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ABSTRACTIntroduction Allogeneic hematopoietic stem cell transplant (HSCT) and gene therapy (GT) are two potentially curative approaches for sickle cell disease (SCD), but they have never been compared in clinical trials.Objective To compare the safety and efficacy of HSCT and GT to assist clinicians and patients in making informed treatment decisions.Methods Phase I-III clinical trials and case reports/series were included. Regimens included HSCT from all stem cell sources, lentiviral gene therapy, and gene editing, with any conditioning regimen. We searched Medline and EMBASE databases as of 1st June 2020 for studies reporting HSCT and GT outcomes in SCD. The Newcastle-Ottawa scale was used to assess the risk of bias. Descriptive statistics and post-hoc imputation for standard deviations of mean change in FEV1 and FVC were performed.Results In total, 56 studies (HSCT, n = 53; GT, n = 3) representing 1,198 patients met inclusion criteria (HSCT, n = 1,158; GT, n = 40). Length of follow-up was 3,881.5 and 58.7 patient-years for HSCT and GT, respectively. Overall quality of evidence was low, with no randomized controlled trials identified. Two-year overall survival for HSCT was 91%; mortality was 2.5% for GT. Acute chest syndrome and vaso-occlusive episodes were reduced post-HSCT and GT. Meta-analysis was not possible due to lack of comparator and heterogeneity in outcome measures reporting. Very few studies reported post-transplant end-organ function. Six secondary malignancies (5 post-HSCT, 1 post-GT) were reported.Discussion Reporting of SCD-related complications and patient-important outcomes is lacking for both strategies. We advocate for standardized reporting to better compare outcomes within and between treatment groups.

Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and post-transplantation cyclophosphamide (PTCy) in myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN) overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in seven of 120 (6%) patients. At 3 years, nonrelapse mortality (NRM) was 25% (95% confidence interval [CI]: 17-34), relapse 27% (95% CI: 18-36), grade 3-4 acute graftversus- host disease 12% (95% CI: 6-18), chronic graft-versus-host disease requiring systemic immunosuppression 14% (95% CI: 7-20), progression-free survival (PFS) 48% (95% CI: 39-59), and overall survival (OS) 56% (95% CI: 47-67). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, subdistribution hazard ratio [sdHR] =3.28; 95% CI: 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR=2.61; 95% CI: 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR=1.98, 95% CI: 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR=2.01; 95% CI: 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR=2.20; 95% CI: 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.

Abstract A 17‐gene stemness (LSC17) score determines risk in acute myeloid leukaemia patients treated with standard chemotherapy regimens. The present study further analysed the impact of the LSC17 score at diagnosis on outcomes following allogeneic haematopoietic cell transplantation (HCT). Out of 452 patients with available LSC17 score, 123 patients received allogeneic HCT. Transplant outcomes, including overall (OS), leukaemia‐free survival (LFS), relapse incidence (RI) and non‐relapse mortality (NRM), were compared according to the LSC17 scored group. The patients with a low LSC17 score had higher OS (56.2%) and LFS (54.4%) at 2 years compared to patients with high LSC17 score (47.2%, p = 0.0237 for OS and 46.0%, p = 0.0181 for LFS). The low LSC17 score group also had a lower relapse rate at 2 years (12.7%) compared to 25.3% in the high LSC17 score group (p = 0.017), but no difference in NRM (p = 0.674). Worse outcomes in the high LSC17 score group for OS, LFS and relapse were consistently observed across all stratified sub‐groups. The use of more intensive conditioning did not improve outcomes for either group. In contrast, chronic graft‐versus‐host‐disease was associated with more favourable outcomes in both groups. The 17‐gene stemness score is highly prognostic for survival and relapse risk following allogeneic HCT.

