RESUMEN
PURPOSE OF REVIEW: Viral infections continue to burden allogeneic hematopoietic cell transplant (HCT) recipients. We review the epidemiology, diagnosis, and management of human herpesvirus (HHV)-6, HHV-8 and parvovirus B19 following HCT. RECENT FINDINGS: Advances in HCT practices significantly improved outcomes but impact viral epidemiology: post-transplant cyclophosphamide for graft-versus-host disease prevention increases HHV-6 reactivation risk while the impact of letermovir for CMV prophylaxis - and resulting decrease in broad-spectrum antivirals - is more complex. Beyond the well established HHV-6 encephalitis, recent evidence implicates HHV-6 in pneumonitis. Novel less toxic therapeutic approaches (brincidofovir, virus-specific T-cells) may enable preventive strategies in the future. HHV-8 is the causal agent of Kaposi's sarcoma, which is only sporadically reported after HCT, but other manifestations are possible and not well elucidated. Parvovirus B19 can cause severe disease post-HCT, frequently manifesting with anemia, but can also be easily overlooked due to lack of routine screening and ambiguity of manifestations. SUMMARY: Studies should establish the contemporary epidemiology of HHV-6, and other more insidious viruses, such as HHV-8 and parvovirus B19 following HCT and should encompass novel cellular therapies. Standardized and readily available diagnostic methods are key to elucidate epidemiology and optimize preventive and therapeutic strategies to mitigate the burden of infection.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Herpesvirus Humano 6 , Herpesvirus Humano 8 , Parvovirus B19 Humano , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Parvovirus B19 Humano/aislamiento & purificación , Infecciones por Parvoviridae/epidemiología , Infecciones por Parvoviridae/diagnóstico , Antivirales/uso terapéutico , Infecciones por Roseolovirus/epidemiología , Infecciones por Roseolovirus/virología , Infecciones por Roseolovirus/diagnóstico , Trasplante Homólogo/efectos adversos , Infecciones por Herpesviridae/epidemiología , Infecciones por Herpesviridae/virologíaRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be curative for patients with hematologic malignancies. The ideal conditioning regimen before allo-HSCT has not been established. We conducted a Phase II study to evaluate the tolerability and efficacy of clofarabine and treosulfan as conditioning regimen before allo-HSCT. The primary objective was to evaluate the cumulative incidence of nonrelapse mortality (NRM) on day +100. Forty-four patients (36 with acute myelogenous leukemia, 5 with acute lymphoblastic leukemia, 3 with myelodysplastic syndromes) were enrolled. The median patient age was 47 years, and the median duration of follow-up was 27 months. The conditioning regimen was based on clofarabine 40 mg/m2 (days -6 to -2) and treosulfan 14 g/m2 (days -6 to -4). Allogeneic hematopoietic stem cells were derived from a sibling (nâ¯=â¯22) or a well-matched unrelated donor (nâ¯=â¯22). Graft-versus-host disease (GVHD) prophylaxis consisted of antithymocyte globulin, rituximab, cyclosporine, and a short-course of methotrexate. The regimen allowed for rapid engraftment and a 100-day NRM of 18%, due mainly to bacterial infections. The incidences of grade II-IV acute GVHD and chronic GVHD were 16% and 19%, respectively. The rates of overall survival (OS), progression-free survival, and relapse at 2 years were 51%, 31%, and 50%, respectively. Significantly different outcomes were observed between patients with low-intermediate and patients with high-very high Disease Risk Index (DRI) scores (1-year OS, 78% and 24%, respectively). Our findings show that the use of treosulfan and clofarabine as a conditioning regimen for allo-HSCT is feasible, with a 78% 1-year OS in patients with a low-intermediate DRI score. However, 1-year NRM was 18%, and despite the intensified conditioning regimen, relapse incidence remains a major issue in patients with poor prognostic risk factors.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Busulfano/análogos & derivados , Busulfano/uso terapéutico , Clofarabina , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Persona de Mediana Edad , Acondicionamiento PretrasplanteRESUMEN
INTRODUCTION: the identification of a suitable donor in an appropriate timing represents a crucial step in the preparation of allogeneic stem cell transplantation (HSCT). At our Institution, for patients lacking an HLA-identical sibling, a haploidentical donor is considered in the absence of a 10/10-matched or a one-locus HLA-mismatched unrelated donor (UD), but the optimal timing of work-up of potential familiar haploidentical donor(s) by the Apheresis Team is actually unknown. PATIENTS & METHODS: we analyzed here n = 167 UD searches launched at our Hospital between July 2013 and July 2018 and looked for any correlation between the number of HLA confirmatory tests received and the final type of donor selected for HSCT, in an attempt to identify those situations where prompt evaluation of haploidentical donor(s) is warranted. RESULTS: a total of n = 117 transplants were performed and haploidentical HSCTs were n = 16 (14 %). In n = 93 cases (56 %) the number of HLA confirmatory tests received were two; they were one, zero and three for n = 52, n = 14 and n = 8 patients, respectively. Only 5 % of haploidentical donors were used when two confirmation test samples were received whereas this percentage rises to 17 % when only one sample reached the HLA lab. When no confirmation tests were available, haploidentical transplant occurred in 100 % of cases. CONCLUSIONS: besides the situations with no HLA confirmation tests, the evaluation of any haploidentical donor(s) should be promptly started also when only one HLA confirmatory test is received, in order to optimise the potential work-up process and avoid delay in transplantation.
