RESUMO
Relapse after CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multiantigen targeting and programmed cell death protein-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in relapsed/refractory LBCL (NCT03289455). End points include toxicity (primary) and response rates (secondary). Fifty-two patients received AUTO3 and 48/52 received pembrolizumab. Median age was 59 years (range, 27-83), 46/52 had stage III/ IV disease and median follow-up was 21.6 months. AUTO3 was safe; grade 1-2 and grade 3 cytokine release syndrome affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), and hemophagocytic lymphohistiocytosis affected 2 patients. Outpatient administration was tested in 20 patients, saving a median of 14 hospital days per patient. Overall response rates were 66% (48.9%, complete response [CR]; 17%, partial response). Median duration of remission (DOR) for CR patients was not reached and for all responding patients was 8.3 months (95% confidence interval [CI]: 3.0-not evaluable). 54.4% (CI: 32.8-71.7) of CR patients and 42.6% of all responding patients were projected to remain progression-free at ≥12 months. AUTO3 ± pembrolizumab for relapsed/refractory LBCL was safe and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion in vivo, and selection of CAR binders active at low antigen densities.
Assuntos
Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Imunoterapia Adotiva , Linfócitos T , Antígenos CD19 , Lectina 2 Semelhante a Ig de Ligação ao Ácido SiálicoRESUMO
In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.
Assuntos
Produtos Biológicos , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Adulto , Humanos , Seguimentos , Imunoterapia Adotiva/efeitos adversos , Linfoma Difuso de Grandes Células B/patologia , Antígenos CD19/uso terapêuticoRESUMO
BACKGROUND: In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS: In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS: Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS: In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
Assuntos
Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos T/transplante , Adulto , Idoso , Antígenos CD19 , Biomarcadores/sangue , Intervalo Livre de Doença , Feminino , Humanos , Interleucinas/sangue , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Doenças do Sistema Nervoso/induzido quimicamente , Neutropenia/induzido quimicamente , Receptores de Antígenos de Linfócitos T/sangue , Taxa de Sobrevida , Linfócitos T/imunologia , Adulto JovemRESUMO
BACKGROUND: Axicabtagene ciloleucel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy. In the previous analysis of the ZUMA-1 registrational study, with a median follow-up of 15·4 months (IQR 13·7-17·3), 89 (82%) of 108 assessable patients with refractory large B-cell lymphoma treated with axicabtagene ciloleucel achieved an objective response, and complete responses were noted in 63 (58%) patients. Here we report long-term activity and safety outcomes of the ZUMA-1 study. METHODS: ZUMA-1 is a single-arm, multicentre, registrational trial at 22 sites in the USA and Israel. Eligible patients were aged 18 years or older, and had histologically confirmed large B-cell lymphoma-including diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, and transformed follicular lymphoma-according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue; refractory disease or relapsed after autologous stem-cell transplantation; an Eastern Cooperative Oncology Group performance status of 0 or 1; and had previously received an anti-CD20 monoclonal antibody containing-regimen and an anthracycline-containing chemotherapy. Participants received one dose of axicabtagene ciloleucel on day 0 at a target dose of 2â×â106 CAR T cells per kg of bodyweight after conditioning chemotherapy with intravenous fludarabine (30 mg/m2 body-surface area) and cyclophosphamide (500 mg/m2 body-surface area) on days -5, -4, and -3. The primary endpoints were safety for phase 1 and the proportion of patients achieving an objective response for phase 2, and key secondary endpoints were overall survival, progression-free survival, and duration of response. Pre-planned activity and safety analyses were done per protocol. ZUMA-1 is registered with ClinicalTrials.gov, number NCT02348216. Although the registrational cohorts are closed, the trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. FINDINGS: Between May 19, 2015, and Sept 15, 2016, 119 patients were enrolled and 108 received axicabtagene ciloleucel across phases 1 and 2. As of the cutoff date of Aug 11, 2018, 101 patients assessable for activity in phase 2 were followed up for a median of 27·1 months (IQR 25·7-28·8), 84 (83%) had an objective response, and 59 (58%) had a complete response. The median duration of response was 11·1 months (4·2-not estimable). The median overall survival was not reached (12·8-not estimable), and the median progression-free survival was 5·9 months (95% CI 3·3-15·0). 52 (48%) of 108 patients assessable for safety in phases 1 and 2 had grade 3 or worse serious adverse events. Grade 3 or worse cytokine release syndrome occurred in 12 (11%) patients, and grade 3 or worse neurological events in 35 (32%). Since the previous analysis at 1 year, additional serious adverse events were reported in four patients (grade 3 mental status changes, grade 4 myelodysplastic syndrome, grade 3 lung infection, and two episodes of grade 3 bacteraemia), none of which were judged to be treatment related. Two treatment-related deaths (due to haemophagocytic lymphohistiocytosis and cardiac arrest) were previously reported, but no new treatment-related deaths occurred during the additional follow-up. INTERPRETATION: These 2-year follow-up data from ZUMA-1 suggest that axicabtagene ciloleucel can induce durable responses and a median overall survival of greater than 2 years, and has a manageable long-term safety profile in patients with relapsed or refractory large B-cell lymphoma. FUNDING: Kite and the Leukemia & Lymphoma Society Therapy Acceleration Program.
