Blinatumomab Therapy Is Associated with Favorable Outcomes after Allogeneic Hematopoietic Cell Transplantation in Pediatric Patients with B Cell Acute Lymphoblastic Leukemia.

Blinatumomab, a bispecific T cell engager that binds CD19 in leukemic cells and CD3 in cytotoxic T cells and leads to leukemic blast lysis, is often used in pediatric patients with relapsed/refractory (R/R) B cell acute lymphoblastic leukemia (B-ALL) prior to allogeneic hematopoietic cell transplantation (allo-HCT). Concerns about the potential risk of blinatumomab-related immune-mediated toxicities after allo-HCT have not been adequately addressed. These include graft-versus-host disease (GVHD), delayed engraftment, and graft failure or rejection. Pediatric-specific data reporting post-HCT outcomes of patients treated with blinatumomab are scarce and limited to small cohorts. We sought to investigate the clinical outcomes of pediatric patients with R/R B-ALL who received blinatumomab therapy pre-HCT, focusing on overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM), as well as the incidence of immune-mediated post-HCT complications including GVHD, delayed neutrophil or platelet engraftment, graft failure, and graft rejection. We also investigated blinatumomab's effects on B cell reconstitution based on achievement of i.v. immunoglobulin (IVIG) independence post-HCT. This single-center, retrospective study included patients with B-ALL receiving blinatumomab therapy before undergoing allo-HCT, with transplantation performed between 2016 and 2021 at our institution. Patients receiving blinatumomab for relapse after allo-HCT were excluded. Patients receiving chemotherapy alone before allo-HCT during the same period composed the control group. Seventy-two patients were included, 31 of whom received blinatumomab before allo-HCT. Survival estimates were obtained using the Kaplan-Meier method, and the log-rank test was used to analyze differences between groups. Categorical variables were compared between groups using the chi-square test or Fisher exact test, and continuous variables were compared using the Wilcoxon rank-sum test. Cumulative incidences were estimated using the competing risks method, and Gray's test was used to analyze differences between groups. A Cox proportional hazards regression model was used for univariate and multivariable analyses for OS. Landmark analysis was performed at the set time points of 30 days and 100 days post-allo-HCT. Most patients in the study cohort had high-risk relapsed B-ALL. Blinatumomab therapy induced minimal residual disease (MRD)-negative remissions in all patients, whereas 5 patients (12.2%) receiving chemotherapy alone had persistent MRD pre-allo-HCT. Time from the start of therapy to the date of allo-HCT was shorter for patients who received blinatumomab compared with those who received chemotherapy (P < .0001). Blinatumomab therapy was associated with greater LFS compared to chemotherapy alone (P = .049), but when limited to 1 year, LFS was not significantly different from control (P = .066). There appeared to be higher OS, lower CIR, and lower NRM in patients receiving blinatumomab compared to the control group; however, the differences were not significant. None of the variables assessed in multivariable analysis was associated with differences in OS. When compared to the controls, blinatumomab therapy did not result in a higher incidence of acute or chronic GVHD, delayed neutrophil or platelet engraftment, or graft failure or rejection. The time to IVIG infusion independence post-allo-HCT was similar in the 2 groups. This study supports the use of blinatumomab salvage therapy for R/R B-ALL before allo-HCT given its efficacy in inducing MRD-negative remissions and optimizing LFS, as well as its lack of association with an increased incidence of post-allo-HCT adverse immune-mediated toxicities. Larger, prospective studies are needed to confirm these findings and to investigate blinatumomab's effects in long-term post-allo-HCT events.

Moving CAR-Ts to the outpatient clinic.

As centres obtain more experience with commercial CARs, there has been increasing interest in trying to move as much as the procedure as possible to the outpatient clinic to reduce costs, maximize reimbursement and increase patient satisfaction. The report by Ly et al. details how their centre implemented outpatient CAR therapy and were able to reduce admission time without affecting outcomes. Commentary on: Ly et al. Outpatient CD19-directed CAR T-cell therapy is feasible in patients of all ages. Br J Haematol 2023;203:688-692.

Donor-Host Lineage-Specific Chimerism Monitoring and Analysis in Pediatric Patients Following Allogeneic Stem Cell Transplantation: Influence of Pretransplantation Variables and Correlation with Post-Transplantation Outcomes.

