Erfan Nur

Introduction: Anti-thymocyte globulin (ATG) and post-transplantation cyclophosphamide (PTCy) are both used as in-vivo lymphodepleting treatment in allogeneic hematopoietic stem cell transplantation (HSCT), particularly in the matched unrelated donor (MUD) setting. Methods: In this retrospective study, we compared the incidences of infections and viral reactivations and evaluated immune cell reconstitution in the first-year post-transplant between ATG- and PTCy-based conditioning regimens in nonmyeloablative MUD transplantations. Infection incidence was evaluated for the periods 0-100 vs. 101-365 days post-transplant. Results: A total of 185 patients (ATG=95, PTCy=90), transplanted between 2014 and 2021, were included. In the first 100 days after transplantation, the cumulative incidence of bacterial infections was higher in the PTCy group (ATG 17% vs. PTCy 32%, p=0.01) while CMV reactivations were more frequent in the ATG group (36% vs. 16%, p<0.001). Beyond 100-days post-transplant, incidence of bacterial infections was higher in the ATG group (18% vs. 1%, p<0.001). Fungal infection incidence was similar in both groups/periods. The 1-year densities of viral infections (3.54 vs. 1.89, p<0.01) and CMV reactivations (2.21 vs. 0.68, p<0.01) were higher in the ATG compared to the PTCy group. After 1-year, circulating CD4+ T-cell counts were significantly lower in the ATG than in the PTCy group (p<0.001). Discussion: In conclusion, this study shows that overall PTCy is associated with better immune reconstitution and reduced rate of viral infections/CMV reactivations compared to ATG-based conditioning. Together with our previous findings of a lower risk of acute GvHD following PTCy compared to ATG-based conditioning, these data may favor PTCy over ATG as GvHD prophylaxis.

The RACE study (NCT02009747) compared horse antithymocyte globulin (hATG) plus cyclosporine A (CsA) ± eltrombopag as initial immunosuppressive treatment (IST) for severe aplastic anemia. Here we report the final 2‐year analysis of this prospective randomized phase III study. One hundred ninety‐seven treatment‐naive patients were randomized to standard IST (hATG 40 mg/kg × 4 days and CsA 5 mg/kg/day; arm A; n = 101) or standard IST + eltrombopag at the dose of 150 mg/day (arm B; n = 96) from day +14 until 6 months (or 3 months, in case of complete response). The median follow‐up was 23.2 months. The 2‐year cumulative incidence of complete response was significantly superior in arm B (62.4% vs. 35.3%; p < 0.001). The 2‐year overall survival (OS) was 86% in arm A and 91% in arm B ( p = 0.081), with hazard ratio (HR), adjusted for age and disease severity, of 0.54 ( p = 0.064). The 2‐year disease‐free survival (DFS) was 56% vs. 37% (adjusted HR = 0.49; p < 0.001), while event‐free survival (EFS) was 48% vs. 32% ( p < 0.001), with adjusted HR = 0.54 ( p < 0.001), both significantly superior for arm B. The cumulative incidence of relapse was comparable in the two arms, while evolution to clinical paroxysmal nocturnal hemoglobinuria was 8% in arm A and 1% in arm B ( p = 0.041). The risk of clonal evolution remained negligible, with one patient in arm A and two in arm B developing karyotypic abnormalities. The initial hematological response benefit of eltrombopag added to IST as front‐line treatment of AA is associated with better 2‐year OS, DFS, and EFS without increased risk of secondary myeloid malignancies.

Hydroxyurea (HU) is the most widely prescribed disease‐modifying treatment in sickle cell disease (SCD), though treatment responses vary due to metabolism and adherence. We examined HU blood levels and treatment response in patients with homozygous sickle cell disease (HbSS). We measured HU in whole blood of 955 SCD patients enrolled in GenoMed4All using mass spectrometry. HU detection was defined as Z‐score > 2.5 relative to untreated healthy controls. Among HbSS patients not receiving recent transfusion therapy ( n = 539), HU was detected in 39% (143/369) of HU‐prescribed patients ≥ 10 years (median age 31.8 [10.0–69.9]). In only 24% (23/109) of young patients (< 10 years, median age 5.9 [1.2–9.9]), HU was detected, despite comparable HU dosing (18.8 vs. 20.3 mg/kg/day). Detectable HU was associated with increased MCV ( p < 0.001), and in patients ≥ 10 years also with increased HbF, despite low HbF (< 10%) in 25%. Neutropenia occurred in 8.0% of patients with detectable HU, 4.5% with undetected HU. Only one patient had severe neutropenia (< 0.5 × 10e9/l). In young patients, neutropenia occurred in 1.4% with undetected HU, and in 8.7% with detected HU. This is the largest study to date that reports data on HU levels in HbSS patients. Most HU‐prescribed patients, particularly young patients, had undetectable HU levels. Low MCV, HbF, and absent toxicity in children and limited toxicity in adults suggest that treatment for patients with undetectable HU is suboptimal. These findings warrant the need to optimize dosing and adherence to improve treatment in SCD, especially in young patients.

Patients with sickle cell disease (SCD) are at increased risk of COVID-19–related mortality compared with healthy individuals, even after vaccination. To what extent impaired vaccine-induced immunity contributes to this risk is unknown. We prospectively investigated vaccine immunogenicity in 31 patients with SCD who received COVID-19 mRNA vaccines. All patients used hydroxyurea. We quantified humoral and cellular immune responses 4 weeks after the second and third vaccinations and compared the results with those of age-, sex-, and vaccine-matched healthy individuals. Irrespective of higher naïve and lower memory B-cell subsets, serum neutralizing spike glycoprotein 1 immunoglobulin G antibody concentrations and frequencies of spike-specific memory B cells were similar to those in healthy individuals at each time point. Frequencies of CD4+ and CD8+ T cells in patients with SCD were also comparable with controls; however, type 1 cytokine production by spike-specific T cells was reduced. Reduced cytokine production and lower antibody production correlated with higher serum fetal hemoglobin levels, suggesting an association with hydroxyurea use. Although a third vaccination improved neutralizing antibody and memory B-cell responses, T helper 1 cytokine production tended to remain lower in patients than in controls. Our data point toward delayed or reduced vaccine-induced immunity, in line with previous reports, which may contribute to the increased risk of COVID-19–related mortality reported in these patients. This trial was registered at www.ccmo.nl as NL-OMON51241.