Assuntos
Antígenos CD19/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Folicular/terapia , Linfoma Difuso de Grandes Células B/terapia , Adulto , Idoso , Antígenos CD19/administração & dosagem , Antígenos CD19/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Produtos Biológicos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Seguimentos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/mortalidade , Masculino , Pessoa de Meia-Idade , Análise de Sobrevida , Resultado do Tratamento , Vidarabina/administração & dosagem , Vidarabina/efeitos adversos , Vidarabina/análogos & derivados , Vidarabina/uso terapêuticoRESUMO
The optimal viral load threshold at which to initiate preemptive cytomegalovirus (CMV) therapy in hematopoietic cell transplantation (HCT) recipients remains to be defined. In an effort to address this question, we conducted a retrospective study of 174 allogeneic HCT recipients who underwent transplantation at a single center between August 2012 and April 2016. During this period, preemptive therapy was initiated at the discretion of the treating clinician. A total of 109 patients (63%) developed CMV viremia. The median time to reactivation was 17 days (interquartile range, IQR, 7-30 days) post-HCT. A peak viremia ≥150 IU/mL was strongly associated with a reduced probability of spontaneous clearance (relative risk, .16; 95% confidence interval, .1-.27), independent of established clinical risk factors, including CMV donor serostatus, exposure to antithymocyte globulin, and underlying lymphoid malignancy. The median time to clearance of viremia was significantly shorter in those who started therapy at CMV <350 IU/mL (19 days; IQR, 11-35 days) compared with those who started antiviral therapy at higher viremia thresholds (33 days; IQR, 21-42 days; P = .02). The occurrence of treatment-associated cytopenias was frequent but similar in patients who started preemptive therapy at CMV <350 IU/mL and those who started at CMV >350 IU/mL (44% versus 57%; P = .42). Unresolved CMV viremia by treatment day 35 was associated with increased risk of therapeutic failure (32% versus 0%; P = .001). Achieving eradication of CMV viremia by treatment day 35 was associated with a 74% reduction in 1-year nonrelapse mortality (NRM) (adjusted hazard ratio [HR], .26; 95% confidence interval [CI], .1-.8; P = .02), whereas therapeutic failure was associated with a significant increase in the probability of 1-year NRM (adjusted HR, 26; 95% CI, 8-87; P <.0001). We conclude that among allogeneic HCT patients, a peak CMV viremia ≥150 IU/mL is associated with a >80% reduction in the probability of spontaneous clearance independent of ATG administration, CMV donor serostatus, and lymphoid malignancy, and is a reasonable cutoff for preemptive therapy. Delaying initiation of therapy until a CMV value ≥350 IU/mL is associated with more protracted CMV viremia, and unresolved viremia by treatment day 35 is associated with a significant increase in NRM.
Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Transplante de Células-Tronco Hematopoéticas , Carga Viral , Adulto , Aloenxertos , Infecções por Citomegalovirus/sangue , Infecções por Citomegalovirus/etiologia , Infecções por Citomegalovirus/mortalidade , Infecções por Citomegalovirus/prevenção & controle , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Taxa de SobrevidaAssuntos
Produtos Biológicos/administração & dosagem , Linfoma Difuso de Grandes Células B , Proteínas de Neoplasias/imunologia , Evasão Tumoral/efeitos dos fármacos , Adulto , Antígenos CD19/imunologia , Produtos Biológicos/efeitos adversos , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Recidiva , Evasão Tumoral/genéticaRESUMO
Lasiodiplodia theobromae is a known plant pathogen in tropical and subtropical areas. Few cases have been reported in humans (usually keratitis and endophthalmitis) with only two cases of fungal sinusitis in immunocompromised and immunocompetent patients published to date. We report a case of invasive sinusitis secondary to L. theobromae in an allogeneic hematopoietic cell transplant recipient successfully treated with surgical debridement and triazole antifungals with a review of available literature.
Assuntos
Ascomicetos/isolamento & purificação , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções Fúngicas Invasivas/diagnóstico , Rinite/diagnóstico , Sinusite/diagnóstico , Antifúngicos/administração & dosagem , Ascomicetos/classificação , Desbridamento , Humanos , Infecções Fúngicas Invasivas/microbiologia , Infecções Fúngicas Invasivas/patologia , Infecções Fúngicas Invasivas/terapia , Masculino , Pessoa de Meia-Idade , Rinite/microbiologia , Rinite/patologia , Rinite/terapia , Sinusite/microbiologia , Sinusite/patologia , Sinusite/terapia , Transplantados , Transplante Homólogo/efeitos adversos , Resultado do Tratamento , Triazóis/administração & dosagemRESUMO
Regulatory T (Treg) cells play a central role in immune tolerance and prevention of aberrant immune responses. Several studies have suggested that the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT) can be ameliorated by increasing Tregs. We have developed an approach of in vivo expansion of Tregs with RGI-2001, a novel liposomal formulation of a synthetic derivative of alpha-galactosylceramide, a naturally occurring ligand that binds to CD1 and activates and expands invariant natural killer cells. In preclinical studies, a single intravenous infusion of RGI-2001 expanded Treg and could ameliorate GVHD in a mouse model of allogeneic HCT. To explore the role of RGI-2001 in clinical HCT, we initiated a phase 2A clinical trial (n = 29), testing 2 different doses of RGI-2001 administered as a single infusion on day 0 of allogeneic HCT. RGI-2001 was well tolerated and without infusion reactions or cytokine release syndrome. A subset of patients (8 of 29, 28%) responded to RGI-2001 by inducing a markedly increased number of cells with a Treg phenotype. The Treg had a high Ki-67 index and were almost exclusively Helios+ and Foxp3+, indicating that their accumulation was due to expansion of natural Treg. Notably, the incidence of grade 2 to 4 GVHD in the 8 patients who responded to RGI-2001 was 12.5%, compared with 52.4% in the 21 patients who did not respond. No grade 3 or 4 GVHD was observed in the responder group, compared with a 9.5% incidence among nonresponders. Immunosuppression with sirolimus was also associated with a low incidence of GVHD, suggesting that RGI-2001 may have synergized with sirolimus to promote Treg expansion.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Galactosilceramidas/administração & dosagem , Doença Enxerto-Hospedeiro/prevenção & controle , Sirolimo/administração & dosagem , Linfócitos T Reguladores/citologia , Doença Aguda , Adulto , Idoso , Transplante de Medula Óssea/métodos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Fatores de Transcrição Forkhead , Galactosilceramidas/farmacologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Humanos , Fator de Transcrição Ikaros , Pessoa de Meia-Idade , Células T Matadoras Naturais/citologia , Sirolimo/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Transplante Homólogo , Adulto JovemAssuntos
Anormalidades Congênitas/etiologia , Anormalidades Congênitas/patologia , Fusariose/diagnóstico , Fusariose/patologia , Hospedeiro Imunocomprometido , Doenças Nasais/diagnóstico , Doenças Nasais/patologia , Anormalidades Congênitas/diagnóstico por imagem , Feminino , Fusarium/isolamento & purificação , Histocitoquímica , Humanos , Pessoa de Meia-Idade , Doenças Nasais/diagnóstico por imagem , Tomografia Computadorizada por Raios XRESUMO
