Transplantation For Sickle Cell Disease Research Articles

Posterior reversible encephalopathy syndrome post stem cell transplantation in sickle cell disease: case series and literature review.

Posterior reversible encephalopathy syndrome (PRES) is a serious neurological syndrome that may develop following immunosuppressive therapy for stem cell transplantation (SCT). We report 8 patients with sickle cell disease (SCD) who developed PRES, which is likely to be related to immunosuppression. This is retrospective cohort analysis of the SCD registry at the King Faisal Specialist Hospital and Research Center (KFSHRC) in Riyadh, Saudi Arabia. Inclusion criteria included all adults SCD patients who underwent SCT from 2011 until 2022. We explored all cases of PRES in patients with SCT. PRES was diagnosed with MRI imaging showing reversible vasogenic cerebral edema associated with neurological symptoms including severe headache, seizures, encephalopathy, delirium, and visual disturbances. During ten years follow-up (2011-2022) we found 8 patients with PRES (age range between 14 to 37 years at diagnosis) PRES occurred 8 to 124 days following SCT in 7 cases and one patient developed PRES 8 months prior to SCT. All patients were on immunosuppressive medications, including tacrolimus, cyclosporine, sirolimus and or mycophenolate mofetil. Headache, seizures, visual hallucinations, confusion, and drowsiness were the most common presenting symptoms. MRI showed abnormalities in the occipital, parietal and frontal lobes in most cases. Recovery was complete in all patients and no recurrences were noted. Two patients had graft versus host disease (GVHD). We compared risk factors for PRES among the 8 cases and 136 SCT in SCD patients who did not develop PRES. There was a significant association between PRES and imaging abnormalities, including previous bi-hemispheric infarctions (p = 0.001), and cerebral microbleeds (CBMs). PRES was strongly associated with presence (p = 0.006), size (p = 0.016) and number (p = 0.005) of CMBs. PRES can develop days to weeks following SCT in patients with SCD, and is associated with immunosuppressive therapy, previous bi-hemispheric infarctions and CMB. Prompt recognition and intervention leads to good recovery.

Incidence and risk factors of pain crisis after hematopoietic cell transplantation for sickle cell disease

AbstractVaso-occlusive episodes (VOC) or pain crises are the most common indications for hematopoietic cell transplantation (HCT) for sickle cell disease (SCD). Elimination of pain crisis after HCT is an important patient-centered outcome and may improve understanding of the natural history of pain syndromes in SCD. We examined deidentified records of 763 patients followed-up for a median of 36.7 months (range, 0.3-168.6 months), with 69.6% patient's age <18 years at HCT, 83.3% patient's Karnofsky-Lansky performance score (KPS) ≥90, overall survival 92.9%, event-free survival 72.4%, graft failure (GF) 22.4%, AGVHD 21.4%, CGVHD 27%, and pain crisis 8.65%. On unadjusted logistic regression, increased risk of pain crisis after HCT was observed in patient's aged >10 years at HCT (range, 11-17 years; OR, 9.43; 95% CI, 3.20-27.79; P < .0001), in age ≥18 years (OR, 16.62; 95% CI, 5.85-47.16; P < .0001), in those with history of pain crisis 2 years before HCT (OR, 13.16; 95% CI, 4.08-42.42; P < .0001), alternate donors (haploidentical [OR, 4.80; 95% CI, 2.48-9.31; P < .0001], unrelated matched [OR, 2.71; 95% CI, 1.23-5.97; P = .0132], and mismatched unrelated [OR, 3.19; 95% CI, 1.44-7.05; P = .0041], and those with GF (n = 41 [5.37%]; OR, 7.15; 95% CI, 4.20-12.18; P < .0001). Pain crisis was less frequent with KPS of ≥90 (OR, 0.31; 95% CI, 0.18-0.55; P < .0001). Multivariable logistic regression models confirmed age at HCT, KPS, graft type, donor type, history of VOC 2 years before HCT, and GF as independent predictors of pain crisis after HCT and generated predictive models and nomograms for pain crisis after HCT for SCD, which can support shared decision making.

