ABSTRACT
Background: The emergence of the COVID-19 pandemic saw an increased use of cryopreserved (cryo) peripheral blood (PB) grafts for allogeneic hematopoietic stem cell transplantation (HSCT). Outcomes of patients receiving either fresh or cryo grafts have yielded heterogeneous results. Herein, we retrospectively compared the outcomes of patients receiving fresh and cryo grafts at a single center.(Table Presented)Methods: Between 2019 and 2021, we reviewed data from 380 patients;167 (44%) received a fresh, and 213 (56%) received a cryo graft. Patients underwent myeloablative or nonmyeloablative HSCT from either matched or mismatched, related or unrelated donors. Cell doses were determined by number of donor cells collected and recipient weight at infusion. Engraftment, disease risk (DR) and acute GVHD were classified based on established criteria. Donor chimerism was collected at approximately day 28 and day 80 after HSCT. Unadjusted and adjusted estimates of overall survival (OS), relapse, and non-relapse mortality (NRM) as a function of time were obtained. The adjusted odds (grades III-IV acute GVHD) and the adjusted cause-specific hazard of failure (all other outcomes) were compared between the 2 groups. with the use of logistic (Figure Presented) or Cox regression, respectively. These models were adjusted for various factors known to be associated with each outcome. Result(s): The characteristics of patients between the 2 groups are shown in Table 1. There was a higher proportion of patients with high/very high DR in the fresh graft group (Table 1). Median time to neutrophil engraftment was 17 and 18 days in fresh vs. cryo, respectively. The adjusted hazard ratio (HR) of neutrophil engraftment (fresh vs. cryo) was 1.07 (95% CI, 0.86-1.34, p=0.54). Median time to platelet engraftment was 13 and 15 days, respectively, and the adjusted HR of platelet engraftment was 1.32 (1.06-1.65, p=0.01). Day 28 chimerism data were available for 272 patients (113 fresh and 159 cryo). At day 28, donor CD3 chimerism was below 50% in 5 out of 113 (4.4%) and 17 out of 159 (10.7%) patients receiving fresh and cryo grafts, respectively (p= 0.06). At day 80, 3 out of 121 (2.5%) patients in the fresh group and 4 out of 165 (2.4%) in the cryo group had CD3 chimerism below 50%. The adjusted HRs (fresh vs. cryo) for death and NRM were 0.83 (0.54-1.28, p=0.40) and 0.71 (0.38-1.33, p=0.29), respectively (Figures 1 and 2). The adjusted HR for relapse was 0.65 (0.42-0.99, p=0.05) (Figure 3). The adjusted odds ratio (fresh vs. cryo) for grades III-IV GVHD was 1.65 (0.94-2.9, p=0.07). Conclusion(s): In this single-center retrospective study we observed numerically better outcomes with fresh grafts relative to cryo grafts for all examined endpoints with the exception of grades III-IV aGVHD, although none of the differences were definitive with the possible exception of relapse and platelet engraftment. Further studies are needed to confirm our observations.Copyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Hematopoietic cell transplant (HCT) recipients are at increased risk of morbidity and mortality from COVID-19. They may have lower SARS-CoV-2-directed antibody levels due to protein loss from the gastrointestinal (GI) tract as a result of preparative regimen-related toxicity and graft-vs.-host disease (GVHD). In fact, previous studies suggested that GI GVHD or diarrhea from other etiologies were associated with a reduction in the half-life of monoclonal antibodies (mAbs). Hence, understanding the pharmacokinetic (PK) profile of mAbs targeting SARS-CoV-2 in this vulnerable population is critical for dose-selection and predicting the duration of protection against COVID-19. This analysis aims to use a population pharmacokinetics (popPK) approach to evaluate the PK of sotrovimab and the effect of covariates in HCT recipients. In a Phase I trial (COVIDMAB), all participants received 500 mg sotrovimab IV prophylactically within one week prior to starting transplant conditioning. Sotrovimab serum concentrations were determined weekly for up to 12 weeks in autologous (n=5) and allogeneic (n=15) HCT recipients (129 observations). Sotrovimb PK and the effect of covariates were analyzed using popPK modeling in NONMEM (version 7.4). GVHD and diarrhea severity data were collected weekly via survey and included as time-dependent covariates during the covariate screening process. The final PK model with covariates was validated using simulation-based validation and goodness of fit plots. PK data were compared to non-transplant patients from 1891 patients with COVID-19 in COMET-ICE, COMET-PEAK, BLAZE-4, and COMET-TAIL and 38 healthy individuals enrolled in GlaxoSmithKline Pharma Study 217653. A two-compartment model best described sotrovimab PK in HCT recipients. In