC) molecular subtype, has been shown to portend poor prognosis because of its more aggressive nature and resistance to standard cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (CHOP)-like chemotherapy compared with the GCB subtype. The recurrent MyD88 L265P mutation, present in 29% of ABC DLBCL, was reported as an independent poor prognostic factor for patients with newly diagnosed DLBCL. For patients whose disease relapses or is refractory to first-line chemotherapy, high-dose chemotherapy with autologous stem cell transplantation (ASCT) is frequently offered as salvage therapy. However, the impact of MyD88 mutation status on post-ASCT outcome has not been reported. Here, we retrospectively analyzed, with up to 20 years of follow-up, 165 patients who underwent ASCT for relapsed/refractory DLBCL at our institution. We found that MyD88 mutation status did not correlate with overall survival (OS), post-ASCT OS, or progression-free survival (PFS). Patients with non-GCB subtype had significantly worse OS from initial diagnosis and after ASCT. Notably, high International Prognostic Index score was predictive of poor pre- and post-transplant PFS and post-transplant OS.
Assuntos
Linfoma Difuso de Grandes Células B/genética , Fator 88 de Diferenciação Mieloide/genética , Transplante de Células-Tronco/métodos , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Mutação , Prognóstico , Terapia de Salvação , Análise de Sobrevida , Transplante Autólogo , Adulto JovemAssuntos
Antineoplásicos , Leucemia Mieloide Aguda , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Decitabina/uso terapêutico , Humanos , Quimioterapia de Indução , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Indução de Remissão , Terapia de Salvação , Resultado do Tratamento , Proteína Supressora de Tumor p53/genéticaRESUMO
Acute myeloid leukemia (AML) is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths due to leukemias in the United States. This portion of the NCCN Guidelines for AML focuses on management and provides recommendations on the workup, diagnostic evaluation, and treatment options for younger (age <60 years) and older (age ≥60 years) adult patients.
Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/terapia , Fatores Etários , Gerenciamento Clínico , HumanosRESUMO
Conditioning-related gut toxicity can result in a protein-losing enteropathy manifesting as a decline in serum albumin in the peritransplant period. Inspired by the pathogenesis of acute graft-versus-host disease (aGVHD), we hypothesized that the magnitude of decline in serum albumin from the day of conditioning initiation until its nadir in the first 2 weeks after hematopoietic cell transplantation HCT (DeltaAlb) predicts the risk for subsequent severe aGVHD. We reviewed the medical records of all 88 patients with acute myeloid leukemia or myelodysplastic syndrome who underwent highly mucotoxic myeloablative (busulfan/cyclophosphamide or cyclophosphamide/total body irradiation) allogeneic HCT from a matched related donor (MRD) or matched unrelated donor (MUD) at our institution between January 1, 2012 and January 1, 2015. Severe aGVHD was associated with MUD (47% versus 14% with MRD; P = .001) and DeltaAlb, which was significantly greater among patients who developed versus did not develop severe aGVHD (1.2 ± .5 versus .8 ± .4 g/dL, respectively; P < .001). In multivariate analysis DeltaAlb remained a significant predictor of severe aGVHD (odds ratio, 5.68; 95% CI, 1.65 to 19.64; P = .006; area under the ROC curve, .74; 95% CI, .63 to .86; P < .001). The best cutoff for DeltaAlb to predict severe aGVHD was .9, with a sensitivity, specificity, and overall classification accuracy of 77%, 66%, and 69%, respectively. The model was validated using the bootstrap technique, with no significant change in its performance. These results were not generalizable to a cohort of 30 patients who received less mucotoxic myeloablative or reduced-intensity conditioning. In conclusion, with mucotoxic myeloablative HCT, each .1-g/dL increase in DeltaAlb was associated with an approximately 23% increase in the odds of developing severe aGVHD. As an early biomarker of gut damage, DeltaAlb can be incorporated in composite risk models for aGVHD prediction, with hopes for ultimately allowing for individualized GVHD prophylaxis and potential intervention according to the predicted risk.
