RESUMEN
The activity of anti-CD19 CAR T cell therapy in chronic lymphocytic leukemia (CLL) with Richter's transformation (RT) to aggressive large B cell lymphoma (LBCL) is largely unknown. In a multicenter retrospective study, we report the safety and efficacy of CAR T cell therapy in patients with RT (n=30) compared to patients with aggressive B cell lymphoma (n=283) and patients with transformed indolent Non-Hodgkins Lymphoma (iNHL) (n=141) between April 2016 and January 2023. Two-thirds of patients received prior therapy for CLL before RT and 89% of them received B-cell receptor and B-cell lymphoma 2 (BCL-2) inhibitors. Toxicities of CAR T cell therapy in RT were similar to other lymphomas, with no fatalities related to cytokine release syndrome or immune effector-cell associated neurotoxicity synderome. The 100-day overall response rate and complete response rates in patients with RT were 57% and 47%, respectively. With a median follow up of 19 months, the median overall survival (OS) was 9.9 months in patients with RT compared to 18 months in de-novo LBCL and not reached in patients with transformed iNHL. The OS at 12 months was 45% in patients with RT compared with 62% and 75% in patients with de novo LBCL and transformed iNHL, respectively. In a multivariate analysis, worse OS was associated with RT histology, elevated LDH, and more prior lines of therapy. CAR T cell therapy can salvage a proportion of patients with CLL and RT exposed to prior targeted agents; however, efficacy in RT is inferior compared to de novo LBCL and transformed iNHL.
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Sinusoidal Obstructive Syndrome (SOS) is a life-threatening complication after hematopoietic stem-cell transplantation (HSCT), characterized by post-sinusoidal portal hypertension. FibroScan is used to assess portal hypertension non-invasively. We assessed transient elastography (TE) applicability in diagnosing SOS. The study included 27 adult patients, 11 underwent TE for high SOS risk pre-HSCT, 17 underwent TE post-HSCT due to bilirubin ≥2 mg/dl with no definite diagnosis of SOS. The first group had median Liver Stiffness Measurement (LSM) of 7.4 kPa (range, 3.3-22.5). Based on LSM results, conditioning regimen was modified for six patients and two of them developed SOS. Only one patient who did not have protocol adjustment experienced SOS. No patient with LSM < 7 kPa developed SOS. The second group had median LSM of 7.7 kPa (4.4-31.5). Median LSM after HSCT was significantly higher in patients who subsequently developed established SOS (n = 10) compared to patients who did not (n = 8), with values of 10.7 kPa (5.6-31.5) and 5.9 kPa (4.4-13.8), respectively (p = 0.02). An LSM cut-off of 7.5 kPa had a sensitivity and specificity of 75 and 80% for diagnosing SOS. In conclusion, pre-HSCT LSM can help adjustment of conditioning regimen in patients with high-risk for SOS. Post-HSCT LSM can help in early diagnosis of SOS.
