TCR α⁺β⁺/CD19⁺ cell–depleted hematopoietic stem cell transplantation for pediatric patients

Abstract

TCR α+β+/CD19+ cell depletion is an emerging technique for ex vivo graft manipulation in HSCT. We report 20 pediatric patients who underwent TCR α+β+/CD19+ cell–depleted HSCT in four Australian centers. Conditioning regimen was dependent on HSCT indication, which included immunodeficiency (n = 14), Fanconi anemia (n = 3), and acute leukemia (n = 3). Donor sources were haploidentical parent (n = 17), haploidentical sibling (n = 2), or matched unrelated donor (n = 1). Mean cell dose was 8.2 × 108/kg TNC, 12.1 × 106/kg CD34+ cells, and 0.4 × 105/kg TCR α+β+ cells. All patients achieved primary neutrophil and platelet engraftment, with average time to neutrophil engraftment 11 days (range 8‐22) and platelet engraftment 24 days (range 12‐69). TRM at 1 year was 15%. Rate of grade II‐IV aGVHD at 1 year was 20% with no grade III‐IV aGVHD seen. CMV reactivation occurred in 81% of CMV‐positive recipients, with one patient developing CMV disease. Average time to CD4 recovery (>400 × 106/L) was 258 days. Overall survival for the cohort at 5 years was 80%. This report highlights the initial experience of TCR α+β+/CD19+ cell–depleted HSCT in Australian centers, with high rates of engraftment, low rates of aGVHD, and acceptable TRM.

Updates in hematopoietic cell transplant and cellular therapies that enhance the risk for opportunistic infections

“…Success has been demonstrated in hematologic malignancies including acute leukemias [29][30][31] and several nonmalignant diseases including primary immune deficiency disorders, [32][33][34][35][36] hemoglobinopathies, [37][38][39] and bone marrow failure disorders. 28,40,41 A potential concern, however, is the delay in T-and B-cell immune reconstitution after HCT, particularly for polyclonal T-cells with a broad repertoire against multiple pathogens (that are also immunotolerant to the transplant recipient). The infectious disease physician should be cognizant of high rates of CMV viremia reactivation (around 50%) and disease (around 6%), 42 adenovirus infection, 28,36,43 and potential for BK Polyomavirus infection 44 From an infectious disease perspective, patients undergoing CAR-T cell treatment have a different spectrum of complications than traditional allogeneic or autologous stem cell transplant patients.…”

“…Haploidentical HCT with TCRαβ + T‐cell depletion / CD19 + B cell depletion has gained considerable traction in Europe and is increasingly deployed in both Canada and the United States, particularly in pediatrics. Success has been demonstrated in hematologic malignancies including acute leukemias 29–31 and several nonmalignant diseases including primary immune deficiency disorders, 32–36 hemoglobinopathies, 37–39 and bone marrow failure disorders 28,40,41 . A potential concern, however, is the delay in T‐ and B‐cell immune reconstitution after HCT, particularly for polyclonal T‐cells with a broad repertoire against multiple pathogens (that are also immunotolerant to the transplant recipient).…”

Pharmacokinetic analysis driven letermovir dosing in pediatric hematopoietic cell transplantation patients with resistant CMV disease

“…2 CMV reactivation is highest in pediatric CMV R + patients receiving haploidentical T-cell receptor αβ + (TCRαβ + )/ CD19 + depleted grafts, reported to occur in up to 81%. 3,4 Delayed CMV-specific immune reconstitution or receipt of augmented immunosuppressive therapy (IST) places children at risk for prolonged antiviral exposure from both treatment and secondary prophylaxis (SP). Valganciclovir is the preferred oral agent for SP in young children compared to other anti-CMV therapies which are available only as intravenous formulations.…”

“…Although pre‐emptive therapy (PET) with ganciclovir or foscarnet has significantly reduced CMV end‐organ disease (CMV‐EOD), CMV still negatively affects overall transplant outcomes 2 . CMV reactivation is highest in pediatric CMV R + patients receiving haploidentical T‐cell receptor αβ + (TCRαβ + )/CD19 + depleted grafts, reported to occur in up to 81% 3,4 . Delayed CMV‐specific immune reconstitution or receipt of augmented immunosuppressive therapy (IST) places children at risk for prolonged antiviral exposure from both treatment and secondary prophylaxis (SP).…”

Pharmacokinetic Analysis Driven Letermovir Dosing in Pediatric Hematopoietic Cell Transplantation Patients with resistant CMV disease.

“…2 CMV reactivation is highest in pediatric CMV R+ patients receiving haploidentical T-cell receptor αβ+ (TCRαβ+)/CD19+ depleted grafts, reported to occur in up to 81%. 3,4 Delayed CMVspecific immune reconstitution or receipt of augmented immunosuppressive therapy (IST) places children at risk for prolonged antiviral exposure from both treatment and secondary prophylaxis (SP). Valganciclovir is the preferred oral agent for SP compared to other anti-CMV therapies which are only in intravenous formulation.…”