Donor clonal hematopoiesis may be transferred to the recipient through allogeneic hematopoietic stem cell transplantation (HSCT), but the potential for adverse long-term impact on transplant outcomes remains unknown. A total of 744 samples from 372 recipients who received HSCT and the corresponding donors were included. Bar-coded error-corrected sequencing using a modified molecular inversion probe capture protocol was performed, which targeted 33 genes covering mutations involved in clonal hematopoiesis with indeterminate potential (CHIP) and other acute myeloid leukemia-related mutations. A total of 30 mutations were detected from 25 donors (6.7%): the most frequently mutated gene was TET2 (n=7, 28%), followed by DNMT3A (n=4, 16%), SMC3 (n=3, 12%) and SF3B1 (n=3, 12%). With a median follow-up duration of 13 years among survivors, the presence of CHIP in the donor was not associated with recipient overall survival (P=0.969), relapse incidence (P=0.600) or non-relapse mortality (P=0.570). Donor CHIP did not impair neutrophil (P=0.460) or platelet (P=0.250) engraftment, the rates of acute (P=0.490), or chronic graft-versus-host disease (P=0.220). No significant difference was noted for secondary malignancy following HSCT between the two groups. The present study suggests that the presence of CHIP in allogeneic stem donors does not adversely affect transplant outcomes after HSCT. Accordingly, further study is warranted to reach a clearer conclusion on whether molecular profiling to determine the presence of CHIP mutations is necessary for the pretransplant evaluation of donors prior to stem cell donation.

Introduction: Prediction of outcomes following allogeneic hematopoietic cell transplantation (HCT) remains a major challenge. Machine learning (ML) is a computational procedure that may facilitate the generation of HCT prediction models. We sought to investigate the prognostic potential of multiple ML algorithms when applied to a large single-center allogeneic HCT database. Methods: Our registry included 2,697 patients that underwent allogeneic HCT from January 1976 to December 2017. 45 pretransplant baseline variables were included in the predictive assessment of each ML algorithm on overall survival (OS) as determined by area under the curve (AUC). Pretransplant variables used in the EBMT ML study (Shouval et al., 2015) were used as a benchmark for comparison. Results: On the entire dataset, the random forest (RF) algorithm performed best (AUC 0.71 ± 0.04) compared to the second-best model, logistic regression (LR) (AUC = 0.69 ± 0.04) (p < 0.001). Both algorithms demonstrated improved AUC scores using all 45 variables compared to the limited variables examined by the EBMT study. Survival at 100 days post-HCT using RF on the full dataset discriminated patients into different prognostic groups with different 2-year OS (p < 0.0001). We then examined the ML methods that allow for significant individual variable identification, including LR and RF, and identified matched related donors (HR = 0.49, p < 0.0001), increasing TBI dose (HR = 1.60, p = 0.006), increasing recipient age (HR = 1.92, p < 0.0001), higher baseline Hb (HR = 0.59, p = 0.0002), and increased baseline FEV1 (HR = 0.73, p = 0.02), among others. Conclusion: The application of multiple ML techniques on single-center allogeneic HCT databases warrants further investigation and may provide a useful tool to identify variables with prognostic potential. [ABSTRACT FROM AUTHOR]

PURPOSE: We sought to compare the pharmacokinetics (PKs) of DRL-rituximab (DRL_RI; potential biosimilar) and innovator rituximab MabThera (Roche, Grenzach-Wyhlen, Germany; reference medicinal product [RMP]) in patients with diffuse large B-cell lymphoma (DLBCL). Efficacy, pharmacodynamics (PDs), safety, and immunogenicity were also compared. PATIENTS AND METHODS: We conducted a double-blind, parallel-group study in patients with untreated DLBCL who were eligible to receive cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Patients were randomly assigned at a one-to-one ratio to receive DRL_RI or RMP for six 21-day cycles of rituximab plus CHOP, with 18 months of follow-up after day 1, cycle 6 (C6). Primary end point was C1 PKs, measured as area under the plasma concentration–time curve from day 0 to 21 (AUC0-21 days) and maximum plasma concentration (Cmax). Equivalence was defined as 90% CIs for the DRL_RI/RMP geometric mean ratios (GMRs) within 80% and 125%. Secondary end points included efficacy noninferiority measured by objective response rate (ORR) at C6 and event-free survival and overall survival at 87 weeks, PK equivalence at C6 and PD equivalence (rate of B-cell depletion and repletion), safety, and immunogenicity. The trial was stopped after sufficient patients for primary end point evaluation were enrolled. Secondary end points are reported as observed. RESULTS: A total of 151 patients were randomly assigned (DRL_RI, n = 76; RMP, n = 75). DRL_RI/RMP GMRs for AUC0-21 days and Cmax in C1 were 99.77 (90% CI, 87.60 to 113.63) and 96.19 (90% CI, 88.65 to 104.38), respectively. ORR at C6 for DRL_RI and RMP were 82.0% and 84.8%, respectively. Rates of B-cell depletion/repletion, immunogenicity, and adverse events were comparable in both groups. CONCLUSION: DRL_RI and RMP had equivalent PKs, with comparable efficacy, PDs, safety, and immunogenicity.