HLA Matching Research Articles

A Phase II Clinical Trial of "Off-the-Shelf" NK Cells with Allogeneic Stem Cell Transplantation to Decrease Disease Relapse in Patients with High-Risk Myeloid Malignancies

Background Acute myeloid leukemia, myelodysplastic syndrome, and TKI resistant CML continue to be among the most aggressive forms of blood cancer. Allogeneic hematopoietic stem cell transplantation (alloSCT) remains one of the most effective treatments available. Much of the benefit of AlloSCT is due to the immune-mediated graft-versus-leukemia effect to prevent relapse. Nevertheless, disease relapse remains the most important cause of treatment failure after alloSCT. A potential solution to reduce the risk of relapse may be found in Natural Killer (NK) cells, which have a demonstrable ability to eliminate leukemic and virally infected cells. However, naturally produced NK cells seen in patients early post-transplant are functionally impaired. A potential solution would be to provide donor-derived, expanded and activated NK cells in the peri-transplant setting. Natural killer cells are a unique class of lymphocytes, with cytotoxic, and immunoregulatory function which can mediate potent anti-leukemia effects. NK cells are regulated by Killer-cell Immunoglobulin-like Receptors (KIR) receptor-ligand interactions and mediate cytotoxicity. Alloreactive NK cells have been reported to enhance engraftment, reduce GVHD and prevent relapse of leukemia post transplant. This study will utilize NK cells from third party donors as adjuvant treatment to eradicate leukemia and prevent disease relapse after transplantation. Study Design and Methods Our clinical trial is registered as NCT05115630. Inclusion criteria includes age 18 to 65 years old, weighing at least 42 kg, with High risk AML, MDS, or TKI-resistant/intolerant CML who have either an HLA matched related donor, HLA matched unrelated donor, a haploidentical related donor, or a one antigen mismatched unrelated donor. HLA matching includes HLA A, B, C, and DR-B1. Exclusion criteria include patients who are HIV positive or has active hepatitis B or C, uncontrolled infections, liver cirrhosis, CNS involvement within 3 months prior to the transplant, or positive pregnancy test in a woman with child bearing potential. We will also exclude any patient with inability to comply with medical therapy or follow-up, patient with a known history of allergic reactions to any constituents of the product, including a known history of allergic reactions to cellular products or DMSO, other malignancy/cancer diagnosis <2 years ago. We will also exclude any patient requiring systemic corticosteroids with prednisone dose >10 mg or equivalent or who has KDS-1001 Donor specific antibodies (dsa) >5000 MFI units, or has KDS-1001 Donor anti-C1q positive. Statistical considerations and exploratory endpoints This is a single-arm Phase II trial of 3rd party natural killer (NK) cells at a fixed dose added to an allogeneic stem cell transplant for AML/MDS/CML. The goal is to reduce the risk of relapse of the malignancy post transplant, and to improve relapse free survival. The primary endpoint is the adverse event Failure = [graft failure, grade 3-4 GVHD, relapse or non-relapse death within 100 days post-transplant]. The stopping rule for time-to-failure (defined as graft failure, gr 3-4 GHVD, or non-relapse death) will be implemented to avoid waiting 100 days (3 months) to evaluate each patient to perform safety monitoring. The design will be based on T with 3 months follow-up, applying the design of Thall et al. Possibly right-censored values of T for patients treated in the trial will be monitored continuously throughout the trial. The accrual rate is expected to be approximately 2 patients per month, with each patient's follow-up continued until all patients have been followed for 3 months from their date of first NK cell administration. The distributions of time to failure and RFS time will be estimated using the method of Kaplan and Meier. Exploratory analyses with immunophenotyping for NK cell chimerism and persistence will be done as feasible. Immune reconstitution studies or additional future research may be performed.