Treatment resistance and toxicities remain a risk following chimeric antigen receptor (CAR) T-cell therapy. Herein, we report pharmacokinetics, pharmacodynamics, and product and apheresis attributes associated with outcomes among patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axicabtagene ciloleucel (axi-cel) in ZUMA-7. Axi-cel peak expansion associated with clinical response and toxicity, but not response durability. In apheresis material and final product, a naive T-cell phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved response durability, event-free survival, progression-free survival, and a lower number of prior therapies. This phenotype was not associated with high-grade cytokine release syndrome (CRS) or neurologic events. Higher baseline and postinfusion levels of serum inflammatory markers associated with differentiated/effector products, reduced efficacy, and increased CRS and neurologic events, thus suggesting targets for intervention. These data support better outcomes with earlier CAR T-cell intervention and may improve patient care by informing on predictive biomarkers and development of next-generation products. SIGNIFICANCE: In ZUMA-7, the largest randomized CAR T-cell trial in LBCL, a naive T-cell product phenotype (CCR7+CD45RA+) expressing CD27 and CD28 associated with improved efficacy, decreased toxicity, and a lower number of prior therapies, supporting earlier intervention with CAR T-cell therapy. In addition, targets for improvement of therapeutic index are proposed. This article is featured in Selected Articles from This Issue, p. 4.
Assuntos
Imunoterapia Adotiva , Linfoma Difuso de Grandes Células B , Humanos , Imunoterapia Adotiva/efeitos adversos , Antígenos CD28 , Receptores CCR7 , Linfoma Difuso de Grandes Células B/terapia , Pesquisadores , Síndrome da Liberação de Citocina , Antígenos Comuns de LeucócitoRESUMO
The study aimed to determine the association of chronic graft-versus-host disease (cGVHD) diagnosis and severity with the development of subsequent neoplasms (SN) and nonmalignant late effects (NM-LE) in 2-year disease-free adult survivors following hematopoietic cell transplantation (HCT) for a hematologic malignancy. To do so, we conducted a retrospective analysis of 3884 survivors of HCT for hematologic malignancy in the Center of International Blood and Marrow Transplant Research database. We conducted a landmark analysis at the 2-year post-transplantation date, comparing first SN and NM-LE in survivors with and without cGVHD. The cumulative incidence (CuI) of SN and NM-LE were estimated through 10 years post-HCT in both groups, with death or disease relapse as a competing risk. Cox proportional hazards models were used to evaluate the associations of cGVHD and its related characteristics with the development of SN and NM-LE. The estimated 10-year CuI of SN in patients with GVHD (n = 2669) and patients without cGVHD (n = 1215) was 15% (95% confidence interval [CI], 14% to 17%) versus 9% (7.2% to 11%) (P < .001). cGVHD by 2 years post-HCT was independently associated with SN (hazard ratio [HR], 1.94; 95% CI, 1.53 to 2.46; P < .0001) with a standardized incidence ratio of 3.2 (95% CI, 2.9 to 3.5; P < .0001). Increasing severity of cGVHD was associated with an increased risk of SN. The estimated 10-year CuI of first NM-LE in patients with and without cGVHD was 28 (95% CI, 26% to 30%) versus 13% (95% CI, 11% to 15%) (P < .001). cGVHD by 2 years post-HCT was independently associated with NM-LE (HR, 2.23; 95% CI, 1.81 to 2.76; P < .0001). Multivariate analysis of cGVHD-related factors showed that increasing severity of cGVHD, extensive grade, having both mucocutaneous and visceral involvement, and receiving cGVHD treatment for >12 months were associated with the greatest magnitude of risk for NM-LE. cGVHD was closely associated with both SN and NM-LE in adult survivors of HCT for hematologic malignancy. Patients identified as having more severe involvement and both mucocutaneous and visceral organ involvement may warrant enhanced monitoring and screening for SNs and NM-LEs. However, caution is warranted when interpreting these results, as patients with cGVHD may have more vigilant post-transplantation health care and surveillance for late effects.
