RESUMEN
CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has led to unprecedented rates of complete remission (CR) in children and adults with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (B-ALL), yet the majority of adults relapse after initial response. One proposed method to extend the durability of remission in adults following response to CAR-T therapy is consolidation with allogeneic hematopoietic cell transplantation (alloHCT). Considering the limited published data for the utility of post CAR-T therapy consolidative alloHCT in r/r B-ALL, especially data related to patients receiving a second alloHCT, we sought to describe outcomes of patients with r/r B-ALL at our institution who received their first or second alloHCT following response to CAR-T therapy. We performed a retrospective analysis of adult patients with r/r B-ALL who responded to either investigational or standard of care (SOC) CD19-targeted CAR-T therapy and underwent consolidation with alloHCT while in CR without interim therapy. We identified 45 patients, of whom 26 (58%) and 19 (42%) received their first and second alloHCT as consolidation post CAR-T therapy, respectively. The median age was 31 years (range: 19-67) and 31 (69%) patients were Hispanic. Ph-like was the most common genetic subtype and comprised over half of cases (53%; n = 24). The median number of prior therapies pre-transplant was 5 (range: 2-7), and disease status at the time of alloHCT was CR1, CR2 or ≥CR3 in 7 (16%), 22 (49%) and 16 (35%) patients, respectively. The median time from CAR-T therapy until alloHCT was 93 (range: 42-262) days. The conditioning regimen was radiation-based myeloablative (MAC) in 22 (49%) patients. With a median follow-up of 2.47 years (range: 0.13-6.93), 2-year overall survival (OS), relapse free survival (RFS), cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 57.3% (95% CI: 0.432-0.760), 56.2% (95% CI: 0.562-0.745), 23.3% (95% CI: 0.13-0.42), and 20.4% (95% CI: 0.109-0.384), respectively. Two-year OS (52% vs. 68%, P = .641), RFS (54% vs. 59%, P = .820), CIR (33.5% vs. 8.5%, P = .104), and NRM (12.5% vs. 32.2%, P = .120) were not significantly different between patients who underwent their first vs. second transplant, respectively. In univariate analysis, only Ph-like genotype was associated with inferior RFS (P = .03). AlloHCT post CAR-T response is associated with a relatively low early mortality rate and encouraging survival results in high-risk adults with r/r B-ALL, extending to the second alloHCT for fit and eligible patients.
Asunto(s)
Antígenos CD19 , Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Humanos , Adulto , Femenino , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Antígenos CD19/inmunología , Inmunoterapia Adoptiva/métodos , Adulto Joven , Trasplante Homólogo/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/mortalidad , Recurrencia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Receptores Quiméricos de Antígenos/uso terapéutico , Adolescente , AncianoRESUMEN
Peripheral T cell lymphomas (PTCL) have a poor prognosis with current treatments. High-dose chemotherapy followed by autologous hematopoietic cell transplant (AHCT) is used as a consolidation strategy after achieving clinical remission with first-line therapy, as well as in chemosensitive relapse if allogeneic transplant is not an option. CD25 is a targetable protein often highly expressed in PTCL. In this phase 1 clinical trial, we tested the addition of beta-emitting 90Y-labeled chimeric anti-CD25 basiliximab (aTac) to BEAM (carmustine, etoposide, cytarabine, melphalan) as conditioning for AHCT in patients with PTCL. Twenty-three AHCT-eligible patients were enrolled, and 20 received therapeutic 90Y-aTac-BEAM AHCT. Radiation doses of 0.4, 0.5 and 0.6 mCi/kg were tested. With no observed dose-limiting toxicities, 0.6 mCi/kg was deemed the recommended phase 2 dose. The most prevalent adverse effect, grade 2 mucositis, was experienced by 80% of patients. As of this report, 6 (30%) of the treated patients had died, 5 due to progressive disease and 1 due to multiple organ failure [median time of death 17 mo (range: 9-21 mo)] post-AHCT. Median follow-up was 24 mo (range: 9-26 mo) overall and 24 mo (range: 13-26 mo) for surviving patients. For patients who received therapeutic 90Y-aTac-BEAM AHCT, the 2-year progression-free and overall survival were 59% (95% CI: 34-77%) and 68% (95% CI: 42-84%), respectively. 90Y-aTac-BEAM appears to be safe as an AHCT conditioning regimen for PTCL, with no increased toxicity over the toxicities historically seen with BEAM alone in this patient population. This trial was registered at www.clinicaltrials.gov as # NCT02342782.
