Abstracts of the Cell Therapy Transplant Canada 2022 Annual Conference

On behalf of Cell Therapy Transplant Canada (CTTC), we are pleased to present the Abstracts of the CTTC 2022 Annual Conference. The conference was held in-person 15–18 June 2022, in Niagara Falls, Ontario. Poster authors presented their work during a lively and engaging welcome reception on Thursday, 16 June, and oral abstract authors were featured during the oral abstract session in the afternoon on Friday, 17 June 2022. Thirty-three (33) abstracts were selected for presentation as posters and six (6) as oral presentations. The top abstracts in each of four (4) categories, (1) Basic/Translational sciences, (2) Clinical Trials/Observations, (3) Laboratory/Quality, and (4) Pharmacy/Nursing/Other Transplant Support, received awards for both the oral and poster presentations. All of these were marked as “Award Recipient” with the relevant category. We congratulate all the presenters on their research and contribution to the field.

. Evaluation of CD56 bright CD16 − NK reg cell ability to suppress CD4 + T cell proliferation. The graph is representative of the results of five experiments using cells derived from five healthy donors for the NK cell suppression assays, and two experiments using cells derived from two healthy donors for the T reg cell suppression assay. The error bars are indicative of standard deviation, and the brackets are indicative of significant differences in suppression between the three different cell groups at all ratios tested (p < 0.05 = *, p < 0.0005 = ***). The graph directly compares the suppressive capacity of CD56 bright CD16 − NK reg cells, CD56 dim CD16 + NK cells, and T reg cells towards allogeneic CD4 + T cell proliferation at the 1:1, 1:2, 1:4, and 1:8 ratios as compared to the activated CD4 + T cells. The CD4 + T cell division index is scaled to 100% for calculation purposes, with all other condition indices scaled accordingly. This calculation was completed using the following standard formula: percentage of suppression = 1 − (division index of responder cells cultured with suppressor cells/division index of responder cells cultured without suppressor cells) × 100%.