Assuntos
Síndrome de Bronquiolite Obliterante , Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Adulto , Humanos , Estudos Retrospectivos , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/etiologia , Aloenxertos/patologia , Recidiva Local de Neoplasia/complicações , Neoplasias Hematológicas/complicações , Neoplasias Hematológicas/epidemiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Progressão da DoençaRESUMO
The overall survival (OS) has improved significantly in multiple myeloma (MM) over the last decade with the use of proteasome inhibitor and immunomodulatory drug-based combinations, followed by high-dose melphalan and autologous hematopoietic stem cell transplantation (auto-HSCT) and subsequent maintenance therapies in eligible newly diagnosed patients. However, clinical trials using auto-HSCT followed by lenalidomide maintenance have shown an increased risk of second primary malignancies (SPM), including second hematological malignancies (SHM). We evaluated the impact of SPM and SHM on progression-free survival (PFS) and OS in patients with MM after auto-HSCT using CIBMTR registry data. Adult patients with MM who underwent first auto-HSCT in the United States with melphalan conditioning regimen from 2011 to 2018 and received maintenance therapy were included (n = 3948). At a median follow-up of 37 months, 175 (4%) patients developed SPM, including 112 (64%) solid, 36 (20%) myeloid, 24 (14%) SHM, not otherwise specified, and 3 (2%) lymphoid malignancies. Multivariate analysis demonstrated that SPM and SHM were associated with an inferior PFS (hazard ratio [HR] 2.62, P < .001 and HR 5.01, P < .001, respectively) and OS (HR 3.85, P < .001 and HR 8.13, P < .001, respectively). In patients who developed SPM and SHM, MM remained the most frequent primary cause of death (42% vs 30% and 53% vs 18%, respectively). We conclude the development of SPM and SHM leads to a poor survival in patients with MM and is an important survivorship challenge. Given the median survival for MM continues to improve, continued vigilance is needed to assess the risks of SPM and SHM with maintenance therapy post-auto-HSCT.
Assuntos
Neoplasias Hematológicas , Mieloma Múltiplo , Segunda Neoplasia Primária , Adulto , Humanos , Estados Unidos , Mieloma Múltiplo/tratamento farmacológico , Melfalan/efeitos adversos , Segunda Neoplasia Primária/etiologia , Segunda Neoplasia Primária/tratamento farmacológico , Transplante Autólogo , Lenalidomida/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológicoRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with a poor prognosis and considered incurable with conventional chemotherapy. Small observational studies reported allogeneic hematopoietic cell transplantation (allo-HCT) offers durable remissions in patients with BPDCN. We report an analysis of patients with BPDCN who received an allo-HCT, using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). We identified 164 patients with BPDCN from 78 centers who underwent allo-HCT between 2007 and 2018. The 5-year overall survival (OS), disease-free survival (DFS), relapse, and nonrelapse mortality (NRM) rates were 51.2% (95% confidence interval [CI], 42.5-59.8), 44.4% (95% CI, 36.2-52.8), 32.2% (95% CI, 24.7-40.3), and 23.3% (95% CI, 16.9-30.4), respectively. Disease relapse was the most common cause of death. On multivariate analyses, age of ≥60 years was predictive for inferior OS (hazard ratio [HR], 2.16; 95% CI, 1.35-3.46; P = .001), and higher NRM (HR, 2.19; 95% CI, 1.13-4.22; P = .02). Remission status at time of allo-HCT (CR2/primary induction failure/relapse vs CR1) was predictive of inferior OS (HR, 1.87; 95% CI, 1.14-3.06; P = .01) and DFS (HR, 1.75; 95% CI, 1.11-2.76; P = .02). Use of myeloablative conditioning with total body irradiation (MAC-TBI) was predictive of improved DFS and reduced relapse risk. Allo-HCT is effective in providing durable remissions and long-term survival in BPDCN. Younger age and allo-HCT in CR1 predicted for improved survival, whereas MAC-TBI predicted for less relapse and improved DFS. Novel strategies incorporating allo-HCT are needed to further improve outcomes.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Humanos , Pessoa de Meia-Idade , Transplante Homólogo , Recidiva Local de Neoplasia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Aguda , Transtornos Mieloproliferativos/patologia , Doença Crônica , Recidiva , Células Dendríticas/patologiaRESUMO