Assuntos
Doença Enxerto-Hospedeiro/diagnóstico , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Albumina Sérica/análise , Condicionamento Pré-Transplante/efeitos adversos , Doença Aguda , Adulto , Idoso , 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/complicações , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Agonistas Mieloablativos/uso terapêutico , Agonistas Mieloablativos/toxicidade , Síndromes Mielodisplásicas/complicações , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Condicionamento Pré-Transplante/métodos , Transplante Homólogo , Adulto JovemRESUMO
Allogeneic stem cell transplantation (allo-SCT) is a potentially curative treatment for high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). For patients with relapsed disease after transplantation, intensive chemotherapy followed by donor lymphocyte infusion (DLI) or a second allo-SCT may result in a durable response in some patients. High-intensity chemotherapy and less aggressive therapy with hypomethylating agents (HAs) with and without DLI are often used for relapse after allo-SCT. Here we compared the treatment outcomes of intensive chemotherapy with that of HAs in relapsed AML and MDS after allo-SCT. Patients who had received a second SCT within 90 days of the relapse date were excluded. The primary endpoints were overall response rate (ORR) and overall survival (OS). Secondary endpoints were complete remission (CR) rate and progression-free survival (PFS). One hundred patients were included: 73 patients received chemotherapy and 27 patients received an HA. Fifty-six percent of patients in the chemotherapy group and 33% of patients in the HA group received at least 1 DLI after treatment. Treatment with chemotherapy resulted in a higher ORR (51% versus 19%, P = .004) and a higher CR rate (40% versus 7%, P = .002). The median OS (6 versus 3.9 months, P = .01) and PFS (4.9 versus 3.8 months, P = .02) were longer in the chemotherapy group. Similar benefit of chemotherapy over HAs was maintained in all treatment outcomes after controlling for the use of DLI. The use of chemotherapy followed by DLI offered the greatest benefit (ORR, 68%; CR, 59%, 1-year OS, 44%; and median OS, 9.8 months). In conclusion, in our hands, with limited numbers, the use of more conventional salvage chemotherapy, with DLI when possible, for the treatment of relapsed AML and MDS after allo-SCT is associated with better outcomes than nonchemotherapy (HA) options.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Transfusão de Linfócitos/métodos , Síndromes Mielodisplásicas/terapia , Terapia de Salvação/métodos , Adolescente , Adulto , Idoso , Antineoplásicos/uso terapêutico , Feminino , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/tratamento farmacológico , Recidiva , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
Use of high-dose post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis has expanded the use of unmanipulated haploidentical hematopoietic cell transplantation. The immediate post-transplantation course in T cell-replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling cytokine-release syndrome (CRS), previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received granulocyte colony-stimulating factor-mobilized T cell-replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T cell therapies, we found 65 of 75 (87%) met criteria for CRS, although most cases were only mild (grades 1 or 2). However, 9 patients (12%) experienced severe (grades 3 or 4) CRS. Median survival was 2.6 months (95% confidence interval [CI], .43 to 5.8) in patients with severe CRS, compared with 13.1 months (95% CI, 8.1 to not reached) in patients with mild CRS. Transplantation-related mortality was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI, 1.43 to 14.67) compared with that in the mild CRS cohort. Severe CRS patients had a significant delay in median time for neutrophil engraftment. Serum IL-6 levels were measured in 10 haplo-HCT patients and were elevated in the early post-transplantation setting. Seven patients with CRS were treated with tocilizumab, resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT and is associated with worse outcomes. Anti-IL-6 receptor therapy is associated with rapid resolution of the CRS symptoms.
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Citocinas/metabolismo , Depleção Linfocítica/métodos , Transplante de Células-Tronco de Sangue Periférico/efeitos adversos , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante Haploidêntico/efeitos adversos , Transplante Haploidêntico/métodos , Adulto , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Feminino , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/sangue , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco de Sangue Periférico/mortalidade , Análise de Sobrevida , Síndrome , Linfócitos T , Transplante Haploidêntico/mortalidade , Adulto JovemRESUMO
Leukostasis is a poorly understood and life-threatening complication of acute hyperleukocytic leukemia. The incidence of hyperleukocytosis and leukostasis differs among various subtypes of leukemias. While the pathophysiology of leukostasis is not fully understood, recent research has elucidated many novel pathways that may have therapeutic implications in the future. Respiratory and neurological compromise represents the classical clinical manifestations of leukostasis. If it is not diagnosed and treated rapidly, the one-week mortality rate is approximately 40%. Targeted induction chemotherapy is an important component of the successful treatment of leukostasis, although other modalities of cytoreduction are being used and investigated. Copyright © 2016 John Wiley & Sons, Ltd.