The impact of donor-host chimerism in post-hematopoietic stem cell transplantation (HSCT) outcomes is poorly understood. We were interested in studying whether pre-HSCT variables influenced lineage-specific donor-host chimerism and how lineage-specific chimerism impacts post-HSCT outcomes. Our main objective was to study pre-HSCT variables as predictors of lineage-specific donor-host chimerism patterns and to better characterize the relationship between post-HSCT lineage-specific chimerism and adverse outcomes, including graft failure and disease relapse. We conducted a retrospective data analysis of all patients who underwent allogeneic HSCT at the Pediatric Transplantation and Cellular Therapy service at Memorial Sloan Kettering Cancer Center between January 2010 and June 2015 and had at least 2 measurements of split-lineage chimerism. The trend of lineage-specific donor-host chimerism post-HSCT and the impact of age, disease, graft type, and pretransplantation conditioning regimen on chimerism at 3 months and 12 months post-HSCT were studied. The Wilcoxon signed-rank test, Mann-Whitney-Wilcoxon test, and Cox proportional hazard models were used for statistical analyses. A total of 137 patients were included (median age, 11.3 years). Most patients had a hematologic malignancy (n = 95), and fewer had a nonmalignant disorder (n = 27) or primary immune deficiency (n = 15). Myeloablative conditioning regimens (n = 126) followed by T cell-depleted (TCD) peripheral blood stem cell or bone marrow grafts (n = 101) were most commonly used. Mixed chimerism (MC) of total peripheral blood leukocytes (PBLs) did not predict loss of donor chimerism in all lineages and when stable was not associated with graft failure or rejection in this analyses. Split chimerism with complete donor chimerism (CC) of myeloid, B, and natural killer cells, but not T cells, occurred early post-HSCT, but full donor T cell chimerism was achieved at 12 months post-HSCT by most patients. MC within the T cell lineage was the major contributor to PBL MC, with lower median donor T cell chimerism at 3 months than at 12 months (91%) post-HSCT (51% versus 91%; P < .0001). Predictors of MC at 3 and 12 months were (1) age <3 years (P = .01 for PBLs and P = .003 for myeloid lineage); (2) nonmalignant disorder (P = .007 for PBLs); and (3) the use of reduced-intensity conditioning regimens. TCD grafts produced lower donor T cell chimerism at 3 months post-HSCT compared with unmodified grafts (P < .0001), where T cell lineage CC was achieved early post-HSCT. The donor T cell chimerism was similar at 12 months in the 2 types of grafts. Umbilical cord blood grafts had CC in all lineages at all time points post-HSCT. Loss of donor B cell chimerism was associated with increased risk of relapse in hematologic malignancies (hazard ratio, 1.33; P = .05). Age, underlying disease, conditioning regimen, and graft manipulation can impact post-HSCT donor-host chimerism and be predictors for early MC. MC in total PBLs and T cells was not related to graft failure or disease relapse. Whole-blood PBL chimerism analysis is not sufficient to assess the significance of post-HSCT donor-host status; rather, lineage-specific chimerism, particularly for myeloid, T, and B cells, should be analyzed to guide interventions and inform outcomes.

AYA Considerations for Aggressive Lymphomas.

PURPOSE OF REVIEW: Lymphoma is the one of the most common cancer diagnoses among adolescents and young adults (AYAs) aged 15-39. Despite significant advances in outcomes observed in older adults and younger children, improvements in AYAs have lagged behind. The reasons for this are likely multifactorial including disparities in access to health insurance, low rates of enrollment to clinical trials, potential differences in disease biology, and unique psychosocial challenges. Here we will review Hodgkin lymphoma (HL) and primary mediastinal B cell lymphoma (PMBCL), two of the most common aggressive lymphomas that occur in AYAs. We will discuss the current knowledge about disease biology in AYAs, adult and pediatric treatment strategies, novel targeted therapies, and ongoing AYA clinical trials in these lymphoma subtypes. We also will review unique considerations for treatment-related toxicities in AYAs and psychosocial issues relevant to this population. RECENT FINDINGS: Pediatric and adult trials in HL and PMBCL have demonstrated that treatment with dose-intense chemotherapeutic regimens with or without radiation results in high cure rates but can also be associated with long-term toxicity which must be considered in this young population. Novel targeted agents such as the antibody-drug conjugate brentuximab vedotin and/or antibodies targeted against PD-1/PD-L1 have demonstrated activity in the relapsed setting and are currently being evaluated in the upfront setting, which may reduce our reliance on therapies associated with long-term toxicity. AYA-focused clinical trials are currently underway to better elucidate the optimal therapy for lymphomas in this age group. There is an urgent need for clinical trials including AYAs in order to increase the knowledge of age-specific outcomes, toxicities, disease biology, and the need to develop comprehensive AYA care models that meet the unique and complex care needs of this patient population.

Management of post-transplant lymphoproliferative disorders.

PURPOSE OF REVIEW: Post-transplant lymphoproliferative disease (PTLD) is a major complication of hematopoietic stem cell and solid organ transplantation. The incidence of transplantation in childhood has been steadily rising, making PTLD the most common form of lymphoproliferation in childhood. The purpose of this review is to summarize the role of the Epstein-Barr virus (EBV) in the pathophysiology and discuss the management of PTLD. RECENT FINDINGS: More than 90% of pediatric PTLD is EBV-positive. In immunocompetent hosts, the virus is controlled by cytotoxic T-cells, the cells targeted by immunosuppression to avoid graft-versus-host disease and/or organ rejection in transplant patients. The majority of pediatric transplant candidates are EBV-negative prior to transplant increasing the risk of EBV-induced lymphoproliferation upon seroconversion after transplant. Treatment options include reduction of immunosuppression, anti-CD20 monoclonal antibodies, and/or chemotherapy. Advanced understanding of the importance of cellular immunity in controlling lymphoproliferation has led to the development of cellular therapies targeting virus-specific antigens. SUMMARY: PTLD is the most common form of lymphoproliferation in childhood due to the rising incidence of transplantation. EBV plays a pivotal role in the pathophysiology. Cellular therapies targeting viral antigens may replace chemotherapy in the treatment of PTLD in the near future.