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PURPOSE OF REVIEW: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma in adults. Although curable in the majority of cases, a substantial portion of patients will experience disease relapse and will die from their lymphoma. This review is aimed at summarizing the role of allogeneic hematopoietic stem cell transplant (allo-HSCT) in patients with relapsed DLBCL with a focus on its role in the era of CAR T-cell therapy RECENT FINDINGS: Allo-HSCT is primarily reserved for patients who experience disease progression or relapse after CAR T-cell therapy, largely due to the high non-relapse mortality (NRM) associated with the procedure. Disease status at the time of allo-HSCT is prognostic with complete remission (CR) associated with better outcomes. Reduced-intensity conditioning (RIC) is likely as effective as myeloablative conditioning (MAC) with less toxicity. In patients with multiply relapsed disease, including after auto-HSCT and CAR T-cell therapy, approximately one-third can be cured with allo-HSCT. Allo-HSCT should be considered a treatment modality for fit adults without major comorbid conditions whose disease can be controlled with emerging treatment modalities (e.g., bispecifics, antibody-drug conjugates).
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Adulto , Humanos , Inmunoterapia Adoptiva/métodos , Recurrencia Local de Neoplasia/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Linfoma de Células B Grandes Difuso/terapia , PronósticoRESUMEN
Treatment of neoplastic diseases resistant to conventional chemotherapies is still an open challenge. The increasing development of chemical molecules or monoclonal antibodies able to recognize precise molecular targets of cancer disease has played an increasingly important role in treating patients suffering from solid or hematological tumors, and constitutes the basis of so-called 'targeted therapy'. Immunotherapy has become a cornerstone for treating refractory or relapsed cancer disease patients after standard chemotherapies. Immune checkpoint (including PD-1) inhibitors are essential drugs that significantly improve the therapeutic possibilities for neoplastic patients. Still, foreseeable or unpredictable adverse effects can potentially arise during or after the end of therapy. Specifically, toxicity involving several organs is capable of delaying or preventing the continuation of programmed treatment, as described in this case, where we will discuss the possibility of toxicity affecting various organs (kidney, muscle tissue, and thyroid) attributed to nivolumab and which resulted in temporary ineligibility for allogeneic transplantation.
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Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Hipotiroidismo , Miositis , Insuficiencia Renal , Humanos , Inhibidores de Puntos de Control Inmunológico , Receptor de Muerte Celular Programada 1 , Enfermedad de Hodgkin/tratamiento farmacológico , Enfermedad de Hodgkin/patología , Trasplante Homólogo , Miositis/tratamiento farmacológico , Insuficiencia Renal/tratamiento farmacológico , Hipotiroidismo/tratamiento farmacológicoRESUMEN
BACKGROUND: Identification of non-human leukocyte antigen (HLA) genetic risk factors could improve survival after allogeneic blood or marrow transplant (BMT) through matching at additional loci or individualizing risk prediction. We hypothesized that non-HLA loci contributed significantly to 1-year overall survival (OS), disease related mortality (DRM) or transplant related mortality (TRM) after unrelated donor (URD)BMT. METHODS: We performed a genome-wide association study (GWAS) in 2,887 acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and acute lymphoblastic leukemia (ALL) patients and their ≥8/8 HLA-matched URDs comprising two independent cohorts treated from 2000-2011. FINDINGS: Using meta-analyses of both cohorts, genome-wide significant associations (p < 5 × 10-8) were identified in: recipient genomes with OS at MBNL1 (rs9990017, HR = 1.4, 95% CI 1.24-1.56, p = 3.3 × 10-8) and donor-recipient genotype mismatch with OS at LINC02774 (rs10927108, HR = 1.34, 95% CI 1.21-1.48, p = 2.0 × 10-8); donor genomes with DRM at PCNX4 (rs79076914, HR = 1.7, 95% CI 1.41-2.05, p = 3.15 × 10-8), LINC01194 (rs79498125, HR = 1.86, 95% CI 1.49-2.31, p = 2.84 × 10-8), ARID5B (rs2167710, HR = 1.5, 95% CI 1.31-1.73, p = 6.9 × 10-9) and CT49 (rs32250, HR = 1.44, 95% CI1.26-1.64, p = 2.6 × 10-8); recipient genomes at PILRB with TRM (rs141591562, HR = 2.33, 95% CI 1.74-3.12, p = 1.26 × 10-8) and donor-recipient genotype mismatch between EPGN and MTHF2DL with TRM (rs75868097, HR = 2.66, 95% CI 1.92-3.58, p = 4.6 × 10-9). Results publicly available at https://fuma.ctglab.nl/browse. INTERPRETATION: These data provide the first evidence that non-HLA common genetic variation at novel loci with biochemical function significantly impacts 1-year URD-BMT survival. Our findings have implications for donor selection, could guide treatment strategies and provide individualized risk prediction after future validation and functional studies. FUNDING: This project was funded by grants from the National Institutes of Health, USA.
