Multicenter, phase 1 study of etavopivat (FT-4202) treatment for up to 12 weeks in patients with sickle cell disease.

ABSTRACT: Etavopivat is an investigational, once daily, oral, selective erythrocyte pyruvate kinase (PKR) activator. A multicenter, randomized, placebo-controlled, double-blind, 3-part, phase 1 study was conducted to characterize the safety and clinical activity of etavopivat. Thirty-six patients with sickle cell disease (SCD) were enrolled into 4 cohorts: 1 single-dose, 2 multiple ascending doses, and 1 open-label (OL). In the OL cohort, 15 patients (median age 33.0 years [range, 17-55]) received 400 mg etavopivat once daily for 12 weeks; 14 patients completed treatment. Consistent with the mechanism of PKR activation, increases in adenosine triphosphate and decreases in 2,3-diphosphoglycerate were observed and sustained over 12 weeks' treatment. This translated clinically to an increase in hemoglobin (Hb; mean maximal increase 1.6 g/dL [range, 0.8-2.8]), with >1 g/dL increase in 11 (73%) patients during treatment. In addition, the oxygen tension at which Hb is 50% saturated was reduced (P = .0007) with a concomitant shift in point of sickling (P = .0034) to lower oxygen tension in oxygen-gradient ektacytometry. Hemolysis markers (absolute reticulocyte count, indirect bilirubin, and lactate dehydrogenase) decreased from baseline, along with matrix metalloproteinase-9 and erythropoietin. In the OL cohort, adverse events (AEs) were mostly grade 1/2, consistent with underlying SCD; 5 patients had serious AEs. Vaso-occlusive pain episode was the most common treatment-emergent AE (n = 7) in the OL cohort. In this, to our knowledge, the first study of etavopivat in SCD, 400 mg once daily for 12 weeks was well tolerated, resulting in rapid and sustained increases in Hb, improved red blood cell physiology, and decreased hemolysis. This trial was registered at www.ClinicalTrials.gov as #NCT03815695.

Community-level socioeconomic distress is associated with nutritional status in adults with sickle cell anemia.

Sickle cell anemia (SCA) negatively impacts the ability to achieve educational and occupational goals increasing vulnerability to socioeconomic challenges. In a cross-sectional analysis of 332 SCA adults, we investigated whether the distressed community index (DCI) was associated with SCA-related complications and nutritional status. More patients with higher DCI had Medicaid insurance. A higher DCI was independently associated with tobacco use and lower body mass index, serum albumin, and vitamin D 25-OH levels after adjusting for insurance status but was not associated with SCA-related complications. Future studies investigating access to healthy foods may help improve health equity in patients with SCA.

Race, Interleukin-6, TMPRSS6 Genotype, and Cardiovascular Disease in Patients With Chronic Kidney Disease.

Background Differences in death rate and cardiovascular disease (CVD) between Black and White patients with chronic kidney disease is attributed to sociocultural factors, comorbidities, genetics, and inflammation. Methods and Results We examined the interaction of race, plasma IL-6 (interleukin-6), and TMPRSS6 genotype as determinants of CVD and mortality in 3031 Chronic Renal Insufficiency Cohort study participants. The primary outcomes were all-cause mortality and a composite of incident myocardial infarction, peripheral artery disease, stroke, and heart failure. During the median follow-up of 10 years, Black patients with chronic kidney disease experienced a significantly higher mortality (34% versus 26%) and CVD composite (41% versus 28%) compared with White patients. After adjustment, TMPRSS6 genotype did not associate with the outcomes. The adjusted hazard ratio for mortality (4.11 [2.48-6.80], P<0.001) and CVD composite (2.52 [1.96-3.24], P<0.001) were higher for the highest versus lowest IL-6 quintile. The adjusted hazards for death per 1-quintile increase in IL-6 in White and Black individuals were 1.53 (1.42-1.64) versus 1.29 (1.20-1.38) (P<0.001), respectively. For CVD composite they were 1.61 (1.50-1.74) versus 1.30 (1.22-1.39) (P<0.001), respectively. In Cox proportional hazard models that included IL-6, there was no longer a racial disparity for death (1.01 [0.87-1.16], P=0.92), but significant unexplained mediation remained for CVD (1.24 [1.07-1.43]; P=0.004). Path models that included IL-6, diabetes, and urine albumin to creatinine ratio were able to identify variables responsible for racial disparity in mortality and CVD. Conclusions Racial differences in mortality and CVD among patients with chronic kidney disease could be explained by good-fitting path models that include selected mediator variables including diabetes and plasma IL-6.

