Background and Aims

Anti-thymocyte globulin (ATG), used in the conditioning of haematopoietic stem-cell transplantation (HSCT) to prevent graft-versus-host-disease (GVHD) and graft failure, has highly variable pharmacokinetics. Overexposure to ATG leads to poor CD4+
T-cell immune reconstitution, which is associated with inferior overall survival. We hypothesised that individualised ATG-dosing would promote CD4+ immune reconstitution, while still preventing GVHD and graft failure.

Methods

We report the results of a prospective, single-arm, phase 2 clinical trial done at the Princess Máxima Center for Pediatric Oncology to investigate individualised dosing of ATG for allogeneic HSCT in paediatric patients. ATG globulin dosing was based on bodyweight, absolute lymphocyte counts, and the stem-cell source, with cumulative doses ranging from 2–10 mg/kg. Patients younger than 18 years receiving a first HSCT with a T-cell repleted graft for any indication were eligible for inclusion. Primary endpoint was CD4+ immune reconstitution (>0·05 × 10⁹ CD4+ T-cells per L twice within 100 days [±3] after transplantation). The primary endpoint needed to be met in 38 of 53 evaluable patients (no death, relapse, or graft failure before day 100).

Results

Between 2015-2018, 51 evaluable patients were included in the study. Median follow-up was 25·6 months (IQR 15·0–37·0) and median age was 7·4 years (IQR 2·8–13·2). 29 (50%) of 58 patients were female. CD4+ immune reconstitution was reached in 41 (80%, 95% CI 67–90, in survival analysis) of 51 evaluable patients, hence the study met its primary endpoint. There was no difference in CD4+ immune reconstitution between patients who received different stem-cell sources (87% [95% CI 61–96] in cord blood, 77% [54–89] in bone marrow [p=0·62]).

Conclusions

Individualised dosing of ATG led to a significant improvement in early CD4+ immune reconstitution without increasing GVHD and graft failure incidence. Promotion of early CD4+ immune reconstitution by individualising anti-thymocyte globulin dose might improve outcomes of allogeneic HSCT.

Background and Aims

Viral infections cause significant mortality in patients with immunodeficiencies. Due to limitations of antiviral therapies, adoptive immune therapy has been developed to provide T-cell immunity. Ex-vivo production of vCTLs is limited by time and quantities for infusion. Miltenyi Biotec developed the CliniMACS Prodigy which isolates virus specific CD4+/CD8+ T cells from donors after incubation with viral antigen peptides. The Multicenter Viral CTL Consortium was created to treat immunocompromised patients.

To demonstrate vCTLs manufactured using the CliniMACS Prodigy for CMV, EBV, AdV, and BK virus is safe and effective for immunocompromised patients with refractory viral infections.

Methods

Patients 0.1-30 years with PID or following SOT or alloHSCT with refractory viral illnesses were eligible. Unmobilized PBMCs were obtained via apheresis. vCTLs were manufactured using the CliniMACS® Prodigy. HLA mismatched related donor cells were infused at 0.5x10⁴ CD3/kg per dose. Infusions of vCTLs Q2 weeks based on response and toxicity (maximum of 5 infusions). CR=PCR negative and PR=PCR ≥1 log decrease.

Results

Thirty-three patients met eligibility with two PID and 31 alloHSCT/SOT. Donors were screened. Four patients became ineligible; n=1 due to death from a viral infection, n=1 parental refusal and n=2 subjects with decreasing viral titers. Seventeen patients received vCTLs from their original haplo BMT donor and 12 received third party haplo-related donor vCTL infusions. Seven patients received CMV CTLs, 15 ADV CTLs, 5 BK CTLs, and 2 EBV vCTLs. Of the evaluable patients, responses were 17-CR, five-PR, three-SD, and one-PD with an ORR 85%. Two of the patients developed grade II-III aGVHD of the skin. There was no extensive cGVHD, infusion reactions, or CRS related to vCTLs.

Conclusions

The manufacturing of vCTLS using the CliniMACS Prodigy for patients with PID or following SOT or alloHSCT is efficient and the treatment appears safe and effective. Supported by FDA R01006363.