Development of a Prototype Clinical Decision Support Tool for a Machine Learning Based Individualized Prediction of Outcomes of Hematopoietic Cell Transplantation for Sickle Cell Disease

Development of a Prototype Clinical Decision Support Tool for a Machine Learning Based Individualized Prediction of Outcomes of Hematopoietic Cell Transplantation for Sickle Cell Disease

Haematopoietic Stem Cell Transplantation for Sickle Cell Disease in a Low Resource Country Nigeria: A 2022 Report from a Single Team in a Public and Private Center.

Haematopoietic Stem Cell Transplantation for Sickle Cell Disease in a Low Resource Country Nigeria: A 2022 Report from a Single Team in a Public and Private Center.

Risk Factors for the Development of Non-Infectious Pulmonary Complications Post-Hematopoietic Cell Transplantation in Sickle Cell Disease

Risk Factors for the Development of Non-Infectious Pulmonary Complications Post-Hematopoietic Cell Transplantation in Sickle Cell Disease

Hematopoietic Stem Cell Transplantation in Sickle Cell Disease: A Multidimentional Review.

While exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) have been approved by the US Food and Drug Administration (FDA) as the first cell-based gene therapies for the treatment of patients 12 years of age and older with sickle cell disease (SCD), this treatment is not universally accessible. Allogeneic hematopoietic stem cell transplant (HSCT) has the potential to eradicate the symptoms of patients with SCD, but a significant obstacle in HSCT for SCD is the availability of suitable donors, particularly human leukocyte antigen (HLA)-matched related donors. Furthermore, individuals with SCD face an elevated risk of complications during stem cell transplantation due to SCD-related tissue damage, endothelial activation, and inflammation. Therefore, it is imperative to consider optimal conditioning regimens and investigate HSCT from alternative donors. This review encompasses information on the use of HSCT in patients with SCD, including the indications for HSCT, conditioning regimens, alternative donors, and posttransplant outcomes.

Posterior reversible encephalopathy syndrome and stem cell transplantation in sickle cell disease: Case series and literature review

Posterior reversible encephalopathy syndrome and stem cell transplantation in sickle cell disease: Case series and literature review

Regimen Intensity and Age Affect Transplant-Related Outcomes after Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Registry Study

