RESUMO
Allogeneic natural killer (NK) cell-based immunotherapy is a promising, well-tolerated adjuvant therapeutic approach for acute myeloid leukemia (AML). For reproducible NK cell immunotherapy, a homogenous, pure and scalable NK cell product is preferred. Therefore, we developed a good manufacturing practice (GMP)-compliant, cytokine-based ex vivo manufacturing process for generating NK cells from CD34+ hematopoietic stem and progenitor cells (HSPC). This manufacturing process combines amongst others IL15 and IL12 and the aryl hydrocarbon receptor antagonist StemRegenin-1 (SR1) to generate a consistent and active NK cell product that fits the requirements for NK cell immunotherapy well. The cell culture protocol was first optimized to generate NK cells with required expansion and differentiation capacity in GMP-compliant closed system cell culture bags. In addition, phenotype, antitumor potency, proliferative and metabolic capacity were evaluated to characterize the HSPC-NK product. Subsequently, seven batches were manufactured for qualification of the process. All seven runs demonstrated consistent results for proliferation, differentiation and antitumor potency, and preliminary specifications for the investigational medicinal product for early clinical phase trials were set. This GMP-compliant manufacturing process for HSPC-NK cells (named RNK001 cells) is used to produce NK cell batches applied in the clinical trial 'Infusion of ex vivo-generated allogeneic natural killer cells in combination with subcutaneous IL2 in patients with acute myeloid leukemia' approved by the Dutch Ethics Committee (EudraCT 2019-001929-27).
Assuntos
Imunoterapia Adotiva , Leucemia Mieloide Aguda , Humanos , Imunoterapia Adotiva/métodos , Células Matadoras Naturais/metabolismo , Leucemia Mieloide Aguda/genética , Antígenos CD34/metabolismo , Células-Tronco HematopoéticasRESUMO
Allogeneic natural killer (NK) cell transfer is a potential immunotherapy to eliminate and control cancer. A promising source are CD34 + hematopoietic progenitor cells (HPCs), since large numbers of cytotoxic NK cells can be generated. Effective boosting of NK cell function can be achieved by interleukin (IL)-15. However, its in vivo half-life is short and potent trans-presentation by IL-15 receptor α (IL-15Rα) is absent. Therefore, ImmunityBio developed IL-15 superagonist N-803, which combines IL-15 with an activating mutation, an IL-15Rα sushi domain for trans-presentation, and IgG1-Fc for increased half-life. Here, we investigated whether and how N-803 improves HPC-NK cell functionality in leukemia and ovarian cancer (OC) models in vitro and in vivo in OC-bearing immunodeficient mice. We used flow cytometry-based assays, enzyme-linked immunosorbent assay, microscopy-based serial killing assays, and bioluminescence imaging, for in vitro and in vivo experiments. N-803 increased HPC-NK cell proliferation and interferon (IFN)γ production. On leukemia cells, co-culture with HPC-NK cells and N-803 increased ICAM-1 expression. Furthermore, N-803 improved HPC-NK cell-mediated (serial) leukemia killing. Treating OC spheroids with HPC-NK cells and N-803 increased IFNγ-induced CXCL10 secretion, and target killing after prolonged exposure. In immunodeficient mice bearing human OC, N-803 supported HPC-NK cell persistence in combination with total human immunoglobulins to prevent Fc-mediated HPC-NK cell depletion. Moreover, this combination treatment decreased tumor growth. In conclusion, N-803 is a promising IL-15-based compound that boosts HPC-NK cell expansion and functionality in vitro and in vivo. Adding N-803 to HPC-NK cell therapy could improve cancer immunotherapy.
