Unrelated and Haploidentical Peripheral Stem Cell Transplant with Tcrαβ/CD19 Depletion for the Treatment of Pediatric Patients with Inborn Errors of Immunity

Background Hematopoietic stem cell transplant (SCT) is curative therapy for many inborn errors of immunity (IEIs). Yet, only a minority of recipients have a suitable HLA matched related donor. Ex vivo TCRαβ/CD19 depletion allows the use of unrelated or partially matched related donors while reducing the risk of GVHD by removing alloreactive αβ T-cells but retaining γδ T-cells. Here, we present a single institution experience with TCRαβ/CD19 depleted PSCT for treatment of IEIs. Methods Patients underwent TCRαβ/CD19 depleted PSCT for IEIs using an unrelated or a haploidentical related donor at the Children's Hospital of Philadelphia between April 2017 and August 2022. TCRαβ/CD19 depletion was performed using a CliniMACs system (Miltenyi). Conditioning was myeloablative busulfan with pharmacokinetic monitoring and fludarabine +/- cyclophosphamide/thiotepa or a reduced intensity melphalan-based regimen with fludarabine. All patients received serotherapy with ATG or alemtuzumab. Post-PSCT immune suppression was none or mycophenolate mofetil (MMF) and/or a calcineurin inhibitor (CNI). Patients were evaluated for at least 1-year post-transplant. Results 41 patients with a variety of IEIs were included (Figure 1). At a median follow-up of 2.5 years, OS was 85% (95% CI 75-97%) and EFS 80% (95% CI 69-94%), but was variable by underlying disease (Figure 2). Three patients experienced graft failure (7.3%), two requiring a second transplant and one receiving donor lymphocyte infusion only. Twenty-eight patients (68.3%) received post-transplant immune suppression for 45 days or less. GVHD incidence was low: grade III acute GVHD (n=3, 7.3%), grade IV (n=0), severe/extensive chronic GVHD (n=2, 4.9%). CMV reactivation occurred in 8 patients (19.5%), with 4 patients (9.8%) developing pulmonary and/or retinal disease; of note, two patients had required CMV-specific CTLs prior to transplant. EBV was detected in 2 patients each (4.8%) post PSCT. One patient, transplanted for EBV-related HLH/CAEBV, developed EBV+ T cell lymphoma. Adenovirus reactivated in 2 patients (4.8%), and 9 patients (22%) had BK cystitis. Eight patients (19.5%) developed VOD; 2 (4.9%) developed pulmonary hypertension (both with CGD). Immune reconstitution is shown in Figure 3. At one year post transplant, 19/32 (59.4%) had a CD3>1000, 24/32 (75%) had a CD4>500, and 25 (78%) were no longer requiring immunoglobulin replacement. All patients with CGD had a measured DHR ≥92% by 30 days post-transplant except for one patient who died prior to day 30. Discussion TCRαβ/CD19 cell depleted PSCT allows the use of unrelated or partially matched related donors for IEIs. Reduction in post-HSCT immune suppression may allow for more rapid immune reconstitution. Optimizing the protocol to mitigate risks of infection, particularly among those with pre-transplant viral infections, and organ toxicity will be important going forward.