Asunto(s)
Antivirales , Infecciones por Citomegalovirus , Vacunas contra Citomegalovirus , Citomegalovirus , Trasplante de Células Madre Hematopoyéticas , Viremia , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/prevención & control , Infecciones por Citomegalovirus/etiología , Niño , Citomegalovirus/inmunología , Viremia/etiología , Femenino , Masculino , Antivirales/uso terapéutico , Antivirales/efectos adversos , Preescolar , Vacunas contra Citomegalovirus/inmunología , Adolescente , Lactante , Inmunogenicidad VacunalRESUMEN
Background: Tisagenlecleucel was approved by the Food and Drug Administration (FDA) in 2017 for refractory B-cell acute lymphoblastic leukemia (B-ALL) and B-ALL in ≥2nd relapse. Outcomes of patients receiving commercial tisagenlecleucel upon 1st relapse have yet to be established. We aimed to report real-world tisagenlecleucel utilisation patterns and outcomes across indications, specifically including patients treated in 1st relapse, an indication omitted from formal FDA approval. Methods: We conducted a retrospective analysis of real-world tisagenlecleucel utilisation patterns across 185 children and young adults treated between August 30, 2017 and March 6, 2020 from centres participating in the Pediatric Real-World CAR Consortium (PRWCC), within the United States. We described definitions of refractory B-ALL used in the real-world setting and categorised patients by reported Chimeric Antigen Receptor (CAR) T-cell indication, including refractory, 1st relapse and ≥2nd relapse B-ALL. We analysed baseline patient characteristics and post-tisagenlecleucel outcomes across defined cohorts. Findings: Thirty-six percent (n = 67) of our cohort received tisagenlecleucel following 1st relapse. Of 66 evaluable patients, 56 (85%, 95% CI 74-92%) achieved morphologic complete response. Overall-survival (OS) and event-free survival (EFS) at 1-year were 69%, (95% CI 58-82%) and 49%, (95% CI 37-64%), respectively, with survival outcomes statistically comparable to remaining patients (OS; p = 0.14, EFS; p = 0.39). Notably, toxicity was increased in this cohort, warranting further study. Interestingly, of 30 patients treated for upfront refractory disease, 23 (77%, 95% CI 58-90%) had flow cytometry and/or next-generation sequencing (NGS) minimum residual disease (MRD)-only disease at the end of induction, not meeting the historic morphologic definition of refractory. Interpretation: Our findings suggested that tisagenlecleucel response and survival rates overlap across patients treated with upfront refractory B-ALL, B-ALL ≥2nd relapse and B-ALL in 1st relapse. We additionally highlighted that definitions of refractory B-ALL are evolving beyond morphologic measures of residual disease. Funding: St. Baldrick's/Stand Up 2 Cancer, Parker Institute for Cancer Immunotherapy, Virginia and D.K. Ludwig Fund for Cancer Research.
RESUMEN
Introduction: Mediport use as a clinical option for the administration of chimeric antigen receptor T cell (CAR T cell) therapy in patients with B-cell malignancies has yet to be standardized. Concern for mediport dislodgement, cell infiltration, and ineffective therapy delivery to systemic circulation has resulted in variable practice with intravenous administration of CAR T cell therapy. With CAR T cell commercialization, it is important to establish practice standards for CAR T cell delivery. We conducted a study to establish usage patterns of mediports in the clinical setting and provide a standard of care recommendation for mediport use as an acceptable form of access for CAR T cell infusions. Methods: In this retrospective cohort study, data on mediport use and infiltration rate was collected from a survey across 34 medical centers in the Pediatric Real-World CAR Consortium, capturing 504 CAR T cell infusion routes across 489 patients. Data represents the largest, and to our knowledge sole, report on clinical CAR T cell infusion practice patterns since FDA approval and CAR T cell commercialization in 2017. Results: Across 34 sites, all reported tunneled central venous catheters, including Broviac® and Hickman® catheters, as accepted standard venous options for CAR T cell infusion. Use of mediports as a standard clinical practice was reported in 29 of 34 sites (85%). Of 489 evaluable patients with reported route of CAR T cell infusion, 184 patients were infused using mediports, with no reported incidences of CAR T cell infiltration. Discussion/Conclusion: Based on current clinical practice, mediports are a commonly utilized form of access for CAR T cell therapy administration. These findings support the safe practice of mediport usage as an accepted standard line option for CAR T cell infusion.