Assuntos
Antineoplásicos/uso terapêutico , Interleucina-15/agonistas , Células Matadoras Naturais/imunologia , Leucemia/terapia , Células Progenitoras Linfoides/imunologia , Neoplasias Ovarianas/terapia , Proteínas Recombinantes de Fusão/uso terapêutico , Animais , Antígenos CD34/metabolismo , Antineoplásicos/farmacologia , Diferenciação Celular , Linhagem Celular Tumoral , Testes Imunológicos de Citotoxicidade , Modelos Animais de Doenças , Feminino , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/transplante , Leucemia/imunologia , Células Progenitoras Linfoides/transplante , Camundongos , Camundongos SCID , Neoplasias Ovarianas/imunologia , Proteínas Recombinantes de Fusão/farmacologiaRESUMO
The purpose of this study was to determine the role of pre-emptive donor lymphocyte infusion (pDLI) after partial T-cell-depleted allogeneic SCT in patients with multiple myeloma (MM). A cohort of 24 MM patients was treated with partial T-cell-depleted myeloablative SCT between December 1997 and April 2002. These patients were intended to receive pDLI after SCT. The overall response rate after SCT was 83% (20 of 24 patients) with 10 patients (42%) in complete remission (CR). Transplant-related mortality within 1 year after SCT was 29%. Thirteen patients (54%) received pDLI and four patients in partial remission reached CR. GVHD>grade I after pDLI developed in 4 out of 13 patients (30%). Four patients received therapeutic DLI, without preceding pDLI. Eleven patients (46%) are alive, with a median follow-up of 67 months (range, 48-100 months). Seven of these patients (29%) are in continuous CR (CCR), which was confirmed by a negative patient-specific IgH PCR in four patients. All seven patients in CCR received pDLI. Although myeloablative SCT in MM induces high toxicity, we show that the concept of T-cell depletion followed by pDLI is promising and needs to be investigated in a reduced-intensity conditioning setting.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Depleção Linfocítica , Mieloma Múltiplo/terapia , Linfócitos T/transplante , Adulto , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Quimeras de Transplante , Condicionamento Pré-Transplante/métodos , Transplante HomólogoRESUMO
Donor lymphocyte infusion (DLI) after allogeneic SCT induces complete remissions in approximately 80% of patients with relapsed CML in chronic phase, but some patients do not respond to DLI. We studied absolute numbers of dendritic cell (DC) subsets and chimerism in T cells and two subsets of blood DCs (myeloid DCs (MDCs) and plasmacytoid DCs (PDCs)) in relation to DLI-induced alloreactivity. Based on T cell and DC chimerism, we identified three groups. Four patients were completely donor chimeric in T cells and DC subsets. These patients had an early stage of relapse, and three of the four patients attained complete molecular remission (CMolR) without significant GVHD. Six patients were completely donor in T cells and mixed chimeric in DC subsets. All patients entered CMolR, but this was associated with GVHD in four and cytopenia in three patients. Five patients had mixed chimerism in T cells and complete recipient chimerism in MDC; only two patients entered CMolR. Our data suggest that the combination of donor T cells and mixed chimerism in DC subsets induces a potent graft-versus-leukemia (GVL) effect in association with GVHD. DLI in patients with an early relapse and donor chimerism in both T cells and DC subsets results in GVL reactivity without GVHD.
Assuntos
Células Dendríticas/imunologia , Efeito Enxerto vs Leucemia/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transfusão de Linfócitos , Linfócitos T/imunologia , Quimeras de Transplante/imunologia , Adulto , Idoso , Doadores de Sangue , Feminino , Doença Enxerto-Hospedeiro/imunologia , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de RemissãoRESUMO
BACKGROUND: In trauma, as interventions are carried out to stop bleeding, ongoing resuscitation with blood products is of vital importance. As transfusion policy in exsanguinating patients cannot be based on laboratory tests, transfusion of blood products is performed empirically or 'blindly'. The aim of this study was to delineate 'blind' transfusion practice in the hectic clinical situation of exsanguination. METHODS: Seventeen trauma patients were selected who died due to uncontrolled bleeding despite haemostatic interventions within 24h after admission and who received more than 12 U of RBC. Transfusion data were compared with a theoretically optimal transfusion model with a fixed ratio between units of RBC, FFP, and platelets. The difference between the observed and expected amounts of blood products was calculated. RESULTS: The patients (82%) received insufficient amounts of FFP and platelets when compared to the calculated amounts. The total numbers of transfused FFP and platelets were on average 50% lower than the calculated amounts. Regression models showed an increase of FFP and platelets with increasing amounts of RBC but not in sufficient quantities. CONCLUSION: Exsanguinating trauma patients receiving massive transfusions are subject to 'blind' transfusion. This is associated with insufficient transfusion of both FFP and platelets, which may aggravate bleeding. A 'blind' transfusion strategy consisting of a validated guideline with a predefined ratio of the different blood products, timing of laboratory tests as well as a sound logistic protocol facilitating this procedure, involving the blood bank and treating physicians, is needed urgently.