Background: Serotherapies such as anti-thymocyte globulin (ATG) and alemtuzumab (AL) are added to conditioning chemotherapy for matched related donor (MRD) hematopoietic cell transplantation (HCT) for sickle cell disease (SCD) to facilitate engraftment and prevent graft-vs-host disease (GVHD). Most reports show ATG added to myeloablative (MA) conditioning; however, the use of AL has increased with investigation of different intensity regimens. The aim of this study was to compare HCT-related outcomes across common conditioning approaches to determine superiority. Methods: Retrospective data on baseline patient and HCT characteristics, and HCT outcomes were collected on 352 SCD patients &amp;gt;1 yr post-HCT at 14 Sickle cell Transplant Advocacy and Research (STAR) Alliance centers. Patients with a non-MRD (n=117) or without serotherapy (n=26) were excluded, leaving 209. MA included busulfan (BU) cumulative dose (CD) &amp;gt;8mg/kg or TBI ≥800 cGy; other regimens were termed non-MA (nMA). Summary statistics were presented as median (IQR) for continuous variables and count (%) for categorical variables. Comparisons were made using two-sample hypothesis tests, with p-value of &amp;lt; 0.05 as significant. Time-to-event analyses followed out to 3 years (censored after) and considered 4 outcomes. The first 3 were estimated via the Kaplan-Meier method: (1) overall survival (OS); (2) rejection-free survival (RFS); with death and rejection as events; (3) severe GVHD-free, RFS (GRFS), with death, RFS and severe GVHD as events; and (4) GVHD was estimated by Fine-Gray competing risk analyses, considering death as a competing event and censoring for rejection. Results: 209 patients received MRD HCT with MA+AL (66, 32%), nMA+AL (49, 23%), MA+horse (hATG) (71, 34%), or MA+rabbit (rATG) (23, 11%). Median recipient and donor age at HCT were 8.4yr (IQR: 5.1, 13.0) and 9.3 (5.1, 15.0) and similar across cohorts. MA+AL had a less severe clinical phenotype and nMA+AL had decreased pulmonary function; other baseline characteristics were similar (data not included). Conditioning for MA+AL included bu/cyclophosphamide (cy) (64%) or bu/fludarabine (flu) (36%), for MA+hATG bu/cy (68%) or bu/cy/flu (32%), for MA+rATG bu/cy (83%) or bu/flu (17%), and for nMA+AL melphalan/flu (92%) plus thiotepa (TT) (8%). GVHD prophylaxis was primarily calcineurin inhibitor and methotrexate or mycophenolate mofetil (91.4%). In MA, serotherapy was proximal timed with AL starting day -5 or -6 at a median (IQR) CD of 1.05mg/kg (0.8, 1.5), hATG starting day -3 at 90mg/kg (90), or rATG starting day -5 at 10mg/kg (9.6, 10.1); in nMA, AL was distal timed starting day -22 at a CD of 1.98mg/kg (1.0, 2.8). Stem cells were bone marrow in all, and GCSF primed in 15.4% of MA+AL and 4% of nMA+AL. Total nucleated and CD3 cell doses were similar across cohorts. nMA+AL had shorter median follow up at 2y (1, 4) vs 3y (2, 6) overall. nMA+AL had earliest time to neutrophil engraftment, required less platelet infusions, and had a shorter hospital stay at median 13d (12, 15), 8 infusions (4,13), and 21d (18, 26), respectively. Readmissions were highest for MA+AL at 77% (vs 64% overall). Graft rejection occurred only in nMA+AL (4, 8.2%) and MA+rATG (2, 8.7%). Table 3-yr CI of grade III/IV aGVHD was highest in nMA at 12% (CI: 0.05, 0.23) vs 0-7%, p=0.130 and for any cGVHD was significantly higher in nMA+AL at 33% (0.19, 0.46) vs 9-19%, p=0.001. 3-year OS was excellent at 94.4% (91.3, 97.7) and comparable per cohort. 3-year RFS was lowest though not significantly in nMA+AL at 87% (0.78, 0.97) vs 91-97%, p=0.260. 3-year GRFS was significantly lower in nMA+AL at 69% (0.57, 0.83) vs 83-94%, p=0.001. When age controlled GRFS in nMA+AL ≥13y was significantly lower at 59% (0.40, 0.88) vs 74-100%, p=0.007. Figure Conclusions: Despite small cohort sizes and retrospective nature, this study allowed for direct comparison of common approaches to MRD HCT for SCD. Outcomes were collectively excellent. nMA had earlier engraftment, less transfusion needs, and shorter hospital stay, although significantly more cGVHD and lower 3-yr GRFS influenced by older age. Current clinical trials in nMA+AL include TT and abatacept to mitigate this difference. We previously reported an association between MA and cardiac dysfunction (Stenger et al. Transplant Cell Ther 2023). Potential benefit of nMA must be balanced against risk of rejection and GVHD, thus providers should carefully consider such when selecting conditioning.

Individualized Prediction of Outcomes of Hematopoietic Cell Transplantation for Sickle Cell Disease: A Machine Learning Approach

