RESUMO
Despite advances in the understanding of the pathophysiology of cytomegalovirus (CMV) infection, it remains as one of the most common infectious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The aim of this study was to determine the genotype of cytokines and chemokines in donor and recipient and their association with CMV reactivation. Eighty-five patients receiving an allo-HSCT from an HLA-identical sibling donor were included in the study. Fifty genes were selected for their potential role in the pathogenesis of CMV infection. CMV DNAemia was evaluated until day 180 after allo-HSCT. CMV reactivation was observed in 51/85 (60%) patients. Of the 213 genetic variants selected, 11 polymorphisms in 7 different genes (CXCL12, IL12A, KIR3DL1, TGFB2, TNF, IL1RN, and CD48) were associated with development or protection from CMV reactivation. A predictive model using five of such polymorphisms (CXCL12 rs2839695, IL12A rs7615589, KIR3DL1 rs4554639, TGFB2 rs5781034 for the recipient and CD48 rs2295615 for the donor) together with the development of acute GVHD grade III/IV improved risk stratification of CMV reactivation. In conclusion, the data presented suggest that the screening of five polymorphisms in recipient and donor pre-transplantation could help to predict the individual risk of CMV infection development after HLA-identical allo-HSCT.
Assuntos
Infecções por Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Citomegalovirus/genética , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/genética , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunogenética , Estudos Retrospectivos , Transplante Homólogo/efeitos adversosRESUMO
Post-transplant cyclophosphamide (PTCY) effectively prevents graft-versus-host disease after unmanipulated HLA-haploidentical HSCT. The use of PTCY in the unrelated donor HSCT setting is less explored. We conducted a retrospective study of 132 consecutive patients undergoing a matched or 9/10 mismatched unrelated donor HSCT in 4 centers in Spain, 60 with anti-thymocyte globulin (ATG)-based prophylaxis combined with MTX-CsA, and 72 using a PTCY-based regimen. Peripheral blood stem cells were used as graft in most patients (111 patients, 84%); mMUD donors were balanced between groups. Cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days were lower in the PTCy group (46% vs. 67%, p = 0.008; 3% vs. 34%, p = 0.003), without statistically significant differences in the 2-year cumulative incidence of chronic moderate-severe GVHD. At 2 years, no significant differences were observed in overall survival, event-free survival, cumulative incidence of relapse, and non-relapse mortality. GVHD was the most frequent cause of NRM in the ATG group. No differences were observed between groups in the composite endpoint of GVHD-free and relapse-free survival. In this study, PTCy combined with additional immunosuppression after MUD/mMUD HSCT showed a reduction of aGVHD rate with safety results comparable to those obtained with the ATG-based prophylaxis.
Assuntos
Soro Antilinfocitário/administração & dosagem , Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco de Sangue Periférico , Doadores não Relacionados , Adolescente , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Hepatic veno-occlusive disease or sinusoidal obstruction syndrome (VOD/SOS) is a threatening complication after both autologous and allogeneic hematopoietic stem cell transplantation (HSCT), with high mortality rates despite early medical treatment, including the use of defibrotide (DF). We retrospectively analyzed 185 unmanipulated haploidentical (haplo-) HSCT with post-transplantation cyclophosphamide as graft-versus-host disease prophylaxis performed consecutively between 2011 and June 2019 in a single center. Seventeen patients (9.2%) were diagnosed with VOD/SOS. Based on revised European Society for Blood and Marrow Transplantation severity criteria, the VOD/SOS cases were classified as mild in 2 patients (11.7%), moderate in 2 (11.7%), severe in 2 (11.7%), and very severe in 11 (64.9%). Thirteen patients (76%) were treated with DF, including all patients with severe or very severe VOD/SOS, except 1 patient with CNS hemorrhage. Sixteen patients (94%) were alive at day +100 after HSCT. Seven patients (41%) with very severe VOD/SOS were treated with transjugular intrahepatic portosystemic shunt (TIPS) owing to rapid clinical or analytical deterioration or refractory hepatorenal syndrome despite medical treatment, including DF. TIPS insertion was performed at a median time since VOD/SOS diagnosis of 4 days (range, 1 to 28 days) without technical complications in any case. The median hepatic venous pressure gradient before and after TIPS treatment was 24 mmHg (range, 14 to 29 mmHg) and 7 mmHg (range, 2 to 11 mmHg), respectively, with a median drop of 16 mmHg (range, 9 to 19 mmHg). Following TIPS insertion, all patients showed clinical improvement with hepatomegaly, ascites, and renal failure resolution, and all showed analytical improvement with reduced alanine aminotransferase (ALT), creatinine, and