Urinary Kringle Domain-Containing Protein HGFL: A Validated Biomarker of Early Sickle Cell Anemia-Associated Kidney Disease.

INTRODUCTION: Chronic kidney disease (CKD) is a prevalent complication of sickle cell anemia (SCA). Hyperfiltration that delayed detection of CKD is common in SCA patients. Identification of novel urinary biomarkers correlating with glomerular filtration rates may help to detect and predict progression of renal disease. METHODS: Reanalysis of mass spectra of urinary samples obtained from University of Illinois at Chicago identified kringle domain-containing protein HGFL. RESULTS: HGFL levels correlated with hyperfiltration, were significantly reduced at CKD stage 1 compared to stage 0, negatively correlated with progression of CKD and were suitable for differentiation of stage 1. Better prediction of CKD progression to stage 2 was observed for HGFL-based risk prediction compared to the estimated glomerular filtration rate (eGFR)-based prediction. Results from a Howard University patient cohort supported the utility of HGFL-based test for the differentiation of stage 1 of CKD. CONCLUSION: Urinary HGFL may contribute additional information beyond eGFR and improve diagnosis of early-stage CKD in SCA patients.

Iron status, fibroblast growth factor 23 and cardiovascular and kidney outcomes in chronic kidney disease.

Disordered iron and mineral homeostasis are interrelated complications of chronic kidney disease that may influence cardiovascular and kidney outcomes. In a prospective analysis of 3747 participants in the Chronic Renal Insufficiency Cohort Study, we investigated risks of mortality, heart failure, end-stage kidney disease (ESKD), and atherosclerotic cardiovascular disease according to iron status, and tested for mediation by C-terminal fibroblast growth factor 23 (FGF23), hemoglobin and parathyroid hormone. Study participants were agnostically categorized based on quartiles of transferrin saturation and ferritin as "Iron Replete" (27.1% of participants; referent group for all outcomes analyses), "Iron Deficiency" (11.1%), "Functional Iron Deficiency" (7.6%), "Mixed Iron Deficiency" (iron indices between the Iron Deficiency and Functional Iron Deficiency groups; 6.3%), "High Iron" (9.2%), or "Non-Classified" (the remaining 38.8% of participants). In multivariable-adjusted Cox models, Iron Deficiency independently associated with mortality (hazard ratio 1.28, 95% confidence interval 1.04-1.58) and heart failure (1.34, 1.05- 1.72). Mixed Iron Deficiency associated with mortality (1.61, 1.27-2.04) and ESKD (1.33, 1.02-1.73). High Iron associated with mortality (1.54, 1.24-1.91), heart failure (1.58, 1.21-2.05), and ESKD (1.41, 1.13-1.77). Functional Iron Deficiency did not significantly associate with any outcome, and no iron group significantly associated with atherosclerotic cardiovascular disease. Among the candidate mediators, FGF23 most significantly mediated the risks of mortality and heart failure conferred by Iron Deficiency. Thus, alterations in iron homeostasis associated with adverse cardiovascular and kidney outcomes in patients with chronic kidney disease.

Race/ethnicity and underlying disease influences hematopoietic stem/progenitor cell mobilization response: A single center experience.