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Diagnóstico por Imagen de Elasticidad , Trasplante de Células Madre Hematopoyéticas , Enfermedad Veno-Oclusiva Hepática , Humanos , Enfermedad Veno-Oclusiva Hepática/etiología , Enfermedad Veno-Oclusiva Hepática/diagnóstico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Diagnóstico por Imagen de Elasticidad/métodos , Hígado/diagnóstico por imagen , Anciano , Acondicionamiento Pretrasplante/efectos adversos , Acondicionamiento Pretrasplante/métodos , Adulto JovenRESUMEN
Acute graft-versus-host disease (aGvHD) is a serious complication of allogeneic hematopoietic stem-cell transplantation with limited treatment options. The gut microbiome plays a critical role in aGvHD pathogenesis. Fecal microbiota transplantation (FMT) has emerged as a potential therapeutic approach to restore gut microbial diversity. In this prospective pilot study, 21 patients with steroid-resistant or steroid-dependent lower gastrointestinal aGvHD received FMT in capsule form. At 28 days after the first FMT, the overall response rate was 52.4%, with 23.8% complete and 28.6% partial responses. However, sustained responses were infrequent, with only one patient remaining aGvHD-free long-term. FMT was generally well-tolerated. Microbiome analysis revealed dysbiosis in pre-FMT patient stool samples, with distinct microbial characteristics compared to donors. Following FMT, there was an increase in beneficial Clostridiales and a decrease in pathogenic Enterobacteriales. These findings highlight the potential of FMT as a treatment option for steroid-resistant aGvHD. Trial registration number NCT #03214289.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Microbiota Fecal/efectos adversos , Proyectos Piloto , Estudios Prospectivos , Tracto Gastrointestinal , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , EsteroidesRESUMEN
Patients with relapsed/refractory follicular lymphoma (R/R-FL) often require multiple treatment lines. We performed a phase 1b/2 single-center clinical trial of autologous point-of-care anti-CD19 chimeric antigen receptor (CAR) T-cells in R/R-FL patients treated patients with ≥ 2 treatment lines. All 26 patients enrolled received CAR T-cell infusion at a median of 11 days after leukapheresis. Seventy-seven percent of patients had POD24. At enrollment, disease stage was III-IV in 85% of the patients, 77% had high-risk FLIPI score, and 77% had progressive disease. Grade III-IV cytokine release and immune effector cell-associated neurotoxicity syndromes occurred in 12% and 16% of the patients, respectively. Overall response rate at 1-month was 88%. The median follow-up was 15.4 months. One-year overall and progression-free survival were 100% and 63%, respectively. In conclusion, point-of-care CAR T-cell, manufactured within 11 days, induced a high response rate with an acceptable safety profile in patients with high-risk R/R-FL.
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Linfoma Folicular , Receptores Quiméricos de Antígenos , Humanos , Linfoma Folicular/terapia , Linfoma Folicular/tratamiento farmacológico , Sistemas de Atención de Punto , Inmunoterapia Adoptiva/efectos adversos , Tratamiento Basado en Trasplante de Células y Tejidos , Antígenos CD19RESUMEN
Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) relapsing after a first transplant (HSCT1). However, patients allocated to HSCT2 may be a selected group with better prognosis and the added efficacy of HSCT2 is not well established. We retrospectively analyzed 407 consecutive patients with relapsed AML/MDS after HSCT1. Sixty-two patients had HSCT2 (15%) and 345 did not. The 2-year cumulative incidence rates of non-relapse mortality and relapse after HSCT2 were 26% (95% confidence interval [95% CI]: 17-39%) and 50% (95% CI: 39-65%), respectively. The 5-year overall survival rates were 25% (95% CI: 14-36%) and 7% (95% CI: 4-10%) in the HSCT2 and no-HSCT2 groups, respectively. Multivariate analysis identified female gender (hazard ratio [HR]=0.31, P=0.001), short remission duration after HSCT1 (HR=2.31, P=0.05), acute graft-versus-host disease after HSCT1 (HR=2.27, P=0.035), HSCT2 from a haplo-identical donor (HR=13.4, P=0.001) or matched unrelated donor (HR=4.53, P=0.007) and relapse after HSCT1 in earlier years (HR=2.46, P=0.02) as factors predicting overall survival after HSCT2. Multivariate analysis of all patients including HSCT2 as a timedependent variable identified relapse within 6 months after HSCT1 (HR=2.32, P<0.001), acute graft-versus-host disease before relapse (HR=1.47, P=0.005), myeloablative conditioning in HSCT1 (HR=0.67, P=0.011), female gender (HR=0.71, P=0.007), relapse in earlier years (HR=1.33, P=0.031) and not having HSCT2 (HR=1.66, P=0.010) as predictive of overall survival after relapse. In conclusion, HSCT2 is associated with longer survival compared to non-transplant treatments and may be the preferred approach in a subset of patients with relapsed AML/MDS after HSCT1.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Humanos , Femenino , Terapia Recuperativa , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicos/terapia , Recurrencia , Acondicionamiento Pretrasplante , Enfermedad Injerto contra Huésped/etiologíaRESUMEN