international normalized ratio values, except for patient 2, whose indication for TIPS was refractory hepatorenal syndrome with a normal ALT level. The 6 patients who had initiated DF before TIPS insertion completed 21 days of treatment. All patients met the criteria for complete remission (CR) at a median of 8 days after TIPS insertion (range, 2 to 82 days). The 100-day overall survival was 100%. For patients with rapid progressive VOD/SOS, early TIPS insertion allowed completion of DF therapy. The use of TIPS together with DF resulted in CR and no associated complications with no VOD/SOS-associated mortality despite high severity. In our experience, timely and individualized use of TIPS significantly improves outcomes of very severe VOD/SOS after haplo-HSCT. Therefore, TIPS should be promptly considered in rapidly progressive cases.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Hepatopatia Veno-Oclusiva , Derivação Portossistêmica Transjugular Intra-Hepática , Ciclofosfamida/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Hepatopatia Veno-Oclusiva/tratamento farmacológico , Hepatopatia Veno-Oclusiva/etiologia , Humanos , Polidesoxirribonucleotídeos/uso terapêutico , Estudos RetrospectivosRESUMO
Accurate prognostic tools are crucial to assess the risk/benefit ratio of allogeneic hematopoietic cell transplantation (allo-HCT) in patients with myelofibrosis (MF). We aimed to evaluate the performance of the Myelofibrosis Transplant Scoring System (MTSS) and identify risk factors for survival in a multicenter series of 197 patients with MF undergoing allo-HCT. After a median follow-up of 3.1 years, 47% of patients had died, and the estimated 5-year survival rate was 51%. Projected 5-year risk of nonrelapse mortality and relapse incidence was 30% and 20%, respectively. Factors independently associated with increased mortality were a hematopoietic cell transplantation-specific comorbidity index (HCT-CI) ≥3 and receiving a graft from an HLA-mismatched unrelated donor or cord blood, whereas post-transplant cyclophosphamide (PT-Cy) was associated with improved survival. Donor type was the only parameter included in the MTSS model with independent prognostic value for survival. According to the MTSS, 3-year survival was 62%, 66%, 37%, and 17% for low-, intermediate-, high-, and very high-risk groups, respectively. By pooling together the low- and intermediate-risk groups, as well as the high- and very high-risk groups, we pinpointed 2 categories: standard risk and high risk (25% of the series). Three-year survival was 62% in standard-risk and 25% in high-risk categories (P < .001). We derived a risk score based on the 3 independent risk factors for survival in our series (donor type, HCT-CI, and PT-Cy). The corresponding 5-year survival for the low-, intermediate-, and high-risk categories was 79%, 55%, and 32%, respectively (P < .001). In conclusion, the MTSS model failed to clearly delineate 4 prognostic groups in our series but may still be useful to identify a subset of patients with poor outcome. We provide a simple prognostic scoring system for risk/benefit considerations before transplantation in patients with MF.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Mielofibrose Primária , Humanos , Mielofibrose Primária/terapia , Prognóstico , Condicionamento Pré-Transplante , Transplante Homólogo , Resultado do TratamentoRESUMO
Cytokine release syndrome (CRS) is a systemic inflammatory response with aberrant immune activation and immune hyperstimulation, that leads to increased cytokine levels and inflammation. CRS has been described after antibody and cellular-based therapies. The use of posttransplant cyclophosphamide (PTCy) as graft-vs-host disease (GVHD) prophylaxis in haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has led to the extension of allogeneic HSCT to patients without HLA-identical donors. Furthermore, PTCy has also been introduced in matched and unrelated donor HSCT. However, description of incidence and clinical impact of CRS on outcomes in these patients is scarce. We retrospectively analyzed 107 consecutive haplo-HSCT and 39 HLA-identical HSCT with PTCy from 2010 to 2017 in our institution. We used published CRS criteria to identify 76% and 14% of patients who developed CRS after haplo-HSCT and HLA-identical HSCT, respectively. Most patients presented CRS grades 1 and 2. Only one patient from the whole series presented grade 3 CRS and required tocilizumab therapy. The use of peripheral blood stem cells (PBSC), as well as total nucleated cells infused were associated with an increased risk of CRS. Patients who presented CRS developed grade II-IV acute GVHD more frequently than those who did not (60% vs 28.6% respectively, P = .012). The development of CRS was not significantly associated with nonrelapse mortality or overall survival. CRS is a frequent complication after PBSC haploidentical T-repleted HSCT, but significantly less frequent after HLA-identical HSCT. Most cases are mild. Prompt identification allows adequate management of severe forms.