BACKGROUND: Whether race/ethnicity plays a role in hematopoietic stem/progenitor cells (HSPC) mobilization in autologous donors has not been studied. We hypothesize that donor characteristic including race/ethnicity, age, sex, body mass index, and diagnostic groups influences HSPC mobilization. Diagnostic groups include healthy allogeneic donors, autologous multiple myeloma (MM) and non-MM donors. STUDY DESIGN AND METHODS: Here, we conducted a single-center retrospective study in 64 autologous patients and 48 allogeneic donors. Autologous donors were patients diagnosed with MM or non-MM. All donors were grouped as African American (AA), White (W), or "Other"(O). RESULTS: Multivariate analysis demonstrated diagnostic group differences for CD34+ cell yields between race/ethnicity. Specifically, non-MM patients had the lowest CD34+ cell yields in AA and O, but not in W. For pre-apheresis peripheral blood (PB) CD34+ cell numbers, race/ethnicity had a significant effect both in bivariate and multivariate analyses. Non-MM patients had the lowest, and AA patients had the highest PB CD34+ cells. The results support the view that past therapies used in MM are likely more conducive of recovery of HSPC. CONCLUSIONS: Our study shows that race/ethnicity and diagnostic group differences influenced CD34+ cell mobilization response across donor types. Interestingly, autologous MM donors with the aid of plerixafor displayed comparable CD34 yields to allogeneic donors. Even though both MM and non-MM donors received plerixafor, non-MM donors had significantly lower CD34 yields among AA and O donors but not in W donors. Larger studies would be required to validate the role of diagnostic groups and race/ethnicity interactions.

Non-myeloablative human leukocyte antigen-matched related donor transplantation in sickle cell disease: outcomes from three independent centres.

Non-myeloablative haematopoietic progenitor cell transplantation (HPCT) from matched related donors (MRD) has been increasingly utilized in sickle cell disease (SCD). A total of 122 patients received 300 cGy of total body irradiation (TBI), alemtuzumab, unmanipulated filgrastim-mobilized peripheral blood HPC and sirolimus. The median follow-up was four years; median age at HPCT was 29 years. Median neutrophil and platelet engraftment occurred on day 22 and 19 respectively; 41 patients required no platelet transfusions. Overall and sickle-free survival at one and five years were 93% and 85% respectively. Age, sex, pre-HPCT sickle complications, ferritin and infused HPC numbers were similar between graft failure and engrafted patients. Mean donor myeloid chimaerism at one and five years post HPCT were 84% and 88%, and CD3 was 48% and 53% respectively. Two patients developed grade 1 and 2 skin graft-versus-host disease (GVHD) with no chronic GVHD. Median days of recipients taking immunosuppression were 489; 83% of engrafted patients have discontinued immunosuppression. Haemoglobin, haemolytic parameters and hepatic iron levels improved post HPCT. Pulmonary function testing, hepatic histology and neurovascular imaging remained stable, suggesting cessation of further sickle-related injury. Fourteen patients had children. In this largest group of adult SCD patients, this regimen was highly efficacious, well-tolerated despite compromised organ functions pre HPCT, and without clinically significant GVHD.

Improved health care utilization and costs in transplanted versus non-transplanted adults with sickle cell disease.

Patients with sickle cell disease (SCD) have access to fewer health care resources and therapies compared to other diseases, which contributes to increased morbidity and health care utilization. We compared health care utilization (inpatient hospital days, emergency care visits) and health care-related costs between SCD adults that underwent hematopoietic stem cell transplantation (HSCT) using a nonmyeloblative conditioning regimen versus those referred for HSCT but did not proceed due to lack of an HLA-matched sibling donor, denial by insurance, red blood cell antibodies to the potential donor, or declining further evaluation. Between 8/2011 and 4/2016, 83 SCD patients were referred for allogeneic HSCT and 16 underwent the procedure. The HSCT and non-HSCT groups were similar by age, sex, prior SCD-related therapy and complications. Compared to pre HSCT, significantly fewer inpatient hospital days (median of 1 versus 22 days, P = 0.003) and emergency care visits (median of 1 versus 4 visits, P = 0.04) were observed by the 2nd year post-HSCT. Similar results were observed in comparison to the standard-of-care group (median of 1 versus 12 hospital days, P = 0.002; median of 1 versus 3 emergency visits, P = 0.03). Lower health care costs were observed by the 2nd year post-HSCT (median of $16,281 versus $64,634 pre-HSCT (P = 0.01) and versus $54,082 in the standard-of-care group (P = 0.05). A median reduction of -$20,833/patient/year (IQR, -$67,078-+$4,442/patient/year) in health care costs compared to pre-HSCT was observed in the 2nd year post-HSCT. In conclusion, allogeneic HSCT leads to improvements in health care utilization and costs compared to standard-of-care therapy in high-risk SCD adults.