Asunto(s)
Inmunoterapia Adoptiva , Linfocitos T , Humanos , Niño , Estudios Retrospectivos , Infusiones Intravenosas , Administración IntravenosaRESUMEN
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for hematologic malignancies and nonmalignant disorders. Rapid immune reconstitution (IR) following allogeneic HCT has been shown to be associated with improved clinical outcomes and lower infection rates. A global phase 3 trial (ClinicalTrials.gov NCT02730299) of omidubicel, an advanced cell therapy manufactured from an appropriately HLA-matched single umbilical cord blood (UCB) unit, showed faster hematopoietic recovery, reduced rates of infection, and shorter hospitalizations in patients randomized to omidubicel compared with those randomized to standard UCB. This optional, prospective substudy of the global phase 3 trial characterized the IR kinetics following HCT with omidubicel compared with UCB in a systematic and detailed manner. This substudy included 37 patients from 14 global sites (omidubicel, n = 17; UCB, n = 20). Peripheral blood samples were collected at 10 predefined time points from 7 to 365 days post-HCT. Flow cytometry immunophenotyping, T cell receptor excision circle quantification, and T cell receptor sequencing were used to evaluate the longitudinal IR kinetics post-transplantation and their association with clinical outcomes. Patient characteristics in the 2 comparator cohorts were overall statistically similar except for age and total body irradiation (TBI)-based conditioning regimens. The median patient age was 30 years (range, 13 to 62 years) for recipients of omidubicel and 43 years (range, 19 to 55 years) for UCB recipients. A TBI-based conditioning regimen was used in 47% of omidubicel recipients and in 70% of UCB recipients. Graft characteristics differed in their cellular composition. Omidubicel recipients received a 33-fold higher median dose of CD34+ stem cells and one-third of the median CD3+ lymphocyte dose infused to UCB recipients. Compared with UCB recipients, omidubicel recipients exhibited faster IR of all measured lymphoid and myelomonocytic subpopulations, predominantly in the first 14 days post-transplantation. This effect involved circulating natural killer (NK) cells, helper T (Th) cells, monocytes, and dendritic cells, with superior long-term B cell recovery from day +28. At 1 week post-HCT, omidubicel recipients exhibited 4.1- and 7.7 -fold increases in the median Th cell and NK cell counts, respectively, compared to UCB recipients. By 3 weeks post-HCT, omidubicel recipients were 3-fold more likely to achieve clinically relevant Th cell and NK cell counts ≥100 cells/µL. Similar to UCB, omidubicel yielded a balanced cellular subpopulation composition and diverse T cell receptor repertoire in both the short term and the long term. Omidubicel's CD34+ cell content correlated with faster IR by day +7 post-HCT, which in turn coincided with earlier hematopoietic recovery. Finally, early NK and Th cell reconstitution correlated with a decreased rate of post-HCT viral infections, suggesting a plausible explanation for this phenomenon among omidubicel recipients in the phase 3 study. Our findings suggest that omidubicel efficiently promotes IR across multiple immune cells, including CD4+ T cells, B cells, NK cells, and dendritic cell subtypes as early as 7 days post-transplantation, potentially endowing recipients of omidubicel with early protective immunity.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Adolescente , Adulto , Humanos , Persona de Mediana Edad , Adulto Joven , Antivirales , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Estudios Prospectivos , Trasplante Homólogo/efectos adversosRESUMEN
