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1.
Artigo em Inglês | MEDLINE | ID: mdl-33039516

RESUMO

The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients age ≤70 years at diagnosis who underwent allo-HCT (n = 119) compared with those who did not (n = 142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower risk (CPSS low/intermediate-1) or higher risk (intermediate-2/high) showed significantly improved outcomes after transplantation in higher-risk patients, with a 37% reduced hazard for death. However, although higher CPSS was associated with worse outcomes in the nontransplantation group, the score was of limited utility for post-transplantation risk stratification. This study may provide further support for the potentially beneficial role of allo-HCT in terms of long-term survival in higher-risk patients but also underscores the need for transplantation-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of patients with CMML. © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

2.
Blood Adv ; 4(20): 5011-5024, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33057635

RESUMO

Somatic TP53 mutations and 17p deletions with genomic loss of TP53 occur in 37% to 46% of acute myeloid leukemia (AML) with adverse-risk cytogenetics and correlate with primary induction failure, high risk of relapse, and dismal prognosis. Herein, we aimed to characterize the immune landscape of TP53-mutated AML and determine whether TP53 abnormalities identify a patient subgroup that may benefit from immunotherapy with flotetuzumab, an investigational CD123 × CD3 bispecific dual-affinity retargeting antibody (DART) molecule. The NanoString PanCancer IO360 assay was used to profile 64 diagnostic bone marrow (BM) samples from patients with TP53-mutated (n = 42) and TP53-wild-type (TP53-WT) AML (n = 22) and 45 BM samples from patients who received flotetuzumab for relapsed/refractory (R/R) AML (15 cases with TP53 mutations and/or 17p deletion). The comparison between TP53-mutated and TP53-WT primary BM samples showed higher expression of IFNG, FOXP3, immune checkpoints, markers of immune senescence, and phosphatidylinositol 3-kinase-Akt and NF-κB signaling intermediates in the former cohort and allowed the discovery of a 34-gene immune classifier prognostic for survival in independent validation series. Finally, 7 out of 15 patients (47%) with R/R AML and TP53 abnormalities showed complete responses to flotetuzumab (<5% BM blasts) on the CP-MGD006-01 clinical trial (NCT #02152956) and had significantly higher tumor inflammation signature, FOXP3, CD8, inflammatory chemokine, and PD1 gene expression scores at baseline compared with nonresponders. Patients with TP53 abnormalities who achieved a complete response experienced prolonged survival (median, 10.3 months; range, 3.3-21.3 months). These results encourage further study of flotetuzumab immunotherapy in patients with TP53-mutated AML.

3.
Ann Hematol ; 99(9): 2173-2180, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621177

RESUMO

Resistant disease is still a main obstacle in acute myeloid leukemia (AML) treatment. Therefore, individual genetic variations affecting therapy response are gaining increasing importance. Both SNPs and ABC transporter genes could already be associated with drug resistance. Here, we report allelic variants of MRP1 (ABCC1) SNPs rs129081, rs212090, and rs212091 with significant influences on survival in AML patients. DNA was extracted from bone marrow samples (n = 160) at diagnosis. Genotyping 48 SNPs within seven different ABC transporter genes using real-time PCR revealed rs129081 GG variant with a significant higher OS (p = 0.035) and DFS (p = 0.01). Comparing TT and AA rs212090 variants showed significant influences on DFS (p = 0.021). SNP rs212091 GG expression was associated with worse OS (p = 0.006) and a significant difference in DFS between alleles GG and AA (p = 0.018). The multivariable models confirmed a significant influence on OS for rs212091 (AA HR = 0.296, 95% CI 0.113-0.774, p = 0.013 and GG p = 0.044). Rs129081 variant CG, TT of rs212090, AA, and AG of rs212091 demonstrated significant impact on DFS (p = 0.024, p = 0.029, p = 0.017, and p = 0.042, respectively). This analysis demonstrates a significant influence of MRP1 SNPs on survival in AML. As they were not associated to prognostic characteristics, we suggest these SNPs to be independent prognostic markers for AML.