Axicabtagene ciloleucel (axi-cel) is an anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for relapsed/refractory large B cell lymphoma (LBCL) and has treatment with similar efficacy across conventional LBCL subtypes. Toward patient stratification, we assessed whether tumor immune contexture influenced clinical outcomes after axi-cel. We evaluated the tumor microenvironment (TME) of 135 pre-treatment and post-treatment tumor biopsies taken from 51 patients in the ZUMA-1 phase 2 trial. We uncovered dynamic patterns that occurred within 2 weeks after axi-cel. The biological associations among Immunoscore (quantification of tumor-infiltrating T cell density), Immunosign 21 (expression of pre-defined immune gene panel) and cell subsets were validated in three independent LBCL datasets. In the ZUMA-1 trial samples, clinical response and overall survival were associated with pre-treatment immune contexture as characterized by Immunoscore and Immunosign 21. Circulating CAR T cell levels were associated with post-treatment TME T cell exhaustion. TME enriched for chemokines (CCL5 and CCL22), γ-chain receptor cytokines (IL-15, IL-7 and IL-21) and interferon-regulated molecules were associated with T cell infiltration and markers of activity. Finally, high density of regulatory T cells in pre-treatment TME associated with reduced axi-cel-related neurologic toxicity. These findings advance the understanding of LBCL TME characteristics associated with clinical responses to anti-CD19 CAR T cell therapy and could foster biomarker development and treatment optimization for patients with LBCL.
Assuntos
Produtos Biológicos , Linfoma Difuso de Grandes Células B , Receptores de Antígenos Quiméricos , Antígenos CD19 , Contagem de Células , Humanos , Imunoterapia Adotiva/efeitos adversos , Interferons/uso terapêutico , Interleucina-15 , Interleucina-7/uso terapêutico , Linfoma Difuso de Grandes Células B/terapia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , Microambiente TumoralRESUMO
The effect of chronic graft-versus-host disease (cGVHD) on the risk of nonrelapse mortality (NRM) and relapse has not been specifically studied in older adults, who are increasingly undergoing allogeneic hematopoietic cell transplantation (alloHCT) and surviving long-term to develop cGVHD. In this Center for International Blood and Marrow Transplant Research (CIBMTR) analysis, we tested our hypothesis that the risk of NRM was higher with the development of cGVHD, particularly among older adults (age ≥60 years). We included 4429 adults age ≥40 years who underwent a first HLA-matched peripheral blood stem cell alloHCT for acute myelogenous leukemia or myelodysplastic syndrome between 2008 and 2017. We compared outcomes of 4 groups-older adults (≥60 years) and younger adults (40 to 59 years) with cGVHD and older and younger adults without cGVHD-to determine the effect of older age and cGVHD on various outcomes. We used Cox proportional hazard models to determine the risk of NRM, relapse, and overall survival (OS). We treated cGVHD as a time-dependent covariate. The severity of cGVHD was based on the CIBMTR clinical definitions. cGVHD was significantly associated with a higher risk of NRM and lower risk of relapse regardless of age. The risk of NRM was higher for older adults versus younger adults. Adults who developed cGVHD as a group had longer OS compared with age-matched cohorts without cGVHD. Older adults had worse OS regardless of cGVHD. Among adults with cGVHD, clinically moderate or severe cGVHD was associated with a significantly higher risk of NRM and lower risk of relapse; severe cGVHD was associated with shorter OS, whereas mild to moderate cGVHD was associated with longer OS. Among both younger and older adults, the development of cGVHD was associated with a higher risk of NRM, lower risk of relapse, and longer OS. Older adults had a higher risk of NRM, but the increased risk of NRM associated with cGVHD did not differ based on age. The development of mild to moderate cGVHD offered the most favorable balance between minimizing NRM and decreasing the risk of relapse. The relapse risk was lowest for adults with severe cGVHD, but high NRM resulted in shorter OS. Developing strategies to avoid clinically severe cGVHD is critically important. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.