Indirectly Recognizable Epitopes Derived from Recipient Mismatched HLA-B Are Associated with Adverse Prognosis in Single-Unit Cord Blood Transplantation

Backgrounds Despite cord blood is an important alternative stem cell source for the patients without HLA matched donors, engraftment failure is the most significant obstacle in cord blood transplantation (CBT). Donor-specific anti-HLA antibody and hemophagocytic syndrome (HPS) after severe pre-engraftment immune reaction are the major causes of engraftment failure. However, the allo-immunity associated with graft rejection has not been fully understood. In HLA-mismatched transplantation, mismatched HLA is an important target for allo-immunity but the immunogenicity is different depending on the mismatched HLA pair of donor and recipient. Therefore, we hypothesized that by evaluating the antigenicity of mismatched HLA, we could improve donor selection criteria for CBT. Methods: We performed a retrospective analysis of clinical data on 4,100 single-unit CBT in Japan between 2001 and 2017 deposited in Transplant Registry Unified Management Program (TRUMP). Using the PIRCHE algorithm (PIRCHE AG, Berlin), the number of mismatched HLA-derived epitopes to be presented by HLA was predicted. PIRCHE was quantified separately for the mismatched recipient loci (HLA-A, -B, -C, -DRB1) and the presenting donor-HLA (ClassI or ClassII, matched or mismatched HLA). Specifically, we evaluated binding affinities of peptides that could be made from recipient mismatched HLA to donor HLA using netMHCpan and netMHCIIpan. Epitopes with IC50 < 500 nM for Class I and < 1000 nM for Class II were defined as PIRCHE-I and PIRCHE-II, respectively. Results: The death-censored median observation period was 2.7 years (0.5-17.1), median age at transplantation was 53 years (16-75), and 96.4% of patients were infused with HLA-mismatched cord blood. The present cohort includes patients with AML (49.6%), ALL (14.0%), Lymphoma (12.9%), MDS (10.8%), CML (2.2%), and other diseases (10.5%). Full-intensity conditioning was performed in 50.4% of patients. All patients received calcineurin inhibitors (CNI) for graft-versus-host disease (GvHD) prophylaxis, 1410 (34.5%) of them received MMF and 2110 (51.5%) received MTX in combination with CNI. The number of PIRCHEs derived from each HLA-loci showed zero-inflated distributions. Patients with PIRCHE-I derived from recipient mismatched HLA-B (rB-PIRCHE-I) had a higher non-relapse mortality (NRM, Hazard ratio [HR] = 1.19, p = 0.004) and lower progression free survival (PFS, HR = 1.12, p = 0.002). They tended to have higher risk for engraftment failure and infection was leading cause of death. rB-PIRCHE-I was not associated with incidence of acute and chronic GvHD. Interestingly, rB-PIRCHE-I on matched HLA (rB-PIRCHE-I on match) was significantly associated with prognosis (PFS, HR = 1.11, p = 0.005), but those presented on mismatched HLA were not (PFS, HR = 1.07, p = 0.1). The numbers of infused nucleated cells and CD34+ cells in the graft were higher in the patients with rB-PIRCHE-I on match, but there was no difference in other patient backgrounds with or without rB-PIRCHE-I on match. In patients transplanted with HLA-B mismatched cord blood, rB-PIRCHE-I on match was prognostic. In patients who received MMF, rB-PIRCHE-I on match was associated with engraftment failure (Figure 1) and poor prognosis (NRM, HR = 1.48, p < 0.001; PFS, HR = 1.26, p < 0.001), whereas there was no prognostic impact in the patients with MTX. In order to elucidate the mechanism by which rB-PIRCHE-I increases engraftment failure in patients with MMF, we performed a detailed analysis of 100 patients who underwent CBT with MMF in the cohort of Kyushu University Hospital. As a result, we found that the frequency of HPS was significantly higher in patients with rB-PIRCHE-I on match (HR = 5.75, p = 0.001) Discussion: In the early period after CBT, donor antigen-presenting cells (APCs) are not reconstituted and donor T-cell is restricted to donor HLA. Therefore, we speculate that recipient APCs are inducing severe allo-immune reaction by presenting rB-PIRCHE-I on matched HLAs which are recognizable to donor T-cells. Furthermore, NK cells in the graft have been reported to prevent GvHD via suppression of recipient APCs, and MMF has the ability to suppress NK cells; it is possible that MMF enhanced the allo-immune response induced by recipient APCs. (Figure 2) Conclusion: HLA-mismatched cord blood without rB-PIRCHE-I is more desirable as a donor; when selecting a donor with rB-PIRCHE-I, it may be better to use MTX instead of MMF. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Does Race/Ethnicity Impact Umbilical Cord Blood Transplant Outcomes in a Contemporary Era?