Chimeric antigen receptor-associated hemophagocytic lymphohistiocytosis (HLH)-like toxicities (LTs) involving hyperferritinemia, multiorgan dysfunction, coagulopathy, and/or hemophagocytosis are described as occurring in a subset of patients with cytokine release syndrome (CRS). Case series report poor outcomes for those with B-cell acute lymphoblastic leukemia (B-ALL) who develop HLH-LTs, although larger outcomes analyses of children and young adults (CAYAs) with B-ALL who develop these toxicities after the administration of commercially available tisagenlecleucel are not described. Using a multi-institutional database of 185 CAYAs with B-ALL, we conducted a retrospective cohort study including groups that developed HLH-LTs, high-grade (HG) CRS without HLH-LTs, or no to low-grade (NLG) CRS without HLH-LTs. Primary objectives included characterizing the incidence, outcomes, and preinfusion factors associated with HLH-LTs. Among 185 CAYAs infused with tisagenlecleucel, 26 (14.1%) met the criteria for HLH-LTs. One-year overall survival and relapse-free survival were 25.7% and 4.7%, respectively, in those with HLH-LTs compared with 80.1% and 57.6%, respectively, in those without. In multivariable analysis for death, meeting criteria for HLH-LTs carried a hazard ratio of 4.61 (95% confidence interval, 2.41-8.83), controlling for disease burden, age, and sex. Patients who developed HLH-LTs had higher pretisagenlecleucel disease burden, ferritin, and C-reactive protein levels and lower platelet and absolute neutrophil counts than patients with HG- or NLG-CRS without HLH-LTs. Overall, CAYAs with B-ALL who developed HLH-LTs after tisagenlecleucel experienced high rates of relapse and nonrelapse mortality, indicating the urgent need for further investigations into prevention and optimal management of patients who develop HLH-LTs after tisagenlecleucel.
Asunto(s)
Linfoma de Burkitt , Linfohistiocitosis Hemofagocítica , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores Quiméricos de Antígenos , Humanos , Niño , Adulto Joven , Linfohistiocitosis Hemofagocítica/etiología , Estudios Retrospectivos , Receptores de Antígenos de Linfocitos T , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Linfoma de Burkitt/complicaciones , Enfermedad CrónicaRESUMEN
Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Humanos , Estudios de Seguimiento , Estudios Prospectivos , Supervivencia sin Enfermedad , Estudios Multicéntricos como AsuntoRESUMEN
Remarkable complete response rates have been shown with tisagenlecleucel, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, in patients up to age 26 years with refractory/relapsed B-cell acute lymphoblastic leukemia; it is US Food and Drug Administration approved for this indication. Currently, patients receive a single dose of tisagenlecleucel across a wide dose range of 0.2 to 5.0 × 106 and 0.1 to 2.5 × 108 CAR T cells per kg for patients ≤50 and >50 kg, respectively. The effect of cell dose on survival and remission is not yet well established. Our primary goal was to determine if CAR T-cell dose affects overall survival (OS), event-free survival (EFS), or relapse-free-survival (RFS) in tisagenlecleucel recipients. Retrospective data were collected from Pediatric Real World CAR Consortium member institutions and included 185 patients infused with commercial tisagenlecleucel. The median dose of viable transduced CAR T cells was 1.7 × 106 CAR T cells per kg. To assess the impact of cell dose, we divided responders into dose quartiles: 0.134 to 1.300 × 106 (n = 48 [27%]), 1.301 to 1.700 × 106 (n = 46 [26%]), 1.701 to 2.400 × 106 (n = 43 [24%]), and 2.401 to 5.100 × 106 (n = 43 [24%]). OS, EFS, and RFS were improved in patients who received higher doses of tisagenlecleucel (P = .031, .0079, and .0045, respectively). Higher doses of tisagenlecleucel were not associated with increased toxicity. Because the current tisagenlecleucel package insert dose range remains broad, this work has implications in regard to targeting higher cell doses, within the approved dose range, to optimize patients' potential for long-standing remission.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos de Linfocitos T , Estados Unidos , Humanos , Niño , Adulto , Estudios Retrospectivos , Receptores de Antígenos de Linfocitos T/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfocitos T , Recurrencia , Enfermedad CrónicaRESUMEN