Anti-CD19 chimeric antigen receptor T cell (CAR-T) therapy has transformed the care of patients with relapsed/refractory large B cell lymphoma (LBCL). However, approximately 60% of CAR-T recipients ultimately will experience disease recurrence or progression. Salvage therapies after CAR-T treatment failures are of limited efficacy and have a short duration of response. The objective of the present study was to evaluate the role of allogeneic hematopoietic cell transplantation (allo-HCT) after CAR-T therapy in LBCL patients. This was a multicenter observational study reporting the outcome of 39 adult LBCL patients who underwent allo-HCT following anti-CD19 CAR-T therapy. The median patient age was 47 years (range, 20 to 68 years). HLA-matched sibling, HLA-matched unrelated, and alternative donors were used in 36%, 36%, and 28% of transplantations, respectively. Conditioning regimens were primarily of low or intermediate intensity. Disease status at allo-HCT was complete response in 41%, partial response in 38%, and progressive disease in 21%. Allo-HCT was performed at a median of 127 days (range, 82 to 206 days) after CAR-T therapy. A high incidence of hepatic toxicity (28%), including sinusoidal obstruction syndrome (15.4%; 95% confidence interval; [CI], 6.2% to 28.5%), was observed. The 1-year cumulative incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) was 38.5% (95% CI, 23.2% to 53.6%) and 15.4% (95% CI, 6.1% to 28.5%), respectively. The 2-year cumulative incidence of moderate-severe chronic GVHD was 11.1% (95% CI, 3.3% to 24.3%). Overall, 2-year nonrelapse mortality and relapse/progression incidence were 26% (95% CI, 13% to 41%) and 43% (95% CI, 27% to 59%), respectively. With a median follow-up of 32 months, the 2-year overall survival (OS) and progression-free survival (PFS) were 45% (95% CI, 31% to 66%) and 31% (95% CI, 19% to 50%), respectively. In multivariable analyses, pre-HCT elevated lactate dehydrogenase level and transformed lymphoma were predictive of OS and PFS, respectively. Our data suggest that allo-HCT after anti-CD19 CAR-T treatment failure is feasible with a relatively promising efficacy but possibly high toxicity rate.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Adulto , Humanos , Adulto Joven , Persona de Mediana Edad , Anciano , Recurrencia Local de Neoplasia/complicaciones , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad Injerto contra Huésped/etiología , Linfoma de Células B Grandes Difuso/terapiaRESUMEN
Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.
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Linfoma de Células B Grandes Difuso , Receptores Quiméricos de Antígenos , Adulto , Humanos , Anciano , Receptores Quiméricos de Antígenos/uso terapéutico , Lenalidomida/uso terapéutico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Inmunoterapia Adoptiva , Inducción de Remisión , Antígenos CD19RESUMEN
Tisagenlecleucel (tisa-cel) is an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for patients with relapsed/refractory large B-cell lymphoma. Outcomes of patients with out-of-commercial specification (OOS) CAR T products are not well characterized. We therefore assessed 37 adult patients who underwent leukapheresis for tisa-cel therapy in a single center. In nine (24%) patients, manufactured tisa-cel was considered OOS. Three of them (33%) received tisa-cel after institutional review board approval; 2/9 (22%) did not receive tisa-cel due to disease progression; and 4/9 (44%) received academic point-of-care (POC) CAR T-cell as salvage therapy, at a median of 35 days following OOS notification. Three of those four patients achieved a complete response. In univariate analysis, risk factors for OOS were ≥ 4 prior therapies or previous bendamustine exposure. In conclusion, we report high OOS incidence of 24% in real-life setting. Forty-four percent of those patients received POC CAR T-cell as salvage therapy.