Background: Studying the impact of race/ethnicity on stem cell transplant outcomes helps us improve health care disparities and access to transplant. The use of umbilical cord blood (UCBT) was designed to allow mismatched UCB units and improve access to transplant for patients lacking a fully matched donor. Previous CIBMTR studies (Ballen et al, BBMT, 2012) showed that Black patients had a lower overall survival (OS) than White patients following single UCBT; however, outcomes were similar when UCB units of comparable cell dose and HLA match were used. The current study draws on a larger, more modern cohort and compares outcomes among non-Hispanic White (White), non-Hispanic Black (Black), Hispanic/Latinx (Latinx) and Asian patients. Methods: CIBMTR data from 2007 to 2017 were used. Patients were between ages 1 and 80; 983 received single and 1259 double UCBT, following either a myeloablative (N=1752) or reduced intensity conditioning (N=759). The primary outcome was OS at 2 years, which was estimated using the Kaplan-Meier method with the log-rank test used for univariate comparisons. Secondary outcomes included disease free survival, transplant related mortality (TRM), acute and chronic graft vs host disease (GVHD), and GVHD free, relapse free survival (GRFS). Multivariate analysis was performed to determine factors associated with outcomes and whether race/ethnicity influences these outcomes. Results: A total of 1705 adults and 807 children were included. For adults, in univariate analysis, 2-year OS was 41.5% (99% CI, 37.6-45.3) for Whites, 36.1% (99% CI, 28.2-44.5) for Latinx, 45.8% (99% CI, 36.7-55.1) for Blacks, and 44.5% (99% CI, 33.6-55.6) for Asians. In multivariate analysis of adults, Latinx patients had inferior OS compared to other racial/ethnic groups (p=0.005) (Figure 1). OS improved over time across all racial/ethnic groups (p=0.009; 2016-2017 vs. 2007-2009 HR 0.68, 99% CI 0.51-0.91). Relapse and TRM rates were higher in Latinx compared to other groups but did not reach statistical significance. GVHD rates were comparable among the different racial/ethnic groups. There was no survival advantage to receiving a UCB unit from a donor of similar race/ethnicity, for any racial/ethnic groups In children, the 2-year OS in univariate analysis was 66.1% (99% CI, 59.7-72.2) for Whites, 57.1% (99%CI, 49-64.9) for Latinx, 46.8% (99%CI, 35.3-58.4) for Blacks, and 53.8% (99%CI, 32.7-74.2) for Asians. In multivariate analysis of children, no difference in OS was observed among racial/ethnic groups (p = 0.05) (Figure 2). Similarly, there was no difference in relapse (p=0.40) and TRM rates (p=0.14). Grade 3-4 Acute GVHD was higher in Blacks compared with Whites (p= 0.0016, HR 2.25, 99% CI 1.36-3.74). There was no survival advantage to receiving a UCB unit from a donor of similar race/ethnicity, for any racial/ethnic groups. Conclusion: 1. UCBT provides a donor for diverse patients. 2. In adults, OS has improved over time for all racial/ethnic groups. 3. In adults, OS is comparable among Whites, Blacks, and Asians and lower for Latinx patients. 4. In children, OS is comparable among Whites, Blacks, Latinx, and Asians. 5. In children, Grade 3 and 4 acute GVHD was higher in Black patients. 6.There was no survival benefit to matching UCB unit and patient by race/ethnicity for adults and children, although the numbers were small in the non-White cohorts. As our study reveals race/ethnicity matching has minimal to no impact on outcomes post UCB transplant it may be advantageous for UCB banks to target collection of larger units over race/ethnicity quotas. Future studies will study biologic or socioeconomic explanations for the lower OS in adult Latinx patients and the higher acute GVHD in pediatric black patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Hematopoietic Cell Transplantation in First Remission in AML in Mexico: Very Low Rates Derived from Early Relapses and Lack of Access

Background: Acute myeloid leukemia (AML) is the most frequent indication for allogeneic hematopoietic cell transplantation (alloHCT) in the world. According to international recommendations, intermediate and high-risk patients, <75 years and fit should receive consolidation with alloHCT. The role of autologous HCT in AML is less clear. We previously reported in a multicenter retrospective study a very low HCT rate (8.2%) despite most patients being potential candidates. The HCT rates in Latin America are considerably lower than in US or Europe (63.9 vs. 511.2 and 390.0/10 million). The main objective of this study was to analyze the reasons why the patients that were potential HCT candidates were not transplanted. Methods We included the patients from our previous retrospective multicenter