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Prueba de Histocompatibilidad/métodos , Trasplante Haploidéntico/métodos , Femenino , Humanos , Masculino , Estudios Retrospectivos , Donante no EmparentadoRESUMEN
Of the two human herpesvirus 6 (HHV-6) species, human herpesvirus 6B (HHV-6B) encephalitis is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Guidelines for the management of HHV-6 infections in patients with hematologic malignancies or post-transplant were prepared a decade ago but there have been no other guidelines since then despite significant advances in the understanding of HHV-6 encephalitis, its therapy, and other aspects of HHV-6 disease in this patient population. Revised guidelines prepared at the 2017 European Conference on Infections in Leukaemia covering diagnosis, preventative strategies and management of HHV-6 disease are now presented.
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Neoplasias Hematológicas/complicaciones , Herpesvirus Humano 6 , Guías de Práctica Clínica como Asunto , Infecciones por Roseolovirus/diagnóstico , Infecciones por Roseolovirus/etiología , Infecciones por Roseolovirus/terapia , Antivirales/farmacología , Antivirales/uso terapéutico , Transformación Celular Viral , Terapia Combinada , Europa (Continente) , Enfermedad Injerto contra Huésped/etiología , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Huésped Inmunocomprometido , Resultado del TratamientoRESUMEN
Cells in the tumor microenvironment may be reprogrammed by tumor-derived metabolites. Cholesterol-oxidized products, namely oxysterols, have been shown to favor tumor growth directly by promoting tumor cell growth and indirectly by dampening antitumor immune responses. However, the cellular and molecular mechanisms governing oxysterol generation within tumor microenvironments remain elusive. We recently showed that tumor-derived oxysterols recruit neutrophils endowed with protumoral activities, such as neoangiogenesis. Here, we show that hypoxia inducible factor-1a (HIF-1α) controls the overexpression of the enzyme Cyp46a1, which generates the oxysterol 24-hydroxycholesterol (24S-HC) in a pancreatic neuroendocrine tumor (pNET) model commonly used to study neoangiogenesis. The activation of the HIF-1α-24S-HC axis ultimately leads to the induction of the angiogenic switch through the positioning of proangiogenic neutrophils in proximity to Cyp46a1+ islets. Pharmacologic blockade or genetic inactivation of oxysterols controls pNET tumorigenesis by dampening the 24S-HC-neutrophil axis. Finally, we show that in some human pNET samples Cyp46a1 transcripts are overexpressed, which correlate with the HIF-1α target VEGF and with tumor diameter. This study reveals a layer in the angiogenic switch of pNETs and identifies a therapeutic target for pNET patients.