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Inmunoterapia Adoptiva , Linfoma de Células B Grandes Difuso , Adulto , Humanos , Antígenos CD19 , Linfoma de Células B Grandes Difuso/patología , Recurrencia Local de Neoplasia/etiología , Sistemas de Atención de Punto , Receptores de Antígenos de Linfocitos TRESUMEN
Anti CD19 chimeric antigen receptor (CAR) T-cell therapy has transformed the care of relapsed and refractory aggressive B-cell lymphoma. However, financial toxicity and manufacturing time represent barriers to its widespread implementation. Study applicability, toxicity, and efficacy of a locally produced autologous CD19-directed CAR T-cell product were studied. We performed a phase 1b/2 clinical trial with a point-of-care (POC) CAR T-cell product that contains a CD28 costimulatory domain. Adult patients with aggressive B-cell lymphoma or transformed low-grade lymphoma who received at least 2 prior regimens were eligible. A total of 73 patients, with a median age of 49 years, met inclusion criteria. CAR T-cell production time from apheresis was 10 days (interquartile range 10-11), negating the need for bridging chemotherapy. Overall and complete response rates were 62.5% and 37.5%. Median progression-free and overall survival were 3.7 and 12.1 months, respectively. Overall and progression-free survival at 12 months were 52.1% (confidence interval [CI]: 40.8%-66.5%) and 40% (CI: 30%-53.7%), respectively. Patients who achieved response had longer progression-free and overall survival. Grade 3-4 cytokine release syndrome was observed in 9.5% of the patients, and immune effector cell-associated neurotoxicity syndrome grade 3-4 in 21.9%. No deaths occurred due to CAR T-cell toxicity. Fifteen patients (20%) underwent allogeneic stem cell transplantation at a median time of 60 days after CAR T-cell therapy; 8 were alive at last follow-up. Of the 6 patients who underwent the transplantation in complete response 2 deceased because of toxicity. POC CAR T-cells are a feasible therapeutic option in aggressive B-cell lymphoma. They provide good efficacy while minimizing production time and the need for bridging therapy.
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Linfoma de Células B , Receptores Quiméricos de Antígenos , Adulto , Antígenos CD19 , Síndrome de Liberación de Citoquinas/etiología , Humanos , Linfoma de Células B/terapia , Persona de Mediana Edad , Sistemas de Atención de Punto , Receptores Quiméricos de Antígenos/uso terapéutico , Linfocitos TRESUMEN
The immunogenicity and safety of Pfizer-BioNTech BNT162b2 mRNA vaccine in allogeneic haematopoietic stem cell transplantation (HSCT) recipients are unknown. We prospectively followed 152 HSCT recipients who were at least six months following transplantation and with no active acute graft-versus-host disease (GVHD). Blood samples were taken 2-4 weeks after the second vaccination and analyzed for receptor-binding domain (RBD) antibodies and neutralizing antibodies (NA). 272 immunocompetent healthcare workers served as controls. At a median of 28 days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 [95% CI (confidence interval), 2·16-3·16]. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70-6·28), P < 0·0001. The GMT of NA in HSCT recipients and controls was 116·0 (95% CI 76·5-175·9), and 427·9 (95% CI 354·3-516·7) respectively (P < 0001). Multivariate logistic regression analysis revealed that HSCT recipients with no chronic GVHD and no immunosuppressive therapy at the time of vaccination had significantly higher levels of NA following the second vaccination. Adverse events were minimal and were less common than in healthy controls. In conclusion; the BNT162b2 mRNA vaccination is safe and effective in HSCT recipients, especially those who are immunosuppression-free. A significant fraction developed protecting NA.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacuna BNT162/uso terapéutico , COVID-19/prevención & control , Trasplante de Células Madre Hematopoyéticas , Inmunogenicidad Vacunal , Anciano , Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacuna BNT162/efectos adversos , Vacuna BNT162/inmunología , COVID-19/sangre , COVID-19/inmunología , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Terapia de Inmunosupresión , Masculino , Persona de Mediana Edad , Estudios Prospectivos , SARS-CoV-2/inmunología , Receptores de TrasplantesRESUMEN