registry that were potential HCT candidates considering: AML diagnosis between January 2013 and December 2017, <66 years, candidates for intensive chemotherapy and with intermediate or high cytogenetic risk. We reviewed the charts to collect information about HCT decisions and the factors associated with access to transplantation. Results We included 301 patients from 10 public centers with a median age of 42 years (14-65), 51.8% were women, 93.2% with an ECOG performance status 0-2 and 91% with an HCT-CI <3. The majority (86.7%) were classified as NOS-AML and 11.6% were secondary AML. Considering cytogenetics: 66.5% had an intermediate risk and 33.5% unfavorable risk. Induction related mortality was: 17.6% and 13.5% were primary refractory. The majority of the patients (80%) were treated in centers with a local transplant progarm. HLA testing was performed in 103 patients (34.2%). The main reasons for not performing the tests were: early relapse or primary refractory in 26.3% and lack of access or financial resources in 26.3%. In 7.5% of the cases, the patient refused to be tested. Age >60 years and HCT-CI >3 were associated with a lower likelihood of undergoing HLA matching (OR 0.2 95% CI 0.04-0.69, p=.006 and OR 0.02 95% CI 0.01-0.46, p<.001, respectively), in contrast with the presence of a local transplant program (OR 3.6 95% CI 1.7-7.71, p<.001). An HLA matched sibling-donor was identified in 45.1%, a haploidentical donor in 32.4% and no donor in 22.5% Only 23.6% of the patients had a HCT consultation and only 36 patients (12%) received HCT as consolidation in first remission: 30 alloHCT and 6 autoHCT. Only 47.9% of the patients receiving a transplant consultation were transplanted; 20/37 relapsed before HCT. The patients with a matched sibling-donor had a higher probability to receive consolidation with HCT when compared to patients with haploidentical or no sibling donor: 50%, 15.2% and 13% (OR 6 95% CI 2.3-15.5, p<.001). All patients without a matched or half-matched sibling donor who underwent transplantation received autoHCT. The median time from diagnosis to HCT consolidation was 7.2 months (2.9-25.1 months). A landmark OS analysis since CR showed a significant benefit from HCT (autoHCT or alloHCT): 3-year OS of 76.9% vs. 37.8%; HR 0.3 (0.1-0.6), p=.001. There was no significant difference between autoHCT and alloHCT with a 3-year OS of 83.3% and 75.4%. Discussion Only 12% of the patients that are potentially candidates are actually receiving HCT in Mexico. HLA testing is performed in only one third of the patients. Lack of access or financial resources and relapses before HLA testing or before HCT are the main reasons. The long-term OS of patients receiving HCT in excellent, however there is a clear bias if with consider the patients that had not the chance to reach the transplant due to early relapses. We have a very big challenge in the region, which is to ensure that the majority of patients who are potential candidates for HCT can access it through timely access to HLA testing and early access to alternative donor HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Orca-Q Demonstrates Favorable GvHD-and-Relapse-Free Survival in Haploidentical Transplants without Post-Transplant Cyclophosphamide

^Salhotra, Srour, Lowsky and Abedi contributed equally Background: Allogeneic hematopoietic stem cell transplantation (alloHSCT) can be curative for a variety of malignant and nonmalignant disorders, but until recent years, access has been limited to patients with HLA-matched donors. The increased utilization of post-transplant cyclophosphamide (PTCy) has enabled patients to receive alloHSCT with haploidentical (haplo) related donors; however, high rates of cGVHD following myeloablative conditioning (MAC) regimens and high rates of relapse following reduced intensity conditioning regimens have been observed with this approach. Thus, GVHD-and-relapse free survival (GRFS) rates in this population at 1-year post-transplant remain low. Haplo alloHSCT with PTCy is also associated with high incidence of cytokine release syndrome (CRS) and infections. Orca-Q -an investigational precision engineered cell therapy- represents an alternative strategy which may be administered with single agent prophylaxis and does not require PTCy. The cellular composition of Orca-Q consists of enriched CD34+ stem cells combined with specific T- cell subsets and is intended to reconstitute the blood and immune systems. Orca-Q is hypothesized to reduce GVHD, relapse, and serious infections. Methods: Adult patients (18 to 65 years) with high-risk hematologic malignancies undergoing myeloablative conditioning (MAC) alloHSCT were enrolled between January 2019 to July 2022 on the haplo donor