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BACKGROUND: The side effects of conditioning regimens on the success rate of allogeneic transplantation around the world have been challenging. In this study, we aimed to investigate the side effect of Bu/Cy and Bu/Flu regimens on our patients who underwent allogeneic bone marrow transplantation. METHODS: We analyzed 180 patients receiving bone marrow transplantation in Taleghani Hospital, in Tehran, Iran between April 2016 and December 2019. Patients in group A received a combination of intravenous busulfan 0.8 mg/kg QID over two hours for 4 consecutive days (12.8 mg/kg in total)(Savani et al., 2006) and cyclophosphamide 60 mg/kg per day for two consecutive days. Patients in group B received busulfan the same as the first group in combination with fludarabine equal to 40 mg/m² per day. Patients were followed up at regular intervals up to two years after transplantation. RESULT: Various items were evaluated for patients, including cardiopulmonary function, psychological disorders, GVHD, and endocrine disorders such as hypothyroidism, fertility, or gonad dysfunction. Primary hypothyroidism developed in 13.3% and 11.1% of the Bu/Cy and Bu/Flu groups, respectively (p=0.230). None of the patients in either group experienced infertility or gonad dysfunction. In group A versus group B, pulmonary diseases were detected in 4.4% versus 6.6% of BMT recipients, respectively (p = 0.223). In both groups, mitral and tricuspid regurgitation were observed in patients (8.9% vs. 11.1%; p = 0.189). Incidence of Psychological disorders was no significant difference between the two groups. 32.2% of group A versus 34.45% of group B had skin and liver GVHD, respectively (p = 0.235). CONCLUSION: The therapeutic-related adverse effects of the two conditioning regimens in patients who underwent allogeneic bone marrow transplant were almost similar. To improve quality of life and overall survival among BMT patients, careful evaluation of treatment-related complications should be part of the regular follow-up of them.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante de Médula Ósea/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Neoplasias Hematológicas/terapia , Adolescente , Adulto , Anciano , Busulfano/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/radioterapia , Femenino , Estudios de Seguimiento , Neoplasias Hematológicas/patología , Humanos , Irán/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Calidad de Vida , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante Homólogo , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
PURPOSE OF REVIEW: Chronic myelomonocytic leukemia (CMML) is a rare and often aggressive myeloid malignancy. Historically, prognostic markers and therapeutic paradigms have been applied from myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPNs). Interest has increased recently in developing tailored approaches for the MDS/MPN overlap syndrome of CMML. RECENT FINDINGS: Multiple prognostic scores have been validated specifically for CMML in the past 5 years. These incorporate somatic mutations, with ASXL1 mutations repeatedly correlating with poor prognosis. Accurate prognostication can guide treatment. Hypomethylating agents (HMAs) and curative allogeneic blood or marrow transplantation (BMT) remain the most available standard treatments. Recently, a number of novel approaches using unapproved therapies (i.e., lenalidomide, ruxolitinib, sotatercept, and tipifarnib) have demonstrated some efficacy in CMML. Increased recognition and interest in CMML have led to the development of a number of new prognostic models and potential treatment options. Standard treatment options remain limited and clinical trials should be strongly considered whenever available.