Assuntos
Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Síndromes Mielodisplásicas , Adulto , Idoso , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/terapia , Recidiva , Condicionamento Pré-Transplante , Estados UnidosRESUMO
Chronic graft-versus-host disease (cGVHD) occurs in up to 25% of children following allogeneic hematopoietic cell transplantation (HCT) and continues to be a major cause of late morbidity and poor quality of life among long-term survivors of pediatric HCT. Late effects (LEs) of HCT are well documented in this population, and cGVHD has been identified as a risk factor for subsequent neoplasms (SNs) and several nonmalignant LEs (NM-LEs); however, the reported correlation between cGVHD and LEs varies among studies. We compared LEs occurring ≥2 years following childhood HCT for a hematologic malignancy in 2-year disease-free survivors with and without cGVHD and further evaluated the association of cGVHD features on the development of LEs. This systematic retrospective analysis used data from the Center of International Blood and Marrow Transplant Research (CIBMTR) on a large, representative cohort of 1260 survivors of pediatric HCT for hematologic malignancy to compare first malignant LEs and NM-LEs in those with a diagnosis of cGVHD and those who never developed cGVHD. The cumulative incidences of any first LE, SN, and NM-LE were estimated at 10 years after HCT, with death as a competing risk for patients with cGVHD versus no cGVHD. Cox proportional hazards models were used to evaluate the impact of cGVHD and its related characteristics on the development of first LEs. The estimated 10-year cumulative incidence of any LE in patients with and without cGVHD was 43% (95% CI, 38% to 48.2%) versus 32% (95% confidence interval [CI], 28.5% to 36.3%) (P < .001), respectively. The development of cGVHD by 2 years post-HCT was independently associated with any LE (hazard ratio [HR], 1.38; 95% CI, 1.13 to 1.68; P = .001) and NM-LE (HR, 1.37; 95% CI, 1.10 to 1.70; P = .006), but not SN (HR, 1.30; 95% CI, .73 to 2.31; P = .38). cGVHD-related factors linked with the development of an NM-LE included having extensive grade cGVHD (HR, 1.60; 95% CI, 1.23 to 2.08; P = .0005), severe cGVHD (HR, 2.25; 95% CI, 1.60 to 3.17; P < .0001), interrupted onset type (HR, 1.57; 95% CI, 1.21 to 2.05; P = .0008), and both mucocutaneous and visceral organ involvement (HR, 1.59; 95% CI, 1.24 to 2.03; P = .0002). No significant association between cGVHD-specific variables and SN was identified. Finally, the duration of cGVHD treatment of cGVHD with systemic immunosuppression was not significantly associated with SNs or NM-LEs. cGVHD was more closely associated with NM-LEs than with SNs among survivors of pediatric HCT for hematologic malignancy. In this analysis, the development of SNs was strongly associated with the use of myeloablative total body irradiation. cGVHD-related characteristics consistent with a state of greater immune dysregulation were more closely linked to NM-LEs.
Assuntos
Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Criança , Doença Enxerto-Hospedeiro/epidemiologia , Neoplasias Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Qualidade de Vida , Estudos RetrospectivosRESUMO
SARS-CoV-2 emerged as a worldwide pandemic in late 2019 and initially was described as a primary respiratory illness. The clinical manifestations of COVID-19 are now known to encompass nearly all organ systems, including the central nervous system. We present a case of an allogeneic hematopoietic stem cell transplant recipient who recovered from documented SARS-CoV-2 infection and later presented with symptoms of meningitis. While cerebrospinal fluid analysis did not reveal any bacterial or viral etiologies, evidence of an inflammatory state, including ophthalmologic findings of episcleritis, indicate what is likely the first reported case of aseptic meningitis associated with SARS-CoV-2 infection after initial clinical recovery.