PURPOSE: Nonresponse and relapse after CD19-chimeric antigen receptor (CAR) T-cell therapy continue to challenge survival outcomes. Phase II landmark data from the ELIANA trial demonstrated nonresponse and relapse rates of 14.5% and 28%, respectively, whereas use in the real-world setting showed nonresponse and relapse rates of 15% and 37%. Outcome analyses describing fate after post-CAR nonresponse and relapse remain limited. Here, we aim to establish survival outcomes after nonresponse and both CD19+ and CD19- relapses and explore treatment variables associated with inferior survival. METHODS: We conducted a retrospective multi-institutional study of 80 children and young adults with B-cell acute lymphoblastic leukemia experiencing nonresponse (n = 23) or relapse (n = 57) after tisagenlecleucel. We analyze associations between baseline characteristics and these outcomes and establish survival rates and salvage approaches. RESULTS: The overall survival (OS) at 12 months was 19% across nonresponders (n = 23; 95% CI, 7 to 50). Ninety-five percent of patients with nonresponse had high preinfusion disease burden. Among 156 morphologic responders, the cumulative incidence of relapse was 37% (95% CI, 30 to 47) at 12 months (CD19+; 21% [15 to 29], CD19-; 16% [11 to 24], median follow-up; 380 days). Across 57 patients experiencing relapse, the OS was 52% (95% CI, 38 to 71) at 12 months after time of relapse. Notably, CD19- relapse was associated with significantly decreased OS as compared with patients who relapsed with conserved CD19 expression (CD19- 12-month OS; 30% [14 to 66], CD19+ 12-month OS; 68% [49 to 92], P = .0068). Inotuzumab, CAR reinfusion, and chemotherapy were used as postrelapse salvage therapy with greatest frequency, yet high variability in treatment sequencing and responses limits efficacy analysis across salvage approaches. CONCLUSION: We describe poor survival across patients experiencing nonresponse to tisagenlecleucel. In the post-tisagenlecleucel relapse setting, patients can be salvaged; however, CD19- relapse is distinctly associated with decreased survival outcomes.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras B , Receptores de Antígenos de Linfocitos T , Humanos , Niño , Adulto Joven , Adolescente , Estudios Retrospectivos , Receptores de Antígenos de Linfocitos T/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Inmunoterapia Adoptiva , Recurrencia , Antígenos CD19 , Enfermedad CrónicaRESUMEN
Infants with B-cell acute lymphoblastic leukemia (B-ALL) have poor outcomes because of chemotherapy resistance leading to high relapse rates. Tisagenlecleucel, a CD19-directed chimeric antigen receptor T-cell (CART) therapy, is US Food and Drug Administration approved for relapsed or refractory B-ALL in patients ≤25 years; however, the safety and efficacy of this therapy in young patients is largely unknown because children <3 years of age were excluded from licensing studies. We retrospectively evaluated data from the Pediatric Real-World CAR Consortium to examine outcomes of patients with infant B-ALL who received tisagenlecleucel between 2017 and 2020 (n = 14). Sixty-four percent of patients (n = 9) achieved minimal residual disease-negative remission after CART and 50% of patients remain in remission at last follow-up. All patients with high disease burden at time of CART infusion (>M1 marrow) were refractory to this therapy (n = 5). Overall, tisagenlecleucel was tolerable in this population, with only 3 patients experiencing ≥grade 3 cytokine release syndrome. No neurotoxicity was reported. This is the largest report of tisagenlecleucel use in infant B-ALL and shows that this therapy is safe and can be effective in this population. Incorporating this novel immunotherapy into the treatment of infant B-ALL offers a promising therapy for a highly aggressive leukemia.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Antígenos CD19/inmunología , Antígenos CD19/uso terapéutico , Niño , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico , Estudios Retrospectivos , Estados UnidosRESUMEN
