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While chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of B-cell malignancies, many patients relapse and therefore strategies to improve antitumor immunity are needed. We previously designed a novel autologous bispecific CAR targeting CD19 and CD22 (CAR19-22), which was well tolerated and associated with high response rates but relapse was common. Interleukin-15 (IL15) induces proliferation of diverse immune cells and can augment lymphocyte trafficking. Here, we report the results of a phase 1 clinical trial of the first combination of a novel recombinant polymer-conjugated IL15 receptor agonist (NKTR-255), with CAR19-22, in adults with relapsed / refractory B-cell acute lymphoblastic leukemia. Eleven patients were enrolled, nine of whom successfully received CAR19-22 followed by NKTR-255. There were no dose limiting toxicities, with transient fever and myelosuppression as the most common possibly related toxicities. We observed favorable efficacy with eight out of nine patients (89%) achieving measurable residual disease negative remission. At 12 months, progression-free survival for NKTR-255 was double that of historical controls (67% vs 38%). We performed correlative analyses to investigate the effects of IL15 receptor agonism. Cytokine profiling showed significant increases in IL15 and the chemokines CXCL9 and CXCL10. The increase in chemokines was associated with decreases in absolute lymphocyte counts and CD8+ CAR T-cells in blood and ten-fold increases in CSF CAR-T cells, suggesting lymphocyte trafficking to tissue. Combining NKTR-255 with CAR19-22 was safe, feasible and associated with high rates of durable responses (NCT03233854).
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The treatment landscape of relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL) has evolved significantly over the past decade after the approval of brentuximab vedotin (BV) and the programmed death-1 (PD-1) inhibitors. We evaluated how outcomes and practice patterns have changed for patients with R/R cHL who underwent autologous hematopoietic cell transplantation (AHCT) at our institution from 2011 to 2020 (N = 183) compared with those from 2001 to 2010 (N = 159) and evaluated prognostic factors for progression-free survival (PFS) and overall survival (OS) in both eras. OS was superior in the modern era with a trend toward lower nonrelapse mortality beyond 2 years after transplant. Among patients who progressed after AHCT, 4-year postprogression survival increased from 43.3% to 71.4% in the modern era, reflecting increasing use of BV and the PD-1 inhibitors. In multivariable analysis for patients that underwent transplant in the modern era, age ≥45 years, primary refractory disease, and lack of complete remission pre-AHCT were associated with inferior PFS, whereas receipt of a PD-1 inhibitor-based regimen pre-AHCT was associated with superior PFS. Extranodal disease at relapse was associated with inferior OS. Our study demonstrates improved survival for R/R cHL after AHCT in the modern era attributed to more effective salvage regimens allowing for better disease control pre-AHCT and improved outcomes for patients who progressed after AHCT. Excellent outcomes were observed with PD-1 inhibitor-based salvage regimens pre-AHCT and support a randomized trial evaluating immunotherapy in the second line setting.
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Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin , Humanos , Pessoa de Meia-Idade , Doença de Hodgkin/patologia , Transplante Autólogo , Inibidores de Checkpoint Imunológico/uso terapêutico , Recidiva Local de Neoplasia/terapia , Brentuximab Vedotin/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversosRESUMO
Autologous hematopoietic cell transplantation (AHCT) is often used as a consolidation for patients with peripheral T-cell lymphomas (PTCLs) due to the poor prognosis associated with this heterogenous group of disorders. However, a significant number of patients will experience post-AHCT disease relapse. Here, we report a retrospective study of consecutive 124 patients with PTCLs who underwent AHCT from 2008 to 2020. With a median follow-up of 6.01 years following AHCT, 49 patients (40%) experienced disease relapse. As expected, more patients who were not in first complete remission experienced post-AHCT relapse. Following relapse, majority of the patients (70%) receiving systemic therapies intended as bridging to curative allogeneic HCT. However, only 18 (53%) patients eventually underwent allogeneic HCT. The estimated 3-year OS among patients proceeding to allogeneic HCT was 72% (95% CI 46%-87%). Our report details the pattern of post-AHCT relapse and the management of relapsed disease using different therapeutic modalities.