Complications of Sickle cell disease (SCD) are ameliorated by modifying therapies but, hematopoietic cell transplantation (HCT) remains the only therapeutic option with curative intent. The therapeutic dilemma faced by families regarding HCT is partly related to the uncertainty regarding outcomes and adverse events. Computational machine-learning (ML) methods add to population-level outcomes by helping determine generalizable predictive patterns and quantifying uncertainty in those estimates. The incorporation of uncertainty as well as predictions allows clinicians to assess the confidence level of the predictions, avoid over-reliance on potentially incorrect results, allows for risk management and mitigation by considering the potential range of outcomes. Thus, such models may permit better decision-making by considering different scenarios and their probabilities, and increase transparency and accountability, by providing insight into how the model arrived at its predictions. Our objective was to develop a personalized, predictive machine learning model derived from center for international bone marrow transplant research (CIBMTR)datasets which meets acceptable AUC, calibration slope and discrimination. Methods We applied ML methods to clinical parameters and both categorical and time-to-event outcomes in a de-identified CIBMTR dataset of patients undergoing HCT. A supervised random forest model was created with baseline covariates as independent variables. Model selection was performed by both the clinician and data scientists to create a model using prognostically relevant variables. Since the number and percentage of negative outcomes in HCT for SCD is smaller than the positive outcomes, the model is imbalanced and biased towards predicting positive outcomes. To counter the imbalance, we constructed a training dataset taking each outcome variable of interest, and included randomly sampled positive outcomes, typically 1.5-3 times the total instances of the variable of interest. We ran the test dataset, and used a random forest on 20 such trials. To account for the effect of the undersampling, we propose a positive threshold δ, and assigned a final prediction of a negative outcome if the average sum for an element is greater than delta. We performed a 2 times Repeated 10 Fold Cross Validation, to demonstrate our model's versatility and response to unknown data. The accuracy score may be misleading as it may result from the model being able to correctly predict the numerical majority of the positive outcomes, and does not indicate the ability to detect negative outcomes. We therefore estimated balanced accuracy which is the arithmetic mean of sensitivity and specificity. Thus, a higher balanced accuracy results only when both the negative and positive outcomes are predicted with a high accuracy. We also measured Area under the Receiver Operator Characteristic Curve (ROC AUC), a measure of the ability of a binary classifier to distinguish between classes. We define model confidence as the average probability across 20 trials, as well as our confidence in the model. We describe predictive probability percentage as : model confidence*our confidence in the model*100. Results We examined de-identified records of 1641 patients who underwent HCT and were reported to the CIBMTR. Patients were followed for a median of 47.8 months (0.3-312.9) Patient characteristics included 73.4% patient's age at HCT &amp;lt;18 years, Karnofsky-Lansky (KPS) score ≥ 90 in 74.7%, overall survival 91.2%, event-free survival 75.5%, graft failure (GF) 17.9%, AGVHD 18.3%, and CGVHD 22.3%. Predictive model performance is described in Table 1. Predictive variables that made a significant contribution, and predicted outcomes in three hypothetical scenarios are described in Figure 1. Overall, the predictive model provided acceptable AUC, Balanced accuracy, positive predictive value and sensitivity. Conclusions We report the development, testing, and validation of an ML model for individualized prediction of outcomes of HCT for SCD. The model provides acceptable AUC, accuracy, balanced accuracy, positive predictive value and sensitivity. This predictive model has the potential to aid clinicians in making shared decisions with their patients regarding HCT for SCD.

Donor Hemoglobin Genotype Does Not Impact Outcomes Following Matched Related Donor Hematopoietic Cell Transplantation for Sickle Cell Disease: A STAR Study