comparison to non-transplant patients, sotrovimab clearance (CL) was 14.0% higher in HCT recipients. Weight was a significant covariate on sotrovimab CL and (Figure Presented) volume of distribution in the central compartment (V2). With every 10 kg increase in body weight, sotrovimab CL and V2 were estimated to increase by 9.5% and 5.5%, respectively. Diarrhea severity was also a significant covariate on sotrovimab CL. HCT recipients with grade 3 diarrhea showed an increase in CL by 1.5-fold compared to those without diarrhea. Based on popPK analyses, sotrovimab CL was higher in HCT recipients compared to non-transplant patients. Higher bodyweight as well as diarrhea resulted in increased sotrovimab CL. There were only 3 patients with GI GVHD, and larger studies are needed to determine whether diarrhea due to GI GVHD or conditioning toxicity was responsible for the observed increase in sotrovimab CL. Further validation of these findings in a larger number of HCT recipients is also warranted to help optimize mAb dosing for COVID-19 prophylaxis and determine whether presence of large-volume diarrhea may require intensified dosing strategiesCopyright © 2023 American Society for Transplantation and Cellular Therapy
ABSTRACT
Background: CD6 is a co-stimulatory receptor predominantly expressed on T cells. CD6high CD4+ T cells were recently shown to drive Th1/Th17 immune responses in inflammatory bowel disease and may have a similar role in acute graft-versus-host disease (aGHVD). The CD6 ligand, activated leukocyte cell adhesion molecule (ALCAM), is expressed on antigen presenting cells, as well as epithelial and endothelial cells of aGVHD target organs (e.g. skin, GI tract). Previous studies in patients receiving allogeneic hematopoietic cell transplants showed that ex vivo depletion of donor CD6+ T cells lowered the incidence of aGVHD, providing a rationale for therapeutically targeting CD6 in aGVHD. Itolizumab is a humanized IgG1 monoclonal antibody that binds CD6 and blocks interaction with ALCAM to inhibit T cell activity and trafficking that is being evaluated as treatment for aGVHD. Aims: Here we present interim study results from the Primary Cohort of EQUATE, an ongoing US-based Phase 1b/2 study of itolizumab in combination with steroids for newly diagnosed aGVHD. Methods: Phase 1b is an open-label, dose-escalation study evaluating doses from 0.4 to 2.4 mg/kg (IV Q2 weeks through Day 57). The Primary Cohort enrolled patients with Grade III-IV aGVHD that received itolizumab within 72 hours of first steroid dose. The Expansion Cohort also includes subjects with Grade II aGVHD and an Ann Arbor [AA] Score of 2 or 3 and who received itolizumab within 7 days of first steroid dose. Results: A total of 10 subjects in the Primary Cohort have completed treatment through Day 85: 0.4 mg/kg (n=4), 0.8 mg/kg (n=3), and 1.6 mg/ kg (n=3). Baseline characteristics were mean age of 48, 90% male, 90% white, 80% with peripheral blood graft source, 80% with HLA matched donor, mean time to GVHD onset of 43 days, and 100% with GI involvement. Mean MAGIC algorithm probability (MAP) was 0.468, and 70% had an AA score of 3. One subject in the 0.4 mg/kg cohort received only one itolizumab dose, whereas all other subjects received 2-5 doses. Across all doses, the overall response rate (ORR) was 80% at Day 29, with 70% of subjects experiencing a complete response (CR) and 10% experiencing a very good partial response (VGPR). ORR was 70% at Day 85 with 100% of responders experiencing CR (Fig 1B). Response was consistent through Day 169. MAP scores also decreased through Day 85 with a median % decrease from baseline of 18%. At Day 85, median % steroid dose reduction was 89%. Itolizumab dose-dependently decreased CD6 levels on T cells within 24 hours of first dose, which was maintained throughout the treatment period, with a more pronounced effect in the 0.8 and 1.6 mg/kg (Fig 1C). Safety profile is consistent with that of itolizumab observed to date across other trials and with adverse events (AEs) common in this patient population. All subjects experienced at least 1 AE. Most AEs were mild to moderate in severity. One mild infusion reaction AE was noted. Serious AEs were noted in 5 subjects, including recurrent gut GVHD (n=1), sepsis (n=2;1 was considered a DLT) and fever (n=1), COVID-19 (n=1) and nocardiosis (n=1), physical deconditioning (n=1), and atrial flutter (n=1). There was one death reported due to an SAE of intestinal infarction deemed not related to study drug. Another death occurred >100 days post dose due to progressive aGVHD and was also not related to study drug. Summary/Conclusion: In summary, the safety and efficacy observed to date and benefit-risk profile support continued study and evaluation in future randomized controlled trials.