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Leucemia/terapia , Leucostasia/terapia , Adulto , Feminino , Humanos , MasculinoRESUMO
The NCCN Guidelines for Chronic Myeloid Leukemia (CML) provide recommendations for the management of chronic-phase and advanced-phase CML in adult patients. The median age of disease onset is 67 years. However, because CML occurs in all age groups, clinical care teams should be prepared to address issues relating to fertility and pregnancy with patients who are of reproductive age at the time of diagnosis. CML is relatively rare in children and there are no evidence-based recommendations for the management of CML in pediatric population. These NCCN Guidelines Insights discuss special considerations for the management of CML during pregnancy and for the management of CML in the pediatric population.
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Anormalidades Induzidas por Medicamentos/epidemiologia , Fertilidade/efeitos dos fármacos , Leucemia Mieloide de Fase Crônica/tratamento farmacológico , Complicações Neoplásicas na Gravidez/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Idoso , Criança , Medicina Baseada em Evidências/normas , Feminino , Humanos , Guias de Prática Clínica como Assunto , Gravidez , Prognóstico , Inibidores de Proteínas Quinases/administração & dosagem , Suspensão de TratamentoRESUMO
Decitabine is a hypomethylating agent that irreversibly inhibits DNA methyltransferase I, inducing leukemic differentiation and re-expression of epigenetically silenced putative tumor antigens. We assessed safety and efficacy of decitabine maintenance after allogeneic transplantation for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Decitabine maintenance may help eradicate minimal residual disease, decrease the incidence of graft-versus-host disease (GVHD), and facilitate a graft-versus-leukemia effect by enhancing the effect of T regulatory lymphocytes. Patients with AML/MDS in complete remission (CR) after allotransplantation started decitabine between day +50 and +100. We investigated 4 decitabine doses in cohorts of 4 patients: 5, 7.5, 10, and 15 mg/m(2)/day × 5 days every 6 weeks, for a maximum 8 cycles. The maximum tolerated dose (MTD) was defined as the maximum dose at which ≤ 25% of people experience dose-limiting toxicities during the first cycle of treatment. Twenty-four patients were enrolled and 22 were evaluable. All 4 dose levels were completed and no MTD was reached. Overall, decitabine maintenance was well tolerated. Grade 3 and 4 hematological toxicities were experienced by 75% of patients, including all patients treated at the highest dose level. Nine patients completed all 8 cycles and 8 of them remain in CR. Nine patients died from relapse (n = 4), infectious complications (n = 3), and GVHD (n = 2). Most occurrences of acute GVHD were mild and resolved without interruption of treatment; 1 patient died of acute gut GVHD. Decitabine maintenance did not clearly impact the rate of chronic GVHD. Although there was a trend of increased FOXP3 expression, results were not statistically significant. In conclusion, decitabine maintenance is associated with acceptable toxicities when given in the post-allotransplantation setting. Although the MTD was not reached, the dose of 10 mg/m(2) for 5 days every 6 weeks appeared to be the optimal dose rather than 15 mg/m(2), where most hematological toxicities occurred.
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Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/análogos & derivados , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/tratamento farmacológico , Quimioterapia de Manutenção/métodos , Síndromes Mielodisplásicas/tratamento farmacológico , Adulto , Idoso , Aloenxertos , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/efeitos adversos , Azacitidina/uso terapêutico , Terapia Combinada , Decitabina , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Feminino , Gastroenteropatias/induzido quimicamente , Doença Enxerto-Hospedeiro/etiologia , Doenças Hematológicas/induzido quimicamente , Humanos , Infusões Intravenosas , Leucemia Mieloide Aguda/terapia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Estudos Prospectivos , Adulto JovemRESUMO
Pretransplant remission status in patients with acute myeloid leukemia (AML) is 1 of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) before undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in CR, 45 were in CRp, and 19 were in MLFS before allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival rates (49%, 46%, and 47%, respectively; P = .88) and 3-year event-free survival rates (45%, 36%, and 40%, respectively; P = .53). However, the cumulative incidence of nonrelapse mortality was significantly higher in patients in MLFS compared with those in CR (58% versus 22%, P = .0004), whereas the cumulative incidence of relapse in patients in MLFS was significantly lower compared with those in CR (11% versus 36%, P = .03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery before allo-HCT.