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Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT SELEction and Timing Based on Sickle Cell-Related Multiple Chronic Conditions.

ABSTRACT: Hematopoietic stem cell transplant (HSCT) is the only cure for patients with sickle cell disease (SCD). Although most SCD patients experience progressive end-organ damage and shortened lifespans, not all patients follow the same disease course, tempo, or outcome. Therefore, the dilemma facing physicians is weighing the selection of patients and timing for the procedure against donor type and transplant-related mortality and morbidity that go up with increasing age. On the other hand, the dilemma facing the patients and families is how acceptable HSCT that carries some mortality risks to them. We have analyzed the chronic conditions due to SCD in 449 patients to determine whether SCD-related multiple chronic conditions (MCC) can be risk-stratified to identify the group of patients predicted to not only have shortened lifespans but also functional limitation and poor quality of life so that these at-risk patients can be offered HSCT early and before MCC develops. We identified that the age of onset of the first SCD-related chronic conditions strongly predicted for the risks for disease-related MCC. SCD patients who suffered their first disease-related chronic condition before age 30 years developed MCC at a rate of 19.1 times faster than those at a later age. These patients are therefore high-risk patients and should be offered HSCT early in the course of their disease before multiple organ damage intervenes, even if matched-related donors are not available. This patient selection and timing approach provides a forum for an easy-to-understand and real-time discussion, including the choice of donor type, with SCD patients and families when considering HSCT.

SUBMITTER: Jang T

PROVIDER: S-EPMC8504222 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AbstractPreliminary evidence from a series of 4 adults with sickle cell disease (SCD) suggests that hematopoietic stem cell transplant (HSCT) improves cerebral hemodynamics. HSCT largely normalizes cerebral hemodynamics in children with SCD. We tested the hypothesis in adults with SCD that cerebral blood flow (CBF), oxygen extraction fraction (OEF), and cerebral metabolic rate of oxygen (CMRO2) measured using magnetic resonance imaging, normalized to healthy values, comparing measurements from ∼1 month before to 12 to 24 months after HSCT (n = 11; age, 33.3 ± 8.9 years; 389 ± 150 days after HSCT) with age-, race- and sex-matched values from healthy adults without sickle trait (n = 28; age, 30.2 ± 5.6 years). Before transplant, 7 patients had neurological indications for transplant (eg, overt stroke) and 4 had nonneurological reasons for haploidentical bone marrow transplant (haplo-BMT). All received haplo-BMT from first-degree relatives (parent, sibling, or child donor) with reduced-intensity preparation and maintained engraftment. Before transplant, CBF was elevated (CBF, 69.11 ± 24.7 mL/100 g/min) compared with that of controls (P = .004). Mean CBF declined significantly after haplo-BMT (posttransplant CBF, 48.2 ± 13.9 mL/100 g/min; P = .003). OEF was not different from that of controls at baseline and did not change significantly after haplo-BMT (pretransplant, 43.1 ± 6.7%; posttransplant, 39.6 ± 7.0%; P = .34). After transplant, CBF and OEF were not significantly different from controls (CBF, 48.2 ± 13.4 mL/100 g/min; P = .78; and OEF, 39.6 ± 7.0%; P > .99). CMRO2 did not change significantly after haplo-BMT (pretransplant, 3.18 ± 0.87 mL O2/100 g/min; posttransplant, 2.95 ± 0.83; P = .56). Major complications of haplo-BMT included 1 infection-related death and 1 severe chronic graft-versus-host disease. Haplo-BMT in adults with SCD reduces CBF to that of control values and maintains OEF and CMRO2 on average at levels observed in healthy adult controls. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