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Transplante de Células-Tronco Hematopoéticas , Linfoma de Células T Periférico , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Adulto , Estudos Retrospectivos , Idoso , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/mortalidade , Recidiva , Transplante Autólogo , Recidiva Local de Neoplasia/terapia , Adulto JovemRESUMO
The prognosis of patients with large B-cell lymphoma (LBCL) that progresses after treatment with chimeric antigen receptor (CAR) T-cell therapy targeting CD19 (CAR19) is poor. We report on the first 3 consecutive patients with autologous CAR19-refractory LBCL who were treated with a single infusion of autologous 1 × 106 CAR+ T cells per kilogram targeting CD22 (CAR22) as part of a phase 1 dose-escalation study. CAR22 therapy was relatively well tolerated, without any observed nonhematologic adverse events higher than grade 2. After infusion, all 3 patients achieved complete remission, with all responses continuing at the time of last follow-up (mean, 7.8 months; range, 6-9.3). Circulating CAR22 cells demonstrated robust expansion (peak range, 85.4-350 cells per microliter), and persisted beyond 3 months in all patients with continued radiographic responses and corresponding decreases in circulating tumor DNA beyond 6 months after infusion. Further accrual at a higher dose level in this phase 1 dose-escalation study is ongoing and will explore the role of this therapy in patients in whom prior CAR T-cell therapies have failed. This trial is registered on clinicaltrials.gov as #NCT04088890.
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Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Linfoma Difuso de Grandes Células B/terapia , Lectina 2 Semelhante a Ig de Ligação ao Ácido Siálico/imunologia , Ensaios Clínicos Fase I como Assunto , Humanos , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Prognóstico , Indução de RemissãoRESUMO
We present a patient with widespread PCGD-TCL of the bilateral arms and legs, who underwent radiotherapy with 34 Gy in 17 fractions using circumferential VMAT and 3-D printed bolus to the four extremities prior to planned stem cell transplant, who was then found to have progression in the liver, lung, and skin, followed by drastic regression of all in and out-of-field lesions on imaging 1.5 months later. The cause of regression may be related to a radiation-induced abscopal effect from the immunomodulatory effects of radiation, or related to immune reactivation in the setting of cessation of systemic immunosuppressive agents.
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Plasma cell leukemia (PCL) is a rare and very aggressive plasma cell disorder. The optimal treatment approach, including whether to pursue an autologous (auto) or allogeneic (allo) stem cell transplantation (SCT) is not clear, given the lack of clinical trial-based evidence. This single-center retrospective study describes the outcomes of 16 patients with PCL (n = 14 with primary PCL) who underwent either autoSCT (n = 9) or alloSCT (n = 7) for PCL in the era of novel agents, between 2007 and 2019. The median age of the cohort was 58 years. High-risk cytogenetics were found in 50% of the patients. All patients received a proteasome inhibitor and/or immunomodulatory drug-based regimen before transplantation. At the time of transplantation, 10 patients (62%) obtained at least a very good partial response (VGPR). The response after autoSCT (3 months) was at least a VGPR in 6 patients (67%; complete response [CR] in 5). All patients undergoing alloSCT achieved a CR at 3 months. Maintenance therapy was provided to 5 patients (56%) after autoSCT. The median progression-free survival after transplantation was 6 months in the autoSCT group, compared with 18 months in the alloSCT group (P = .09), and median overall survival (OS) after transplantation in the 2 groups was 19 months and 40 months, respectively (P = .41). The median OS from diagnosis was 27 months and 49 months, respectively (P = .50). Of the 11 deaths, 10 patients (91%) died of relapsed disease. AlloSCT was not observed to offer any significant survival advantage over autoSCT in PCL, in agreement with recent reports, and relapse remains the primary cause of death in these patients.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Plasmocitária , Preparações Farmacêuticas , Intervalo Livre de Doença , Humanos , Leucemia Plasmocitária/terapia , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante de Células-Tronco , Transplante Autólogo , Transplante Homólogo , Resultado do TratamentoRESUMO