Assuntos
Transfusão de Eritrócitos/estatística & dados numéricos , Hemorragia/terapia , Traumatismo Múltiplo/complicações , Transfusão de Plaquetas/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Evolução Fatal , Feminino , Hemorragia/etiologia , Humanos , MasculinoRESUMO
Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) is the only curative option for several hematological malignancies. Unfortunately, allo-SCT is often associated with GvHD, and patients often relapse. We therefore aim to improve the graft-versus-tumor effect, without increasing the risk of GvHD, by targeting hematopoietic lineage-restricted and tumor-associated minor histocompatibility antigens using peptide-loaded dendritic cell (DC) vaccinations. In the present multicenter study, we report the feasibility, safety and efficacy of this concept. We treated nine multiple myeloma patients with persistent or relapsed disease after allo-SCT and a previous DLI, with donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI. Vaccinations were well tolerated and no occurrence of GvHD was observed. In five out of nine patients, we were able to show the induction of mHag-specific CD8+ T cells in peripheral blood. Five out of nine patients, of which four developed mHag-specific T cells, showed stable disease (SD) for 3.5-10 months. This study shows that mHag-based donor monocyte-derived DC vaccination combined with DLI is safe, feasible and capable of inducing objective mHag-specific T-cell responses. Future research should focus on further improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses.
Assuntos
Antígenos de Neoplasias/imunologia , Doadores de Sangue , Células Dendríticas , Antígenos HLA/imunologia , Imunidade Celular , Transfusão de Linfócitos , Mieloma Múltiplo , Transplante de Células-Tronco , Vacinação , Adulto , Idoso , Aloenxertos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Peptídeos/imunologiaRESUMO
This study shows the long-term updated outcomes of a multicenter retrospective study which analyzed 843 patients with myelodysplastic syndrome (MDS) who underwent transplantation with an HLA-identical sibling donor with either reduced-intensity conditioning (RIC) in 213 patients, or standard myeloablative conditioning (MAC) in 630 patients. In multivariate analysis, the 13-year relapse rate was significantly increased after RIC (31% after MAC vs 48% in RIC; HR, 1.5; 95% CI, 1.1-1.9; P=0.04), but with no differences in overall survival (OS) (30% after MAC vs 27% in RIC; P=0.4) and PFS (29 vs 21%, respectively, P=0.3). Non-relapse mortality was higher in MAC (40 vs 31%; P=0.1), especially in patients older than 50 years (50 vs 33%, P<0.01). In addition, long-term follow-up confirms the importance of other variables on 13-year OS, mainly MDS risk category, disease phase, cytogenetics and receiving a high donor cell dose, irrespective of the conditioning regimen used.
Assuntos
Síndromes Mielodisplásicas/terapia , Condicionamento Pré-Transplante/métodos , Idoso , Estudos de Casos e Controles , Seguimentos , Teste de Histocompatibilidade , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Irmãos , Análise de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/mortalidadeRESUMO
We describe the use and outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for multiple myeloma (MM) in Europe between January 1990 and December 2012. We identified 7333 patients, median age at allo-HSCT was 51 years (range: 18-78), of whom 4539 (62%) were males. We distinguished three groups: (1) allo-HSCT upfront (n=1924), (2) tandem auto-allo-HSCT (n=2004) and (3) allo-HSCT as a second line treatment and beyond (n=3405). Overall, there is a steady increase in numbers of allo-HSCT over the years. Upfront allo-HSCT use increased up to year 2000, followed by a decrease thereafter and represented 12% of allo-HSCTs performed in 2012. Tandem auto-allo-HSCT peaked around year 2004 and contributed to 19% of allo-HSCTs in 2012. Allo-HSCT as salvage after one or two or three autografts was steadily increasing over the last years and represented 69% of allo-HSCTs in 2012. Remarkable heterogeneity in using allo-HSCT was observed among the different European countries. The 5-year survival probabilities from time of allo-HSCT for the three groups after year 2004 were 42%, 54% and 32%, respectively. These results show that the use of allo-HSCT is increasing in Europe, especially as second line treatment and beyond. There is an unmet need for well-designed prospective studies investigating allo-HSCT as salvage therapy for MM.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Mieloma Múltiplo/terapia , Adolescente , Adulto , Idoso , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Taxa de Sobrevida , Transplante Homólogo , Resultado do Tratamento , Adulto JovemRESUMO