PURPOSE: Tisagenlecleucel is a CD19-specific chimeric antigen receptor T-cell therapy, US Food and Drug Administration-approved for children, adolescents, and young adults (CAYA) with relapsed and/or refractory (RR) B-cell acute lymphoblastic leukemia (B-ALL). The US Food and Drug Administration registration for tisagenlecleucel was based on a complete response (CR) rate of 81%, 12-month overall survival (OS) of 76%, and event-free survival (EFS) of 50%. We report clinical outcomes and analyze covariates of outcomes after commercial tisagenlecleucel. METHODS: We conducted a retrospective, multi-institutional study of CAYA with RR B-ALL across 15 US institutions, who underwent leukapheresis shipment to Novartis for commercial tisagenlecleucel. A total of 200 patients were included in an intent-to-treat response analysis, and 185 infused patients were analyzed for survival and toxicity. RESULTS: Intent-to-treat analysis demonstrates a 79% morphologic CR rate (95% CI, 72 to 84). The infused cohort had an 85% CR (95% CI, 79 to 89) and 12-month OS of 72% and EFS of 50%, with 335 days of median follow-up. Notably, 48% of patients had low-disease burden (< 5% bone marrow lymphoblasts, no CNS3, or other extramedullary disease), or undetectable disease, pretisagenlecleucel. Univariate and multivariate analyses associate high-disease burden (HB, ≥ 5% bone marrow lymphoblasts, CNS3, or non-CNS extramedullary) with inferior outcomes, with a 12-month OS of 58% and EFS of 31% compared with low-disease burden (OS; 85%, EFS; 70%) and undetectable disease (OS; 95%, EFS; 72%; P < .0001 for OS and EFS). Grade ≥ 3 cytokine release syndrome and neurotoxicity rates were 21% and 7% overall and 35% and 9% in patients with HB, respectively. CONCLUSION: Commercial tisagenlecleucel in CAYA RR B-ALL demonstrates efficacy and tolerability. This first analysis of commercial tisagenlecleucel stratified by disease burden identifies HB preinfusion to associate with inferior OS and EFS and increased toxicity.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores Quiméricos de Antígenos , Adolescente , Niño , Costo de Enfermedad , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéutico , Estudios Retrospectivos , Adulto JovenRESUMEN
Chimeric antigen receptor (CAR) T cells provide a therapeutic option in hematologic malignancies. However, treatment failure after initial response approaches 50%. In allogeneic hematopoietic cell transplantation, optimal fludarabine exposure improves immune reconstitution, resulting in lower nonrelapse mortality and increased survival. We hypothesized that optimal fludarabine exposure in lymphodepleting chemotherapy before CAR T-cell therapy would improve outcomes. In a retrospective analysis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia undergoing CAR T-cell (tisagenlecleucel) infusion after cyclophosphamide/fludarabine lymphodepleting chemotherapy, we estimated fludarabine exposure as area under the curve (AUC; mg × h/L) using a validated population pharmacokinetic (PK) model. Fludarabine exposure was related to overall survival (OS), cumulative incidence of relapse (CIR), and a composite end point (loss of B-cell aplasia [BCA] or relapse). Eligible patients (n = 152) had a median age of 12.5 years (range, <1 to 26), response rate of 86% (n = 131 of 152), 12-month OS of 75.1% (95% confidence interval [CI], 67.6% to 82.6%), and 12-month CIR of 36.4% (95% CI, 27.5% to 45.2%). Optimal fludarabine exposure was determined as AUC ≥13.8 mg × h/L. In multivariable analyses, patients with AUC <13.8 mg × h/L had a 2.5-fold higher CIR (hazard ratio [HR], 2.45; 95% CI, 1.34-4.48; P = .005) and twofold higher risk of relapse or loss of BCA (HR, 1.96; 95% CI, 1.19-3.23; P = .01) compared with those with optimal fludarabine exposure. High preinfusion disease burden was also associated with increased risk of relapse (HR, 2.66; 95% CI, 1.45-4.87; P = .001) and death (HR, 4.77; 95% CI, 2.10-10.9; P < .001). Personalized PK-directed dosing to achieve optimal fludarabine exposure should be tested in prospective trials and, based on this analysis, may reduce disease relapse after CAR T-cell therapy.