The Hematopoietic Cell Transplantation (HCT)-Specific Comorbidity Index (HCT-CI) has been extensively studied in myeloablative and reduced-intensity conditioning regimens, with less data available regarding the validity of HCT-CI in nonmyeloablative (NMA) allogeneic transplantation. We conducted a retrospective analysis to evaluate the association between HCT-CI and nonrelapse mortality (NRM) and all-cause mortality (ACM) in patients receiving the total lymphoid irradiation and antithymocyte globulin (TLI/ATG) NMA transplantation preparative regimen. We abstracted demographic and clinical data from consecutive patients, who received allogeneic HCT with the TLI/ATG regimen between January 2008 and September 2014, from the Stanford blood and marrow transplantation database. We conducted univariable and multivariable Cox proportional hazards regression models to evaluate the association between HCT-CI and NRM and ACM. In all, 287 patients were included for analysis. The median age of the patients was 61 (range, 22 to 77) years. The median overall survival was 844 (range, 374 to 1484) days. Most patients had Karnofsky performance score of 90 or above (85%). Fifty-two (18%) patients relapsed within 3 months and 108 (38%) patients relapsed within 1 year, with a median time to relapse of 163 (range, 83 to 366) days. Among the comorbidities in the HCT-CI identified at the time of HCT, reduced pulmonary function was the most common (n = 89), followed by prior history of malignancy (n = 39), psychiatric condition (n = 38), and diabetes (n = 31). Patients with higher HCT-CI scores had higher mortality risks for ACM (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.14 for HCT-CI score 1 or 2 and HR, 1.85; 95% CI, 1.11 to 3.08 for HCT-CI score ≥ 3, compared with 0, respectively). Among individual HCT-CI variables, diabetes (HR, 2.31; 95% CI, 1.79 to 2.89; P = .003) and prior solid tumors (HR, 1.75; 95% CI, 1.02 to 3.00; P = .043) were associated with a higher risk of ACM. Higher HCT-CI scores were significantly associated with higher risk of death. HCT-CI is a valid tool for predicting ACM in NMA TLI/ATG allogeneic HCT.
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Comorbidade , Transplante de Células-Tronco Hematopoéticas/métodos , Condicionamento Pré-Transplante/métodos , Adulto , Idoso , Transplante de Células-Tronco Hematopoéticas/mortalidade , Humanos , Pessoa de Meia-Idade , Prognóstico , Análise de Regressão , Estudos Retrospectivos , Medição de Risco , Taxa de Sobrevida , Transplante Homólogo , Adulto JovemRESUMO
BACKGROUND: Voriconazole has previously been associated with increased risk for cutaneous squamous cell carcinoma (SCC) in solid organ transplant recipients. Less is known about the risk in patients after hematopoietic cell transplantation (HCT). OBJECTIVE: We evaluated the effect of voriconazole on the risk for nonmelanoma skin cancer (NMSC), including SCC and basal cell carcionoma, among those who have undergone allogeneic and autologous HCT. METHODS: In all, 1220 individuals who had undergone allogeneic HCT and 1418 who had undergone autologous HCT were included in a retrospective cohort study. Multivariate analysis included voriconazole exposure and other known risk factors for NMSC. RESULTS: In multivariate analysis, voriconazole use increased the risk for NMSC (hazard ratio, 1.82; 95% confidence interval, 1.13-2.91) among those who had undergone allogeneic HCT, particularly for SCC (hazard ratio, 2.25; 95% confidence interval, 1.30-3.89). Voriconazole use did not appear to confer increased risk for NMSC among those who had undergone autologous HCT. LIMITATIONS: This is a retrospective study. CONCLUSION: Voriconazole use represents an independent factor that may contribute to increased risk specifically for SCC in the allogeneic HCT population.