Assuntos
Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Feminino , Humanos , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Taxa de Sobrevida/tendências , Adulto Jovem
4.
Blood ; 136(7): 823-830, 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32496541

RESUMO

In fit patients with newly diagnosed acute myeloid leukemia (AML), immediate treatment start is recommended due to the poor prognosis of untreated acute leukemia. We explored the relationship between time from diagnosis to treatment start (TDT) and prognosis in a large real-world data set from the German Study Alliance Leukemia-Acute Myeloid Leukemia (SAL-AML) registry. All registered non-acute promyelocytic leukemia patients with intensive induction treatment and a minimum 12 months of follow-up were selected (n = 2263). We analyzed influence of TDT on remission, early death, and overall survival (OS) in univariable analyses for each day of treatment delay, in groups of 0 to 5, 6 to 10, 11 to 15, and >15 days of TDT, adjusted for influence of established prognostic variables on outcomes. Median TDT was 3 days (interquartile range, 2-7). Unadjusted 2-year OS rates, stratified by TDT of 0 to 5, 6 to 10, 11 to 15, and >15 days, were 51%, 48%, 44%, and 50% (P = .211). In multivariable Cox regression analysis accounting for established prognostic variables, the TDT hazard ratio as a continuous variable was 1.00 (P = .617). In OS analyses, separately stratified for age ≤60 and >60 years and for high vs lower initial white blood cell count, no significant differences between TDT groups were observed. Our study suggests that TDT is not related to survival. As stratification in intensive first-line AML treatment evolves, TDT data suggest that it may be a feasible approach to wait for genetic and other laboratory test results so that clinically stable patients are assigned the best available treatment option. This trial was registered at www.clinicaltrials.gov as #NCT03188874.

6.
Leukemia ; 34(6): 1553-1562, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31896782

RESUMO

The fusion genes CBFB/MYH11 and RUNX1/RUNX1T1 block differentiation through disruption of the core binding factor (CBF) complex and are found in 10-15% of adult de novo acute myeloid leukemia (AML) cases. This AML subtype is associated with a favorable prognosis; however, nearly half of CBF-rearranged patients cannot be cured with chemotherapy. This divergent outcome might be due to additional mutations, whose spectrum and prognostic relevance remains hardly defined. Here, we identify nonsilent mutations, which may collaborate with CBF-rearrangements during leukemogenesis by targeted sequencing of 129 genes in 292 adult CBF leukemia patients, and thus provide a comprehensive overview of the mutational spectrum ('mutatome') in CBF leukemia. Thereby, we detected fundamental differences between CBFB/MYH11- and RUNX1/RUNX1T1-rearranged patients with ASXL2, JAK2, JAK3, RAD21, TET2, and ZBTB7A being strongly correlated with the latter subgroup. We found prognostic relevance of mutations in genes previously known to be AML-associated such as KIT, SMC1A, and DHX15 and identified novel, recurrent mutations in NFE2 (3%), MN1 (4%), HERC1 (3%), and ZFHX4 (5%). Furthermore, age >60 years, nonprimary AML and loss of the Y-chromosomes are important predictors of survival. These findings are important for refinement of treatment stratification and development of targeted therapy approaches in CBF leukemia.


Assuntos
Fatores de Ligação ao Core/genética , Leucemia Mieloide Aguda/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
7.
Biol Blood Marrow Transplant ; 26(4): 691-697, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31730919