The combination of hypomethylating agents and venetoclax has revolutionized the therapeutic landscape of acute myeloid leukemia (AML), especially for patients previously deemed unfit for curative-intent treatment. Some of these patients undergo allogeneic hematopoietic cell transplant (alloHCT); yet, there are scarce data regarding transplantation outcomes. We conducted a multicenter nationwide retrospective cohort study, including patients with AML who underwent alloHCT in CR1 after frontline treatment with azacitidine plus venetoclax only (aza-ven group). We collected a historical control group of patients who achieved CR1 after first-line intensive chemotherapy only, followed by alloHCT (intensive group). Patients in the aza-ven group (n = 24) were transplanted between 2019 and 2021. Compared to the intensive group, patients in the aza-ven group were older (median age 71.7 vs. 58.4 years), had higher incidence of therapy-related AML and AML with antecedent hematologic disorder and had more often adverse cytogenetics. They had a higher percentage of allografts from matched-unrelated donors, and reduced intensity conditioning was more commonly used. The estimated 12 months non relapse mortality was 19.1% in the aza-ven group and 11.8% in the intensive group. The estimated 12 months relapse-free survival and overall survival were 58% and 63% in the aza-ven group and 54% and 70% in the intensive group, respectively. The cumulative incidence of acute GVHD at 6 months and of chronic GVHD at 12 months were 58% and 40% in the aza-ven group and 62% and 42% in the intensive group, respectively. Analysis of the aza-ven group revealed that HCT-CI score and ELN risk category were predictive of RFS in both univariate analysis as well as multivariate analysis. Our data suggests that alloHCT for AML patients achieving first CR with aza-ven appears feasible, with short-term post-transplant outcomes similar to those expected after traditional intensive chemotherapy.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Azacitidina/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Sulfonamidas/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Estudios Retrospectivos , Acondicionamiento Pretrasplante , Trasplante HomólogoRESUMEN
Autologous stem cell transplantation (ASCT) is a standard of care in newly-diagnosed multiple myeloma (MM) patients. Several studies before the introduction of novel therapies in MM, demonstrated a pegylated G-CSF to be successful in mobilizing peripheral blood stem cells (PBSCs). Lipegfilgrastim is a novel long-acting G-CSF that is produced by the conjugation of a single 20-kDa polyethelene glycol to the natural O-glycosylation site of G-CSF. Twenty-four MM patients were included for PBSCs mobilization with a single SC injection of 6 mg lipegfilgrastim. PBSC collection was started when the CD34+ count was > 10 × 106 cells/L. The target progenitor cells were 6 × 106 cells/kg. The median day of apheresis was + 3 (range 2-5) following lipegfilgrastim. Median peripheral blood CD34+ count pre-mobilization was of 22.65 (range 3.36-105) × 106 cells/L. The median number of leukaphaeresis procedures was 2 (range 1-4). The median mobilized CD34+ cells/kg were 8.26 (range 0.77-12.42). One patient failed to mobilize and two patients mobilized < 6 × 106 cells/kg. Toxicity was mild and transient. Twenty-three patients underwent ASCT following high dose melphalan. All patients engrafted. As lipegfilgrastim is administered only once, it is conceivable that it improves both compliance and quality-of-life (NCT02488382).