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Antifúngicos/uso terapêutico , Carcinoma Basocelular/epidemiologia , Carcinoma de Células Escamosas/epidemiologia , Transplante de Células-Tronco Hematopoéticas , Neoplasias Cutâneas/epidemiologia , Voriconazol/uso terapêutico , Adulto , Fatores Etários , Idoso , Feminino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Micoses/prevenção & controle , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais , Transplante Autólogo , Transplante HomólogoRESUMO
Loss of CD26 surface expression on the circulating malignant T-cell is the most widely accepted diagnostic marker in patients with leukemic cutaneous T-cell lymphoma (CTCL). CTCL cases with reemergence of CD7 and/or CD26 surface expression are unusual and of uncertain prognosis. We report the case of an erythrodermic leukemic mycosis fungoides patient who had achieved temporary remission after several months on multimodality immunotherapy and extracorporeal photopheresis, but who relapsed with aggressive disease phenotypically characterized by CD4+ T-cells with high CD26 expression. Polymerase chain reaction studies and high-throughput sequencing analyses from peripheral blood mononuclear cells at presentation and relapse consistently showed an identical clonal T-cell receptor suggesting evolution of her original malignant clone which lacked CD26 expression. Interestingly, quantitative expression of the sialomucin, CD164, mirrored her clinical picture, thus favoring its reliability as a novel biomarker in CTCL.
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Biomarcadores Tumorais , Linfócitos T CD4-Positivos , Dermatite Esfoliativa , Dipeptidil Peptidase 4/biossíntese , Regulação Enzimológica da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Leucemia de Células T , Micose Fungoide , Proteínas de Neoplasias/biossíntese , Neoplasias Cutâneas , Idoso , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/patologia , Dermatite Esfoliativa/metabolismo , Dermatite Esfoliativa/patologia , Feminino , Humanos , Leucemia de Células T/metabolismo , Leucemia de Células T/patologia , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologiaRESUMO
Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.
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Soro Antilinfocitário/administração & dosagem , Transplante de Células-Tronco Hematopoéticas/métodos , Irradiação Linfática/métodos , Síndromes Mielodisplásicas/terapia , Transtornos Mieloproliferativos/terapia , Condicionamento Pré-Transplante/métodos , Idoso , Análise de Variância , Feminino , Humanos , Estimativa de Kaplan-Meier , Irradiação Linfática/efeitos adversos , Masculino , Pessoa de Meia-Idade , Quimeras de Transplante , Transplante HomólogoRESUMO
B cells are involved in the pathogenesis of chronic GVHD (cGVHD). We hypothesized that prophylactic anti-B-cell therapy delivered 2 months after transplantation would decrease allogeneic donor B-cell immunity and possibly the incidence of cGVHD. Therefore, in the present study, patients with high-risk chronic lymphocytic leukemia (n = 22) and mantle-cell lymphoma (n = 13) received a total lymphoid irradiation of 80 cGy for 10 days and antithymocyte globulin 1.5 mg/kg/d for 5 days. Rituximab (375 mg/m(2)) was infused weekly on days 56, 63, 70, and 77 after transplantation. The incidence of acute GVHD was 6%. The cumulative incidence of cGVHD was 20%. Nonrelapse mortality was 3%. Rituximab treatment after allogeneic transplantation significantly reduced B-cell allogeneic immunity, with complete prevention of alloreactive H-Y Ab development in male patients with female donors (P = .01). Overall survival and freedom from progression at 4 years for chronic lymphocytic leukemia patients were 73% and 47%, respectively; for mantle-cell lymphoma patients, they were 69% and 53%, respectively.