Sickle cell disease (SCD) is an inherited hemoglobin (Hb) disorder which leads to significant morbidity and early mortality. Hematopoietic cell transplantation (HCT) is the only curative treatment with long-term outcome data, demonstrating excellent symptom-free survival particularly when a matched related donor (MRD) is available. Most MRD have sickle cell trait (Hb AS), but trait donor HCT is considered acceptable by the FDA and without negative impact. Further, initial gene addition and editing approaches for SCD have resulted in a trait-like status with benefit. Sickle trait, however, is associated with complications such as papillary necrosis, bacteriuria, splenic infarction, and exercise-induced death. The primary aim of this study was to compare long-term outcomes following MRD HCT for SCD based on donor Hb genotype, to objectively describe any impact on outcomes. Retrospective data was available for this analysis on 182 SCD patients ≥1 year post MRD HCT at 10 participating Sickle Transplant Advocacy and Research (STAR) Alliance centers. Summary statistics were presented as mean (standard deviation) for continuous variables and count (%) for categorical variables. Comparisons were made between Hb AA and Hb AS donor groups using both parametric and non-parametric tests for continuous variables and Chi-square test/exact test for categorical variables, with p-value &amp;lt;0.05 set as significant. Amongst 182 patients undergoing MRD HCT, 67% (n=122) had a Hb AS donor ( Table). In the overall cohort, median age at HCT was 8.7 (4.8) years and most patients had HbSS (n=174; 96%) with a severe clinical phenotype (n=97; 54%). HCT was performed using bone marrow (n=166; 92%) with myeloablative conditioning (n=156; 86%) in the majority. Patients with a severe disease phenotype and Hb AS donor were significantly more likely to have recurrent vaso-occlusive pain crises as an indication for HCT (p=0.033), otherwise there were no differences in baseline patient or HCT characteristics between cohorts. With mean post-HCT follow up of 4.5 (3.9) and 5.1 (4.1) years in Hb AA and Hb AS donor cohorts (p=0.145), no significant differences were seen in recipient outcomes including time to neutrophil and platelet engraftment, number of or time to last platelet transfusion, myeloid or unsorted % donor chimerism, number with acute (day 100) or chronic GVHD (1 year), or time to discontinue immunosuppression (data not shown). Disease recurrence and need for 2 nd HCT were rare in both cohorts (AA: 2 [3%] and 2 [3%]; AS: 3 [3%] and 4 [3%]; p=0.665 and 1.0, respectively). Two (3%) and 5 (4%) patients died in the AA and AS cohorts, respectively (p=1.0). Aside from a statistically (but not clinically) significant difference in Hb at day 30 (p=0.044), no difference was seen in longitudinal Hb or markers of hemolysis (LDH and ARC; Figure). No significant difference was seen in median number of RBC units transfused (AA: 4.0 [2.0-6.0]; AS: 3.0 [2.0-6.0]; p=0.454) or days to last transfusion (AA: 23.0 [14.0-77.0]; AS: 22.0 [13.0-75.0]; p=0.86). SCD complications were rare post-HCT, with no difference seen between cohorts in number (%) with VOC (AA: 1 [2%; had 2 separate VOC events]; AS: 3 [3%]; p=1.0), ACS (none reported), chronic pain (AA: 0 [0%]; AS: 1 [&amp;lt;1%]; p=1.0), or other SCD-related complications (AA: 2 [3%]; AS: 9 [7%; had 11 separate other events]; p=0.456). Stroke occurred in a significantly higher proportion with an AA versus AS donor (5 [8%] and 2 [2%], respectively; p=0.04). No significant differences were seen in longitudinal (1 and 2 years and at last follow up) post-HCT cardiac (EF, SF, TRJ velocity), pulmonary (FEV1, FVC, DLCO), or renal (GFR) function between cohorts (data not shown). Our results indicate that in MRD HCT for SCD, AS and AA donors yield comparable long-term outcomes. In this retrospective and registry-based study design, detailed analyses did not show differences between the two cohorts at baseline or at any timepoint post-HCT. While there were some outcome differences between the cohorts, they were either not clinically significant or did not have a scientific rationale, and thus were likely due to chance alone (denoted by bolding in Table). Given the young age of our cohort at HCT and thus a smaller proportion with SCD-related organ dysfunction, our results may not be applicable to an older cohort with significant organ dysfunction which will require a separate analysis.

Outcomes after RIC and Abatacept-Based Acute and Chronic Gvhd Prophylaxis in Allogeneic Transplantation for Sickle Cell Disease - Can Calcineurin Inhibitor Use be Curtailed?