Figure 2.
Evaluation of cell-to-cell contact dependence for CD56 bright CD16 − NK reg cell suppression. The graph is representative of the results of five different experiments using cells derived from five different donors. The error bars are indicative of standard deviation, and the brackets are indicative of significant differences in the suppressive capacity of NK reg cells co-cultured with CD4 + T cells in a standard plate or a transwell plate as compared to the CD4 + T cell control (p < 0.0005 = ***, NS = not significant). The graph directly compares the suppressive capacity of the CD56 bright CD16 − NK reg cells towards allogeneic CD4 + T cells in a standard 96-well plate versus in a transwell 96-well plate. once by day + 60. Secondary outcomes of OS, overall GvHD, GI GvHD and high-moderate TMA were evaluated using Cox regression analysis. Due to sample availability, subgroup analysis was performed on 108 consecutive patients by investigating their day + 30 plasma levels of IL-22, IL-22BP, and Reg3a via ELISA. Results: Fifty-seven of the 232 (25%) of the patients were AdV+ with their patient demographics ( Figure 1). The median day with range of adenovirus onset, GI GvHD and TMA were 19 (0-60), 24 (0-1856), and 34 (13-261) days, respectively. OS and aGvHD were not impacted by AdV reactivation with HR 1.21 (0.66-2.24), p = 0.539 and HR 1.14 (0.68-1.93), p = 0.620. However, acute GI GvHD and moderate-high degree of TMA were increased in the AdV+ population, HR 1.65 (1.03-2.66, p = 0.037) and HR 1.84 (1.09-3.10), p = 0.022, respectively. In the subset of patients who had biomarker evaluation at day + 30, IL-22 and Reg3a were elevated in the AdV+ cohort, (p = 0.021 and 0.004, respectively) and modestly positively correlated with each other (r = 0.17, p = 0.093). IL22-BP was significantly decreased in the AdV+ population, p = 0.012 (Figure 2). Conclusions: Our analysis suggests that early AdV reactivation initiates a cascade of localized GI inflammation, which is shown by evidence of elevated IL-22 and Reg3a, and reciprocal reduction of IL-22BP, triggering a proinflammatory state ( Figure 3). The GI inflammation likely increases the presence of inflammatory T cells and contributes to the increased risk for acute GI GvHD. GI inflammation leading to systemic AdV pathogenesis can plausibly contribute to a rise in cytokines and interferon levels driving TMA, as has been shown with BK virus. Our data offer a comprehensive explanation of the adverse impact early AdV reactivation.   Hypoxic Ischemic Encephalopathy (HIE) is the leading cause of acquired neonatal brain injury. In this condition, the lack of oxygen to the brain around the time of birth results in a phase of primary energy failure marked by apoptosis and neuronal death. Following this initial phase, reperfusion activates the microglia and a potent inflammatory cascade. This secondary energy failure due to inflammation is responsible for the majority of neuronal cell death and is, therefore, a target for intervention. Immature myeloid cells that expand in inflammatory conditions can exert a profound anti-inflammatory response and may be harnessed to minimize the second phase of neuronal cell death. This pilot study measured circulating hematopoietic stem/progenitor cells (HSPC) and innate immune regulatory cells (G-MDSCs, M-MDSCs, Tregs) in the first three days of life by flow cytometry to establish the number of circulating HSPCs and immunosuppressive cells. An initial analysis of 60 newborn infants treated for a range of disorders demonstrated a decline in circulating CD34 + cells with age, ranging from 1-2% in cord blood (birth sample) to 0.05% by 10 h of life as HSPCs home to the bone marrow. Granulocytic myeloidderived suppressor cells (G-MDSCs) (CD15 + HLADR − , LOX-1 + ) follow a less pronounced decline over time averaging 1871 G-MDSCs/µl of blood in the first 24 h of life compared to 866 G-MDSCs/µL of blood by three days of age. Interestingly, this population appears to be larger in infants with HIE (red points) compared to non-HIE infants. In contrast, both monocytic myeloid-derived suppressor cells (M-MDSCs) (CD14 + , HLADR − ) and T-regulatory cells (Tregs) (CD25 + , CD127 − ) circulate in lower ranges and remain stable over time consisting of 3.47-1079 MDSCs/µL and 8.34-234 Tregs/µL. This data establishes a baseline of circulating HSPCs and immunosuppressive populations in the first three days of life. In the next phase of this project, samples will be collected and analyzed exclusively from infants with severe HIE over several time points to establish ranges in this patient population compared to controls. Overall, this data provides preliminary information for a prospective clinical trial with the objective of harnessing host immune modulating cells for potential use as immunotherapy for infants with HIE.
Introduction: Hematopoietic stem cell transplant (HSCT) is a life-saving procedure used to restore hematopoiesis in patients having undergone high-dose myeloablative chemotherapy. Current standard of care dosing of hematopoietic progenitors is based on the count of CD34 + cells/kg, in general administering a minimum of 2.5 million CD34 + cells/kg for growth factor-mobilized products. However, CD34 is expressed on a range of hematopoietic stem/progenitor cells (HSPC) which have variable stemness and repopulation capacity. The objective of this study is to assess the quality and quantity of CD34 + cell populations present in autologous versus healthy allogeneic hematopoietic stem cell sources to further understand the determinants of HSCT outcomes, with the hope of improving engraftment and hematopoietic recovery post-transplant. Methods: CD34 + HSPC from previously cryopreserved G-CSF mobilized autologous and allogeneic HSPC products and cord blood were positively selected for CD34 + cells and then analyzed by flow cytometry using an 8-antibody CD34 hierarchy panel to characterize early hematopoietic progenitor populations within the grafts. Results: Analysis of grafts prior to CD34 isolation revealed significant differences in CD34 + content of the pediatric autologous, allogeneic, and cord blood stem cell products. The proportion of CD34 + cells in autologous grafts (mean 20.8%; range 5-41.3%) was significantly higher than in cord blood (0.7%; 0.15-1.3%) and grafts collected from healthy donors after G-CSF mobilization (2.3%; 0.8-3%). Next, we analyzed the hierarchy of the CD34 + selected cells. Long-term hematopoietic stem cells (LT-HSC, defined as CD34 + CD38 − CD90 + CD45RA − CD49f + ) repopulate the bone marrow and initiate longterm hematopoietic reconstitution. This subset was a minor subpopulation of all CD34 + cells but varied between the grafts. The proportion of LT-HSC was highest in cord blood (1.5% of CD34 + cells; 1.02-2.14%) compared to allogeneic healthy donors (0.8%, 0.3-1.3%) and autologous donors (0.6%, 0.06-0.9%). Of note, the autologous transplant donors were collected on count recovery following both chemotherapy and G-CSF mobilization. Additionally, we observe significant differences in other CD34 + populations, including granulocyte/monocyte and megakaryocyte/erythroid progenitors. Conclusions: CD34 + graft content varies depending on HSC source, with autologous mobilized products containing a much higher proportion of CD34 + cells. Grafts with high CD34 content have fewer non-hematopoietic cells in the treatment dose which can potentially impact immunologic recovery post-HSCT. In addition, analysis of the CD34 + hematopoietic hierarchy shows that most CD34 + cells are committed progenitor cells with limited repopulation potential and myeloid skewing. Moreover, pediatric autologous grafts have the lowest content LT-HSC which provide life-long hematopoiesis. Background: Using EBMT registry data, the DRSS has been proposed to predict relapse risk after allogeneic hematopoietic cell transplantation (HCT) across disease subtypes and remission states ordered in 55 categories and 5 risk levels [1]. For acute myeloid leukemia (AML) the DRSS combines ELN risk group, remission rank, and de novo vs. secondary AML in 19 categories and for myelodysplastic syndrome (MDS) it includes 5 categories. Purpose: We sought to determine the reproducibility of the DRSS in a cohort of subjects transplanted for AML or MDS. Methods: Data from a single-center cohort of consecutive adult AML & MDS patients transplanted between 1 July 2015 and 30 June 2020 was analyzed retrospectively. Baseline characteristics and outcomes were extracted, and Fine-Gray regression was used to determine the association between cumulative incidence of relapse (CIR) and patient, disease, and transplant characteristics. Model selection techniques were used to select the least number of significant predictors of CIR. Results: In this cohort of 134 patients, median follow-up was 2.7 and CIR was 26 % at 4 years (95% confidence interval: 18-35). DRSS was independently associated with CIR after adjustment for several covariates: patient age > 60 years, donor type, regimen intensity, secondary disease, and graft source. DRSS was divided into 3 groups with CIR at 4 years of 18% (95%CI: 8-30) for low risk, 32% (CI: 19-46) for intermediate 1 and 2 risks, and 40% (CI: 17-63) for high and very high-risk groups. Univariate graphic representation of CIR according to DRSS is shown in Figure 1.