Assuntos
Antineoplásicos Alquilantes/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/efeitos adversos , Síndrome da Liberação de Citocina/etiologia , Doença Enxerto-Hospedeiro/etiologia , Neoplasias Hematológicas/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Adulto , Idoso , Terapia Combinada , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/patologia , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/patologia , Neoplasias Hematológicas/patologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Espanha/epidemiologia , Taxa de Sobrevida , Condicionamento Pré-Transplante , Transplante Homólogo , Adulto JovemRESUMO
Invasive fungal infections are one of the main infectious complications in allogeneic stem cell transplantation (SCT). Triazoles (voriconazole, posaconazole) are the main prophylactic and therapeutic options for the treatment of invasive aspergillosis. However, pharmacological interactions and hepatotoxicity limit its use. Isavuconazole (ISV) is a recently approved azole with a promising interaction and safety profile. We present a case with invasive aspergillosis in the post-allogeneic SCT setting in a critically ill patient with severe multiorgan failure due to veno-occlusive disease. The patient was treated with ISV and B amphotericin during severe kidney and liver failure and multiple immunosuppressants, without significant drug-related toxicity and with favorable outcome. The interaction and safety profile of ISV is discussed along the reported experience. ISV can be an effective salvage therapy even in complex clinical situations with multiple potential interactions.
Assuntos
Antifúngicos/uso terapêutico , Aspergilose/terapia , Transplante de Células-Tronco Hematopoéticas , Nitrilas/uso terapêutico , Piridinas/uso terapêutico , Triazóis/uso terapêutico , Adulto , Aspergilose/tratamento farmacológico , Aspergillus fumigatus/genética , Aspergillus fumigatus/isolamento & purificação , DNA Fúngico/metabolismo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Tórax/diagnóstico por imagem , Transplante Homólogo/efeitos adversosRESUMO
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLA-matched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT. Cyclophosphamide (Cy) is an alkylating agent with antineoplastic and immunosuppressive activity, whose bioactivation requires the activity of polymorphic enzymes in the liver to produce phosphoramide mustard, which is a DNA alkylating agent. To identify polymorphisms in the genes of Cy metabolism and correlate them with post-HSCT complications [GVHD, sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis (HC) and transplant-related mortality (TRM)], we designed a custom next-generation sequencing panel with Cy metabolism enzymes. We analyzed 182 patients treated with haplo-HSCT with PT-Cy from 2007 to 2019, detecting 40 variants in 11 Cy metabolism genes. Polymorphisms in CYP2B6, a major enzyme involved in Cy activation, were associated with decreased activity of this enzyme and a higher risk of Graf-versus-host disease (GVHD). Variants in other activation enzymes (CYP2A6, CYP2C8, CYP2C9, CYP2C19) lead to decreased enzyme activity and were associated with GVHD. Polymorphisms in detoxification genes such as glutathione S-transferases decreased the ability to detoxify cyclophosphamide metabolites due to lower enzyme activity, which leads to increased amounts of toxic metabolites and the development of III-IV acute GVHD. GSMT1*0 a single nucleotide polymorphism previously recognized as a risk factor for SOS was associated with a higher risk of SOS. We conclude that polymorphisms of genes involved in the metabolism of cyclophosphamide in our series are associated with severe grades of GVHD and toxicities (SOS and TRM) after haplo-HSCT and could be used to improve the clinical management of transplanted patients.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Alquilantes , Ciclofosfamida/efeitos adversos , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP2C9 , DNA , Glutationa , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Leucemia Mieloide Aguda/terapia , Polimorfismo Genético , TransferasesRESUMO
BACKGROUND: "Hospital-at-home" (HAH) programs have been shown to optimize resource utilization, shorten hospitalization and prevent nosocomial infection. METHODS: We retrospectively analysed data regarding implementation of an HAH unit for caring patients with hematological malignancies in our center, during the COVID-19 pandemic. RESULTS: Between January and November 2020, 105 patients were treated in the HAH unit for a total of 204 episodes. Nine patients with multiple myeloma (MM) received autologous HSCT (auto-HSCT). Three patients with acute myeloid leukemia (AML) received consolidation therapy, 32 patients underwent clinical and analytical monitoring, 20 were transplant recipients early discharged (5 auto-HSCT and 15 allo-HSCT) and 2 had received CART cells therapy. Azacitidine, bortezomib and carfilzomib were administered at home to 54 patients with AML, myelodysplastic syndrome (MDS) or MM. A median of 17 (IQR 13-19) days of admission per patient and a total of 239 visits to the Hematology day-care hospital were avoided. Overall, 28 patients (14% of all episodes) needed admission to the hospital, 4 of them due to COVID-19. CONCLUSIONS: Implementation of a Hematology HAH unit was feasible and safe, and provided thorough advanced care to a high-risk population. Advanced care-at-home strategies can be crucial during times of COVID-19 to minimize treatment interruptions and reduce the risk of cross-infections.