In this prospective study we analyzed pre-emptive donor leukocyte infusions (DLI) in 82 consecutive patients transplanted with partially T cell-depleted grafts for acute myeloid leukemia, acute lymphoid leukemia, chronic myeloid leukemia, refractory anemia with excess of blasts, refractory anemia with excess of blasts in transformation and multiple myeloma. Donors were HLA-identical siblings. Patients without significant acute (>grade 1) and/or chronic GVHD were scheduled to be treated with DLI (35 patients) and 31 actually received DLI. Patients who developed acute GVHD >grade 1 and/or chronic GVHD were not scheduled to receive DLI and served as a comparison group (47 patients). The median interval between BMT and DLI was 22 weeks. The first six patients received 0.7 x 10(8) CD3+ cells/kg body weight (b.w.). Five out of these six patients developed acute GVHD (grade 1: n = 2, grade 3: n = 2 and grade 4: n= 1) which was more frequent and more severe than we had anticipated. In the next 25 patients the number of T lymphocytes was diminished to 0.1 x 10(8) CD3+ cells/kg b.w. which resulted in less frequent and less severe GVHD. Eight patients in this group developed acute GVHD (grade 1: n = 4, grade 2: n = 4) and three patients had limited chronic GVHD. Patients in the DLI group needed more time to establish complete donor chimerism confirmed by a higher number of mixed chimeras at 6 months after BMT. The projected 3-year probability of disease-free survival was 77% for the 35 patients intended to treat with DLI and 45% for the patients of the comparison group (P = 0.024). Relapse rate at 36 months after transplantation was 18% in the patients who were intended to treat with DLI and 44% in the comparison group (P = 0.026). We conclude that pre-emptive DLI is feasible and generates favorable relapse rates in patients who are at high risk for relapse. Furthermore, the incidence and severity of GVHD disease after DLI is dependent on the number of CD3+ cells infused.
Assuntos
Efeito Enxerto vs Leucemia , Transplante de Células-Tronco Hematopoéticas , Leucemia/terapia , Condicionamento Pré-Transplante/métodos , Adolescente , Adulto , Complexo CD3/análise , Quimera , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Leucócitos/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Doadores de TecidosRESUMO
Analysis of changes in recipient and donor hemopoietic cell origin is extremely useful to monitor the effect of stem cell transplantation (SCT) and sequential adoptive immunotherapy by donor lymphocyte infusions (DLI). We developed a sensitive and accurate method to quantify the percentage of recipient and donor cells by real-time PCR using single nucleotide polymorphisms (SNPs) as markers. Allele-specific PCR of seven SNPs resulted in specific markers for donor or recipient in 97% of HLA-identical sibling pairs. Both, recipient- and donor-derived hemopoietic cells can be simultaneously analyzed in 67% sibling pairs. We expect this can be increased to approximately 99% by developing three additional SNP-PCR. Serial dilution of SNP-positive DNA into either SNP-negative DNA or water revealed a detection limit of 0.1-0.01% depending on the amount of input DNA and start C(t) of the used SNP-PCR. Application of our real-time SNP-PCR method for a CML patient treated by allogeneic SCT and DLI demonstrated its feasibility to follow donor T-cell chimerism and early detection of residual and recurrent autologous hemopoiesis in response to treatment. This detailed monitoring of the genetic origin of hemopoietic cells, in particular immune effector cells and target cells after SCT and DLI, may substantially contribute to understanding of the mechanisms that play a role in the success of treatment.