Conclusions:
In adults with AML and MDS, cumulative incidence of relapse after allogeneic HCT can be predicted by DRSS across all donor types and age groups. DRSS is a useful tool for the assessment of disease relapse risk in clinical studies, validated for AML and MDS patients.  Background: The association between donor age (DA) and allogeneic hematopoietic cell transplantation (HCT) outcomes is controversial. Purpose: We sought to determine the association between DA and the incidence of nonrelapse mortality (NRM) in adult acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients treated with HCT Methods: Data from a single-center cohort of adult AML and MDS patients consecutively transplanted (1st HCT) between 1 July 2015 and 30 June 2020 was analyzed retrospectively. Baseline characteristics[ia2] and outcomes were extracted, and cumulative incidence CI of NRM (CI-NRM) was estimated using death before relapse as competing risk. Fine-Gray multivariate models and model selection techniques were used to determine the association between DA and cumulative incidences (CIR) of NRM and GVHD. Confounding variables included were age-adjusted HCT comorbidity index (aaHCT-CI), Karnofsky performance score (KPS), donor type, conditioning intensity, cytomegalovirus (CMV) status in recipient and gender mismatch. Results: Pre-HCT patient characteristics (n = 134) are presented. Median follow-up was 2.7 years, CI-NRM was 18% at 5 years from HCT (95% confidence interval (CI): 10-29) and survival at 5 years was 61% (CI: 48-72). DA was independently associated with CI-NRM (hazard ratio (HR) at 50 years 3.43, p = 0.01; at 60 years 3.98, p = 0.02). The HR for NRM increased with DA reaching statistical significance at 50 years ( Figure 1a). The only other statistically significant variable independently associated with NRM was aaHCT-CI (HR 1.90, p = 0.04). No association was found between DA and incidences of graft-versus-host disease (GVHD). Conclusions: A donor ≥ 50 years of age for patients transplanted for AML or MDS increases the risk of NRM. The pathological mechanisms responsible for this association remain to be elucidated and do not seem to be mediated by GVH. Background: The standard of care (SOC) treatment (Tx) in the curative setting for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after 1st-line (1L) chemoimmunotherapy (CIT) is high-dose therapy with autologous stem cell rescue (HDT-ASCT) if responsive to 2nd-line (2L) CIT; however, as many pts do not respond to or cannot tolerate 2L CIT, outcomes remain poor. Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for R/R LBCL after ≥2 prior systemic therapies. Purpose: To report the results of the primary analysis of ZUMA-7, a global, randomized, Phase 3 trial of axi-cel vs. SOC in patients with 2L R/R LBCL. Methods: Eligible pts ≥ 18 y with LBCL, refractory to or relapsed ≤12 mo of 1L CIT were randomized 1:1 to axi-cel or SOC (2-3 cycles of an investigator-selected, protocol defined, platinum-based CIT regimen followed by HDC-ASCT if CIT-responsive). Although there was no planned trial crossover between arms, pts not responding to SOC could receive CAR T-cell therapy off protocol. The primary endpoint was event-free survival (EFS: time to earliest date of disease progression, death from any cause, or new lymphoma Tx) by blinded central review. Key secondary endpoints, tested hierarchically, were objective response rate (ORR) and overall survival (OS; interim analysis); safety was also a secondary endpoint.  Purpose: To present the patient-reported outcomes (PROs) from ZUMA-7, a Phase 3, randomized, multicenter study comparing axi-cel (an autologous anti-CD19 chimeric antigen receptor [CAR] T-cell therapy) versus SOC as second-line treatment in relapsed/refractory LBCL. Methods: PRO instruments, including the EORTC QLQ-C30 (cancer-specific 30-item questionnaire including global health status, functional, and symptom scales) and the EQ-5D-5L (a general questionnaire with 5 QoL domains plus a global assessment), were administered at baseline (prior to treatment), Day 50, Day 100, Day 150, Month 9, and every 3 months from randomization up to 24 months or time of event-free survival event (disease progression, death from any cause, or new lymphoma therapy), whichever occurred first. The QoL analysis set was defined as all patients who had a baseline PRO and ≥1 measure completed at Day 50, Day 100, or Day 150. Prespecified hypotheses for 3 PRO domains (EORTC QLQ-C30 Physical Functioning, EORTC QLQ-C30 Global Health Status/QoL, and EQ-5D-5L visual analog scale [VAS]) were tested. False discovery rate adjusted the P values across key endpoints; sensitivity analyses controlled for covariates and patterns of missingness. A clinically meaningful change was defined as 10 points for each EORTC QLQ-C30 score and 7 points for EQ-5D-5L VAS score. Exploratory analyses on other domains of EORTC QLQ-C30 and EQ-5D-5L were also performed. Results: Of 359 patients enrolled in the ZUMA-7 study, 296 patients (165 axi-cel, 131 SOC) were included for analysis. There was a statistically significant (p < 0.0001) and clinically meaningful difference in mean change of scores from baseline at Day 100 in favor of axi-cel on all prespecified PRO domains ( Figure 1). Furthermore, scores also significantly favored axi-cel over SOC for EORTC QLQ-C30 Global Health Status/QoL (p = 0.0124) and EQ-5D-5L VAS (p = 0.0004) at Day 150. For the pre-specified endpoints, the mean estimated scores for the axi-cel arm had numerically returned to or exceeded scores at baseline by Day 150 versus on or after Month 9 for the SOC arm. After Month 9, attrition (e.g., an EFS event) in the QoL analysis set was substantial, particularly in the SOC arm. Additional exploratory analyses of PRO endpoints on other domains of EORTC QLQ-C30 and EQ-5D-5L also showed improvements with axi-cel over SOC. Conclusions: PROs from ZUMA-7 showed that treatment with axi-cel results in clinically meaningful improvement in QoL over SOC at Day 100 as measured by multiple validated PRO instruments. The data also suggest faster recovery to pretreatment QoL with axi-cel compared with SOC. Background: ELARA is an ongoing, single-arm, global, multicenter, phase II trial evaluating efficacy and safety of tisagenlecleucel (tisacel) in adult patients (pts) with relapsed/refractory follicular lymphoma (r/r FL). Tisacel demonstrated high response rates in pts with relapsed/refractory follicular lymphoma (r/r FL), with overall response rate (ORR) of 86% and complete response rate (CRR) of 66%. As ELARA did not include a comparator, an adjusted indirect treatment comparison (ITC) using patient-level data from a global retrospective cohort study was conducted. Purpose: This study aimed to compare efficacy outcomes of tisacel from ELARA relative to standard of care (SOC). Methods: As of 29 March 2021, 98 pts were enrolled in ELARA with a median follow-up of 15 months (M). SOC data were obtained from ReCORD-FL, a global retrospective cohort study of clinical outcomes in pts with r/r FL meeting the ELARA eligibility criteria who were treated per SOC at 10 academic centers in North America and Europe. In ReCORD-FL, 187 pts with ≥2 prior lines of treatment were included with a median follow-up from third line of 57 M. A case comparison analysis was performed for 97 ELARA apheresed pts and 143 ReCORD-FL pts using propensity score modelling and an adjusted ITC was performed to assess the effect of tisacel versus SOC by measuring CRR, ORR, progression-free survival (PFS), overall survival (OS), and time to next treatment (TTNT). A subgroup analysis of SOC pts with ≥1 eligible LoT initiated from 2014 (coinciding with the introduction of the Lugano response criteria and regulatory approval of idelalisib) was performed for all endpoints. Results: Baseline characteristics ( Figure 1) were well balanced after weighting. Treatment regimens observed for ReCORD-FL pts were: anti-CD20 antibody (Ab) plus alkylator (31.5% of pts), anti-CD20 Ab without alkylator (25.9%), alkylator without anti-CD20 Ab (17.5%), and regimens other than anti-CD20 Ab and alkylator (25.2%). After adjusting for differences in baseline variables, tisacel was associated with improvement over SOC in CRR (69.1% vs. 37.3%), ORR (85.6% vs. 63.6%), PFS, TTNT and OS (Figure 2), with a numerically higher 6 M PFS rate vs. SOC (85.3% vs. 66.5%), and higher 24 M OS rate (87.8% vs. 64.8%). There was an estimated 80% reduction in risk of death, 40% reduction in risk of progression for tisacel over SOC, and a 69% reduction in risk of death or requiring a new anticancer therapy ( Figure 1). In the sub-analysis of SOC pts with lines of therapy initiated in or after 2014, the superiority of tisacel over SOC was confirmed in all efficacy outcomes (CRR: 69.1% vs. 30.5%; ORR: 85.6% vs. 58.8%; hazard ratios substantially < 1 for OS, PFS, TTNT). Conclusions: These results suggest that tisacel has superior efficacy over SOC in r/r FL for all evaluated endpoints. Moreover, outcome parameters independent of response criteria (OS, TTNT) were also significantly better for tisacel vs. SOC.  developing IFIs. The results were analyzed, focusing on the HM agents that have been approved in the last ten years. Results: Of the participants, the majority (67%) practice in hematology (physicians and pharmacists), but all respondents' specialties are involved in IFI management. Across Canada, the perception is that candidiasis is the most commonly seen IFI, followed by aspergillosis and mucormycosis. Fluconazole, voriconazole, and posaconazole are among the most commonly used antifungals in these centres, with voriconazole identified by most (83%) as a drug requiring therapeutic drug monitoring. Posaconazole is the most frequently used prophylactic antifungal (61%) in acute myeloid leukemia (AML) patients, while fluconazole is the most frequently used agent in allogeneic or autologous stem cell transplant recipients and acute lymphoblastic leukemia (ALL) patients. In their respective centres, respondents can access hematological agents not included in protocols close to 90% of the time. Among the recently approved HM therapies, more than 50% of respondents reported "commonly" using gilteritinib, ibrutinib, midostaurin, ruxolitinib, blinatumomab, brentuximab, and venetoclax. Of these agents, venetoclax and ibrutinib were identified by at least 50% of the respondents as associated with an elevated incidence of IFI. Ninety-four percent of respondents consult their pharmacists to predict DDI, and the most common (94%) technique to manage DDI is to empirically adjust doses. Conclusions: This initial data set shows substantial variability in the usage of hematological and antifungal agents, therapeutic monitoring of agents, and perceived infection risk of new HM agents among Canadian Centres. Expanding the scope of this survey to include more sites would ensure greater reliability and validity to the observations and support the development of consensus recommendations around managing specific DDI when treating fungal infections in high-risk hematological patients.   T cells were selected, activated, transduced, and expanded using a GMP compliant semi-automated, closed process using the Miltenyi Prodigy. Final CLIC-1901 product was tested for identity, potency, purity, and sterility, and only infused if release criteria met. Participants underwent lymphodepletion with fludarabine (40 mg/m 2 /d × 3) and cyclophosphamide (500 mg/m 2 /d × 2), prior to infusion of >1 × 10 6 CAR expressing cells per kilogram of body weight (maximum 2 × 10 8 total CAR expressing cells) non-cryopreserved CLIC-1901. Results: Of 48 patients screened for eligibility, 35 were enrolled. 5 enrolled participants did not receive CLIC-1901 due to manufacturing failures early after protocol launch (n = 2, resolved with first protocol amendment), severe myocarditis before lymphodepletion (n = 1), and death before infusion (n = 2). 30 participants received CLIC-1901 CAR-T therapy: 21 males (70%), median age 66 (range 18-75). The median number of prior therapies was 3 (range 2-6). 13 (43%) patients had failed a stem cell transplant (allogeneic (n = 5), autologous (n = 6), both (n = 2)). The disease indication was DLBCL (n = 10), MCL (n = 8), transformed DLBCL (n = 4), ALL (n = 5), follicular lymphoma (n = 1), Richter's transformation (n = 1) and plasmablastic lymphoma (n = 1). The time from enrollment to CLIC-1901 infusion was a median of 20 days (range 15-48). The median CLIC-1901 dose infused was 2.3 × 10 6 CAR-T cells/kg (range 1.3 × 10 5 -3.6 × 10 6 /kg). Toxicity included CRS (grade 1 n = 9, grade 2 n = 7, grade 3 n = 1, and grade 5 n = 1), at median onset of 1.5 days after CLIC-1901 infusion (range 0-9 days). ICANS occurred in 2 participants (grade 2 n = 1, and grade 4 n = 1). At a median follow-up of 4 months (IQR 4-7), the median progression-free survival was 5 months (95% CI 4-not estimable). Figure 1 shows patient level data.
Conclusions: At a starting dose of 1.2 mg/m 2 /cycle, InO showed acceptable efficacy, with half of pts achieving remission and >70% of those being MRD negative. No new safety signals were identified. The study is proceeding to the randomized phase (N = 91 as of July 2021).  First report of HLH in the context of STK4 deficiency, a rare genetic, combined B and T cell immunodeficiency.
Methods: Case Report.