Assuntos
COVID-19 , Continuidade da Assistência ao Paciente , Neoplasias Hematológicas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , Gerenciamento Clínico , Estudos de Viabilidade , Feminino , Transplante de Células-Tronco Hematopoéticas , Hospitalização , Humanos , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Síndromes Mielodisplásicas/terapia , Estudos Retrospectivos , Transplante Autólogo , Adulto JovemRESUMO
Severe infections and their attributable mortality are major complications in recipients of allogeneic hematopoietic stem cell transplantation (alloSCT). We herein report 236 adult patients who received haploSCT with PTCy. The median follow-up for survivors was 37 months. The overall incidence of bloodstream infections by gram-positive and gram-negative bacteria at 37 months was 51% and 46%, respectively. The incidence of cytomegalovirus infection was 69%, while Epstein Barr virus infections occurred in 10% of patients and hemorrhagic cystitis in 35% of cases. Invasive fungal infections occurred in 11% at 17 months. The 3-year incidence of infection-related mortality was 19%. The median interval from transplant to IRM was 3 months (range 1-30), 53% of IRM occurred >100 days post-haploSCT. Risk factors for IRM included age >50 years, lymphoid malignancy, and developing grade III-IV acute GvHD. Bacterial infections were the most common causes of IRM (51%), mainly due to gram-negative bacilli BSI. In conclusion, severe infections are the most common causes of NRM after haploSCT with PTCy, with a reemergence of gram-negative bacilli as the most lethal pathogens. More studies focusing on the severe infections after haploSCT with PTCy and differences with other types of alloSCT in adults are clearly warranted.
Assuntos
Infecções por Vírus Epstein-Barr , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Antibacterianos/uso terapêutico , Ciclofosfamida , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Herpesvirus Humano 4 , Humanos , Pessoa de Meia-Idade , Condicionamento Pré-TransplanteRESUMO
Myeloid neoplasms (MN) with germline predisposition (MNGP) are likely to be more common than currently appreciated. Many of the genes involved in MNGP are also recurrently mutated in sporadic MN. Therefore, routine analysis of gene panels by next-generation sequencing provides an effective approach to detect germline variants with clinical significance in patients with hematological malignancies. Gene panel sequencing was performed in 88 consecutive and five nonconsecutive patients with MN diagnosis. Disease-causing germline mutations in CEBPα, ASXL1, TP53, MPL, GATA2, DDX41, and ETV6 genes were identified in nine patients. Six out of the nine patients with germline variants had a strong family history. These patients presented great heterogeneity in the age of diagnosis and phenotypic characteristics. In our study, there were families in which all the affected members presented the same subtype of disease, whereas members of other families presented various disease phenotypes. This intrafamiliar heterogeneity suggests that the acquisition of particular somatic variants may drive the evolution of the disease. This approach enabled high-throughput detection of MNGP in patients with MN diagnosis, which is of great relevance for both the patients themselves and the asymptomatic mutation carriers within the family. It is crucial to make a proper diagnosis of these patients to provide them with the most suitable treatment, follow-up, and genetic counseling.