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Leucemia Mielomonocítica Crónica/terapia , Historia del Siglo XX , Humanos , PronósticoRESUMEN
Children with bone marrow failure syndromes and severe aplastic anemia (SAA) are treated with allogeneic blood or marrow transplantation (BMT). However, there is a paucity of studies examining late mortality risk after allogeneic BMT performed in childhood for bone marrow failure syndromes and SAA and evaluating how this risk differs between these diseases. We investigated cause-specific late mortality in 2-year survivors of allogeneic BMT for bone marrow failure syndromes and SAA performed before age 22years between 1974 and 2010 at 2 US transplantation centers. Vital status information was collected from medical records, the National Death Index, and Accurint databases. Overall survival was calculated using Kaplan-Meier techniques. The standardized mortality ratio (SMR) was calculated using age- sex-, and calendar-specific mortality rates from the Centers for Disease Control and Prevention. Among the 2-year survivors of bone marrow failure syndromes (nâ¯=â¯120) and SAA (nâ¯=â¯147), there were 15 and 19 deaths, respectively, yielding an overall survival of 86.4% for bone marrow failure syndromes and 93.1% for SAA at 15years post-BMT. Compared with the general population, patients with bone marrow failure syndromes were at a higher risk for premature death (SMR, 22.7; 95% CI, 13.1 to 36.2) compared with those with SAA (SMR, 4.5; 95% CI, 2.8 to 7.0) (P < .0001). The elevated relative risk persisted at ≥15years after BMT for both diseases. The hazard of all-cause late mortality was 2.9-fold (95% CI, 1.1 to 7.3) higher in patients with bone marrow failure syndromes compared with those with SAA. The high late mortality risk in recipients of allogeneic BMT in childhood for bone marrow failure syndromes calls for intensified life-long follow-up.
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Anemia Aplásica/terapia , Trastornos de Fallo de la Médula Ósea/terapia , Trasplante de Médula Ósea/métodos , Trasplante Homólogo/métodos , Adolescente , Adulto , Anemia Aplásica/mortalidad , Trastornos de Fallo de la Médula Ósea/mortalidad , Trasplante de Médula Ósea/mortalidad , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Mortalidad , Trasplante Homólogo/mortalidad , Adulto JovenRESUMEN
More than 90% of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients receive red blood cell (RBC) or platelet transfusions in the peritransplantation period. We tested the hypothesis that transfusions are associated with the development of severe (grade III-IV) acute graft-versus-host disease (aGVHD) or mortality after allo-HSCT in a retrospective study of 322 consecutive patients receiving an allogeneic bone marrow or granulocyte colony-stimulating factor-mobilized blood stem cell graft for a hematologic malignancy. Counting transfused RBC and platelet units between day -7 pretransplantation and day +27 post-transplantation, but excluding transfusions administered after a diagnosis of aGVHD, yielded medians of 5 RBC units and 2 platelet units transfused. Sixty-three patients (20%) developed a maximal grade III-IV aGVHD with onset up to day +150 post-transplantation (median aGVHD onset of 28 days). HLA mismatch (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.2 to 4.7; P = .01), and transfusion of more than the median number of RBC units (HR, 2.1; 95% CI, 1.1 to 3.7; P = .02) were independently associated with greater risk of grade III-IV aGVHD in a multivariable analysis model. Disease risk strata (HR, 1.7; 95% CI, 1.2 to 2.4 for high risk versus low risk; P = .005) and transfusion of more than the median number of RBC units (HR, 1.4; 95% CI, 1.0 to 2.0; P = .054) were independently associated with inferior overall survival. These data support our hypothesis that peritransplantation RBC transfusions are associated with the risk of developing severe aGVHD and worse overall survival following allo-HSCT, and suggest that strategies to reduce routine RBC transfusion may favorably reduce the incidence and severity of GVHD.