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Filgrastim/administración & dosificación , Movilización de Célula Madre Hematopoyética , Trasplante de Células Madre Hematopoyéticas , Mieloma Múltiple/terapia , Polietilenglicoles/administración & dosificación , Adulto , Anciano , Eliminación de Componentes Sanguíneos , Femenino , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Células Madre Hematopoyéticas/metabolismo , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Trasplante Autólogo , Resultado del TratamientoRESUMEN
INTRODUCTION: Achievement of an initial complete remission (CR) following induction chemotherapy is tightly correlated with survival in acute myeloid leukemia (AML) patients, yet patients in CR with incomplete hematologic recovery (CRi) still experience improved outcomes compared with nonresponding patients. Whether CRi predicts prognosis in patients referred to an allogeneic stem cell transplantation (allo-SCT) is incompletely defined. In this analysis, we evaluated whether clinical outcomes of transplanted AML patients in CR and CRi were significantly different. METHODS: A retrospective single-center analysis of all de novo AML patients who underwent an allo-SCT between 2001 and 2015. The cohort included all adult patients with AML who underwent a first allo-SCT either in first or second CR or CRi at the time of transplantation. RESULTS: The study cohort included 186 CR patients and 44 CRi patients. In univariate analysis, CRi was associated with inferior 3-year survival and 3-year nonrelapse mortality (NRM) compared to CR (41 vs. 62%; p = 0.022 and 27 vs. 10%; p = 0.006, respectively). In multivariate analysis, CRi was associated with decreased rates of survival (hazard ratio [HR] 2.01; 95% CI, 1.24-3.25; p = 0.005) and NRM (HR, 3.5; 95% CI, 1.6-7.8; p = 0.002). CONCLUSION: CRi in transplanted AML patients is potentially a potent predictor of increased NRM and survival.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda/terapia , Adulto , Femenino , Humanos , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Tasa de Supervivencia , Trasplante HomólogoRESUMEN
Risk stratification is important for balancing potential risks and benefits of allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. We retrospectively studied 1119 patients undergoing allogenic-HSCT in a single center for five hematological indications assessing the prognostic role of LDH at admission for survival (OS), progression-free survival (PFS), relapse incidence (RI), and nonrelapse mortality (NRM). In non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML), higher than median LDH had an adverse effect on survival. The prognostic significance was strongest in AML, with higher LDH levels having lower 1-and 3-year survival 69.2% vs. 50.8%, P < 0.001 and 51.9% vs. 39.2%, P < 0.001, respectively, reduced 1-and 3-year PFS 62.4% vs. 42.1%, P < 0.001 48% vs. 35.2%, P < 0.001, respectively, higher cumulative incidence of 1-and 3-year NRM 11% vs. 17.3%, p = 0.01 and 15.7% vs. 19.6%, P = 0.04, and higher 1-and 3-year relapse incidence (RI) 26.7% vs. 40.7%, p < .0001 36.2% vs. 40.7%, respectively, P < 0.0001). In multivariate analysis LDH maintained significant prognostic capacity in OS, PFS and RI. These findings in AML, validated in an independent cohort, suggest that LDH is a readily available tool that could be integrated into transplant risk assessments to aid decision-making and identify high-risk patients who may benefit from post-transplant pharmacological or cellular strategies.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mieloide Aguda , Linfoma no Hodgkin , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , L-Lactato Deshidrogenasa , Linfoma no Hodgkin/terapia , Estudios Retrospectivos , Acondicionamiento PretrasplanteRESUMEN
Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m2, intravenously on days +1 and +2) to cyclosporine/methotrexate backbone in 26 patients after SCT from unrelated donors. We compared outcomes to historical group of 100 patients given cyclosporine/methotrexate alone. Median follow-up was 34 months. There was no difference between the groups in engraftment or toxicities. The cumulative incidence of aGVHD grade II-IV, 6 months post transplant was 11% (95% CI, 4-32) and 39% (95% CI, 30-50), respectively (P = 0.01). The cumulative incidence of chronic GVHD, 2 years post transplant, was 49% (95% CI, 32-75) and 41% (95% CI, 33-52), respectively (P = 0.98). Three-year non-relapse mortality was 11% (95% CI, 4-33) and 18% (95% CI, 12-27, P = 0.45) while 3-year relapse rates were 8% (95% CI, 2-29) and 26% (95% CI, 18-36), respectively (P = 0.06). Three-year survival was 81% (95%CI, 66-96) and 56% (95% CI, 46-66), respectively (P = 0.05). In conclusion, carfilzomib with cyclosporine/methotrexate is safe, may reduce aGVHD, and possibly improve survival after unrelated donor SCT. These initial observations merit further study in larger comparative studies. ClinicalTrial.gov NCT01991301.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Ciclosporina/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Inmunosupresores/uso terapéutico , Metotrexato , Oligopéptidos , Acondicionamiento Pretrasplante/efectos adversos , Donante no EmparentadoRESUMEN
OBJECTIVES: To determine the current role of bisantrene, an anthracene with anthracycline-like activity which was shown in earlier studies to be effective therapy in relapsed/refractory acute myeloid leukemia with no discernible cardiotoxicity, in the treatment of patients with R/R AML. METHODS: This phase 2, single-center study (NCT03820908) enrolled adult R/R AML to receive bisantrene (250 mg/m2 daily for 7 days) which was administered via an intravenous infusion over 2 hours on days 1-7. Disease assessment included routine blood work and bone marrow studies. RESULTS: In all, 10 patients were enrolled with a median of 3 lines of prior therapy including seven patients who had relapsed following allogeneic stem cell transplantation. The most frequently reported grade ≥3 treatment-attributed hematologic AE was thrombocytopenia, whereas the most frequently reported grade ≥3 treatment-attributed non-hematologic AE was mucositis. Of the 10 patients, one (10%) achieved a complete remission and three patients achieved a partial remission resulting in an overall response rate of 40%. Next-generation sequencing of patient samples identified a wide array of mutations associated with activated signaling, splicing, and epigenetic modification. CONCLUSIONS: In view of the observed low toxicity, a follow-up study combining bisantrene with complementary anti-leukemic therapy is planned.
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Antibióticos Antineoplásicos/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antracenos/administración & dosificación , Antracenos/efectos adversos , Antracenos/uso terapéutico , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/efectos adversos , Biopsia , Médula Ósea , Susceptibilidad a Enfermedades , Resistencia a Antineoplásicos , Femenino , Estudios de Seguimiento , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Recurrencia , Retratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
We present three patients with aggressive non-Hodgkin's B-cell lymphoma (NHL) who received anti-CD19 chimeric antigen receptor T (CAR T) cells therapy after failure of several lines of chemotherapy that developed pseudo-progression. One-week clinical and radiological findings were consistent with tumor progression. Positron emission tomography-computed tomography (PET-CT) at 1 month post CAR T cells administration was consistent with treatment response. The rapid tumor growth and subsequent resolution are suggestive of tumor pseudo-progression mediated secondary to infiltration and immune activation of CAR T cells. Overall, 56 adult patients with NHL were enrolled in a phase 1b/2 in house clinical study with CD19 CAR T cells. Out of them 22/56 patients progressed as per PET-CT the 1 month post CAR T cells. In 14 patients, signs of progression started 7-10 days after CAR T cells infusion. In 11/14 patients, it was true progression, while in 3 it was pseudo-progression. Additional studies are warranted to describe the extent of this phenomenon and evaluate correlation with the CAR T activity and long-term disease control.