Assuntos
Células Sanguíneas , Transplante de Células-Tronco Hematopoéticas/normas , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Nucleotídeo Único , Quimeras de Transplante , Alelos , Células Sanguíneas/citologia , Estudos de Viabilidade , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Transfusão de Linfócitos , Células Mieloides/citologia , Reação em Cadeia da Polimerase/normas , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Linfócitos T/citologia , Transplante Homólogo/normasRESUMO
Using red cell phenotyping (RCP) and/or cytogenetics (CYT) we identified 19 patients with persisting mixed chimerism (MC) among 231 patients transplanted with partially T cell-depleted stem cell grafts from HLA-identical siblings. Persisting MC is defined as MC for more than 2 years in patients without any evidence of relapse. Median leukemia-free survival in these patients was 150 (range, 50-218) months. Diagnoses were ALL (n= 10); AML (n = 2); CML (n = 2); NHL (n = 2); MDS (n= 1); MM (n = 1) and SAA (n = 1). Purpose of this study was the long-term follow-up of MC and definition of patterns of chimerism in the various subsets of PBMCs and granulocytes. Using a PCR-STR technique CD3(+)/CD4(+) (T4 lymphocytes), CD3(+)/CD8(+) (T8 lymphocytes), CD45(+)/CD19(+) (B lymphocytes), CD45(+)/CD14(+) (monocytes), CD45(+)/CD15(+) (granulocytes) and CD3(-)/CD56(+) (NK-cells) were analyzed. The majority of patients with persisting MC were conditioned with a less intensive conditioning regimen and had little GVHD. Sequential monitoring of the chimerism resulted in a group of patients (n = 7) with very slow transient mixed chimerism that resulted in complete DC after median 7 years. Another nine patients had a relatively high percentage of persisting autologous cells for a median of 12 years and in three patients we observed a stable low percentage of autologous cells. Only two out of 19 patients (AML-CR1, CML-CP1) relapsed during follow-up. Both patients had a relatively high percentage of autologous cells. Chimerism in granulocytes and PBMC subsets was analyzed at a median of 8 years after SCT in nine patients. In five patients mixed chimerism simultaneously detected by RCP and CYT was associated with MC in all subsets. Within each individual patient the percentages of donor and recipient cells were very different between the different subsets. Two CML-CP1 patients were mixed chimera in only two subsets and in one patient these subsets represented pending relapse. In another two patients mixed chimerism with a very low number of autologous red cells was not found in the PBMCs because of the different sensitivity level of the RCP and the PCR-STR technique. We conclude that in patients with persisting mixed chimerism after partially T cell-depleted SCT a remarkable number of patients had lymphoid malignancies, the majority of the patients were conditioned with less intensive conditioning regimens and the mixed chimerism was not correlated with relapse. Chimerism in granulocytes and PBMC subsets did show great intra-individual differences in the subsets and these data correlated well with RCP and CYT data with the exception of the NK cells.
Assuntos
Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Adolescente , Adulto , Sobrevivência Celular , Intervalo Livre de Doença , Feminino , Seguimentos , Sobrevivência de Enxerto , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Neoplasias Hematológicas/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunofenotipagem , Contagem de Linfócitos , Depleção Linfocítica , Subpopulações de Linfócitos , Masculino , Pessoa de Meia-Idade , Células Mieloides , Reação em Cadeia da Polimerase , Sensibilidade e Especificidade , Linfócitos T , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
Allo-SCT followed by DLIs can establish long-term remissions in multiple myeloma (MM) patients. In many patients, however, the immunotherapeutic graft-versus-tumor (GVT) effect is moderate and not sustained, implying that immune suppression is mediated, among other factors, by regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs). Towards a better understanding and, eventually, manipulation of the immune-regulatory mechanisms in transplanted MM patients, we retrospectively sought a correlation between DLI outcome and circulating CD14(+) MDSCs, CD14(-) MDSCs and Tregs in 53 MM patients before their first DLI. We found significantly elevated frequencies of highly suppressive CD14(+) MDSCs, CD14(-) MDSCs and Tregs in pre-DLI samples from patients. Higher frequencies of Tregs, but not of MDSCs, were significantly associated with non-responsiveness to DLI. Furthermore, a lower frequency of Tregs predicted the development of chronic GVHD, which, in turn, displayed a high association with GVT. Elevated Treg frequencies before DLI were also associated with significantly shorter PFS and OS. Hence, our data reinforce the idea of active suppression of antitumor responses by Tregs in MM patients and therefore suggest that targeting patient Tregs before DLI may improve outcome of DLI.