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Transfusión de Eritrocitos/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Adulto , Anciano , Femenino , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Atención Perioperativa/efectos adversos , Atención Perioperativa/métodos , Transfusión de Plaquetas , Estudios Retrospectivos , Riesgo , Análisis de Supervivencia , Trasplante Homólogo/efectos adversos , Adulto JovenRESUMEN
Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometime untreatable, disease due to toxic conditioning regimens, graft vs. host disease and required use of mismatched bone marrow in some cases. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PC) and produces a suppressive microenvironment ideal for incoming grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach to creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) can mobilize functional HS-PC, accelerate hematologic recovery, and enhance donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize HSCT.
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In two recent publications, we demonstrated that after allogeneic stimulation, regulatory T cells (Tregs) increase expression of aldehyde dehydrogenase (ALDH), the major in vivo mechanism of cyclophosphamide detoxification, thereby becoming cyclophosphamide resistant. Differential ALDH expression may explain why cyclophosphamide has pro- and anti-inflammatory effects that are temporally and contextually dependent.
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We investigated the incidence of phototoxic skin reactions in pediatric BMT recipients treated with voriconazole. Nine out of 40 patients (22.5%), all Caucasian, developed skin lesions in sun-exposed distributions. Dermatologic findings included sunburn-like erythema, pseudo-porphyria, linear papulovesicular lesions, severe erosive cheilitis, dermatoheliosis and lentigines. Patients were treated with sun avoidance, high-potency sunscreens, and topical steroids with significant improvement in all cases. Prolonged voriconazole use requires close monitoring for chronic skin toxicities. Long-term risks including the risk of skin cancer need to be investigated.
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Antifúngicos/efectos adversos , Trasplante de Médula Ósea , Trastornos por Fotosensibilidad/inducido químicamente , Pirimidinas/efectos adversos , Luz Solar/efectos adversos , Triazoles/efectos adversos , Aloinjertos , Antifúngicos/administración & dosificación , Niño , Femenino , Humanos , Masculino , Trastornos por Fotosensibilidad/patología , Trastornos por Fotosensibilidad/prevención & control , Pirimidinas/administración & dosificación , Estudios Retrospectivos , Neoplasias Cutáneas/prevención & control , Protectores Solares/administración & dosificación , Triazoles/administración & dosificación , VoriconazolRESUMEN
PURPOSE: We assessed the three-alkylator combination of busulfan, melphalan and thiotepa or TBI, melphalan and thiotepa conditioning for allogeneic stem cell transplantation in 7 adult patients with refractory or relapsed acute leukemias. MATERIALS AND METHODS: Six patients were transplanted for acute myeloid leukemia, one for acute lymphoblastic leukemia and included 5 of relapsed refractory, 2 of relapsed after first-BMT. All but 1 cases received G-CSF stimulated CD34+ allogeneic peripheral blood progenitor cells (PBPCs) in addition to stimulated allogeneic marrow. RESULTS: All patients except one engrafted (median time to ANC >0.5 10 (9)/L=11days, to platelets >30 X 10 (9)/L=14 days) successfully and complete remission was obtained in 6 patients. Grade I-II acute GVHD and controllable regimen-related toxicity especially oral mucositis (grade II-III) developed in all cases, but 2 patients including one second- allogeneic BMT patient expired early by transplant-related toxicity of hepatic or multiorgan failure along the course of sepsis. CONCLUSION: Although the observation period on these cases are limited, the data presented show that the combination of busulfan, melphalan and thiotepa is tolerable as a preparative regimen for allogeneic marrow transplantation in high-risk leukemic patients. We think that these encouraging results need to be confirmed in prospective studies in the future.