Background and Aims

Paediatric cancer patients receive autologous hematopoietic stem cell transplantation as part of normal treatment routine. When patients fail to mobilise a sufficient number of CD34⁺cells, alternative mobilisation agents such as plerixafor are used. Single injection of pegylated G-CSF (Peg-G-CSF) is used for improved patient comfort. While the efficacy and safety of these is well established in adults, limited data for its use in paediatric patients are available. We aim to study (i) success of mobilisation, (ii) hematologic reconstitution and (iii) stem cell quality and -phenotype, comparing good (GM) and poor mobilisers (PM) and different mobilisation regimens.

Methods

In this multi-centre retrospective study we analysed data of 281 non-leukemic paediatric patients. For a subgroup of patients (n=36), mobilised CD34⁺cells were studied by flow cytometry for expression of homing- and lineage markers. Moreover, apheresis products of patients with neuroblastoma were tested for tumour cell presence by qPCR.

Results

Use of Peg-G-CSF increased CD34⁺cell yield 2.6-fold compared to daily G-CSF (p<0.001). The addition of plerixafor to G-CSF was successful (i.e. harvest yield >2*10⁶ CD34+cells/kg) in 75% of PM, showing a 2.2-fold increase in CD34⁺cells compared to G-CSF only (p=0.005). No significant effects of Peg-G-CSF or plerixafor on hematologic reconstitution were observed. Within the PM group, plerixafor led to an increase of CXCR4+ and primitive CD34⁺cells in the apheresis product, but the levels did not exceed those of GM. Lineage marker expression and proliferation rate of CD34⁺cells in the graft remained unaltered. Tumor cells were not mobilized by plerixafor.

Conclusions

Our study provides unique data about Peg-G-CSF and plerixafor in paediatric patients, not only in regards to mobilisation efficiency, but also hematologic reconstitution, stem cell phenotype and -quality. We recommend the use of Peg-G-CSF over G-CSF because of superior harvest yields and less patient discomfort. Plerixafor is considered safe and effective in paediatric patients.

Background and Aims

VOD/SOS, a potentially fatal complication of HCT, primarily occurs after high-dose alkylating-based conditioning regimens (eg, busulfan-melphalan, thiotepa) followed by allogeneic HCT or autologous HCT (auto-HCT). Auto-HCT is part of standard-of-care treatment for patients with high-risk neuroblastoma. This post hoc analysis presents outcomes in paediatric patients with neuroblastoma who received defibrotide treatment for VOD/SOS after auto-HCT.

Methods

This post-marketing registry study collected retrospective/prospective real-world data on defibrotide-treated patients from 53 French HCT centres. VOD/SOS diagnosis was per investigator discretion using standard criteria. Disease severity was retrospectively/prospectively categorised using paediatric EBMT severity criteria. Outcomes included Day 100 survival and complete response (CR; total serum bilirubin <2 mg/dL and multiorgan failure resolution) and treatment-emergent serious adverse events (TESAEs) of interest.

Results

Of 87 paediatric patients in the defibrotide-treated post-HCT population, 25 (29%) had neuroblastoma and received auto-HCT. Median age was 3.7 (range: 1, 16) years. All patients underwent myeloablative conditioning, 2 (8%) had prior HCT, and 3 (12%) had advanced disease. Median time from auto-HCT to VOD/SOS diagnosis was 17.0 (range: 6, 28) days. At diagnosis, 19 (76%) patients had ascites and 20 (80%) had refractory thrombocytopaenia; 17 (68%) patients presented with anicteric VOD/SOS. Eight (32%) patients had mild/moderate VOD/SOS, 7 (28%) had severe, and 10 (40%) had very severe. By Day 100 post-HCT, the proportion of patients with CR was 92% (95% CI: 74, 99) and KM-estimated survival was 92% (95% CI: 72, 98). Five (20%) patients had TESAEs of interest, including 4 (16%) with haemorrhage and 1 (4%) with infection.

Conclusions

In this post hoc analysis of paediatric patients with neuroblastoma who received defibrotide treatment for VOD/SOS after auto-HCT, Day 100 post-HCT CR and survival were >90% with no new safety signals, despite a predominance of severe/very severe VOD/SOS. These data provide real-world evidence supporting defibrotide treatment of VOD/SOS in this high-risk population.