Introduction: Sickle cell disease (SCD) progression can be curtailed by successful allogeneic transplantation from suitable donors. Allogenic transplantation with reduced intensity immune suppressive conditioning (RIC) from sibling or unrelated donors was considered acceptable with the availability of an Human Leucocyte Antigen (HLA)-matched (8/8 loci) or minimally mismatched (7/8) donor on NCT00920972 and in 2018 the study was modified to include abatacept for acute and chronic graft-versus-host disease (GVHD) prophylaxis based on the incidence of severe chronic GVHD noted (13-38%) and the benefits described with abatacept1-3. An interim review of trial results following the modification of GVHD prophylaxis is presented. Methods: Patients with symptomatic SCD who were &amp;lt;21 years of age were enrolled on appropriate study cohorts based on the level of donor match. Cohort 1 included HLA matched donors and cohort 3 included donors mismatched at 1 of 8 major HLA loci (-A, -B, -C, -DRB1) by high resolution typing. Conditioning included alemtuzumab (distal: day -22 to -19), fludarabine (days -8 to -4) and melphalan (day -3). Thiotepa (day -4) was included for mismatched donors. GVHD prophylaxis included tacrolimus (day -1 and tapered 6-9 months later), methotrexate (days +1, 3 and 6) and abatacept (days -1, +5, 14, 28, 60, 90, 180, 270 and 365)4. Though the half-life of the drug is ~30 days, the interval was adjusted after day 100 to every 90 days to curb allogeneic T cell proliferation following complete elimination of the drug. No previous data exists on this approach. Outcomes tracked were GVHD, mortality and graft rejection (GR) (&amp;lt;25% donor myeloid cells/disease recurrence) Results: Nine related donor transplants (4-18 years, median 9y) and 9 unrelated donor transplants (URD) (7-20 years, median 16y) (5 mismatched) were undertaken consecutively after the addition of abatacept to the standard GVHD regimen. The duration of follow-up ranged from 2-59 months (median 44m). GR was noted in 2 patients. One patient with primary GR subsequently rejected a second graft after myeloablative conditioning. Another patient with secondary GR received a CD34-selected boost post-ATG unsuccessfully but stabilized after a flu/cy/ATG regimen and another CD34-selected boost. The most recent engraftment analysis in 17/18 patients is 98% (range, 46 to 100) for myeloid and 94.5% (range, 56 to 100) for lymphoid lineage cells. No patient developed &amp;gt; grade 2 acute or any chronic GVHD in the MSD group. In the URD group 1 patient each developed &amp;gt;grade 2 aGVHD and extensive cGVHD. Of evaluable patients, one remains on systemic immune suppression therapy &amp;gt;18 months post-transplant. The only mortality noted was after 2 subsequent transplants in the patient with GR. Seventeen patients remain disease free post-transplant. Disease free survival (DFS) is 94%. GVHD-free-DFS is 89%. The incidence of viral reactivation was 65% and 17% before and after day +100 respectively. Immune reconstitution was noted to normalize beyond 6-9 months. Conclusion: Transplant is beneficial in SCD, and an expansion of donor sources can help to increase the number of patients rendered disease-free. GVHD risks preclude consideration of allogeneic transplantation. A GVHD-free cure rate of &amp;gt;88% despite risk factors such as age and HLA-mismatch following RIC and abatacept-based GVHD prophylaxis is encouraging for allogeneic transplantation options for children and adolescents with SCD. Long-term follow-up is in progress.