Assuntos
Efeito Enxerto vs Tumor/imunologia , Mieloma Múltiplo , Células Mieloides/imunologia , Transplante de Células-Tronco , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Aloenxertos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Estudos RetrospectivosRESUMO
In recipients of allogeneic hematopoietic stem cell transplantation with AML in CR1, reduced intensity (RIC) conditioning regimens are usually given to older patients and myeloablative regimens (MAC) to younger patients. We analyzed whether in middle-aged patients aged 40-60 years, MAC was superior to RIC in cytogenetically higher risk AML. Among 2974 patients, 1638 had MAC and 1336 RIC transplants. Cytogenetics were high risk in 508, intermediate risk in 2297 and low risk in 169. Overall survival (OS) was higher in patients with RIC with low-risk cytogenetics but not in the intermediate- or poor-risk AML. Relapse incidence was lower with MAC in poor- and intermediate-risk AML. Nonrelapse mortality (NRM) was higher in MAC in all cytogenetic risk groups. Multivariate analysis confirmed a significant leukemia-free survival and OS advantage for RIC in low risk but no advantage of MAC in intermediate- and poor-risk leukemia. In patients aged 40-60 years, MAC has no advantage over RIC. We confirm lower relapse but higher NRM risks with MAC. MAC is not superior in patients with higher risk cytogenetics, but is inferior to RIC in the small cohort of AML patients with low-risk cytogenetics.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Condicionamento Pré-Transplante/métodos , Adulto , Aloenxertos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de SobrevidaRESUMO
We performed a retrospective analysis of the European Group for Blood and Marrow Transplantation database comparing the outcomes of multiple myeloma patients who received tandem autologous followed by allogeneic PSCT (auto-allo) with the outcomes of patients who underwent a reduced intensity conditioning allograft (early RIC) without prior autologous transplant. From 1996 to 2013, we identified a total of 690 patients: 517 patients were planned to receive auto-allo and 173 received an early RIC allograft without prior autologous transplant. With a median follow-up of 93 months, 5-year PFS survival was significantly better in the auto-allo group, 34% compared with 22% in the early RIC group (P<0.001). OS was also significantly improved in the auto-allo group with a 5-year rate of 59% vs 42% in the early RIC group (P=0.001). The non-relapse mortality rate was lower in the auto-allo group than in the early RIC group, with 1- and 3-year rates of 8% and 13% vs 20% and 28%, respectively (P<0.001). The relapse/progression rate was similar in the two groups, with 5-year rates of 50% for auto-allo and 46% for early RIC (P=0.42). These data suggest that planned tandem autologous allograft can improve overall survival compared with upfront RIC allograft alone in patients with multiple myeloma.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Adulto , Idoso , Aloenxertos , Autoenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Thirty-five patients with myelodysplastic syndromes (MDS) were treated with BMT between 1986 and 1994. Their median age was 41 years (range 23-60). Thirteen patients had transfusion-dependent refractory anaemia (RA). Twenty-two patients suffered from more advanced stages of MDS, 15 being in complete remission (CR) after chemotherapy. In 31 recipients, pretransplant conditioning consisted of cyclophosphamide and TBI with or without the addition of idarubucin; four patients were conditioned with other schedules. Donors were genotypically HLA-identical and MLC-negative siblings in 32, and others in three cases. All patients received a graft depleted of 98% of T lymphocytes using counterflow centrifugation. Fourteen patients are alive and in continuous remission with a median follow-up of 20 months (range 15-113) after BMT. Seven patients relapsed between 3 and 18 months after BMT and subsequently died. Fourteen transplantation-related deaths occurred. Outcome in patients under and over 40 years old was comparable. The probability of disease-free survival (DFS) at 2 years after BMT was 39% (95% confidence interval (CI), 22-56%). Considering patients with HLA-identical and MLC-negative sibling donors transplanted for RA (n = 11) or more advanced stages of MDS in CR (n = 14), the probabilities of DFS were 73% (95% CI, 47-99%) and 42% (95% CI, 15-69%), respectively. This indicates that BMT with lymphocyte-depleted grafts can cure a substantial number of relatively old patients with MDS, especially when grafts from HLA-identical and MLC-negative siblings are used and patients are suffering from RA.
