Elisabeth Dovern

Advances in conditioning regimens have made non‐myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) a viable curative option for adults with sickle cell disease (SCD). However, prospective studies comparing pre‐ and post‐transplant patient‐reported health outcomes are scarce. Therefore, in a prospective, mixed‐methods cohort study in adults with SCD undergoing HSCT, we tested the hypothesis that physical, mental, and social health improves after HSCT relative to baseline. We compared 9 Patient‐Reported Outcomes Measurement Information System (PROMIS®) measures at 6, 12, and 18 months post‐transplant to baseline and general population values. Semi‐structured interviews were conducted pre‐ and post‐transplant that were thematically analyzed (MAXQDA). Seventeen patients (7 females, 10 males; median age 26 years) underwent matched sibling (9) or haploidentical donor (8) transplantation. Compared to baseline, pain interference (p = 0.008), physical function (p < 0.001), fatigue (p = 0.001), anxiety (p = 0.016), anger (p = 0.037), and the ability to (p < 0.001) and satisfaction with (p < 0.001) social roles and activities improved at 18 months. Compared to reference values, physical function, sleep disturbance, fatigue, anxiety, and the ability to and satisfaction with social roles and activities T‐scores were significantly worse at baseline but comparable or better after 18 months. Thematic analysis of the interviews revealed high satisfaction with improved physical and social abilities alongside complex mental health challenges, including processing the psychological aftermath of SCD, dealing with transplant‐related toxicity, adjustment challenges, and identity conflicts. In conclusion, while physical, mental, and social health improves after HSCT, the effects on mental health can be complex and warrant psychosocial support early in the process of curative therapies.

In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative–related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier–based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate–severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Nonmyeloablative, matched sibling donor hematopoietic stem cell transplantation with alemtuzumab/total body irradiation (TBI) conditioning is a curative therapy with low toxicity for adults with sickle cell disease (SCD). However, relatively low donor chimerism levels and graft rejection remain important challenges. We hypothesized that adding azathioprine/hydroxyurea preconditioning will improve donor chimerism levels and reduce graft failure rate. In this prospective cohort study, we enrolled consecutive adult patients with SCD undergoing matched sibling donor transplantation at the Amsterdam UMC. Patients received azathioprine 150 mg/day and hydroxyurea 25 mg/kg/day for 3 months prior to alemtuzumab 1 mg/kg and 300 cGy TBI conditioning. Twenty patients with SCD (median age 26 years [range 19–49], 13 females) were transplanted. Median follow‐up was 46.0 months (IQR 21.8–57.9). One‐year overall survival and event‐free survival (graft failure or death) were both 95% (95% confidence interval 86–100). Mean donor myeloid and T‐cell chimerism 1‐year post‐transplant were 95.2% (SD ±10.6) and 67.3% (±15.3), respectively. One patient (5%) experienced graft failure without autologous regeneration, resulting in infections and death. All other patients had a corrected SCD phenotype and were able to discontinue sirolimus. Three patients were successfully treated with alemtuzumab (1 mg/kg) after the transplant because of declining donor chimerism and cytopenias to revert impending graft rejection. Toxicity was mostly related to sirolimus and alemtuzumab. One patient developed steroid‐responsive grade II intestinal acute graft‐versus‐host disease. Collectively, preconditioning with azathioprine/hydroxyurea prior to nonmyeloablative matched sibling donor transplantation resulted in excellent event‐free survival and robust donor T‐cell chimerism, enabling the successful withdrawal of sirolimus. ClinicalTrials.gov: NCT05249452.