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Anticorpos Monoclonais Murinos/administração & dosagem , Linfócitos B/imunologia , Doença Enxerto-Hospedeiro/prevenção & controle , Leucemia Linfocítica Crônica de Células B/terapia , Adulto , Idoso , Anticorpos Monoclonais Murinos/farmacologia , Autoimunidade/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Quimioprevenção/métodos , Doença Crônica , Esquema de Medicação , Estudos de Viabilidade , Feminino , Doença Enxerto-Hospedeiro/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Incidência , Leucemia Linfocítica Crônica de Células B/epidemiologia , Leucemia Linfocítica Crônica de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Rituximab , Condicionamento Pré-Transplante/métodos , Transplante Homólogo/efeitos adversos , Adulto JovemRESUMO
Sézary syndrome (SS) is an aggressive cutaneous T-cell lymphoma (CTCL) of unknown etiology in which malignant cells circulate in the peripheral blood. To identify viral elements, gene fusions, and gene expression patterns associated with this lymphoma, flow cytometry was used to obtain matched pure populations of malignant Sézary cells (SCs) versus nonmalignant CD4(+) T cells from 3 patients for whole transcriptome, paired-end sequencing with an average depth of 112 million reads per sample. Pathway analysis of differentially expressed genes identified mis-regulation of PI3K/Akt, TGFß, and NF-κB pathways as well as T-cell receptor signaling. Bioinformatic analysis did not detect either nonhuman transcripts to support a viral etiology of SS or recurrently expressed gene fusions, but it did identify 21 SC-associated annotated long noncoding RNAs (lncRNAs). Transcriptome assembly by multiple algorithms identified 13 differentially expressed unannotated transcripts termed Sézary cell-associated transcripts (SeCATs) that include 12 predicted lncRNAs and a novel transcript with coding potential. High-throughput sequencing targeting the 3' end of polyadenylated transcripts in archived tumors from 24 additional patients with tumor-stage CTCL confirmed the differential expression of SC-associated lncRNAs and SeCATs in CTCL. Our findings characterize the SS transcriptome and support recent reports that implicate lncRNA dysregulation in human malignancies.
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Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Micose Fungoide/genética , RNA Longo não Codificante/genética , Síndrome de Sézary/genética , Neoplasias Cutâneas/genética , Citometria de Fluxo , Humanos , Micose Fungoide/patologia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome de Sézary/patologia , Neoplasias Cutâneas/patologia , Células Tumorais CultivadasRESUMO
ABSTRACT: CD19 chimeric antigen receptor (CAR) T-cell therapy has proven highly effective for treating relapsed/refractory mantle cell lymphoma (MCL). However, immune effector cell-associated neurotoxicity syndrome (ICANS) remains a significant concern. This study aimed to evaluate the clinical, radiological, and laboratory correlatives associated with ICANS development after CD19 CAR T-cell therapy in patients with MCL. All patients (N = 26) who received standard-of-care brexucabtagene autoleucel until July 2022 at our institution were evaluated. Laboratory and radiographic correlatives including brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) were evaluated to determine the clinical impact of ICANS. Seventeen (65%) patients experienced ICANS after treatment, with a median onset on day 6. Ten (38%) patients experienced severe (grade ≥3) ICANS. All patients with ICANS had antecedent cytokine release syndrome (CRS), but no correlation was observed between ICANS severity and CRS grade. Overall, 92% of EEGs revealed interictal changes; no patients experienced frank seizures because of ICANS. In total, 86% of patients with severe ICANS with postinfusion brain MRIs demonstrated acute neuroimaging findings not seen on pretreatment MRI. Severe ICANS was also associated with higher rates of cytopenia, coagulopathy, increased cumulative steroid exposure, and prolonged hospitalization. However, severe ICANS did not affect treatment outcomes of patients with MCL. Severe ICANS is frequently associated with a range of postinfusion brain MRI changes and abnormal EEG findings. Longer hospitalization was observed in patients with severe ICANS, especially those with abnormal acute MRI or EEG findings, but there was no discernible impact on overall treatment response and survival.