Assuntos
Transplante de Medula Óssea , Síndromes Mielodisplásicas/terapia , Adulto , Fatores Etários , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/imunologia , Família , Feminino , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Antígenos HLA , Humanos , Depleção Linfocítica , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Síndromes Mielodisplásicas/mortalidade , Estudos Retrospectivos , Taxa de Sobrevida , Linfócitos T/imunologia , Doadores de Tecidos , Condicionamento Pré-Transplante , Transplante HomólogoRESUMO
In an effort to reduce the relapse rate after unpurged autologous bone marrow transplantation (ABMT) in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the standard conditioning regimens (cyclophosphamide/busulphan and cyclophosphamide/TBI) were intensified by adding idarubicin. Seventeen patients received a continuous infusion of 21 mg idarubicin/m2/day for 2 consecutive days in addition to the standard preparative regimen. Thirteen patients served as a historical control group. The 2-year disease-free survival (DFS) of 82% in the study group was significantly (P = 0.047) better compared to 46% DFS in the control group. The relapse rate (RR) was also significantly lower (7% vs 45%; P = 0.035) in the study group. The median time to reach a white cell count (WCC) of 0.5 x 10(9)/l was 20 days in the study group vs 17 days (P = NS) in the control group. The median time until recovery of the platelet counts to 20 x 10(9)/l was 152 days in the study group vs 57 days (P = NS) in the control group. The hypoplasia in the study group resulted in a trend towards a higher need for transfusions: a median number of 38 units of erythrocytes vs 23 units in the control group (P = NS) and 23 units of platelet vs 18 units in the control group (P = NS). This pilot study suggests that addition of idarubicin to the standard conditioning regimens may improve DFS and overall survival (OS) of patients with AML treated with ABMT in CR1. These results should be confirmed in a prospective randomized study.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Transplante de Medula Óssea , Leucemia Mieloide/terapia , Condicionamento Pré-Transplante/métodos , Doença Aguda , Adulto , Bussulfano/administração & dosagem , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Transplante Autólogo , Irradiação Corporal TotalRESUMO
One hundred and thirty-one patients were transplanted for AML-CR1, ALL-CR1 or CML-CP1 after conditioning with 120 mg/kg body weight cyclophosphamide and 2 x 4.5 Gy TBI. Conditioning was intensified with the addition of 42 mg/m2 idarubicin. Grafts were T cell-depleted using counterflow centrifugation. Donors were HLA-identical siblings. We compared outcome of BMT in 109 patients aged less than 50 (median, 35) years with that of 22 patients with an age of 50 years or more (median, 53 years). For the patients aged <50 years, 2-year probabilities of treatment-related mortality, relapse, survival and leukemia-free survival were 26% (95% CI, 17% to 35%), 26% (95% CI, 17% to 35%), 64% (95% CI, 55% to 73%), and 56% (95% CI, 47% to 65%). For the patients aged > or =50 years, these figures were 13% (95% CI, 0% to 30%), 24% (95% CI, 6% to 42%), 66% (95% CI, 46% to 86%), and 67% (95% CI, 47% to 87%), respectively. Outcome did not differ significantly between the two age groups. TRM was within the range of that reported in the literature for recipients of T cell-depleted grafts. We conclude that T cell-depleted transplantation after a conditioning regimen that was intensified with the addition of idarubicin is feasible in patients aged > or =50 years. For this age group of patients, results of nonmyeloablative regimens should be compared with that obtained with T cell-depleted grafts.
Assuntos
Transplante de Medula Óssea/fisiologia , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Leucemia Mieloide Aguda/terapia , Depleção Linfocítica , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T/imunologia , Adolescente , Adulto , Fatores Etários , Transplante de Medula Óssea/imunologia , Transplante de Medula Óssea/mortalidade , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Humanos , Idarubicina/uso terapêutico , Leucemia Mieloide Aguda/mortalidade , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
A 37-year-old male developed massive pleural effusion leading to respiratory failure and electromechanical dissociation within 24 h after the second dose of 4200 mg cyclophosphamide (CY) during conditioning for allogeneic bone marrow transplantation for chronic myelogenous leukemia. After resuscitation and bilateral pleural drainage he recovered within 1 day. Subsequently, total body irradiation was given and with a delay of 1 day the transplantation procedure was continued without major complications. No explanation for this idiosyncratic reaction other than the administration of high dose CY in combination with mesna rescue was found. This reaction has not been reported before in the literature.