Allogeneic Hematopoietic Stem Cell Transplantation for Adults with Sickle Cell Disease.

Sickle cell disease (SCD) is an inherited red blood cell disorder that leads to substantial morbidity and early mortality. Acute and chronic SCD-related complications increase with older age, and therapies are urgently needed to treat adults. Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative therapy, but has been used less frequently in adults compared to children. This is, in part, due to (1) greater chronic organ damage, limiting tolerability to myeloablative conditioning regimens, (2) a higher rate of HSCT-related complications in adults versus children with SCD, and (3) limited coverage by public and private health insurance. Newer approaches using nonmyeloablative and reduced-intensity conditioning HSCT regimens have demonstrated better safety and tolerability, with high rates of stable engraftment in SCD adults. This review will focus on the impacts of HSCT, using more contemporary approaches to SCD-related complications in adults.

The experience of adults with sickle cell disease and their HLA-matched adult sibling donors after allogeneic hematopoietic stem cell transplantation.

AIM: To provide a rich description and in-depth understanding of the recipient-donor allogeneic hematopoietic stem cell transplantation experience. BACKGROUND: A stem cell transplant has a high likelihood of improving symptoms of sickle cell disease in adults. While studies have reported the transplant experiences of recipients and donors with haematological malignancies, no published reports have examined the experience of both adult recipients with sickle cell disease and their donors. DESIGN: Exploratory qualitative descriptive analysis. METHODS: We conducted individual interviews with 13 recipients and donors (eight males, five females) representing five recipient-donor dyads and one recipient-donor triad from one Midwest transplant centre between August 2017-February 2018. Interviews were digitally audio-recorded, transcribed verbatim and analysed using conventional content analysis. FINDINGS: Five themes were identified: the downward spiral and a second chance; getting the monster off my back; difficult and manageable; it was worth it; and relating to the healthcare team. CONCLUSIONS: The results provide a description and insights into the complex nature of the stem cell transplant experience in sickle cell disease from the perspectives of both recipients and donors. IMPACT: Health provider awareness of recipient-donor experiences can contribute to family-centred care that supports the health and quality of life for both recipients and donors. This understanding promotes high quality clinical care and improved communications by taking into account the knowledge, values and informed preferences of recipients and donors and contributes to improved decision-making and clinical care. Future research can assess family experiences that support informed choice for potential transplant candidates.

Laparoscopic Sleeve Gastrectomy in Sickle Cell Disease: a Case Series.

With improved care, the number of sickle cell patients with obesity is increasing. The experience with bariatric surgery in this patient population is limited. We describe four adult patients with mild sickling genotypes who underwent laparoscopic sleeve gastrectomy. The patients achieved marked weight loss with percentage of excess weight loss ranging from 56 to 68%. The surgery was associated with decreases in white blood cell counts and lower random glucose concentrations. No short-term or long-term complications related to the surgery were observed. Our report supports bariatric surgery as a feasible weight-loss option in this patient population.

Health-Related Quality of Life and Personal Life Goals of Adults With Sickle Cell Disease After Hematopoietic Stem Cell Transplantation.

Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-matched sibling donor offers a unique therapy to reverse SCD. This mixed-methods study explores recipients' perception of HSCT success, personal life goals, and associated health-related quality of life (HRQOL) more than 1 year after HSCT. Recipients completed the Short Form-36, version 1 (SF-36v1) HRQOL survey followed by a 60- to 90-min face-to-face or telephone audio-recorded interview. Eleven of 15 eligible recipients participated in the study. Although the eight HRQOL subscale scores varied, the three recipients with a successful HSCT and the highest scores were pursuing their personal life goals. The four with avascular necrosis (AVN) had lower scores related to AVN limitations, yet they were pursuing their personal goals. The two reporting a failed HSCT had reverted back to having SCD, and their subscale scores were among the lowest. Our results show that HSCT success, ability to pursue goals, and HRQOL align in predictable ways.

Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative, reduced intensity, and nonmyeloablative conditioning in sickle cell disease.