RESUMO

Radioimmunotherapy (RIT) has the potential to reduce the incidence of relapse after allogeneic hematopoietic cell transplantation (allo-HCT) in patients with advanced-stage multiple myeloma (MM). In this study, we evaluated the efficacy of RIT in combination with chemotherapy-based reduced-intensity conditioning (RIC). RIT was based on the coupling of an anti-CD66 antibody to the beta emitter 188-rhenium (188-re) for targeted bone marrow irradiation. Between 2012 and 2018, 30 patients with MM, most of them heavily pretreated with various therapies including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies, and autologous hematopoietic cell transplantation (auto-HCT), were treated with a RIT-RIC combination before allo-HCT. In addition to a fludarabine plus melphalan- or treosulfan-based RIC, a median dose of 18.1 Gy (interquartile range [IQR], 14.6 to 24.1 Gy) was applied to the bone marrow. After a median duration of follow-up for surviving patients of 2.1 years (IQR, 1.3 to 3.0 years), the 2-year progression-free survival and overall survival rates were 43% (95% confidence interval [CI], 26% to 73%) and 55% (95% CI, 38% to 79%), respectively. The 2-year nonrelapse mortality and cumulative incidence of progression were 17% (95% CI, 3% to 30%) and 46% (95% CI, 25% to 67%), respectively. Renal toxicity and mucositis were the most frequent extramedullary side effects. In conclusion, the addition of RIT to RIC was safe and feasible and resulted in promising outcomes compared with those previously reported for RIC-based allo-HCT without the addition of RIT in patients with relapsed/refractory MM. Nevertheless, despite the addition of RIT, relapse after allo-HCT remained a major determinant of therapeutic failure. Therefore, the development of novel RIT strategies (eg, dual targeting strategies or combinations with adapter chimeric antigen receptor T cell-based therapies) is needed.

8.
Bone Marrow Transplant ; 55(2): 367-375, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31534193

RESUMO

Clostridium difficile (CD) infection is the main cause of nosocomial enterocolitis in western countries and in patients undergoing allogeneic hematopoietic stem cell transplantation (alloHCT). Recipients of alloHCT are at high risk for CD infection but large studies in this population are rare and conflicting results have been reported. We analyzed 727 patients with AML or MDS undergoing alloHCT in our center from 2004 to 2015. Ninety-six patients (13%) had CD infection and 103 patients (14%) were identified as asymptomatic carriers by screening at admission and once a week during aplasia. Patients with CD infection had a shorter median overall survival of 8 months (95% CI, 6-36 months) compared with 25 months (95% CI, 17-35 months) for patients without CD infection, (HR 1.4, p = 0.04). CD positive patients were less likely to develop acute graft-versus-host disease (aGvHD; HR 0.6, p = 0.004) compared with CD-negative patients, but did not show differences in gastrointestinal aGvHD (HR 0.9, p = 0.5). Symptomatic patients developed gastrointestinal aGvHD (HR 2.5, p = 0.02) more often compared with asymptomatic CD positive patients. This analysis demonstrates a high prevalence for CD infection in patients undergoing alloHCT. A significant lower overall survival for patients with CD infection could be demonstrated.