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Linfoma de Célula do Manto , Síndromes Neurotóxicas , Humanos , Adulto , Linfoma de Célula do Manto/terapia , Imunoterapia Adotiva/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal , Antígenos CD19 , Encéfalo , Síndrome da Liberação de CitocinaRESUMO
ABSTRACT: Patients with Epstein-Barr virus (EBV)-positive posttransplant lymphoproliferative disease (EBV+ PTLD) in whom initial treatment fails have few options and historically low median overall survival (OS) of 0.7 months after allogeneic hematopoietic cell transplant (HCT) and 4.1 months after solid organ transplant (SOT). Tabelecleucel is an off-the-shelf, allogeneic EBV-specific cytotoxic T-lymphocyte immunotherapy for EBV+ PTLD. Previous single-center experience showed responses in patients with EBV+ PTLD after HCT or SOT. We now report outcomes from a multicenter expanded access protocol in HCT (n = 14) and SOT (n = 12) recipients treated with tabelecleucel for EBV+ PTLD that was relapsed/refractory (R/R) to rituximab with/without chemotherapy. The investigator-assessed objective response rate was 65.4% overall (including 38.5% with a complete and 26.9% with a partial response), 50.0% in HCT, and 83.3% in SOT. The estimated 1- and 2-year OS rates were both 70.0% (95% confidence interval [CI], 46.5-84.7) overall, both 61.5% (95% CI, 30.8-81.8) in HCT, and both 81.5% (95% CI, 43.5-95.1) in SOT (median follow-up: 8.2, 2.8, and 22.5 months, respectively). Patients responding to tabelecleucel had higher 1- and 2-year OS rates (94.1%) than nonresponders (0%). Treatment was well tolerated, with no reports of tumor flare, cytokine release syndrome, or rejection of marrow and SOT. Results demonstrate clinically meaningful outcomes across a broad population treated with tabelecleucel, indicating a potentially transformative and accessible treatment advance for R/R EBV+ PTLD after HCT or SOT. This trial was registered at www.ClinicalTrials.gov as #NCT02822495.
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Infecções por Vírus Epstein-Barr , Transplante de Células-Tronco Hematopoéticas , Transtornos Linfoproliferativos , Transplante Homólogo , Humanos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transtornos Linfoproliferativos/etiologia , Transtornos Linfoproliferativos/terapia , Feminino , Masculino , Adulto , Pessoa de Meia-Idade , Herpesvirus Humano 4 , Transplante de Órgãos/efeitos adversos , Idoso , Resultado do Tratamento , Adulto JovemRESUMO
Hepatosplenic T-cell lymphoma (HSTCL) is a rare and aggressive type of peripheral T-cell lymphoma with median overall survival (OS) of approximately 1 year. Data on the effectiveness of hematopoietic cell transplantation (HCT) is limited, as is the choice between autologous HCT (auto-HCT) and allogeneic HCT (allo-HCT) in the treatment of this disease. To evaluate the outcome of patients with HSTCL who underwent either auto-HCT or allo-HCT, we performed a multi-institutional retrospective cohort study to assess outcomes of HCT in HSTCL patients. Fifty-three patients with HSTCL were included in the study. Thirty-six patients received an allo-HCT and 17 received an auto-HCT. Thirty-five (66%) were males. Median age at diagnosis was 38 (range 2 to 64) years. Median follow-up for survivors was 75 months (range 8 to 204). The median number of prior lines of therapy was 1 (range 1 to 4). Median OS and progression-free survival (PFS) for the entire cohort were 78.5 months (95% CI: 25 to 79) and 54 months (95% CI: 18 to 75), respectively. There were no significant differences in OS (HR: 0.63, 95% CI: 0.28 to 1.45, P = .245) or PFS (HR: 0.7, 95% CI: 0.32 to 1.57, P = .365) between the allo-HCT and auto-HCT groups, respectively. In the allo-HCT group, the 3-year cumulative incidence of relapse was 35% (95% CI: 21 to 57), while 3-year cumulative incidence of NRM was 16% (95% CI: 7 to 35). In the auto-HCT group, the 3-year cumulative incidence of relapse and NRM were 43% (95% CI: 23 to 78) and 14% (95% CI: 4 to 52), respectively. Both Auto-HCT and Allo-HCT are effective consolidative strategies in patients with HSTCL, and patients should be promptly referred for HCT evaluation.