Project description:Study objectiveAlemtuzumab is a monoclonal antibody that targets the cell surface antigen CD52 on lymphocytes. Although it is used for the treatment of hematologic malignancies, such as chronic lymphocytic leukemia, and incorporated into many hematopoietic stem cell transplant (HSCT) conditioning regimens, few studies have evaluated the pharmacology of alemtuzumab in adult patients with sickle cell disease (SCD). We therefore examined the pharmacokinetics (PK) and pharmacodynamics (PD) of alemtuzumab in adults with SCD who received a matched related donor HSCT to determine if the clearance of alemtuzumab affects transplant outcomes.DesignPK and PD analysis of patient data from a single-center clinical trial.SettingClinical research center.PatientsTwenty-two adult patients with SCD who received one of two nonmyeloablative allogeneic HSCT regimens: alemtuzumab and total body irradiation (Alem-TBI) or pentostatin, cyclophosphamide, alemtuzumab, and total body irradiation (Pento-Cy-Alem-TBI).Measurements and main resultsAlemtuzumab serum concentrations, absolute lymphocyte counts, T-cell (CD3), and myeloid (CD14/15) chimerism were collected at distinct time points and analyzed. A semi-mechanistic PK population model was built to understand inter-individual differences in pharmacology. Alemtuzumab was detectable up to 28 days post-HSCT. The mean alemtuzumab level 7 days after transplant for patients on Alem-TBI was 818 ng/ml, significantly lower than the mean level of 1502 ng/ml for patients on Pento-Cy-Alem-TBI (p < 0.001), but this difference decreased as time progressed. The clearance of alemtuzumab was linear, and the half-life was longer in the Pento-Cy-Alem-TBI group (average half-life = 61.1 h) compared to the Alem-TBI group (average half-life = 44.1 h) (p < 0.001). The CD3 chimerism at 2 and 4 months after transplant positively correlated with alemtuzumab levels collected on day 14 after transplant (R2 = 0.40 and p = 0.004 at 2 months, R2 = 0.36 and p = 0.005 at 4 months), but this significance was lost by 6 months after HSCT. No correlation was seen between alemtuzumab levels and CD14/15 chimerism.ConclusionBetween 2 and 4 months after transplant, higher alemtuzumab levels measured 14 days after transplant correlated with patients having better engraftment, suggesting more lymphodepletion may be needed to reduce graft failure in these two non-myeloablative matched related donor HSCT regimens.

Project description:Hematopoietic cell transplant for sickle cell disease is curative but is associated with life threatening complications most of which occur within the first 2 years after transplantation. In the current era with interest in gene therapy and gene editing we felt it timely to report on sickle cell disease transplant recipients who were alive for at least 2-year after transplantation, not previously reported. Our objectives were to (1) report the conditional survival rates of patients who were alive for 2 or more years after transplantation (2) identify risk factors for death beyond 2 years after transplantation and (3) compare all-cause mortality risks to those of an age-, sex- and race-matched general population in the United States. By limiting to 2-year survivors, we exclude deaths that occur as a direct consequence of the transplantation procedure. De-identified records of 1149 patients were reviewed from a publicly available data source and 950 patients were eligible (https://picsure.biodatacatalyst.nhlbi.nih.gov). All analyses were performed in this secure cloud environment using the available statistical software package(s). The validity of the public database was confirmed by reproducing results from an earlier publication. Conditional survival estimates were obtained using the Kaplan-Meier method for the sub-cohort that had survived a given length (x) of time after transplantation. Cox regression models were built to identify risk factors associated with mortality beyond 2 years after transplantation. The standardized relative mortality risk (SMR) or the ratio of observed to expected number of deaths, was used to quantify all-cause mortality risk after transplantation and compared to age, race and sex-matched general population. Person-years at risk were calculated from an anchor date (i.e., 2-, 5- and 7-years) after transplantation until date of death or last date known alive. The expected number of deaths was calculated using age, race and sex-specific US mortality rates. The median follow up was 5 years (range 2-20) and 300 (32%) patients were observed for more than 7 years. Among those who lived for at least 7 years after transplantation the 12-year probability of survival was 97% (95% CI, 92%-99%). Compared to an age-, race- and sex-matched US population, the risk for late death after transplantation was higher as late as 7 years after transplantation (hazard ratio (HR) 3.2; P= .020) but the risk receded over time. Risk factors for late death included age at transplant and donor type. For every 10-year increment in patient age, an older patient was 1.75 times more likely to die than a younger patient (P= .0004). Compared to HLA-matched siblings the use of other donors was associated with higher risk for late death (HR 3.49; P= .003). Graft failure (beyond 2-years after transplantation) was 7% (95% CI, 5%-9%) and graft failure was higher after transplantation of grafts from donors who were not HLA-matched siblings (HR 2.59, P< .0001). Long-term survival after transplantation is excellent and support this treatment as a cure for sickle cell disease. The expected risk for death recedes over time but the risk for late death is not negligible.

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Hematopoietic Stem Cell Transplant for Sickle Cell Disease: PATIENT SELEction and Timing Based on Sickle Cell-Related Multiple Chronic Conditions.

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