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Transformación Celular Neoplásica/metabolismo , Hidroxicolesteroles/metabolismo , Tumores Neuroendocrinos/etiología , Tumores Neuroendocrinos/metabolismo , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/metabolismo , Animales , Transformación Celular Neoplásica/genética , Colestanotriol 26-Monooxigenasa/genética , Colestanotriol 26-Monooxigenasa/metabolismo , Colesterol 24-Hidroxilasa , Citocinas/metabolismo , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Activación Enzimática , Femenino , Técnica del Anticuerpo Fluorescente , Proteínas Activadoras de GTPasa/genética , Proteínas Activadoras de GTPasa/metabolismo , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunohistoquímica , Masculino , Ratones , Ratones Transgénicos , Neovascularización Patológica/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/patología , Factor A de Crecimiento Endotelial Vascular/genética , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
BACKGROUND: Invasive fungal infections (IFI) represent a common side effect of allogeneic hematopoietic stem cell transplant (allo-SCT), resulting in increased non relapse mortality (NRM) and reduced overall survival (OS) rates. Seventy-five days of Fluconazole 400 mg/d represents the standard primary antifungal prophylaxis (PAP) after allo-SCT, especially for low-risk transplants. However, the ideal dosage of fluconazole has never been tested. METHODS: Here, we report the experience of our institution on 113 consecutive patients receiving an allo-SCT from a HLA identical sibling between 1999 and 2015, where PAP consisted of fluconazole 100 mg/d only during the pre-engraftment phase. At the time of transplant, all patients were considered at low-risk for mold infection according to ECIL-5 guidelines. RESULTS: Cumulative incidence of possible-probable-proven IFI was 11.7%, while proven-probable (PP-IFI) occurred in 5.5% of patients by day 100 post transplant. Of note, only 1 patient developed invasive Candidiasis due to a non-albicans strain and stool-screening tests were negative for colonization by Candida albicans species. The incidence of 1-year acute and 2-year chronic graft-versus-host-disease (GVHD) was 30% and 45%, respectively. Three-year OS and 1-year NRM were 53% and 11.3%, respectively. CONCLUSION: In summary, fungal prophylaxis with fluconazole 100 mg/d results in very low incidence of PP-IFI, GVHD and NRM in low-risk allo-SCT.
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Profilaxis Antibiótica/métodos , Antifúngicos/administración & dosificación , Fluconazol/administración & dosificación , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones Fúngicas Invasoras/prevención & control , Adolescente , Adulto , Anciano , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/prevención & control , Antígenos HLA/inmunología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Incidencia , Infecciones Fúngicas Invasoras/epidemiología , Infecciones Fúngicas Invasoras/microbiología , Donadores Vivos , Linfoma/inmunología , Linfoma/mortalidad , Linfoma/cirugía , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Hermanos , Tasa de Supervivencia , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Trasplante Homólogo/efectos adversos , Trasplante Homólogo/métodos , Resultado del Tratamiento , Adulto JovenRESUMEN
Early T-cell reconstitution following allogeneic transplantation depends on the persistence and function of T cells that are adoptively transferred with the graft. Posttransplant cyclophosphamide (pt-Cy) effectively prevents alloreactive responses from unmanipulated grafts, but its effect on subsequent immune reconstitution remains undetermined. Here, we show that T memory stem cells (TSCM), which demonstrated superior reconstitution capacity in preclinical models, are the most abundant circulating T-cell population in the early days following haploidentical transplantation combined with pt-Cy and precede the expansion of effector cells. Transferred naive, but not TSCM or conventional memory cells preferentially survive cyclophosphamide, thus suggesting that posttransplant TSCM originate from naive precursors. Moreover, donor naive T cells specific for exogenous and self/tumor antigens persist in the host and contribute to peripheral reconstitution by differentiating into effectors. Similarly, pathogen-specific memory T cells generate detectable recall responses, but only in the presence of the cognate antigen. We thus define the cellular basis of T-cell reconstitution following pt-Cy at the antigen-specific level and propose to explore naive-derived TSCM in the clinical setting to overcome immunodeficiency. These trials were registered at www.clinicaltrials.gov as #NCT02049424 and #NCT02049580.