Assuntos
Predisposição Genética para Doença , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Neoplasias Hematológicas/genética , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) has shown favorable results in the treatment of hematological malignancies. Despite the use of post-transplant cyclophosphamide (PTCy), graft versus host disease (GVHD) remains as one of the main complications in this setting. Since the skin appears affected in up to 80% of cases of acute GVHD (aGVHD), its prognosis and diagnosis are essential for the correct management of these patients. Plasma concentration of elafin, an elastase inhibitor produced by keratinocytes, has been described elevated at the diagnosis of skin GVHD, correlated with the grade of GVHD, and associated with an increased risk of death. In this study we explored elafin plasma levels in the largest series reported of T cell-replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed ("discovery cohort"). Elafin levels at days +15 were no associated with chronic GVHD, non-relapse mortality, relapse, therapy-resistant GVHD, or overall survival. In our series, elafin levels at day +30 were not associated with post-transplant complications. On the other hand, elafin plasma levels at day +15 were higher in patients with severe skin aGVHD (21,313 vs.14,974 pg/ml; p = 0.01). Of note, patients with higher elafin plasma levels at day +15 presented a higher incidence of stage III-IV skin aGVHD (HR = 18.9; p < 0.001). These results were confirmed (HR = 20.6; p < 0.001) in an independent group of patients (n = 62), i.e. the "validation cohort." These data suggest that measurement of elafin in patients undergoing haplo-HSCT with PTCy might be useful for an early identification of those patients who are at higher risk of suffering severe skin aGVHD and thus, improve their treatment and prognosis.
Assuntos
Biomarcadores/sangue , Ciclofosfamida/uso terapêutico , Elafina/sangue , Doença Enxerto-Hospedeiro/sangue , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Pele/patologia , Transplante Haploidêntico , Adulto JovemRESUMO
Haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) with high-dose cyclophosphamide (PTCy) has resulted in a low incidence of graft-vs.-host disease (GVHD), graft failure, and non-relapse mortality. However, post-transplantation relapse remains a common cause of treatment failure in high-risk patients. Unraveling the mechanisms of relapse is therefore crucial for designing effective relapse treatment strategies. One of these mechanisms is the loss of the mismatched HLA on the recipient's leukemic cells. To study the incidence and clinical relevance of this phenomenon, we analyzed 181 patients treated with Haplo-HSCT with PTCy (2007-2019), of which 37 relapsed patients after transplantation. According to the kit employed for HLA-loss analysis, among 22 relapsed patients, we identified HLA loss at relapse in 6 of the 22 patients (27%) studied. Based on the results obtained, the genomic loss of HLA was more common in females than males (66 vs. 33%) and HLA-loss relapses occurred later than classical relapses (345 vs. 166 days). Moreover, the patients with HLA-loss had a greater presence of active disease at the time of transplantation and had undergone a larger number of treatment lines than the group with classical relapses (66 vs. 43% and 66 vs. 18%, respectively). Four of these relapses were studied retrospectively, while two were studied prospectively, the results of which could be considered for patient management. Additionally, two relapsed patients analyzed retrospectively had myeloid neoplasms. One patient had not undergone any treatment, and three had undergone donor lymphocyte infusions (DLIs) and chemotherapy. All presented severe GVHD and disease progression. In contrast, the two patients studied prospectively had a lymphoid neoplasm and were not treated with DLIs. One of them was treated with chemotherapy but died from disease progression, and the other patient underwent a second Haplo-HSCT from a different donor and is still alive. We can conclude that the detection of HLA-loss at the onset of relapse after Haplo-HSCT with PTCy could help in clinical practice to select appropriate rescue treatment, thereby avoiding the use of DLIs or a second transplantation from the same donor.
Assuntos
Antígenos HLA/imunologia , Neoplasias Hematológicas/imunologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante Haploidêntico/métodos , Adolescente , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Agonistas Mieloablativos/uso terapêutico , Recidiva Local de Neoplasia/imunologia , Recidiva , Evasão Tumoral/imunologia , Adulto JovemRESUMO
Background: Donor specific antibodies (DSAs) can be responsible for graft failure (GF) in the setting of mismatched hematopoietic stem cell transplantation (HSCT). The aim of our study is to report the experience of the Madrid Group of Hematopoietic Transplant (GMTH) in patients with DSAs undergoing haplo-HSCT. Methods: Patients undergoing haplo-HSCT in centers from the GMTH from 2012 to 2020 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay; monitoring was performed during desensitization on days -14, -7, 0 and in a weekly basis until neutrophil engraftment. Desensitization strategies varied depending on center experience, immunofluorescence intensity, complement fixation and type of antibodies. Results: We identified a total of 20 haplo-HSCT in 19 patients performed with DSAs in 5 centers. 10 (53%) patients presented anti-HLA class I DSAs (6 of them with > 5000 mean fluorescence intensity (MFI)), 4 (21%) presented anti-HLA class II (1 with > 5000 MFI) and 5 (26%) presented both anti-HLA class I and II (5 with > 5000 MFI). 90% of patients received at least two treatments as desensitization strategy and all experienced a decrease of MFI after desensitization (mean reduction 74%). Only one patient who developed progressive increase of MFI after infusion developed GF. Desensitization treatments used included rituximab, immunoglobulins, therapeutic plasma exchange, incompatible platelets, buffy coat and immunosuppressors. Seventeen (90%) patients achieved neutrophil engraftment; one patient died before engraftment because of infection and one patient with class I DSAs developed primary GF despite an intensive desensitization. After a median follow-up of 10 months, OS and EFS were 60% and 58%, respectively, cumulative incidence of relapse was 5% and NRM was 32%. Conclusions: Despite the optimal strategy of DSAs desensitization remains unclear, the use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor.