9.
Lancet Haematol ; 7(1): e28-e39, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31606445

RESUMO

BACKGROUND: Further improvement of preparative regimens before allogeneic haemopoietic stem cell transplantation (HSCT) is an unmet medical need for the growing number of older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. We aimed to evaluate the efficacy and safety of conditioning with treosulfan plus fludarabine compared with reduced-intensity busulfan plus fludarabine in this population. METHODS: We did an open-label, randomised, non-inferiority, phase 3 trial in 31 transplantation centres in France, Germany, Hungary, Italy, and Poland. Eligible patients were 18-70 years, had acute myeloid leukaemia in first or consecutive complete haematological remission (blast counts <5% in bone marrow) or myelodysplastic syndrome (blast counts <20% in bone marrow), Karnofsky index of 60% or higher, and were indicated for allogeneic HSCT but considered at an increased risk for standard myeloablative preparative regimens based on age (≥50 years), an HSCT-specific comorbidity index of more than 2, or both. Patients were randomly assigned (1:1) to receive either intravenous 10 g/m2 treosulfan daily applied as a 2-h infusion for 3 days (days -4 to -2) or 0·8 mg/kg busulfan applied as a 2-h infusion at 6-h intervals on days -4 and -3. Both groups received 30 mg/m2 intravenous fludarabine daily for 5 days (days -6 to -2). The primary outcome was event-free survival 2 years after HSCT. The non-inferiority margin was a hazard ratio (HR) of 1·3. Efficacy was assessed in all patients who received treatment and completed transplantation, and safety in all patients who received treatment. The study is registered with EudraCT (2008-002356-18) and ClinicalTrials.gov (NCT00822393). FINDINGS: Between June 13, 2013, and May 3, 2016, 476 patients were enrolled (240 in the busulfan group received treatment and transplantation, and in the treosulfan group 221 received treatment and 220 transplanation). At the second preplanned interim analysis (Nov 9, 2016), the primary endpoint was met and trial was stopped. Here we present the final confirmatory analysis (data cutoff May 31, 2017). Median follow-up was 15·4 months (IQR 8·8-23·6) for patients treated with treosulfan and 17·4 months (6·3-23·4) for those treated with busulfan. 2-year event-free survival was 64·0% (95% CI 56·0-70·9) in the treosulfan group and 50·4% (42·8-57·5) in the busulfan group (HR 0·65 [95% CI 0·47-0·90]; p<0·0001 for non-inferiority, p=0·0051 for superiority). The most frequently reported grade 3 or higher adverse events were abnormal blood chemistry results (33 [15%] of 221 patients in the treosulfan group vs 35 [15%] of 240 patients in the busulfan group) and gastrointestinal disorders (24 [11%] patients vs 39 [16%] patients). Serious adverse events were reported for 18 (8%) patients in the treosulfan group and 17 (7%) patients in the busulfan group. Causes of deaths were generally transplantation-related. INTERPRETATION: Treosulfan was non-inferior to busulfan when used in combination with fludarabine as a conditioning regimen for allogeneic HSCT for older or comorbid patients with acute myeloid leukaemia or myelodysplastic syndrome. The improved outcomes in patients treated with the treosulfan-fludarabine regimen suggest its potential to become a standard preparative regimen in this population. FUNDING: medac GmbH.


Assuntos
Antineoplásicos/uso terapêutico , Bussulfano/análogos & derivados , Bussulfano/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Vidarabina/análogos & derivados , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vidarabina/uso terapêutico
10.
Cytotherapy ; 22(1): 21-26, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31883948

RESUMO

Isolation of mesenchymal stromal cells (MSCs) from pretreated, hematologic patients is challenging. Especially after allogeneic hematopoietic cell transplantation (HCT), standard protocols using bone marrow aspirates fail to reliably recover sufficient cell numbers. Because MSCs are considered to contribute to processes that mainly affect the outcome after transplantation, such as an efficient lymphohematopoietic recovery, extent of graft-versus-host disease as well as the occurrence of leukemic relapse, it is of great clinical relevance to investigate MSC function in this context. Previous studies showed that MSCs can be isolated by collagenase digestion of large bone fragments of hematologically healthy patients undergoing hip replacement or knee surgeries. We have now further developed this procedure for the isolation of MSCs from hematologic patients after allogeneic HCT by using trephine biopsy specimens obtained during routine examinations. Comparison of aspirates and trephine biopsy specimens from patients after allogeneic HCT revealed a significantly higher frequency of clonogenic MSCs (colony-forming unit-fibroblast [CFU-F]) in trephine biopsy specimens (mean, 289.8 ± standard deviation 322.5 CFU-F colonies/1 × 106 total nucleated cells versus 4.2 ± 9.9; P < 0.0001). Subsequent expansion of functional MSCs isolated from trephine biopsy specimen was more robust and led to a significantly higher yield compared with control samples expanded from aspirates (median, 1.6 × 106; range, 0-2.3 × 107 P0 MSCs versus 5.4 × 104; range, 0-8.9 × 106; P < 0.0001). Using trephine biopsy specimens as MSC source facilitates the investigation of various clinical questions.


Assuntos
Células da Medula Óssea/citologia , Transplante de Células-Tronco Hematopoéticas/métodos , Leucemia/terapia , Células-Tronco Mesenquimais/citologia , Adulto , Idoso , Biópsia , Medula Óssea , Colagenases/farmacologia , Feminino , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas , Adulto Jovem
11.
J Clin Oncol ; 37(29): 2632-2642, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31430225

RESUMO

PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption. METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers. RESULTS: Among 2,426 patients with NPM1mut/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome. CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1mut/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/FLT3-ITDneg/low AML.