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Trasplante de Células Madre Hematopoyéticas , Memoria Inmunológica , Linfopoyesis , Células Madre/fisiología , Linfocitos T/fisiología , Adulto , Donantes de Sangre , Diferenciación Celular/inmunología , Supervivencia Celular/inmunología , Células Cultivadas , Humanos , Recuento de Linfocitos , Células Madre/citología , Células Madre/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Inmunología del Trasplante/inmunología , Trasplante HomólogoAsunto(s)
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/diagnóstico , Prueba de COVID-19 , ARN Viral , Células Madre HematopoyéticasRESUMEN
It has recently been shown that a T cell-replete allogeneic (allo) hematopoietic stem cell transplantation (HSCT) from a haploidentical donor (haplo-ID) could be a valid treatment for hematological malignancies. However, little data exist concerning older populations. We provided transplantation to 31 patients over the age of 55 years from a haplo-ID and compared their outcomes with patients of the same ages who underwent transplantation from a matched related (MRD) or an unrelated donor (UD). All 3 groups were comparable, except for their conditioning. Patients in haplo-ID group received 2 days of post-transplantation high-dose cyclophosphamide followed by cyclosporine A and mycophenolate mofetil, whereas patients in other groups received pretransplantation antithymocyte globulin, cyclosporine A, and additional mycophenolate mofetil in case of 1-antigen mismatch. All patients but 1 in the haplo-ID group engrafted. The incidence of grades 2 to 4 acute graft-versus-host disease (GVHD) was not statistically different between recipients from haplo-ID (cumulative incidence, 23%) and MRD (cumulative incidence, 21%) transplantations but it was lower than after UD HSCT (cumulative incidence, 44%). No patient in the haplo-ID group developed severe chronic GVHD, compared with cumulative incidences of 16% and 14% after MRD (P = .02) and UD (P = .03) grafts, respectively. The cumulative incidences of relapse were similar in the 3 groups, whereas nonrelapse mortality after UD HSCT was 3-fold higher than after haplo-ID or MRD HSCT. Overall, 2-year overall survival (70%), progression-free survival (67%), and progression and severe chronic GVHD-free survival (67%) probabilities after haplo-ID did not statistically differ from MRD transplantation (78%, 64%, and 51%, respectively), although they were higher than after UD transplantation (51% [P = .08], 38% [P = .02], and 31% [P = .007]). We conclude that T cell-replete haplo-ID HSCT followed by post-transplantation high-dose- cyclophosphamide in patients over 55 years is associated with promising results, similar to MRD HSCT, and is deserving prospective evaluation.
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Ciclofosfamida/administración & dosificación , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Linfocitos T/trasplante , Donante no Emparentado , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Humanos , Masculino , Persona de Mediana Edad , Tasa de SupervivenciaRESUMEN
BACKGROUND: The presence of human leukocyte antigen donor-specific antibodies (DSAs) increases the risk of graft failure in T-cell-replete haploidentical hematopoietic stem cell transplantation (haplo-HSCT) CASE REPORT: A 49-year-old female with high-risk acute myeloid leukemia in first complete remission received a haplo-HSCT from her daughter. Pretransplant recipient screening examination showed high DSAs levels against unshared class I leukocyte antigens. RESULTS: The patient underwent a desensitization program consisting of plasma exchange (PEX), polyvalent intravenous (IV) immunoglobulins, and IV tacrolimus and mycophenolate mofetil (MMF). This protocol resulted in the disappearance of the DSA anti HLA B41. Engraftment was prompt with stable full donor chimerism. CONCLUSIONS: This case report suggests that the adopted scheme is safe for reducing DSA levels and facilitating donor engraftment in patients scheduled for haplo-HSCT.
RESUMEN
Recent advances in the development of reduced-intensity conditioning (RIC) have allowed a broader range of patients to access allogeneic hematopoietic stem cell transplantation (HSCT). Reconstitution of an effective immune system post-transplant, including natural killer (NK) cells, is critical for both tumor control and infectious disease control or prevention. The development and functions of NK cells in such settings remain elusive. Here we analyzed NK cell development in HLA-matched HSCT from related or unrelated donors, after RIC that included antithymocyte globulin (N = 45 patients). Our data reveal that NK cells quickly recover after RIC-HSCT, irrespective of donor type. Rapidly re-emerging NK cells, however, remain immature for more than 6 months. Effector functions resemble that of immature NK cells because they poorly produce IFN-γ and TNF-α in response to target cell stimulation, despite a rapid acquisition of degranulation ability and MIP-1ß production. Strikingly, rapid reconstitution of cytokine production correlates with a lower relapse incidence (P = .01) and a better survival rate (P < .0001) at 1 year post-transplant, whereas degranulation capacity was associated with less relapse (P = .05). Our study demonstrates rapid quantitative reconstitution of the NK cell compartment despite administration of potent immune suppressive drugs as part of the conditioning regimen and after transplantation. However, there is a prolonged persistence of functional defects, the correction of which positively correlates with clinical outcome.