Results:
The patient is a 22-year-old Syrian-Canadian male with homozygous frameshift STK4 mutations (NM_006282:exon9:c.1103delT:p.M368fs); his parents are both heterozygous carriers. Complications related to his immunodeficiency include ITP, eczema, corneal erosions, recurrent mouth sores, and HPV warts. In 2018, he was diagnosed with diffuse large B-cell lymphoma (DLBCL) based on a biopsy of liver lesions. He was treated with 6 cycles of R-CHOP followed by a PET scan showing complete metabolic response. In 2020, he was diagnosed with relapsed DLBCL and was treated with salvage chemotherapy with evidence of remission. After a discussion involving the immunology, lymphoma, and transplant teams, he underwent an allogeneic HSCT in June 2020 as a potentially curative option for both his relapsed lymphoma and primary immunodeficiency. The donor was his sister, who was a carrier of the heterozygous STK4 mutation. Post-HSCT complications included biopsy-proven GVHD of the gut in June 2020 and of the skin in January 2021 as well as CMV and adenovirus infections.
He was re-admitted in September 2021 with fever and maculopapular rash involving bilateral hands and feet. Extensive workup did not reveal any signs of underlying infectious etiology, recurrence of lymphoma, or marrow graft failure. He met diagnostic criteria for HLH including fever, significantly elevated ferritin (peak value 243,000 ug/L), elevated triglycerides, presence of hemophagocytes in bone marrow aspirate, and reduced NK cell degranulation activity. Therapy for HLH was initiated with dexamethasone followed by the addition of Anakinra and Ruxolitinib. He experienced clinical remission and improvement in lab parameters including the normalization of CRP and down-trending of ferritin.
Conclusions: This case illustrates the need to consider HLH as a differential in allogeneic HSCT recipients presenting with febrile illness of unclear etiology. Screening for HLH using serum ferritin would be particularly important in those patients with underlying immunodeficiency and/or prior histories of GVHD, CMV or other viral reactivation. Timely recognition and therapy initiation for HLH would be important given its associated high mortality.