RESUMO
The SCHOLAR-1 international retrospective study highlighted poor clinical outcomes and survival among patients with refractory large B-cell lymphoma (LBCL) treated with conventional chemotherapy. Axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, demonstrated durable responses in patients with refractory LBCL in the pivotal phase 1/2 ZUMA-1 study (NCT02348216). Here, we compared SCHOLAR-1 with the 2-year outcomes of ZUMA-1. Prior to comparison of clinical outcomes, propensity scoring (based on a broad set of prognostic covariates) was used to create balance between ZUMA-1 and SCHOLAR-1 patients. In the pivotal phase 2 portion of ZUMA-1, 101 patients received axi-cel and were evaluable for response and survival. In SCHOLAR-1, 434 and 424 patients were evaluable for response and survival, respectively. ZUMA-1 patients were more heavily pretreated than were SCHOLAR-1 patients. The median follow-up was 27.1 months in ZUMA-1. The objective response rate (ORR) and complete response rate were 83% and 54% in ZUMA-1 vs 34% and 12% in SCHOLAR-1, respectively. The 2-year survival rate was 54% in ZUMA-1 and 20% in SCHOLAR-1, and a 73% reduction in the risk of death was observed in ZUMA-1 vs SCHOLAR-1. These results were consistent with those of an additional standardization analysis in which strata were limited to 2 prognostic factors (refractory categorization and presence/absence of stem cell transplant after refractoriness to chemotherapy) to conserve sample size. Despite the limitations of a nonrandomized analysis, these results indicate that axi-cel produces durable responses and a substantial survival benefit vs non-CAR T-cell salvage regimens for patients with refractory LBCL.
Assuntos
Linfoma Difuso de Grandes Células B , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Estudos Retrospectivos , Terapia de Salvação , Taxa de Sobrevida , Linfócitos TRESUMO
Progressive multifocal leukoencephalopathy (PML) remains a life-threatening central nervous system infection in immunocompromised patients. Although outcomes have improved in cases that immune reconstitution is feasible with anti-retroviral therapy (ART) in HIV + patients or natalizumab removal in those with multiple sclerosis, in individuals with hematological malignancies, the prognosis is usually dismal. Anti-viral treatments have been largely ineffective, but immunotherapy-based approaches with checkpoint inhibitors and adoptive virus-specific T cells' transfer are currently explored in clinical trials. PML has not been described as a cause of encephalopathy after CAR T therapy. We report the first case of PML 7 months after lymphodepleting chemotherapy with fludarabine/cyclophosphamide and anti-CD19-directed CAR T therapy in a patient with relapsed diffuse large B-cell lymphoma who relapsed fast after a previous autologous hematopoietic stem cell transplant. She remains alive 12 months after diagnosis with stabilization of her symptoms with a combination of therapies targeting viral replication and immunotherapy.
Assuntos
Transferência Adotiva/métodos , Antígenos CD19/uso terapêutico , Hospedeiro Imunocomprometido , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Leucoencefalopatia Multifocal Progressiva/etiologia , Leucoencefalopatia Multifocal Progressiva/terapia , Receptores de Antígenos Quiméricos/administração & dosagem , Linfócitos T , Idoso , Antígenos CD19/administração & dosagem , Antineoplásicos/uso terapêutico , Produtos Biológicos , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Linfoma Difuso de Grandes Células B/terapia , Recidiva , Transplante AutólogoRESUMO
Anti-CD19 Chimeric Antigen Receptor T cells (CAR-T) have shown dramatic efficacy in treating refractory aggressive B cell Lymphomas leading to FDA approval of axicabtagene ciloleucel and tisagenlecleucel. While long-term remission rate for both is higher than 33%, this treatment is associated with life-threatening complications including cytokine-release syndrome, encephalopathy, and lethal cerebral edema. Here we describe a case series of bone marrow failure syndromes with or without co-existing clonal myelodysplastic syndrome. Bone marrow failure was defined as absolute neutrophil count (ANC) <500 neutrophils/µL day 42 after infusion of CAR-T cells or filgrastim support to reach that number. We use "persistent cytopenias after T-cell therapy (PCTT)" to describe this syndrome which has an incidence of 38% with axicabtagene ciloleucel. Platelets <75,000/µL at the time of initiation of lymphodepleting chemotherapy and occurrence of maximum severity of cytokine-release syndrome (CRS) on day 0 or 1 after infusion of CAR-T cells are independent predictors of PCTT.