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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 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.

BACKGROUND Ruxolitinib, a JAK1/2 inhibitor, is used to treat chronic graft-versus-host-disease (cGVHD) in adult allogeneic hematopoietic stem cell transplant patients, but experience in children is limited, perhaps due to lack of pediatric dosing information. In this report we describe our pediatric and young adult dosing strategy experience in cGVHD. METHODS Ruxolitinib was administered orally at 5mg twice daily for children ≥25kg or 2.5mg twice daily if

Introduction A reduced toxicity busulfan, fludarabine regimen with alemtuzumab or anti-thymocyte globulin (Gungor et al.) was efficacious in patients undergoing allogeneic HCT for CGD. We report our experience with a similar approach for patients with non-CGD primary immune deficiencies needing a reduced toxicity myeloablative approach. Methods We retrospectively reviewed records of consecutive patients who underwent allogeneic HCT for primary immune deficiencies with a preparative regimen containing busulfan, fludarabine and alemtuzumab or anti-thymocyte globulin(ATG) at two transplant centers between 2015-2018. Busulfan was given twice daily over 4 days with target AUC of 1800 to 2000 μMol/min (based on q12 hr. dosing) or once daily over 4 days with a target AUC of 3600-4400 μMol/min (based on q24 hr. dosing). Fludarabine 180 mg/m2 or 160 mg/m2 was given divided over 6 days or 4 days, respectively. Serotherapy included alemtuzumab 0.3 - 0.5 mg/kg or ATG 7.5 mg/kg given divided over 3 days. GVHD prophylaxis consisted of cyclosporine and mycophenolate mofetil. Results Thirty-five patients (WAS=11, HLH=10, CD40L deficiency=6, IPEX/VEOIBD=4, IFNGR1 def./ SCN/CID/LAD=1) received busulfan, fludarabine and alemtuzumab or ATG for allogeneic HCT (first HCT in 26 patients and second HCT in 9 of 10 patients with HLH). Median age was 2.0 years (range, 0.3 years – 19.8 years). Patients received a graft from an HLA-matched related (n=10), unrelated (n=23), or single allele mismatched related or unrelated donor (n=2). All except one patient engrafted at a median of 13 days (range,11-34 days). One patient developed veno-occlusive disease and two patients developed diffuse alveolar hemorrhage. Seven patients (20%) developed grade 2-3 acute GVHD and 2 patients (5.7%) developed chronic GVHD. One patient developed primary graft failure and two patients secondary graft failure. Eighteen patients (51%) maintained >95% donor chimerism following allogeneic HCT. Sixteen patients (46%) developed mixed chimerism, predominantly in the T-cell lineage, but T-cell donor chimerism progressively increased post-HCT. At 1-year post-transplant, 13 of 16 patients (81%) with mixed chimerism had donor myeloid chimerism >90% and T-cell chimerism >75%. Two patients underwent a second transplant for graft failure. Overall survival was 86%(30 of 35) and event free survival was 77%(27 of 35) at 1 year. Conclusion Our experience suggests that a reduced toxicity busulfan, fludarabine regimen with alemtuzumab or ATG as serotherapy offers a promising approach with low toxicity, durable myeloid engraftment, low incidence of grade 2-4 GVHD and excellent overall survival, and can be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.

Background CCR5 inhibition is a promising approach to prevent visceral acute GVHD in adults after allogeneic hematopoietic stem cell transplant (HSCT). Objective We performed a phase I/II study of maraviroc, an oral CCR5 inhibitor, to prevent visceral GVHD in children undergoing HSCT and have reported results of the phase I study previously. Methods We used our previously established dose (∼ 300 mg/m2) of maraviroc in the phase II study. Oral maraviroc was added to standard acute GVHD prophylaxis from day-3 twice daily for eligible patients until day+30 after HSCT. Trough levels of maraviroc were collected on day 0 +7, 14 and 21. Patients were observed until day+100 for acute GVHD. We assessed functional CCR5 blockade by our previously published pharmacodynamic assay. We explored mechanisms of resistance to maraviroc by comparing serum IL-15 levels, plasma CXCL9 and CXCL10 at day+30 between GVHD and no GVHD patients. CD38 expression on CD4+ T-cells measured by flow cytometry at day+30. Results Thirty-one patients were enrolled prospectively, 14 on the phase I and 17 on the phase II study. Phase II study Demographics are shown in Figure 1. Median maraviroc trough concentrations were therapeutic at > 100 ng/mL on day+7 and day+14 (Figure 2A). Functional CCR5 blockade was observed in all except one patient at day zero and day+14 (Figure 2B, 3A). Two patients developed grade 1 acute skin GVHD and were successfully treated with corticosteroids. Four patients developed gastrointestinal (GI) GVHD (Upper GI GVHD n=2, lower GI GVHD n=2). Two of these 4 patients with GI GVHD did not receive the planned 34 days of maraviroc. No adverse effects to maraviroc were observed. Seven patients discontinued maraviroc at a median of day+14 (range day+1- day+29) due to study rules regarding hepatotoxicity (n=5), renal function decline (n=1) and withdrawal from study (n=1). Phase I± Phase II study Incidence of GI GVHD in all 31 patients who received maraviroc was 19% (n=6) compared to 22% in historic controls (p=0.29). Four of the 6 GI GVHD patients did not complete maraviroc treatment. CD38 expression on CD4+ T-cells was elevated on day+30 in patients who developed GVHD compared to patients without GVHD (Figure 3B). We observed no difference in IL-15, CXCL10 and CXCL9 levels in patients with and without GVHD. Conclusion Maraviroc administration was feasible in children but was limited by elevated bilirubin levels and transaminases, unrelated to maraviroc. We achieved successful CCR5 blockade but also observed breakthrough of GVHD due to failure to administer maraviroc consistently. Peripheral blood activation of T-cell lymphocytes occurs in patients with imminent acute GVHD despite maraviroc prophylaxis, as might be expected since maraviroc regulates lymphocyte homing but does not suppress activation.

A reduced intensity conditioning regimen consisting of alemtuzumab, fludarabine, and melphalan has been shown to be associated with superior survival in patients with hemophagocytic lymphohistiocytosis, but is complicated by a high risk of mixed chimerism and secondary graft failure. We hypothesized that peri-transplant alemtuzumab levels impact the risks of both acute GVHD and mixed chimerism in patients with HLH undergoing RIC HCT. We tested this hypothesis in a companion correlative biology study to the Blood and Marrow Transplant Clinical Trials Network (CTN) prospective 1204 trial, Reduced-Intensity Conditioning for Children and Adults with Hemophagocytic Syndromes or Selected Primary Immune Deficiencies. The HCT RIC regimen included alemtuzumab (mg/kg subcutaneous, maximum cumulative dose of 90mg, divided over days −14 through −10), fludarabine (150mg/m2 or 5mg/kg in patients Our cohort was 74% male with a median age of 2.1 years (range 0.4-18.9). Nine patients (39%) developed acute GVHD not associated with donor lymphocyte infusion (DLI). Acute GVHD was associated with lower Day 0 alemtuzumab levels. Sixty-seven percent of patients with Day 0 levels 0.67μg/ml (p=0.0078) (Figure 1). Seventeen patients (74%) developed mixed chimerism, defined as whole blood donor chimerism Alemtuzumab level at day 0 significantly impacts the risks of acute GVHD and mixed chimerism. Studies to test precision dosing strategies to target peri-transplant levels of alemtuzumab to appropriate therapeutic ranges are underway, and future implementation may lead to improved outcomes.