Abstract 18 (Poster): Bortezomib Maintenance after Upfront Allogeneic Transplantation in Young or High-Risk Myeloma Patients Leads to Less Chronic GVHD and Immunosuppression
Jean-Sébastien Claveau 1,2 , Richard LeBlanc 2 , Imran Ahmad 2 , Jean-Sébastien Delisle 2 , Nadia M. Bambace 2 , Léa Bernard 2 , Sandra Cohen 2 , Thomas Kiss 2 , Sylvie Lachance 2 , Denis Claude Roy 2 , Guy Sauvageau 2 , Olivier Veilleux 2 and Jean Roy 2 Background: Allogeneic (allo) hematopoietic cell transplant (HCT) has curative potential in myeloma (MM) but remains hampered by high rates of relapse and chronic (c) GVHD. In a recent prospective phase II study in young or high-risk newly diagnosed MM using bortezomib (BTZ) maintenance after tandem auto/allo HCT targeted at decreasing relapse (LeBlanc R, BMT 2021), we observed a 20% lower incidence of cGVHD compared to our historical cohort (Ahmad I, BMT 2016). Purpose: We sought to further explore the impact of BTZ maintenance on the incidence and severity of cGVHD in patients who received maintenance or not. Methods: Using 2015 NIH criteria, we retrospectively reviewed the incidence and organ distribution of cGVHD and duration of systemic immunosuppression in patients receiving BTZ 1.3 mg/m 2 once every 2 weeks for one year after allo HCT or not. After auto HCT, MM patients from both cohorts received an outpatient nonmyeloablative conditioning followed by G-CSF mobilized donor stem cells. GVHD prophylaxis consisted of mycophenolate mofetil and tacrolimus weaned by D + 100 (sibling donors) or D + 180 (unrelated donors). Cumulative incidences of cGVHD were estimated using competing-risk methods.  Figure 1) were significantly lower in BTZ recipients. In univariate analysis, overall mouth (56% vs. 79%, p = 0.026), skin (34% vs. 56%, p = 0.041) and liver (32% vs. 54%, p = 0.039) involvement were less frequent in BTZ patients. The cumulative incidence of prednisone initiation at 5 years was 42.2% in BTZ and 78.3% in no BTZ recipients (p < 0.001). The cumulative incidence of tacrolimus resumption at 5 years was also lower in BTZ than in controls (30.1% vs. 73.6%, p < 0.001). Probability of being alive and off systemic immunosuppressants at 3 years were 73% for BTZ patients vs. 42% for controls (p < 0.001, Figure 2   To provide a more homogenous cohort, this analysis was restricted to patients undergoing transplant for acute myeloid leukemia (AML). Results: Thirty-four patients were accrued in the prospective cohort, with diagnoses of acute myeloid leukemia (n = 24), acute lymphoblastic leukemia (n = 7), or myelodysplastic syndrome (n = 3). The median age was 55 years (range 10-70). Of these, 52% were men, with a median KPS of 90 (range 80-100). The median HCT-CI was 0, with 4 patients having a HCT-CI of greater than 3. The protocol was well tolerated, with a cumulative incidence of non-relapse mortality of 19% at 2 years and 1 case of veno-occlusive disease (which resolved with therapy). The cumulative incidence of relapse at 2 years was 22%. The incidence of grade III/IV acute GVHD was 6%, and chronic extensive GVHD was 29%. Overall survival at 2 years was 63%. Based on the success of this protocol, it was adapted as the standard for patients undergoing haploidentical transplant at these centres, and an additional 20 patients with AML were transplanted. These 44 patients with AML (24 on the original study, 20 in the expansion cohort) were compared to 128 MSD transplants and 267 MUD transplants done with similar transplant characteristics (AML, MAC Flu/Bu, and PBSC), with data obtained from the CTTC registry. In multivariate analysis, adjusting for age, HCT-CI, KPS, and disease risk (by ELN), no difference in overall survival (OS), disease free survival (DFS), relapse rate, or non-relapse mortality was found between donor sources ( Figure 1). Older age was a predictor of inferior DFS and NRM, HCT-CI was associated with NRM, and high-risk disease was associated with a higher relapse rate.