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Citocinas/inmunología , Neoplasias Hematológicas , Trasplante de Células Madre Hematopoyéticas , Células Asesinas Naturales/inmunología , Recuperación de la Función/inmunología , Acondicionamiento Pretrasplante , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/terapia , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Donante no EmparentadoRESUMEN
BACKGROUND: Alternative donors, such as unrelated umbilical cord blood (UCB) and related haploidentical (haplo) donors, are more and more frequently searched for and used for patients who are candidates for allogeneic hematopoietic stem cell transplantation but are without a suitable related or unrelated donor. The aim of the current retrospective study was to compare the outcome of patients after haplo and UCB grafts prepared using a nonmyeloablative conditioning regimen. METHODS: A total of 150 adult patients with high-risk hematologic diseases who underwent allogeneic hematopoietic stem cell transplantation from alternative donors at 2 centers (Paoli-Calmettes Institute [Marseille, France] and Humanitas Cancer Center [Milan, Italy]) were analyzed. Sixty-nine patients had haplo donors and 81 patients had UCB donors. RESULTS: The cumulative incidence of nonrecurrence mortality at 1 year was 23% in the UCB group versus 17% in the haplo group (P = .39). The incidence of grade 2 to 4 acute graft-versus-host disease and extensive chronic graft-versus-host disease in the UCB group versus the haplo group was 52% versus 29% (P = .05) and 12% versus 6% (P<.0001), respectively. The overall survival rate at 2 years was 45% in the UCB group (95% confidence interval [95% CI], 34%-56%) versus 69% in the haplo group (95% CI, 58%-80%) (P = .10). The progression-free survival rate at 2 years was 36% in the UCB group (95% CI, 25%-47%) versus 65% in the haplo group (95% CI, 53%-77%) (P = .01). CONCLUSIONS: The results of the current study suggest that for patients with high-risk hematological diseases without a related or unrelated donor, haploidentical transplants are a promising alternative option that deserves further investigation.
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Trasplante de Células Madre de Sangre del Cordón Umbilical/métodos , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Femenino , Sangre Fetal , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Trasplante Homólogo , Donante no Emparentado , Adulto JovenAsunto(s)
Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Inmunosupresores/administración & dosificación , Inmunosupresores/uso terapéutico , Pronóstico , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
The management of Hodgkin's lymphoma (HL) recurring after allogeneic stem cell transplantation is challenging. We retrospectively describe 18 adults treated with bendamustine followed by escalated donor lymphocyte infusion. Hematological toxicity was manageable (39% grade III to IV neutropenia and 28% grade III to IV thrombocytopenia). The overall response rate was 55%, with 3 complete and 7 partial responses. Median overall and progression-free survival were 11 (range, 1 to 52) and 6 (range, 1 to 28) months, respectively. One-year overall survival of responders (complete or partial) was 70% (95% confidence interval, 42% to 98%), although it was only 16% for nonresponders (n = 8). Our data show that bendamustine followed by donor lymphocyte infusion is feasible and can be efficacious as salvage treatment in HL relapsing after an allograft.
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Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad de Hodgkin/terapia , Compuestos de Mostaza Nitrogenada/uso terapéutico , Acondicionamiento Pretrasplante/métodos , Antineoplásicos Alquilantes/administración & dosificación , Clorhidrato de Bendamustina , Humanos , Linfocitos , Recurrencia Local de Neoplasia , Compuestos de Mostaza Nitrogenada/administración & dosificaciónRESUMEN
Recently, the administration of high-dose cyclophosphamide (Cy) after T cell-replete haploidentical stem cell infusion has been reported to be feasible and effective. In the original study, bone marrow (BM) was used as the source of stem cells. Here, we retrospectively analyzed the use of BM versus peripheral blood stem cells (PBSCs) in a cohort of patients receiving haploidentical T cell-replete transplantation after a nonmyeloablative conditioning regimen with postinfusion Cy. In the PBSC versus BM groups, the incidence of acute graft-versus-host disease (GVHD) was 33% versus 25%, respectively, and the incidence of chronic GVHD was 13% versus 13%, respectively. The median time to achieve a safe and unsupported absolute neutrophil and platelet count was 20 versus 21 days and 27 versus 29 days, respectively. The incidence of engraftment was also similar in the 2 cohorts. The 1-year nonrelapse mortality rate was 12% versus 22%, respectively (P = .96). Finally, nonsignificant differences in survival were observed. In conclusion, the use of PBSCs instead of BM after T cell-replete haploidentical transplantation did not appear to be detrimental in terms of either GVHD or engraftment rate. PBSCs could be a valid alternative to BM after transplantation from a haploidentical donor using postinfusion Cy.