Asunto(s)
Inmunoterapia Adoptiva , Adolescente , Adulto , Niño , Preescolar , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Lactante , Estudios Prospectivos , Recurrencia , Estudios Retrospectivos , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
Chimeric antigen receptor (CAR) T cells have transformed the therapeutic options for relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia. Data for CAR therapy in extramedullary (EM) involvement are limited. Retrospective data were abstracted from the Pediatric Real World CAR Consortium (PRWCC) of 184 infused patients from 15 US institutions. Response (complete response) rate, overall survival (OS), relapse-free survival (RFS), and duration of B-cell aplasia (BCA) in patients referred for tisagenlecleucel with EM disease (both central nervous system (CNS)3 and non-CNS EM) were compared with bone marrow (BM) only. Patients with CNS disease were further stratified for comparison. Outcomes are reported on 55 patients with EM disease before CAR therapy (CNS3, n = 40; non-CNS EM, n = 15). The median age at infusion in the CNS cohort was 10 years (range, <1-25 years), and in the non-CNS EM cohort it was 13 years (range, 2-26 years). In patients with CNS disease, 88% (35 of 40) achieved a complete response vs only 66% (10 of 15) with non-CNS EM disease. Patients with CNS disease (both with and without BM involvement) had 24-month OS outcomes comparable to those of non-CNS EM or BM only (P = .41). There was no difference in 12-month RFS between CNS, non-CNS EM, or BM-only patients (P = .92). No increased toxicity was seen with CNS or non-CNS EM disease (P = .3). Active CNS disease at time of infusion did not affect outcomes. Isolated CNS disease trended toward improved OS compared with combined CNS and BM (P = .12). R/R EM disease can be effectively treated with tisagenlecleucel; toxicity, relapse, and survival rates are comparable to those of patients with BM-only disease. Outcomes for isolated CNS relapse are encouraging.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células Precursoras , Receptores de Antígenos de Linfocitos T , Niño , Humanos , Inmunoterapia Adoptiva/efectos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Recurrencia , Estudios RetrospectivosRESUMEN
High-risk relapsed or refractory (R/R) classical Hodgkin lymphoma (HL) is associated with poor outcomes after conventional salvage therapy and autologous hematopoietic cell transplantation (AHCT). Post-AHCT consolidation with brentuximab vedotin (BV) improves progression-free survival (PFS), but with increasing use of BV early in the treatment course, the utility of consolidation is unclear. CD25 is often expressed on Reed-Sternberg cells and in the tumor microenvironment in HL, and we hypothesized that the addition of 90Y-antiCD25 (aTac) to carmustine, etoposide, cytarabine, melphalan (BEAM) AHCT would be safe and result in a transplantation platform that is agnostic to prior HL-directed therapy. Twenty-five patients with high-risk R/R HL were enrolled in this phase 1 dose-escalation trial of aTac-BEAM. Following an imaging dose of 111In-antiCD25, 2 patients had altered biodistribution, and a third developed an unrelated catheter-associated bacteremia; therefore, 22 patients ultimately received therapeutic 90Y-aTac-BEAM AHCT. No dose-limiting toxicities were observed, and 0.6 mCi/kg was deemed the recommended phase 2 dose, the dose at which the heart wall would not receive >2500 cGy. Toxicities and time to engraftment were similar to those observed with standard AHCT, though 95% of patients developed stomatitis (all grade 1-2 per Bearman toxicity scale). Seven relapses (32%) were observed, most commonly in patients with ≥3 risk factors. The estimated 5-year PFS and overall survival probabilities among 22 evaluable patients were 68% and 95%, respectively, and non-relapse mortality was 0%. aTac-BEAM AHCT was tolerable in patients with high-risk R/R HL, and we are further evaluating the efficacy of this approach in a phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT01476839.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Enfermedad de Hodgkin , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Enfermedad de Hodgkin/tratamiento farmacológico , Humanos , Recurrencia Local de Neoplasia , Radioinmunoterapia , Distribución Tisular , Acondicionamiento Pretrasplante , Microambiente Tumoral , Radioisótopos de Itrio/uso terapéuticoAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Adolescente , Adulto , Niño , Preescolar , Femenino , Humanos , Inmunoterapia Adoptiva , Lactante , Masculino , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
Efficacy of PTCy after mismatched unrelated donor (MMUD) HCT is unknown. In this pilot clinical trial, we enrolled 38 patients with hematologic malignancies scheduled to undergo MMUD-HCT (≥6/8 HLA-matched donors) onto 1 of 2 conditioning strata: myeloablative using fludarabine and fractionated total body irradiation (n = 19) or reduced intensity with fludarabine/melphalan (n = 19). Graft source was peripheral blood stem cells (PBSCs), and GVHD prophylaxis was PTCy, tacrolimus, and mycophenolate mofetil. Patients' median age was 53 years (range, 21-72 years). Median number of HLA mismatches was 2 (range, 1-4) of 12 loci. Twenty-three patients (61%) were considered racial (n = 12) or ethnic (n = 11) minorities. Median time to neutrophil engraftment was 16 days (range, 13-35 days). With a median follow-up of 18.3 months (range, 4.3-25.0 months) for surviving patients, 1-year overall survival (OS) and GVHD-free/relapse-free survival (GRFS) were 87% (95% confidence interval [CI]: 71-94) and 68% (95% CI: 51-81), respectively. Cumulative incidence of nonrelapse mortality at 100 days and 1 year were 0% and 11% (95% CI: 4-27), respectively, whereas relapse/progression was 11% (95% CI: 4-27). Cumulative incidence of 100-day acute GVHD grades 2-4 and 3-4 and 1-year chronic GVHD were 50% (95% CI: 36-69), 18% (95% CI: 9-36), and 48% (95% CI: 34-68), respectively. The rate of moderate/severe chronic GVHD was 3% in the entire cohort. We showed highly promising OS/GRFS rates with an acceptable risk profile after PBSC-MMUD-HCT with PTCy. This trial was registered at www.clinicaltrials.gov as #NCT03128359.