Conclusions:
The use of PBSCs from haploidentical donors with MAC appears to be safe and effective, with outcomes comparable to MSD and MUDs, and low rates of acute and chronic GVHD. The feasibility of this combination provides further evidence supporting the use of haploidentical donors outside the previously studied RIC/BM setting.   Investigations-Neurological-MR of brain and spine were normal. There was striking enhancement of the cauda equine nerve roots in the post contrast phase and the nerve roots appeared thickened. CSF revealed high protein 1.62 g/L and normal WBC 2X10E6/l, negative on viral and infection screen. Nerve conduction demonstrated prolonged tibial and peroneal motor distal latencies. Hematological (lowest counts): Hb 119 g/L, WBC 6.0 × 10 9 /L, neutrophils 4.8 × 10 9 /L and platelets 10 × 10 9 /L, Bone marrow biopsy was normocellular with unremarkable morphology. Chimerism CD3 94.9% donor and CD 98.7% donor A diagnosis of GBS with Immune Thrombocytopenia post vaccination was made. Treatment -She was treated with IVIG 1 gm/kg for 2 days. Her platelets started rising in 1 day, were 114 in 4 days and reached a peak of 221 in 14 days. There was gradual improvement of the weakness, and the patient could walk unsupported in 3 to 4 days. After two weeks of the IVIG treatment, there was recurrence of lower limb weakness, with inability to stand and walk unsupported. A second course of IVIG was administered with gradual improvement starting within 4 days. Repeated nerve conduction studies showed gradual improvement. The possible trigger for this clinical presentation was the vaccination. Aim: To share our experience of this rare complication of simultaneous GBS and Immune thrombocytopenia with a short review of literature. Vaccinations are standard-of-care after HCT but can result in immunological complications. IVIG can lead to rapid improvement.

Abstract 20 (Poster): Respiratory Viral Illnesses Reduction in Outpatient Stem Cell Transplant Recipients during the COVID-19 Pandemic
Background: Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). However, the curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Risk factors for relapse include minimal residual disease (MRD) before or after allogeneic transplantation, patients transplanted in second complete remission or beyond, and reduced intensity conditioning (RIC) regimens. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. After relapse, the options for disease control are limited and overall survival rates are poor. Currently, there are no standard post-transplant therapy for patients with ALL to reduce the likelihood of relapse. Post alloHCT maintenance approaches may provide time for the graft-versusleukemia effect to develop, while possibly treating minimal-residual disease, prolonging leukemia-free-survival and decreasing relapse rates. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. INO has also been used in patients with relapsed/refractory ALL in a phase 3 randomized clinical trial with an overall CR rate of 81% in the INO arm compared to 29% in the standard arm. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. Once the appropriate dose has been found, the study will expand to a phase II.  The predictive ability for OS of the HCT Frailty Scale was found to be higher than the predictive ability of HCT-CI score and KPS (Harrel's Concordance Index: 60.0% vs. 54.5% and 52.8%, respectively).

Conclusions:
The HCT Frailty Scale has been specifically designed to be applied in routine clinical practice to assess adult candidates for alloHCT across all ages. This innovative frailty scale is calculated as the weighted sum of values of eight domains and is a valuable predictive tool when evaluated at the first consultation. The use of this scale can identify frail and pre-frail patients prior to alloHCT.
Background: Chronic graft versus host disease (cGvHD) is a major cause of non-relapse mortality in hematopoietic stem cell transplantation (HSCT) patients. The CARE Trial (Continuous Alloreactive T Cell Depletion and Regulatory T Cell Expansion for the Treatment of Steroid-Refractory or Dependent Chronic GvHD) was a Multicentre Phase II clinical trial through the CTTC network. The trial evaluated in patients with steroid refractory cGvHD an alternative approach to extracorporeal photopheresis (ECP) with TH9402-based photodynamic therapy (TH-PDT), a new type of phototherapy that does not involve frequent apheresis sponsored by the Canadian Donation and Transplantation Research Program (CDTRP) of which CTTC was a collaborator. A primary mechanism for TH-PDT therapy was hypothesized to work by increasing Tregs in vivo although CD56 Bright NK cells, for example, have been shown to be associated with a response in ECP (Iniesta et al., 2018) in effect to ECP. Other immune cellular mechanisms are also well described in cGvHD including populations of naïve and autoimmune B cells, naïve T cells, and CD56 bright NK cell populations.
understand the extent to which the pandemic has impacted demand and usage of unrelated donors and cord blood units at Canadian Blood Services. Methods: Data regarding stem cell donor interest and product usage for unrelated allogeneic hematopoietic cell transplantation was retrieved from the database at Canadian Blood Services using de-identified anonymous information. Results: Unrelated donor searches for Canadian patients remained unchanged by the pandemic, reflecting stable demand. The number of unrelated allogeneic transplants performed within Canada also remained stable while the number of cord blood transplants increased, chiefly for pediatric patients. Requests for donor verification typing, a first signal of potential interest, increased from domestic centres during the first 6 months of the pandemic and decreased from international centres, before returning to baseline levels.
The proportion of transplants for Canadian patients that used stem cell products procured from Canadian donors increased between 3-6 months after the start of the pandemic before returning to baseline and appears to be increasing again more than 1 year after the start of the pandemic. Use of cord blood units for Canadian pediatric patients increased and remains elevated. Purpose: To describe the experience in manufacturing and supplying commercial axi-cel lots to patients treated in Canada. Methods: Fresh apheresis materials were collected from patients intended to receive commercial axi-cel at authorized treatment centres (ATCs) in Canada and shipped to El Segundo, CA, United States for manufacturing. If additional apheresis was needed for remanufacturing, the first apheresis date was considered for each patient, and is subsequently referred to as that patient's lot. The finished product lot remained at the manufacturing facility until Quality Assurance (QA) release as per Health Canada's Good Manufacturing Practice requirements and was then shipped to the ATC, under direct QA import monitoring. This analysis includes 2 years of experience from the date of the first patient who was apheresed to receive commercial axi-cel. Results: From first apheresis after marketing authorization, 7 November 2019, until 5 November 2021, 92 patients were registered on the Kite Konnect ® website and provided apheresis material for axi-cel manufacturing. The median time (Q1, Q3) from apheresis to QA release was 18 days (17, 18), with a range of 17-57 days. The median time (Q1, Q3) from apheresis to finished product delivery was 21 days (21, 23), with a range of 19-60 days.
Among the 92 patients who underwent apheresis, 91 axi-cel lots (99%) were released, which included 90 commercial lots (99%) released by QA and 1 lot (1.1%) that was out of specification (OOS). The OOS lot was released based on a risk/benefit assessment according to Health Canada's Biologics Lot Release Program. One lot (1.1%) was cancelled by the ATC prior to release. Among released lots, 90 lots (99%) were delivered to ATCs, with one lot (1.1%) cancelled by the ATC after QA release but prior to shipment. Remanufacturing was required either from excess frozen PBMCs for 1 lot (1.1%) or from a new apheresis for 1 lot (1.1%), the latter representing the longest apheresis to delivery time of 60 days. In both cases remanufacturing yielded product that met product specifications.