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Linfoma de Células B , Receptores Quiméricos de Antígenos , Adulto , Antígenos CD19 , Humanos , Conducta Imitativa , Inmunoterapia Adoptiva , Linfoma de Células B/terapia , Tomografía Computarizada por Tomografía de Emisión de Positrones , Linfocitos TRESUMEN
A substantial segment of patients with acute myeloid leukemia (AML) will relapse following an initial response to induction therapy or will prove to be primary refractory. High-dose cytarabine and mitoxantrone (HiDAC/MITO) is an established salvage therapy for these patients. We studied all adult patients with relapsed/refractory (R/R) AML who were treated with HiDAC/MITO in our center between the years 2008-2017. To determine whether responding patients harbored a unique molecular signature, we performed targeted next-generation sequencing (NGS) on a subset of patients. The study cohort consisted of 172 patients with a median age of 54 years (range 18-77). The composite complete remission rate was 58%; 11 patients (6%) died during salvage therapy. Median survival was 11.4 months with a 1-year survival rate of 48%. In multivariate analysis favorable risk cytogenetics [Odds ratio (OR)=0.34, confidence interval (CI) 95%, 0.17-0.68; P = 0.002], and de-novo AML (OR = 0.4, CI 95%, 0.16-0.98; P = 0.047) were independently associated with a favorable response. Patients who attained a complete remission had a median survival of 43.7 months compared with 5.2 months for refractory patients (p < 0.0001). Neither the FLT3-ITD and NPM1 mutational status nor the indication for salvage therapy significantly impacted on the response to HiDAC/MITO salvage. NGS analysis identified 20 different mutations across the myeloid gene spectrum with a distinct TP53 signature detected in non-responding patients. HiDAC/MITO is an effective salvage regimen in R/R AML, however patients with adverse cytogenetics or secondary disease may not benefit as much from this approach.
RESUMEN
Data from 11 Israeli centers, where venetoclax was used for relapsed/refractory AML after intensive chemotherapy, were retrospectively collected. During 2016-2019, forty patients were identified. Median age was 67 years (21-82), 60% males, median of 2(1-4) prior lines of treatment and 42% relapsed after allogeneic transplant. 62.5% of the patients received the venetoclax with hypomethylating agents and 22.5% with low dose cytarabine. Median follow-up was 5.5 months. Of the 29 patients who survived for more than two cycles of therapy, 22 (76%) achieved neutrophil recovery and 59% (n = 17) recovered also their platelet count. In 15 (52% of those who survived > 2 months), CR/CRi was confirmed by bone marrow examination. The median OS from venetoclax initiation of all the patients and of those who survived more than 2 months was 5.5 and 6.5 months, respectively. In conclusion, this study demonstrates that venetoclax is safe and active also in AML patients with advanced disease.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia Mieloide Aguda , Anciano , Compuestos Bicíclicos Heterocíclicos con Puentes , Citarabina/uso terapéutico , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Recurrencia Local de Neoplasia , Estudios Retrospectivos , SulfonamidasRESUMEN
Allogeneic hematopoietic stem cell transplantation (allo-SCT) may offer a cure for selected patients with multiple myeloma (MM). Effective prognostic markers to guide patient selection are warranted. We retrospectively studied a cohort of 100 relapsed refractory MM patients who underwent allo-SCT. With a median follow-up of 12.2 years, median overall survival (OS) and progression-free survival (LFS) were 9.2 months and 5.6 months, respectively. 5-years OS and PFS were was 18.0% and 16.8%. The cumulative incidence of 5-years relapse was 45.9% and non-relapse mortality (NRM) 36.0%. In a multivariable Cox model, decreasing albumin, increasing lactate dehydrogenase (LDH), advanced disease, and mismatched donors were predictive of both reduced OS and PFS. The probability of 5-years OS was higher in patients with LDH below vs. the upper limit of normal (22% vs. 5%, p = 0.004). In the multivariable analysis, the hazard of NRM was increased with low albumin, mismatched donor type, and declining estimated glomerular filtration rate (eGFR). Patients with a low eGFR had a 5-year NRM incidence of 31% vs. 56% in patients with higher levels (p = 0.02). Graft-versus-host disease was not associated with improved outcomes. In conclusion, LDH, renal function, and albumin are highly informative of outcomes in MM patients treated with allo-SCT.