12.
Haematologica ; 2019 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467130

RESUMO

Extramedullary disease in patients with acute myeloid leukemia is a known phenomenon. Since the prevalence of extramedullary acute myeloid leukemia has so far been only clinically determined on examination, we performed a prospective study in patients with acute myeloid leukemia. The goal of this prospective study was to determine the prevalence of metabolically active extramedullary acute myeloid leukemia using total body 18FDG-PET/CT imaging at diagnosis prior to initiation of therapy. In order, to define the dynamics of extramedullary acute myeloid leukemia throughout treatment, PET-positive patients underwent a second 18FDG-PET/CT imaging series during follow-up by the time of remission assessment. Findings: A total of 93 patients with acute myeloid leukemia underwent 18FDG-PET/CT scans at diagnosis. The prevalence of PET-positive extramedullary acute myeloid leukemia was 19% in our study with a total of 65 EM AML manifestations and a median number of two extramedullary manifestations per patient (range, 1-12) with a median SUVmax of 6.1 (range, 2-51.4), respectively. When adding those three patients with histologically confirmed extramedullary acute myeloid leukemia who were 18FDG-PET/CT negative in the 18FDG-PET/CT at diagnosis, the combined prevalence for extramedullary acute myeloid leukemia in this study was 22%, resulting in a sensitivity and specificity of 77% and 97%, respectively. Importantly, 60% (6 of 10) patients with histologically confirmed extramedullary acute myeloid leukemia still had active extramedullary disease in their follow-up 18FDG-PET/CT. 18FDG-PET/CT reveals a high prevalence of metabolically active extramedullary disease in acute myeloid leukemia patients. Metabolic activity in extramedullary acute myeloid leukemia may persist even beyond the time-point of hematologic remission, a finding that merits further prospective investigation with respect to its prognostic relevance. This trial is registered at www.clinicaltrials.gov as #NCT01278069.

13.
Mycoses ; 62(7): 576-583, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31034703

RESUMO

False positivity of antigen immunoassays used as an early diagnostic tool to detect invasive fungal infections is known. Interpretation of the assay needs the identification of sources which could affect the specificity of the test. We focused on the influence of parenteral nutrition (PN) and piperacillin-tazobactam (TZP) on fungal immunoassays. Measurable amounts of Candida antigen mannan were detected in several compounds of PN and TZP in a previous in vitro study. In the current study, 84 patients undergoing allogeneic haematopoietic cell transplantation receiving either TZP, PN or both were monitored with Aspergillus and Candida antigen assay. Six patients were analysed closer in a kinetic analysis with more frequent blood sampling to detect mannan. PN in diverse compositions as well as TZP did not increase significantly the amount of mannan and the Aspergillus antigen in serum. We could not confirm the positive results of the in vitro study. Physicians should be aware that mannan antigenemia due to drug infusion could be a transient issue and should be considered in the interpretation of fungal immunoassays, although we could not find clinically relevant effects on mannan levels.


Assuntos
Antibacterianos/administração & dosagem , Antígenos de Fungos/sangue , Candidíase Invasiva/diagnóstico , Reações Falso-Positivas , Aspergilose Pulmonar Invasiva/diagnóstico , Nutrição Parenteral , Combinação Piperacilina e Tazobactam/administração & dosagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Transplante Homólogo/efeitos adversos , Adulto Jovem , Inibidores de beta-Lactamases/administração & dosagem
14.
Nat Commun ; 10(1): 1065, 2019 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-30911002

RESUMO

The major cause of death after allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for acute myeloid leukemia (AML) is disease relapse. We investigated the expression of Inhibitory Receptors (IR; PD-1/CTLA-4/TIM-3/LAG-3/2B4/KLRG1/GITR) on T cells infiltrating the bone marrow (BM) of 32 AML patients relapsing (median 251 days) or maintaining complete remission (CR; median 1 year) after HSCT. A higher proportion of early-differentiated Memory Stem (TSCM) and Central Memory BM-T cells express multiple IR in relapsing patients than in CR patients. Exhausted BM-T cells at relapse display a restricted TCR repertoire, impaired effector functions and leukemia-reactive specificities. In 57 patients, early detection of severely exhausted (PD-1+Eomes+T-bet-) BM-TSCM predicts relapse. Accordingly, leukemia-specific T cells in patients prone to relapse display exhaustion markers, absent in patients maintaining long-term CR. These results highlight a wide, though reversible, immunological dysfunction in the BM of AML patients relapsing after HSCT and suggest new therapeutic opportunities for the disease.