Sickle cell disease (SCD) chronically damages multiple organs over the lifetime of affected individuals. Allogeneic hematopoietic cell transplantation (allo-HCT) is the most studied curative intervention. Fully matched related marrow, peripheral blood derived, or cord blood HCT have the best transplant outcome for symptomatic patients with SCD. For patients with asymptomatic or milder disease who have this donor option available, risks and benefits of HCT should be discussed among the patient, family, treating hematologist, and transplant physician, and decision to proceed to HCT should be individualized. Myeloablative conditioning with busulfan, cyclophosphamide, and ATG has been a commonly employed regimen for children and young adults. Recently, low intensity conditioning with low dose total body irradiation and alemtuzumab is emerging as an efficacious and safe regimen for adults, young adults, and possibly children. Mixed donor chimerism (minimum ≥20% myeloid cells), from myeloablative or nonmyeloablative conditioning regimen, produces robust normal donor erythropoiesis and is sufficient to provide a clinical cure. The proportion of patients remaining on immunosuppression beyond 2 years post-HCT is likely <10% with either myeloablative or low intensity regimens. Late effects from myeloablative or reduced intensity conditioning, or from several more months of immunosuppression in low intensity conditioning may be less common than those observed in HCT for malignant indications. Nonmyeloablative approaches with low toxicities should be the focus of future research efforts. Prevention of GVHD is a shared goal in all approaches of allo-HCT in SCD.

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease.

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3 Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3 Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 109/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.

A prospective study of intravenous pentamidine for PJP prophylaxis in adult patients undergoing intensive chemotherapy or hematopoietic stem cell transplant.

Prophylaxis for Pneumocystis jirovecii pneumonia (PJP) is recommended for patients undergoing hematopoietic stem cell transplantation (HSCT) or intensive chemotherapy. Trimethoprim-sulfamethoxazole and inhaled pentamidine are used frequently, but are limited, by their tolerability and therefore compliance. Intravenous (IV) pentamidine is a potential alternative agent. Here we conducted the first prospective study of the safety and efficacy of IV pentamidine for PJP prophylaxis in adult patients undergoing HSCT or intensive chemotherapy (clinicaltrials.gov NCT02669706). Fifty patients requiring PJP prophylaxis were enrolled and received monthly IV pentamidine at 4 mg/kg (maximum 300 mg) while undergoing intensive chemotherapy or HSCT. Patients were followed for the occurrence of PJP pneumonia and for adverse events. Satisfaction was assessed using the Treatment Satisfaction Questionnaire for Medication (TSQM Version 1.4) survey. Seventeen (34%) patients experienced a grade 1 or 2 adverse event. There were no grade 3/4 events. The TSQM questionnaire indicated that the majority of patients were satisfied with the administration of IV pentamidine (n = 43, 86%, p = 0.01). There were no cases of PJP during the 24 month follow-up period. Our study illustrates the safety, feasibility, and high degree of patient satisfaction when using IV pentamidine for PJP prophylaxis.

A phase 1 trial of autologous stem cell transplantation conditioned with melphalan 200 mg/m2 and total marrow irradiation (TMI) in patients with relapsed/refractory multiple myeloma.

In this phase 1 study, we tested increasing doses of total marrow irradiation (TMI) in addition to standard intravenous melphalan at 200 mg/m2 (Mel200) in the conditioning regimen prior to autologous stem cell transplant (ASCT) for multiple myeloma (NCT02043847). Twelve patients aged 18-75 with relapsed myeloma were enrolled in the study and received Mel200 and TMI 3 Gy (n = 3), 6 Gy (n = 3), or 9 Gy (n = 6) prior to transplant. There were no grade 4 extra-hematologic toxicities and a maximum tolerated dose was not reached. Median time to neutrophil and platelet engraftment was 11 and 13 d, respectively. At day 90, 73% of patients were in CR or VGPR. Median progression free survival (PFS) was 449 d and median overall survival (OS) was 966 d. We conclude that TMI at a dose of 9 Gy can be safely combined with Mel200 in therapeutic regimens for autologous transplant. Initial clinical results will prompt a phase 2 study.