Assuntos
Rejeição de Enxerto/imunologia , Transplante Haploidêntico/métodos , Transplantes/imunologia , Estudos de Coortes , Feminino , Rejeição de Enxerto/mortalidade , Antígenos HLA , Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doadores de TecidosRESUMO
Despite advances in understanding the biology of mature T and natural killer (NK)/T cell neoplasia, current therapies, even the most innovative ones, are still far from ensuring its cure. The only treatment to date that has been shown to control aggressive T cell neoplasms in the long term is allogeneic stem cell transplantation (alloSCT). We aim to report the results of alloSCT for advanced mature T and NK/T neoplasias performed in centers from our national GELTAMO/GETH (Grupo Español de Linfoma y Trasplante de Médula Ósea/Grupo Español de Trasplante Hematopoyético y Terapia Celular) over the past 25 years. As a secondary objective, we analyzed the results of alloSCT from haploidentical donors. We performed a retrospective analysis of all patients who received an alloSCT in Spanish centers (n = 201) from September 1995 to August 2018. The 2-year overall survival (OS) and disease-free survival (DFS) were 65.5% and 58.2%, respectively. The univariate for OS and DFS showed statistically different hazard ratios for conditioning intensity, response pre-alloSCT, comorbidity index, donor/receptor cytomegalovirus status and Eastern Cooperative Oncology Group (ECOG) pre-alloSCT, but only a better ECOG pre-alloSCT remained significant in the multivariate analysis. There was an increased incidence of relapse in those patients who did not develop chronic graft-versus-host disease (GVHD) and an increased risk of death in those developing moderate to severe acute GVHD. The 1-year nonrelapse mortality was 21.9% and was mainly due to GVHD (30%) and bacterial infections (17%). When comparing unrelated donors with haploidentical donors, we found similar results in terms of OS and DFS. There was, however, a reduction of acute GVHD in the haploidentical group (P = .04) and trend to a reduction of chronic GVHD. In conclusion, alloSCT is the only curative option for most aggressive T cell neoplasias. Haploidentical donors offer similar results to related donors in terms of survival with a reduction of acute GVHD.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Condicionamento Pré-Transplante , Humanos , Células Matadoras Naturais , Recidiva Local de Neoplasia , Sistema de Registros , Estudos RetrospectivosRESUMO
We performed a retrospective multicenter study including 140 patients with relapsed/refractory (R/R) diffuse large B cell lymphoma (DLBCL) who underwent allogeneic hematopoietic stem cell transplantation (allo-SCT) from March 1995 to November 2018. Our objective was to analyze long term outcomes. Seventy-four percent had received a previous auto-SCT (ASCT) and the median number of lines pre-allo-SCT was 3 (range 1-9). Three year-event free survival (EFS) and overall survival (OS) were 38% and 44%, respectively. Non-relapse mortality (NRM) at day 100 was 19%. Cumulative incidence of grade III-IV acute graft versus host disease (GVHD) at day 100 was 16% and moderate/severe chronic GVHD at 3 years 34%. Active disease at allo-SCT (HR 1.95, p = 0.039) (HR 2.19, p = 0.019), HCT-CI ≥ 2 (2.45, p = 0.002) (HR 2.33, p = 0.006) and donor age >37 years (HR 2.75, p = 0.014) (HR 1.98, p = 0.043) were the only independent variables both for PFS and OS, respectively. NRM was significantly modified by HCT-CI ≥ 2 (HR 4.8, p = 0.008), previous ASCT (HR 4.4, p = 0.048) and grade III-IV acute GVHD on day 100 (HR 6.13, p = 0.016). Our data confirmed that allo-SCT is a curative option for patients with R/R DLBCL, displaying adequate results for fit patients with chemosensitive disease receiving an allo-SCT from a young donor.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Adulto , Humanos , Linfoma Difuso de Grandes Células B/terapia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Condicionamento Pré-TransplanteRESUMO
Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment strategy in HIV-related lymphoma patients (HIV+ Ly). Nevertheless, current evidence is mainly based on reports from specialized centers, multicentre heterogeneous studies, noncomparative analyses, or registry data-based comparisons. Likewise, the risk of infections reported so far for this population, seems to be similar to that of HIV- patients, and it does not seem to impact on mortality. We report a single-center retrospective comparative analysis of AHCT procedural results, infectious complications and survival in HIV+ Ly matched with a non-HIV comparative cohort. Thirty-three HIV+ patients and 45 matched controls, who underwent ASCT between 2000 and 2016, were included. Transplant-related toxicity, event-free survival, relapse rate, and overall survival were similar in both groups. Engraftment was delayed in HIV+ Ly (neutrophils: 15 vs 12 days (p = 0.0001), and platelets 39 vs 16 days (p = 0.00001)). Bacterial infections during the pre-engraftment period were more frequent in HIV+ Ly (RR 2.24, p = 0.017), as well as viral infections in the postengraftment period (RR 3.22, p = 0.004). CMV reactivation was more frequent in HIV+ Ly (39% vs 15% p = 0.007). In conclusion, ASCT is viable and effective in HIV+ Ly, but it is associated with a higher risk of infection.
Assuntos
Infecções por HIV , Transplante de Células-Tronco Hematopoéticas , Linfoma , Infecções por HIV/complicações , Humanos , Linfoma/complicações , Linfoma/terapia , Recidiva Local de Neoplasia , Estudos Retrospectivos , Transplante de Células-Tronco , Transplante AutólogoAssuntos
Antígenos HLA/análise , Leucemia Mieloide Aguda/terapia , Transfusão de Leucócitos , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Azacitidina/administração & dosagem , Citarabina/administração & dosagem , Sobrevivência de Enxerto , Efeito Enxerto vs Leucemia , Antígenos HLA/genética , Histocompatibilidade , Humanos , Idarubicina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/etiologia , Masculino , Pessoa de Meia-Idade , Indução de Remissão , Doadores de TecidosRESUMO
Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), in the largest series reported of T cell-replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.
Assuntos
Ciclofosfamida/administração & dosagem , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Proteína 1 Semelhante a Receptor de Interleucina-1/sangue , Proteínas Associadas a Pancreatite/sangue , Doença Aguda , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Intervalo Livre de Doença , Feminino , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de Sobrevida , Transplante HaploidênticoRESUMO
Posttransplant cyclophosphamide (PTCy) effectively prevents graft-versus-host disease (GVHD) after HLA-haploidentical hematopoietic stem cell transplantation (HSCT). The use of PTCy in HLA-identical HSCT is less explored. We conducted a retrospective study of 107 consecutive patients undergoing an HLA-identical sibling (10/10) HSCT in 2 centers in Spain, 50 with GVHD prophylaxis with methotrexate-cyclosporin A (MTX-CsA) and 57 using a PTCy-based regimen with additional immunosuppression. Graft source was unmanipulated mobilized peripheral blood stem cells (PBSC) in most patients (97 patients, 91%). Cumulative incidences of grade II to IV and III to IV acute GVHD at 100 days were lower in the PTCy group (22.6% vs 52.2%, P = .0015; 8.8% vs 24.4%, P = .016), without statistically significant differences in the 2-year cumulative incidence of chronic moderate to severe GVHD (16.7% vs 26%, P = .306). At 2 years, no statistically significant differences were observed in OS (78% vs 56%, P = .088), EFS (62.5% vs 48%, P = .054), relapse (28% vs 27%, P = .47), and NRM (8.8% vs 24%, P = .054). The composite endpoint of GVHD and relapse-free survival (GRFS) was favorable for the PTCy group (24% vs 48%, P = .011), PTCy being the sole independent factor identified in the multivariate analysis for this endpoint. In this study, PTCy combination with additional immunosuppression using mostly PBSCs grafts showed a reduction of acute GVHD rate and an impact on GRFS, with safety results comparable with those obtained with MTX-CsA. Further prospective studies are needed to confirm these observations..