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Transplante de Células-Tronco Hematopoéticas , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Adolescente , Estudos Retrospectivos , Criança , Adulto Jovem , Pré-Escolar , Resultado do Tratamento , Neoplasias Esplênicas/terapia , Estados Unidos/epidemiologia , Linfoma de Células T/terapia , Linfoma de Células T/mortalidade , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/terapia , Transplante AutólogoRESUMO
ABSTRACT: Allogeneic hematopoietic cell transplantation (HCT) is a curative therapy for hematological malignancies for which graft-versus-host disease (GVHD) remains a major complication. The use of donor T-regulatory cells (Tregs) to prevent GVHD appears promising, including in our previous evaluation of an engineered graft product (T-reg graft) consisting of the timed, sequential infusion of CD34+ hematopoietic stem cells and high-purity Tregs followed by conventional T cells. However, whether immunosuppressive prophylaxis can be removed from this protocol remains unclear. We report the results of the first stage of an open-label single-center phase 2 study (NCT01660607) investigating T-reg graft in myeloablative HCT of HLA-matched and 9/10-matched recipients. Twenty-four patients were randomized to receive T-reg graft alone (n = 12) or T-reg graft plus single-agent GVHD prophylaxis (n = 12) to determine whether T-reg graft alone was noninferior in preventing acute GVHD. All patients developed full-donor myeloid chimerism. Patients with T-reg graft alone vs with prophylaxis had incidences of grade 3 to 4 acute GVHD of 58% vs 8% (P = .005) and grade 3 to 4 of 17% vs 0% (P = .149), respectively. The incidence of moderate-to-severe chronic GVHD was 28% in the T-reg graft alone arm vs 0% with prophylaxis (P = .056). Among patients with T-reg graft and prophylaxis, CD4+ T-cell-to-Treg ratios were reduced after transplantation, gene expression profiles showed reduced CD4+ proliferation, and the achievement of full-donor T-cell chimerism was delayed. This study indicates that T-reg graft with single-agent tacrolimus is preferred over T-reg graft alone for the prevention of acute GVHD. This trial was registered at www.clinicaltrials.gov as #NCT01660607.
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Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Tacrolimo/uso terapêutico , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/prevenção & controle , Doença Enxerto-Hospedeiro/patologia , Imunossupressores/uso terapêutico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Doadores de TecidosRESUMO
BACKGROUND: Fludarabine in combination with cyclophosphamide (FC) is the standard lymphodepletion regimen for CAR T-cell therapy (CAR T). A national fludarabine shortage in 2022 necessitated the exploration of alternative regimens with many centers employing single-agent bendamustine as lymphodepletion despite a lack of clinical safety and efficacy data. To fill this gap in the literature, we evaluated the safety, efficacy, and expansion kinetics of bendamustine as lymphodepletion prior to axicabtagene ciloleucel (axi-cel) therapy. METHODS: 84 consecutive patients with relapsed or refractory large B-cell lymphoma treated with axi-cel and managed with a uniform toxicity management plan at Stanford University were studied. 27 patients received alternative lymphodepletion with bendamustine while 57 received FC. RESULTS: Best complete response rates were similar (73.7% for FC and 74% for bendamustine, p=0.28) and there was no significant difference in 12-month progression-free survival or overall survival estimates (p=0.17 and p=0.62, respectively). The frequency of high-grade cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome was similar in both the cohorts. Bendamustine cohort experienced lower proportions of hematological toxicities and antibiotic use for neutropenic fever. Immune reconstitution, as measured by quantitative assessment of cellular immunity, was better in bendamustine cohort as compared with FC cohort. CAR T expansion as measured by peak expansion and area under the curve for expansion was comparable between cohorts. CONCLUSIONS: Bendamustine is a safe and effective alternative lymphodepletion conditioning for axi-cel with lower early hematological toxicity and favorable immune reconstitution.
Assuntos
Cloridrato de Bendamustina , Produtos Biológicos , Linfoma Difuso de Grandes Células B , Humanos , Cloridrato de Bendamustina/uso terapêutico , Cloridrato de Bendamustina/administração & dosagem , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Produtos Biológicos/efeitos adversos , Adulto , Imunoterapia Adotiva/métodos , Imunoterapia Adotiva/efeitos adversos , Antígenos CD19/imunologia , Antígenos CD19/uso terapêuticoRESUMO
ABSTRACT: Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.