Excellent outcome of stem cell transplantation for sickle cell disease

Many sickle cell disease (SCD) patients lack matched family donors (MFD) or matched unrelated donors (MUD), implying haploidentical donors (MMFD) as a logical donor choice. We used a reduced toxicity protocol for all donor types. We included 31 patients (2–22 years) with MFD (n = 15), MMFD (10), or MUD (6) HSCT and conditioning with alemtuzumab/ATG, thiotepa, fludarabine and treosulfan, and post-transplant cyclophosphamide for MMFD. After the initial six patients, treosulfan was replaced by targeted busulfan (AUC 65–75 ng*h/ml). After a median follow-up of 26 months (6–123), all patients are alive and off immunosuppression. Two MMFD patients experienced secondary graft failure with recurrence of SCD, both after treosulfan conditioning. Neither acute GVHD ≥ °III nor moderate/severe chronic GVHD was observed. The disease-free, severe GVHD-free survival was 100%, 100%, and 80% in the MFD, MUD, and MMFD groups, respectively (p = 0.106). There was a higher rate of virus reactivation in MMFD (100%) and MUD (83%) compared to MFD (40%; p = 0.005), but not of viral disease (20% vs 33% vs 13%; p = 0.576). Six patients had treosulfan-based conditioning, two of whom experienced graft failure (33%), compared to 0/25 (0%) after busulfan-based conditioning (p = 0.032). Donor chimerism was ≥ 80% in 28/31 patients (90%) at last follow-up. Reduced toxicity myeloablative conditioning resulted in excellent overall survival, negligible GVHD, and low toxicity among all donor groups in pediatric and young adult patients with SCD.

Female Reproductive Health Outcomes after Hematopoietic Cell Transplantation for Sickle Cell Disease: Is Reduced Intensity Better Than Myeloablative Conditioning?

Curative therapy for sickle cell disease (SCD) through hematopoietic cell transplantation (HCT) is associated with a high level of risk for treatment-related gonadal dysfunction and future infertility. Both the myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC) regimens used for SCD HCT are considered to carry a high risk for ovarian damage. Cyclophosphamide equivalent doses (CEDs) are thought to correlate with the degree of gonadal damage in pediatric oncology patients. We aimed to evaluate ovarian outcomes previously reported from our center, characterize the conditioning regimens as MAC or RIC, and calculate the CED for each regimen. The ovarian outcomes diminished ovarian reserve (DOR), as determined by an anti-Müllerian hormone (AMH) below the normal limits for age and assay or <5%, and premature ovarian insufficiency (POI), defined as a follicle-stimulating hormone (FSH) level >40 mIU/ML, are presented by conditioning regimen from 3 clinical studies from our center (2 published and 1 presented as an abstract in 2022). The studies were not mutually exclusive of patients. CEDs were calculated for each regimen. The CED ranged from 3388 to 9705 mg/m2 for MAC regimens and from 5600 to 18,750 mg/m2 for RIC regimens. DOR was observed in all regimens; however, in one study 2 patients had normal AMH levels after a fludarabine/melphalan regimen, and 1 patient had a normal AMH level after a fludarabine/melphalan/thiotepa regimen. Rates of POI were more variable and ranged from 40% to 100% after MAC regimens and from 0 to 100% after RIC regimens. Female patients with SCD who undergo HCT have very high rates of DOR after both MAC HCT and RIC HCT. Two of the 3 RIC regimens evaluated had higher CEDs than were seen in any of the MAC regimens evaluated. Rates of POI were more variable but may increase with time from transplantation. All SCD patients need to be counseled about the risk of infertility and provided information about fertility preservation.

390 - Endothelial Complications of Hematopoietic Cell Transplantation for Sickle Cell Disease

390 - Endothelial Complications of Hematopoietic Cell Transplantation for Sickle Cell Disease

384 - Vaso-Occlusive Pain Requiring Hospitalization or Treatment Is Rare Following Successful Hematopoietic Cell Transplantation for Sickle Cell Disease

384 - Vaso-Occlusive Pain Requiring Hospitalization or Treatment Is Rare Following Successful Hematopoietic Cell Transplantation for Sickle Cell Disease

392 - Avascular Necrosis Following Hematopoietic Cell Transplantation for Sickle Cell Disease

392 - Avascular Necrosis Following Hematopoietic Cell Transplantation for Sickle Cell Disease

379 - The Impact of Current Conditioning Regimen, T Cell Depletion and Graft Versus Host Disease Prophylaxis on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

379 - The Impact of Current Conditioning Regimen, T Cell Depletion and Graft Versus Host Disease Prophylaxis on the Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation for Sickle Cell Disease

Secondary Neoplasms After Hematopoietic Cell Transplant for Sickle Cell Disease.