Assuntos
Anergia Clonal , Regulação Leucêmica da Expressão Gênica , Transplante de Células-Tronco Hematopoéticas , Memória Imunológica/genética , Leucemia Mieloide Aguda/imunologia , Linfócitos T/imunologia , Adulto , Antígenos CD/genética , Antígenos CD/imunologia , Antineoplásicos/uso terapêutico , Células da Medula Óssea/imunologia , Células da Medula Óssea/patologia , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Feminino , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Receptores KIR/genética , Receptores KIR/imunologia , Recidiva , Indução de Remissão , Estudos Retrospectivos , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Linfócitos T/patologia , Transplante Homólogo
15.
Biol Blood Marrow Transplant ; 25(1): 114-120, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30172776

RESUMO

Recently, haploidentical transplantation (haplo) using post-transplant cyclophosphamide (PTCy) has been reported to give very encouraging results in patients with hematological malignancies. Patients who have no HLA-matched donor currently have the choice between a mismatched unrelated donor, an unrelated cord blood (CB) donor, and a haploidentical related donor. The aim of our study is to compare the outcome of patients with myelodysplastic syndrome (MDS) who have been transplanted from a haploidentical donor using PTCy, an HLA-mismatched unrelated donor (marrow or peripheral blood stem cells), or an unrelated mismatched CB donor. A total of 833 MDS patients from the European Group for Blood and Marrow Transplantation (EBMT) registry, transplanted between 2011 and 2016, were identified. The potential benefit of haplo was compared with mismatched unrelated and CB donors in an adjusted and weighted model taking into account potential confounders and other prognostic variables. Haplo was at lower risk of acute graft-versus-host disease (GVHD) than mismatched unrelated donor (P = .010) but at similar risk than CB. Progression-free survival was better after haplo (versus mismatched unrelated, P = .056; versus CB, P = .003) and overall survival tended to be superior after haplo (versus mismatched unrelated, P = .082; versus CB, P = .002). Nonrelapse mortality was not significantly different between haplo and mismatched unrelated donors. Relapse risk was not influenced by the type of donor. In conclusion, patients with MDS from the EBMT registry receiving hematopoietic stem cell transplantation from a haplo donor have significantly better outcome than those receiving hematopoietic stem cell transplantation from a CB donor and at least similar or better outcome than with a mismatched unrelated donor. Prospective studies comparing the type of donors will be needed to confirm this assumption.


Assuntos
Doença Enxerto-Hospedeiro , Antígenos HLA/metabolismo , Transplante de Células-Tronco Hematopoéticas , Teste de Histocompatibilidade , Síndromes Mielodisplásicas , Doadores não Relacionados , Idoso , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/mortalidade , Síndromes Mielodisplásicas/patologia , Síndromes Mielodisplásicas/terapia , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
17.
Lancet Oncol ; 19(12): 1668-1679, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30442503

RESUMO

BACKGROUND: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients. METHODS: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018. FINDINGS: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment. INTERPRETATION: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes. FUNDING: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Azacitidina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Idoso , Antimetabólitos Antineoplásicos/efeitos adversos , Azacitidina/efeitos adversos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Esquema de Medicação , Feminino , Alemanha , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/imunologia , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/imunologia , Neoplasia Residual , Intervalo Livre de Progressão , Estudos Prospectivos , Recidiva , Medição de Risco , Fatores de Risco , Fatores de Tempo
18.
Mycoses ; 61(12): 931-937, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30107071