Sickle cell disease (SCD)‐related organ complications are a major cause of morbidity and mortality in patients with SCD. We sought to assess whether hematopoietic stem cell transplantation (HSCT) stabilizes, attenuates, or exacerbates organ decline. We performed a systematic review and meta‐analysis of trials investigating organ function before and after HSCT in patients with SCD. We searched MEDLINE/PubMed and EMBASE up to September 21, 2023. Continuous data were expressed as standardized mean difference (SMD) and pooled in a weighted inverse‐variance random‐effects model; binomial data were expressed as risk ratio (RR) using the Mantel–Haenszel random‐effects meta‐analyses. Of 823 screened studies, 34 were included in this review. Of these, 17 (774 patients, 23.6% adults, 86.3% HLA‐identical sibling donor, 56.7% myeloablative conditioning regimen) were included in the meta‐analyses. Pulmonary function remained stable. Mean tricuspid regurgitant jet velocity decreased but did not reach statistical significance. In children, estimated glomerular filtration rate decreased (SMD −0.80, p = .01), and the presence of proteinuria increased (RR 2.00, p = <.01), while splenic uptake and phagocytic function improved (RR 0.31, p = <.01; RR 0.23, p = <.01). Cerebral blood flow improved (SMD −1.39, p = <.01), and a low incidence of stroke after transplantation in high‐risk patients was found. Retinopathy and avascular osteonecrosis were investigated in only one study, showing no significant changes. While HSCT can improve some SCD‐related organ dysfunctions, transplantation‐related toxicity may have an adverse effect on others. Future research should focus on identifying individuals with SCD who might benefit most from HSCT and which forms of organ damage are more likely to exacerbate post‐transplantation.

Sickle cell disease (SCD) is characterized by chronic hemolytic anemia associated with impaired cerebral hemodynamics and oxygen metabolism. Hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for patients with SCD. Whereas normalization of hemoglobin levels and hemolysis markers has been reported after HSCT, its effects on cerebral perfusion and oxygenation in adult SCD patients remain largely unexplored. This study investigated the effects of HSCT on cerebral blood flow (CBF), oxygen delivery, cerebrovascular reserve (CVR), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO₂) in 17 adult SCD patients (mean age: 25.0 ± 8.0, 6 females) before and after HSCT and 10 healthy ethnicity‐matched controls (mean age: 28.0 ± 8.8, 6 females) using MRI. For the CVR assessment, perfusion scans were performed before and after acetazolamide as a vasodilatory stimulus. Following HSCT, gray and white matter (GM and WM) CBF decreased (p < .01), while GM and WM CVR increased (p < .01) compared with the baseline measures. OEF and CMRO₂ also increased towards levels in healthy controls (p < .01). The normalization of cerebral perfusion and oxygen metabolism corresponded with a significant increase in hemoglobin levels and decreases in reticulocytes, total bilirubin, and LDH as markers of hemolysis (p < .01). This study shows that HSCT results in the normalization of cerebral perfusion and oxygen metabolism, even in adult patients with SCD. Future follow‐up MRI scans will determine whether the observed normalization of cerebral hemodynamics and oxygen metabolism prevents new silent cerebral infarcts.

Pure red cell aplasia (PRCA) is a serious complication after ABO-mismatched allogeneic hematopoietic stem cell transplantation (HSCT). Following HSCT, persistent anti-donor isohemagglutinins against donor ABO antigens are considered the immunological cause of PRCA. Patients with post-transplant PRCA are at risk for graft rejection and prolonged red blood cell transfusion dependency. No standard treatment exists. Recently however, the anti-CD38 monoclonal antibody daratumumab has been reported to be an effective treatment for post-transplant PRCA in patients with complete donor chimerism. Here, we describe the first case of PRCA in a patient with mixed lymphoid patient/donor chimerism that was successfully treated with daratumumab. This is also the first report of a transplant recipient with sickle cell disease who was treated with this relatively new approach. Fourteen months post-transplantation and twelve months after treatment with daratumumab, our patient has a normal complete blood count and the anti-donor isohemagglutinins remain undetectable despite mixed lymphoid chimerism. Mixed chimerism is a common manifestation in adult patients with sickle cell disease transplanted with non-myeloablative conditioning and a matched sibling donor. The application of non-myeloablative HSCT for patients with sickle cell disease is steadily increasing. Therefore, the incidence of PRCA in this setting might also increase. As the risk of graft rejection due to PRCA can be especially high in patients with mixed chimerism, clinicians should be aware that daratumumab can be an effective treatment in the setting of mixed chimerism.