To report the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. Included are 1,096 transplants for sickle cell disease between 1991 and 2016. There were 22 secondary neoplasms. Types included leukemia/myelodysplastic syndrome (MDS; n = 15) and solid tumor (n = 7). Fine-Gray regression models examined for risk factors for leukemia/MDS and any secondary neoplasm. The 10-year incidence of leukemia/MDS was 1.7% (95% CI, 0.90 to 2.9) and of any secondary neoplasm was 2.4% (95% CI, 1.4 to 3.8). After adjusting for other risk factors, risks for leukemia/MDS (hazard ratio, 22.69; 95% CI, 4.34 to 118.66; P = .0002) or any secondary neoplasm (hazard ratio, 7.78; 95% CI, 2.20 to 27.53; P = .0015) were higher with low-intensity (nonmyeloablative) regimens compared with more intense regimens. All low-intensity regimens included total-body irradiation (TBI 300 or 400 cGy with alemtuzumab, TBI 300 or 400 cGy with cyclophosphamide, TBI 200, 300, or 400 cGy with cyclophosphamide and fludarabine, or TBI 200 cGy with fludarabine). None of the patients receiving myeloablative and only 23% of those receiving reduced-intensity regimens received TBI. Low-intensity regimens rely on tolerance induction and establishment of mixed-donor chimerism. Persistence of host cells exposed to low-dose radiation triggering myeloid malignancy is one plausible etiology. Pre-existing myeloid mutations and prior inflammation may also contribute but could not be studied using our data source. Choosing conditioning regimens likely to result in full-donor chimerism may in part mitigate the higher risk for leukemia/MDS.

Hematopoietic Stem Cell Transplantation for Sickle Cell Disease: A Review

Sickle cell disease is an autosomal recessive disorder widely spread over the world. The disease is associated with continuing morbidity, mutiorgan damage, and mortality. Hematopoietic stem cell transplantation is the only established curative therapy. The probability of 5-year survival post HSCT extends beyond 90%. The therapy is continuously evolving in all aspects of transplantation. This review focuses on the recent trends in multiple facets of the procedure from indications to details of newer technologies. It reviews data related to age at transplantation, indications as proposed by various researchers, donor selection, multiplicity of conditioning regimens, various immunosuppressive methodologies in use and expected outcomes. Transplant at an early age is recommended if MSD is available. The complications profile differs, depending on the age. Practically every single serious complication requiring admission in SCD, is an indication for the transplant. The major challenges faced in HSCT include non-acceptance by the patients and non-availability of fully matched donors. The technology is completely gearing up to make haploidentical transplants more successful with lesser side effects like GVHD, rejections and infections. Different intensity levels of conditioning regimens are in use. Various manipulations with T cells also form the part of transplant. The review reinforces the current knowledge about methodologies, utility and feasibility of HSCT in SCD.

Knowledge to date on secondary malignancy following hematopoietic cell transplantation for sickle cell disease

Allogeneic hematopoietic cell transplantation, gene therapy, and gene editing offer a potential cure for sickle cell disease (SCD). Unfortunately, myelodysplastic syndrome and acute myeloid leukemia development have been higher than expected after graft rejection following nonmyeloablative conditioning and lentivirus-based gene therapy employing myeloablative busulfan for SCD. Somatic mutations discovered in 2 of 76 patients who rejected their grafts were identified at baseline at much lower levels. While a whole-genome sequencing analysis reported no difference between patients with SCD and controls, a study including whole-exome sequencing revealed a higher prevalence of clonal hematopoiesis in individuals with SCD compared with controls. Genetic risk factors for myeloid malignancy development after curative therapy for SCD are currently being explored. Once discovered, decisions could be made about whether gene therapy may be feasible vs allogeneic hematopoietic cell transplant, which results in full donor chimerism. In the meantime, care should be taken to perform a benefit/risk assessment to help patients identify the best curative approach for them. Long-term follow-up is necessary to monitor for myeloid malignancies and other adverse effects of curative therapies for SCD.