RESUMO

BACKGROUND: Screening for Aspergillus (Asp-AG) and Candida antigen (Ca-AG) with immunoassays is established for stem cell recipients at high risk for invasive fungal infections (IFI). While parenteral nutrition (PN) will be applied in case of complications leading to insufficient alimentation, piperacillin-tazobactam (TZP) is started at the onset of febrile neutropenia. OBJECTIVES: The aim of this study was to investigate drug-laboratory interactions between PN and TZP and both immunoassays which could affect the specificity of the assays and lead to the false assumption of an IFI. METHODS: Batches of TZP and PN were tested with both assays in vitro. In total, 380 samples of 83 batches were analysed. RESULTS: None of the examined preparations were tested positive with Asp-AG assay. Measurable amounts of Ca-AG were detected in a lipid emulsion, two different trace element supplements, a fat-soluble vitamin preparation and all tested brands of TZP. CONCLUSIONS: We conclude that false positivity of Asp-AG assay due to TZP and PN does not occur. Cross reactions with Ca-AG assay have been detected in some preparations. The in vivo relevance of Ca-AG positivity has to be reviewed in further studies considering an effect of dilution. Physicians should be aware of a possible cross reaction with Ca-AG assays which could lead to false-positive results.


Assuntos
Antibacterianos/química , Antígenos de Fungos/análise , Aspergillus/química , Candida/química , Soluções de Nutrição Parenteral/química , Combinação Piperacilina e Tazobactam/química , Inibidores de beta-Lactamases/química , Candidíase Invasiva/diagnóstico , Reações Falso-Positivas , Humanos , Aspergilose Pulmonar Invasiva/diagnóstico , Testes Sorológicos/métodos
20.
Biol Blood Marrow Transplant ; 24(9): 1947-1951, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29793046

RESUMO

Despite recent advances, allogeneic hematopoietic stem cell transplantation (allo-HSCT) continues to be accompanied by a high rate of morbidity and mortality. Several scores have been developed to predict outcome after allo-HSCT. The recently revised Pretransplant Assessment of Mortality (PAM) score is based on patient age, donor type, disease risk, cytomegalovirus (CMV) serostatus of patient and donor, and forced expiratory volume in 1 second (FEV1). The aim of this study was to analyze the predictive power of the PAM score in an independent large cohort of patients with acute myelogenous leukemia (AML). We selected adult patients with AML who underwent a first allo-HSCT at the University Hospital of Dresden, a tertiary care hospital with a large transplantation program. All adult patients treated between January 1, 2003, and July 1, 2015, were included. The PAM score was calculated as described previously. Overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) after allo-HSCT were analyzed. Age, AML type, sex match, CMV match, donor type, European Leukemia Net risk classification, type of conditioning, disease stage, and PAM score as a continuous variable were selected a priori for multivariate Cox regression analyses. A total of 544 patients met the inclusion criteria. The median patient age was 57 years. With a median follow-up of 47 months (range, 1 to 161 months), the estimated OS for the whole cohort at 4 years was 43%, with a CIR of 30% and an NRM of 31%. The probability of OS at 4 years was 65% for patients with a PAM score of 0, 52% in those with a PAM score of 1, 33% in those with a PAM score of 2, and 22% in those with a PAM score of 3 (P < .001, log-rank test). Both the CIR and NRM increased with higher PAM scores (P = .005 and P < .001, respectively, Gray test). In multivariate analysis, age (hazard ratio [HR], 1.02 per year; P = .004), disease stage (primary induction failure versus first complete remission (CR1); HR, 1.5; P = .03), and the PAM score (HR 1.04; P = .03) had a significant impact on OS. This is the first independent validation of the revised PAM score allowing for simple and valid estimation of transplantation outcomes. It can serve as an important tool in counseling patients with AML, as well as in designing future trials.


Assuntos
Transplante de Células-Tronco Hematopoéticas/mortalidade , Condicionamento Pré-Transplante/mortalidade , Adolescente , Adulto , Idoso , Comorbidade , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Leucemia Mieloide Aguda , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Condicionamento Pré-Transplante/métodos , Adulto Jovem
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