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Antineoplásicos Alquilantes/uso terapéutico , Trasplante de Médula Ósea , Ciclofosfamida/uso terapéutico , Neoplasias Hematológicas/terapia , Trasplante de Células Madre de Sangre Periférica , Acondicionamiento Pretrasplante , Enfermedad Aguda , Adulto , Anciano , Femenino , Supervivencia de Injerto , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Haplotipos , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Prueba de Histocompatibilidad , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is recommended for patients with high-risk acute myeloid leukemia (AML). In many situations, a matched related (MRD) or matched unrelated donor (MUD) is lacking, in which case unrelated cord blood units (UCB) provide an alternative. We analyzed the outcome of consecutive high-risk AML patients prepared with reduced-intensity conditioning (RIC) regimens and allografted with UCB (n = 32) and compared their outcome with high-risk AML patients who underwent transplantation with MRD/MUD (n = 49) in the same period of time. Grade III to IV acute graft-versus-host disease (GVHD) occurred slightly more frequently in the UCB group (25%) than in the MRD/MUD group (8%) (P = .069). Conversely, we found a lower incidence of extensive chronic GVHD in the UCB group (6%) than in the MRD/MUD group (20%, P = .085). Nonrelapse mortality at 4 years was 16% and 22% in the UCB and MRD/MUD groups, respectively (P = .529). The cumulative incidence of relapse at 4 years was significantly higher in the UCB group (60%) than in the MRD/MUD group (27%, P = .006). Leukemia-free survival (LFS) and overall survival (OS) at 4 years were 25% and 34%, respectively, in the UCB group and 50% and 56%, respectively, in the MRD/MUD group (LFS, P = .029; OS, P = .072). Multivariate analyses adjusted by cytogenetics and disease status at the time of Allo-HSCT revealed that use of UCB remained an independent predictive factor of shorter LFS (hazard ratio, 2.0; 95% confidence interval, 1.1 to 3.6; P = .018), and was associated with a trend for shorter OS (hazard ratio, 1.7; 95% confidence interval, .9 to 3.2; P = .093). Whereas UCB provides an alternative for patients with high-risk AML lacking an MRD/MUD, the high incidence of relapse after RIC-based UCB Allo-HSCT is a concern. Attempts to improve leukemic control with UCB Allo-HSCT are warranted, as well as the evaluation of other alternative donors in this context.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Enfermedad Injerto contra Huésped/terapia , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Acondicionamiento Pretrasplante/métodos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Enfermedad Crónica , Análisis Citogenético , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Prueba de Histocompatibilidad , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Pronóstico , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Trasplante Homólogo , Donante no EmparentadoRESUMEN
We retrospectively analyzed outcomes of a CD34(+)-selected stem cell boost (SCB) without prior conditioning in 32 patients (male/22; median age of 54 years; range, 20 to 69) with poor graft function, defined as neutrophils ≤1.5 x 10(9)/L, and/or platelets ≤30 x 10(9)/L, and/or hemoglobin ≤8.5 g/dL). The median interval between stem cell transplantation and SCB was 5 months (range, 2 to 228). The median number of CD34(+) and CD3(+) cells were 3.4 x 10(6)/kg (.96 to 8.30) and 9 x 10(3)/kg body weight (range, 2 to 70), respectively. Hematological improvement was observed in 81% of patients and noted after a median of 30 days (range, 14 to 120) after SCB. The recipients of related grafts responded faster than recipients of unrelated grafts (20 versus 30 days, P = .04). The cumulative incidence of acute (grade II to IV) and chronic graft-versus-host disease (GVHD) after SCB was 17% and 26%, respectively. Patients with acute GVHD received a higher median CD3(+) cell dose. The 2-year probability of overall survival was 45%. We suggest that SCB represents an effective approach to improve poor graft function post transplantation, but optimal timing of SCB administration, anti-infective, and GVHD prophylaxis needs further evaluation.