Conclusions:
The early experience in manufacturing commercial axi-cel for patients treated in Canada shows high manufacturing success, with a reliable time from apheresis to product delivery (median, 21 days) and a very low percentage (1.1%) of out of specification lots. patients on Day + 15. With all the above three measures, the capacity for ASCT in our institution increased by 22.5% during the study period. Conclusions: Increase in the capacity for ASCT by decreasing the LOS by outpatient conditioning chemotherapy and Early discharge on Day + 15, is possible and feasible in the QI framework. This is an ongoing project at the time of abstract submission and the full outcome of this study would be presented in detail at the CTTC conference.      (Figure 1).

Conclusions:
The ID matrix is a living document that allows users to gauge the significance of established and emerging/re-emerging pathogens throughout the process of donor selection, collection, processing, and transplantation. Constant review of this document will allow for real-time addition of new pathogens. Next steps are to evaluate the impact of the ID matrix by surveying internal and external stakeholders about its utility in the regulatory and clinical settings. Canadian guidelines advise that live vaccines should be administered after at least two years post-HSCT, yet many HSCT recipients are not eligible for re-vaccination due to medication contraindications at this time. Purpose: We aimed to assess Measles Mumps and Rubella (MMR) reactivity in autologous HSCT recipients and eligibility for live vaccine administration at two years post-HSCT in those who required MMR revaccination to inform current guidelines on post-HSCT vaccination. Methods: We completed a retrospective chart review of 69 autologous HSCT recipients at the Windsor Regional Cancer Center transplanted from June 2016 to January 2020 to assess post-transplant MMR reactivity. In those without reactivity or with indeterminate status, we assessed eligibility for revaccination based on administration of contraindicated medications at two years post-HSCT, as stated in the most recent Canadian Immunization Guidelines. Results: The most common indication for autologous HSCT was multiple myeloma, with 68% of patients having this diagnosis. Of those with post-HSCT MMR reactivity assessments (n = 58), 55%, 72%, and 48% had non-reactive or indeterminate status to measles, mumps, or rubella, respectively. While 67% were reactive to at least one of the three, only 10% of these patients were fully reactive to MMR. Of living patients who required revaccination at 2 years post-HSCT (n = 47), 47% were on a contraindicated medication with the most common medications being dexamethasone or prednisone (23%), bortezomib (8.5%) and carfilzomib (8.5%).

Conclusions:
The majority of autologous HSCT recipients lack MMR reactivity post-HSCT and require revaccination, however many recipients are not eligible for revaccination based , related family members (n = 28), cord blood donors (n = 6) or were not reported (n = 9). Acquired cytogenetic, molecular, and morphologic abnormalities were reported. Donor origin was confirmed by cytogenetic analysis via karyotyping, FISH, STR-PCR, and other techniques. A disease in donor-derived cells was described in 35 recipients (56.5%). Despite the relevance for testing and disclosure to donors, only 22 cases (32%) mentioned donor follow-up, and 5 cases confirmed that the donor developed a disease associated with the identified abnormality. Unrelated donor disclosure was mentioned in 3 of 26 cases (12%), where the findings were reported back to the registry. Conclusions: Incidental abnormalities identified in transplanted donor cells may contribute to post-transplant risk of illness in the recipient and may be relevant to donor health. A framework for donor disclosure is proposed that incorporates consideration of analytic validity of the testing, potential significance of the finding, and the extent to which the abnormality is actionable. Adoption of effective processes to safeguard both donor and recipient health outcomes related to this issue is needed.
Background: Hematopoietic Stem Cell Transplant (HCT) frequently demands intensive care needs from patients and their support networks, involves extensive recovery time, and high psychological distress. HCT programs recognize the need to support psychosocial wellbeing, however evidence-based guidance for pre-HCT psychosocial services is sparse. Purpose: We conducted a qualitative environmental scan of programs across Canada, inquiring how transplant programs prepare and assess psychosocial needs for HCT. Methods: HCT program directors across Canada were contacted and asked to identify their psychosocial team members to be contacted for participation. Team members were provided a list of questions about their psychosocial assessment and preparation process with patients and caregivers, to which they could respond by email or interview by phone. Descriptive qualitative analysis was conducted, using steps outlined by Braun and Clarke (2008).