ABSTRACT
Background: CD6 is a co-stimulatory receptor predominantly expressed on T cells. CD6high CD4+ T cells were recently shown to drive Th1/Th17 immune responses in inflammatory bowel disease and may have a similar role in acute graft-versus-host disease (aGHVD). The CD6 ligand, activated leukocyte cell adhesion molecule (ALCAM), is expressed on antigen presenting cells, as well as epithelial and endothelial cells of aGVHDtarget organs (e.g. skin, GI tract). Previous studies in patients receiving allogeneic hematopoietic cell transplants showed that ex vivo depletion of donor CD6+ T cells lowered the incidence of aGVHD, providing a rationale for therapeutically targeting CD6 in aGVHD. Itolizumab is a humanized IgG1 monoclonal antibody that binds CD6 and blocks interaction with ALCAM to inhibit T cell activity and trafficking that is being evaluated as treatment for aGVHD. Methods: Here we present interim study results from EQUATE (as of 2020 Nov 13), an ongoing US-based Phase 1b/2 study of itolizumab in combination with steroids for newly diagnosed severe aGVHD (Grade III-IV). Phase 1b involves an open-label, dose-escalation study evaluating doses from 0.4 to 2.4 mg/kg (IV Q2 weeks through Day 57). Results: Ten subjects have completed treatment through Day 57: 0.4 mg/kg (n=4), 0.8 mg/kg (n=3), and 1.6 mg/kg (n=3). All subjects received corticosteroids at an initial dose of 1-2 mg/kg/day. Baseline characteristics include mean age of 48, 90% male, 90% white, 80% with peripheral blood graft source, 80% with HLA matched donor, mean time to GVHD onset of 43 days, and 100% with GI involvement. Across dosing cohorts, all subjects experienced at least 1 adverse event (AE), with hypomagnesemia (n = 3) and peripheral edema (n = 3) being the most common. Most AEs were mild to moderate in severity. One mild infusion reaction AE was noted. Serious AEs that are not unexpected for severe aGVHD on systemic immune suppression were noted in 5 subjects, including recurrent GVHD (n = 1), sepsis (n = 2;1 was considered a DLT) and fever (n = 1). COVID-19 (n = 1) and disseminated nocardia (n = 1) were also reported. Across cohorts, the overall response rate (ORR;complete response [CR] + partial response [PR] + very good partial response [VGPR]) was 80% at Day 29, with 70% of subjects experiencing CR and 10% experiencing VGPR. ORR was sustained through Day 57. At Day 57, 7 subjects had tapered steroids by ≥80% (Fig 1B). Immunologically, itolizumab dose-dependently decreased CD6 levels on T cells within 24 h of first dose, which was maintained throughout the treatment period, particularly at 0.8 and 1.6 mg/kg (Fig 1C). Conclusions: In summary, the preliminary safety and high response rates of itolizumab with steroid therapy in newly diagnosed severe aGVHD is encouraging. Its early risk-benefit profile supports continued study and evaluation in future randomized controlled trials.