Asunto(s)
Enfermedad Injerto contra Huésped , Células Madre de Sangre Periférica , Ciclofosfamida/uso terapéutico , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Donante no EmparentadoRESUMEN
Currently, there is no consensus on best practices to prevent hemorrhagic cystitis (HC) in patients receiving posttransplant cyclophosphamide (PTCy). We retrospectively reviewed 194 patients undergoing their first hematopoietic cell transplant (HCT) who received PTCy from 2014 to 2018 to describe the incidence and severity of HC, identify potential risk factors, and impact of HC on HCT outcomes. Standard HC prophylaxis was hyperhydration with forced diuresis and mesna at 320% the daily dose of PTCy. Incidence of HC was 31.4% at day +100 of HCT. Median onset of HC was 12 days with 11.5% grade 3 HC and no Grade 4 HC. Patients with chemical HC experienced earlier onset (7 days vs. 34 days, p < 0.001) with a shorter median resolution time (5 days vs. 14 days, p = 0.001) when compared to BK-associated HC. In multivariate analysis, age above 60 years (HR 4.16, p = 0.006) and myeloablative conditioning (HR 2.44, p = 0.054) were associated with higher risk for HC, but overall, HC did not affect nonrelapse mortality or overall survival. In conclusion, hyperhydration with forced diuresis combined with aggressive mesna dosing is an effective strategy in preventing severe PTCy-associated HC, subsequently preventing any negative impact on transplant outcome.
Asunto(s)
Cistitis , Trasplante de Células Madre Hematopoyéticas , Ciclofosfamida/efectos adversos , Cistitis/epidemiología , Cistitis/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Incidencia , Mesna/efectos adversos , Persona de Mediana Edad , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
BACKGROUND: Reactivation of human herpesvirus 6 (HHV-6) occurs in 30%-50% of patients (pts) who receive allogeneic (allo) hematopoietic stem cell transplant (HCT). However, the recommendation for post-transplant HHV-6 monitoring and treatment in pediatric pts is not well established. METHODS: HHV-6 incidence rates and the clinical outcomes were reported for 139 pediatric pts (≤18 years) undergoing first allo-HCT at City of Hope from July 2011 to July 2017, for whom HHV-6 was monitored weekly throughout HCT hospitalization. For 57 pediatric pts, who underwent first HCT from January 2009 to July 2011, HHV-6 was tested as clinically indicated and only rates of HHV-6 viremia were collected. RESULTS: From July 2011 to July 2017, HHV-6 was detected in 88/139 pts (63%). The frequency of HHV-6 viremia was associated with malignant diagnoses, myeloablative conditioning, and cord blood HCT. Treatment with antiviral agents was offered to symptomatic pts with a higher viral load (VL), for whom the time to VL clearance was longer and the frequency of subsequent recurrences was higher. Pts with a lower VL cleared HHV-6 without treatment. HHV-6 viremia was associated with a higher frequency of grade II-IV acute graft-versus-host disease (GVHD) (P = .022), but did not affect overall survival (OS), disease-free survival (DFS), non-relapsed mortality (NRM), myeloid, or platelet (Plt) engraftment. CONCLUSIONS: HHV-6 weekly screening is not necessary for all HCT pts but may be considered for high-risk pts with malignant diagnoses undergoing cord blood HCT; otherwise, HHV-6 should be tested as clinically indicated. Only symptomatic pts (especially with a high VL > 25 000) could benefit from treatment. HHV-6 viremia at the time of initiation and administration of the conditioning regimen cleared promptly without the need to augment the transplant process.