Results:
The majority of participants were social workers in hospital settings and responded by email rather than phone. Two qualitative themes arose in our analysis. (a) Components and processes of assessment. Most sites included some form of assessment, however for some it was a brief meeting with a social worker about practical needs and for others it was an in-depth meeting including caregivers and covering topics such as practical and financial needs, psychological needs and history, ways of coping, and supports. All participants conducted assessments in an unstructured manner rather than using standardized assessment tools. (b) Design and components of educational sessions. These ranged from providing written materials, live monthly information sessions, to two days of orientation covering the multidisciplinary transplant team and available services. Conclusions: Significant variation exists in the way programs across the country prepare and assess their patients' psychosocial pre-transplant needs. This qualitative scan identified several strategies used in diverse ways. Further in-depth research on program outcomes across Canada could help identify which strategies are most successful. To perform stem cell transplants and cellular therapy procedures, Hamilton Health Sciences (HHS) must be Regulated by Health Canada and comply with the international standards identified by the Foundation for the Accreditation of Cellular Therapy (FACT). In September 2018, all HHS Haematology reporting & analytical functions were transitioned to the Regional Oncology & Complex Haematology Analytics (ROCHA) team as data management is critical to the coordination of transplant and cellular therapy. As part of this transition, ROCHA were tasked with the development of a bespoke tool to manage all data collection pertaining to Stem Cell Transplant and Cellular Therapy planning that would meet all quality system requirements. As a result, the integrated Stem (cell) Transplant Activity Repository (iSTAR) was created with the purpose of becoming a "one stop shop" tool for users across the program. iSTAR was designed, built and validated against strict acceptance criteria modeling in collaboration with the Stem Cell Coordinators, Quality Manager and Haematology Physicians at Hamilton Health Sciences. During these collaborative interviews with the CTTC team, we were able to identify required data and metrics to support operational activity. Currently, iSTAR is being used to capture clinical planning information for Autologous transplant, Allogeneic transplant, CAR-T cell therapy, Acute Leukemia and for donor assessment/clearance for Canadian Blood Services. In addition, a module to track funding costs (i.e., graft costs, courier costs, etc.) has been implemented as well as a tracking module which allows users to track outstanding CIBMTR forms and data quality deficiencies. The final module to be implemented in early 2022 will be the Post-Transplant module which will capture patient outcome information as required by FACT, Cancer Care Ontario and HHS researchers. Some of the key highlights of the iSTAR tool include: improved patient safety identifies potential lost funding reduces manual work performed by Stem Cell Coordinators tracks invoices for reimbursement collection of bespoke operational and financial reports secure web-based tool all data is stored in a secure DataMart repository for easy data extraction sends notices to Clinicians to book 100 day, 6 month and annual follow up appointments integrated change control process to ensure all changes and version coding is traceable -Tiered security level privileges ensuring access to correct information -Data integrity audits to validate data components Although iSTAR has been built to reflect the workflow for transplant coordination at HHS, the tool could be customized for any transplant facility. Related to CIBMTR, plans are being developed to re-create all CIBMTR forms within iSTAR with the goal of electronically submitting the information and the ability to store the data in the iSTAR DataMart.

Abstract 37 (Oral): Evaluating the Effectiveness of a Training Program to Support Nurses to Administer Cryopreserved Hematopoietic Stem Cells by Intravenous Push Method (Award Recipient-Pharmacy, Nursing, Other Transplant Support) Cheryl Page and Jessica Rebeiro
Hamilton Health Sciences, Hamilton, ON, Canada Background: There are two main methods of infusion for dimethyl sulfoxide (DMSO) cryopreserved hematopoietic stem cell (HSC) products, gravity drip and intravenous (IV) push. DMSO can cause hypersensitivity reactions. Prolonged exposure to DMSO once the cells are thawed increases the risk of cellular damage. Administration of HSCs by gravity drip is slower, causing less DMSO reactions. The faster IV push method reduces cell damage and decreases staff time. An environmental review found that at most centers, nurses administer by gravity drip, and when IV push is required, HSCs are administered by physicians. Our center's method was IV push by a physician or nurse practitioner (NP). As transplant numbers grew, capacity to perform this skill needed to expand. To maintain the current benefits of the IV push method, registered nurses (RN) were trained to perform this skill. Purpose: To increase capacity at a hematopoietic transplant program, the role of infusing stem cells by IV push method was transitioned from the NPs and physicians to RNs. A successful training program, utilizing simulation, to support these oncology nurses learning this new skill was developed and evaluated. Methods: Nurses attended a four-hour training session, including a didactic portion, simulated infusion, and case studies. Support included a policy, procedure guide, and reaction management guide. At least three infusions were completed with a competency record, precepted by a transplant physician or NP. Evaluation of the training program, performed pre-training, post-training, and follow-up post independent skill performance, utilized the first three levels of the Kirkpatrick Model. The RNs completed evaluations noting patient response. Results: Nurses rated the orientation program positively (Kirkpatrick evaluation level 1). Nurses demonstrated a significant increase in knowledge in cryopreserved HSC infusions from pre-evaluation to post-evaluation (Kirkpatrick evaluation level 2). There was a significant shift in behaviour post-orientation as demonstrated by an increase in three key Background: Allogeneic hematopoietic stem cell transplant (HSCT) requires the identification of a donor prior to proceeding with transplant. However, in the adult HSCT donor setting, minimal clinical guidance exists to support donors who are incapable of interpreting information and provide informed consent for donation. Consequently, the clinical team is challenged ethically in protecting the rights of the donor while striving for the best therapeutic outcome of the recipient. This scenario was experienced at our facility when it was identified that the HLA-matched sibling did not have the capacity to understand or provide consent to donation. Previous communication with the potential donor had been through the legal substitute decision maker (SDM) of the donor. An ethical concern was that the SDM would be unable to give an unbiased opinion. Purpose: To expand donor care standards to include the diverse needs of all potential adult donors, while adhering to ethical principles and legal responsibilities. Methods: To inform the development of a practice standard for accepting cognitively diverse donors, the authors sought guidance from established programs in the pediatric care setting. A case team was assembled with experts from the HSCT program, bioethics, legal, and communication specialists in collaboration with the potential donor and their family. The team consulted with Canadian Medical Protective Association (CMPA) to obtain legal guidance. Findings: There is a significant gap in donor navigation processes when an adult donor does not have the ability to understand and provide informed consent. Case law on this issue is sparse, and legal opinion appears to vary by jurisdiction, although a similar case [1] outlined that the parents of an adult donor with cognitive disabilities did not have legal authority to consent. Utilizing criteria outlined by The American Academy of Pediatrics Committee on Bioethics, the team adapted a framework to structure guidelines for an incapable adult donor. The defined criteria includes (1) there must be no medically equivalent histocompatible relative who is able/willing to donate; (2) the donor and recipient must have a strong existing personal and positive relationship; (3) there must be a reasonable likelihood the recipient will benefit from HSCT; (4) clinical, emotional, and psychological risks to the donor must be minimized; (5) ensure minimal risk to the donor, donor assent must be obtained as far as possible.

Outcomes/Recommendations:
The primary recommendation is for a standard framework to ensure equitable and safe care of a diverse donor population that aligns with ethical principles and legal requirements. Further, when it is identified that a donor may not have the mental capacity to provide informed consent, a donor advocate policy should be developed and initiated. Case outcomes are still in process as we are awaiting a decision from CMPA.