Asunto(s)
Antígenos CD34/inmunología , Enfermedad Injerto contra Huésped/terapia , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Enfermedad Aguda , Adulto , Complejo CD3/inmunología , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/inmunología , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Neutrófilos/citología , Neutrófilos/inmunología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Trasplante HomólogoRESUMEN
Nonmyeloablative (NMA) regimens allow the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients considered unfit for standard myeloablative conditioning (MAC) regimens using high-dose alkylating agents with or without total body irradiation (TBI). Reduced-intensity conditioning (RIC) regimens, based on fludarabine (Flu), busulfan (Bu), and rabbit antithymocyte globulin (r-ATG), represent an intermediate alternative between NMA and MAC regimens. This platform was subsequently optimized by the introduction of i.v. Bu and the use of 5 mg/kg r-ATG, based on the hypothesis that these modifications would improve the safety of RIC allo-HSCT. Here we report a study conducted at our institution on 206 patients, median age 59 years, who underwent allo-HSCT after conditioning with Flu, 2 days of i.v. Bu, and 5 mg/kg r-ATG (FBx-ATG) between 2005 and 2012. The prevalence of grade III-IV acute graft-versus-host disease (GVHD) was 9%, and that of extensive chronic GVHD was 22%. Four-year nonrelapse mortality (NRM), relapse, and overall survival (OS) rates were 22%, 36%, and 54%, respectively. NRM tended to be influenced by comorbidities (hematopoietic cell transplantation-specific comorbidity index [HCT-CI] <3 versus HCT-CI ≥3: 18% versus 27%; P = .075), but not by age (<60 years, 20% versus ≥60 years, 25%; P = .142). Disease risk significantly influenced relapse (2 years: low, 8%, intermediate, 28%, high, 34%; very high, 63%; P = .017). Both disease risk (hazard ratio [95% confidence interval]: intermediate, 2.1 [0.8 to 5.2], P = .127; high, 3.4 [1.3 to 9.1], P = .013; very high, 4.0 [1.1 to 14], P = .029) and HCT-CI (hazard ratio [95% confidence interval]: HCT-CI ≥3, 1.7 (1.1 to 2.8), P = .018) influenced OS, but age and donor type did not. The FBx-ATG RIC regimen reported here is associated with low mortality and high long-term disease-free survival without persistent GVHD in both young and old patients. It represents a valuable platform for developing further post-transplantation strategies aimed at reducing the incidence of relapse, particularly in the setting of high-risk disease.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Antineoplásicos/uso terapéutico , Enfermedad Injerto contra Huésped/patología , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Busulfano/uso terapéutico , Enfermedad Crónica , Femenino , Enfermedad Injerto contra Huésped/inmunología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/mortalidad , Neoplasias Hematológicas/patología , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Análisis de Supervivencia , Trasplante Homólogo , Resultado del Tratamiento , Vidarabina/análogos & derivados , Vidarabina/uso terapéuticoRESUMEN
Conditioning regimen including fludarabine, intravenous busulfan (Bx), and 5 mg/kg total dose of rabbit antithymocyte globulin (r-ATG) (FBx-ATG) results in low incidence of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (Allo-HSCT) from HLA-matched related or unrelated donors (MUD). However, whether this platform produces similar results in the setting of one mismatch unrelated donor (MMUD) Allo-HSCT is not known. We retrospectively analyzed patients aged less than 65 years who were diagnosed with hematological malignancies and received FBx-ATG regimen prior to Allo-HSCT from MUD (N = 74) or MMUD (N = 40). We compared outcome of MUD versus MMUD patients. There was no difference in the cumulative incidence of grades II-IV acute GVHD (MUD: 34% vs. MMUD: 35%, P = 0.918), but MMUD patients developed more grade III-IV acute GVHD (MUD: 5% vs. MMUD: 15%, P = 0.016). The cumulative incidences of overall chronic GVHD (MUD: 33% vs. MMUD: 22%, P = 0.088) and extensive chronic GVHD (MUD: 20% vs. MMUD: 19%, P = 0.594) were comparable. One-year NRM was similar in both groups (MUD: 16% vs. MMUD: 14%, P = 0.292); similarly, progression-free survival (MUD: 59% vs. MMUD: 55%, P = 0.476) and overall survival (MUD: 63% vs. MMUD: 61%, P = 0.762) were not different between both groups. With a median follow up of 24 months, 35 of 74 MUD patients (47%) and 19 of 40 MMUD patients (48%) were free of both disease progression and immunosuppressive treatment. We conclude that the FBx-ATG regimen results in low incidences of NRM and GVHD in both MUD and the MMUD recipients.