dose expansion arm of a multicenter phase 1 study of Orca-Q (NCT03802695). Haplo was defined as ≥ 4/8 but < 7/8 matched related donor at HLA-A, -B, -C, and -DRB1 typed using DNA-based high-resolution. Patients received only single agent tacrolimus (starting on day -1 and taper day +60 if no GVHD) as GVHD prophylaxis. PTCy was not permitted. The Orca-Q drug product was manufactured centrally at Orca Bio Manufacturing Site in Sacramento, CA from G-CSF mobilized peripheral blood apheresis. Results: The Orca-Q drug product was successfully manufactured and delivered to all subjects with a vein-to-vein time of less than 72 hours. A total of 21 patients (11 AML, 8 ALL, 2 CML in blast crisis) with > 30 days of follow up were included in this analysis. All were 4/8 HLA match at HLA-A, -B, C, and DRB1. Median age of subjects was 44 years (range 21 - 63) and median follow-up was 333 days (range 39 - 1020). Disease risk index (DRI) score was available in 20 showing 2 very high, 3 high, 13 intermediate, and 2 low risk categories. The M:F ratio was 12:9. Patients received either TBI (n=13) or non-TBI (n=8) based MAC regimens. 2 patients had Gr 1 CRS (CTCAE v5). Median neutrophil and platelet engraftment times were 13 days (range 8 - 25) and 16 days (range 12 - 25), respectively. 1 secondary engraftment failure was observed. The estimated incidence of BMT CTN MOP3 infections was 27% at 1 year. The estimated incidence of gr 2-4 aGVHD at 6 months was 14% which compares favorably with literature reports of 21% to 63% for gr 2-4 aGVHD in patients undergoing haplo transplant with PTCy-based prophylaxis.[1-5] Likewise, gr 3-4 aGVHD was rare with Orca-Q with only 1 case of gr 3 aGVHD and no gr 4 aGVHD. Of the 16 patients who had at least 3 months follow up, only 1 developed mild cGVHD. No patients had moderate-to-severe cGVHD, a notable improvement compared to historic rates of 24% to 31% for moderate-to-severe cGVHD with PTCy, despite the fact that Orca-Q patients receive only single agent GVHD prophylaxis.[1-4] 2 patients experienced disease relapse and there was a total of 5 deaths (2 due to relapse, 1 Aspergillus pulmonary infection, 1 respiratory failure associated with renal failure, and 1 COVID infection). GVHD-and-relapse free survival (GRFS) was 71% at 1 year with Orca-Q (Figure 1) which compares favorably to a GRFS of 46% reported by Sanz in the context of MAC haplo alloHSCT with PTCy.[2] Conclusions: Initial Orca-Q data demonstrates good clinical outcomes with single agent tacrolimus and no PTCy or MMF. Patients treated with Orca-Q experienced a low adverse event profile, low incidence and severity of both aGVHD and cGVHD, and improved GRFS rates, offering a potential new treatment option for patients undergoing haplo alloHSCT. This phase 1 study of Orca-Q continues to enroll patients with haplo donors across the US. References (1) Gooptu, M., et al. (2) Sanz, J., et al. (3) Wagner, J.E., et al. (4) Baker, M., et al. (5) Bashey, A., et al. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of Allele-Level HLA-Matching on Outcomes after Double Unrelated Cord Blood Transplantation in Adults with Malignant Diseases

Introduction: In single unrelated cord blood transplantation (sCBT), an increasing number of HLA-mismatches (MM) has been associated with inferior overall survival (OS) attributed to higher transplant-related mortality (TRM). These findings have prompted current guidelines to endorse high resolution HLA typing in the selection of CB (cord blood) units, including double CBT (dCBT). However, a comprehensive appraisal of the effect of allele-level HLA matching following dCBT was likely hindered by the relatively small sample sizes in previous studies. Herein we aimed to analyze the impact of allele-level HLA-matching on outcomes of a large cohort of dCBT recipients to improve CB unit selection and further explore the unique dCBT biology. Methods: We included patients ≥18 years-old receiving a dCBT between 2006-2019 with the availability of HLA typing minimally at HLA-A, -B, -C at the antigen-level and HLA-DRB1 at the allele-level for the recipient and both CB units. A validated high-resolution imputation tool, HaploStats, was used to adjudicate allele-level match status for a subset of cord and recipient pairs (n = 173) having only antigen-level typing at HLA-A, -B or -C. A sensitivity analysis for OS was performed excluding imputed cases, and results were unchanged. HLA matching was classified according to the CB unit with the greatest degree of HLA mismatch with the patient, meaning that only the most mismatched unit was considered and that the interunit matching was not considered. Continuous covariates were dichotomized to find an optimal cutoff value by using the Contal-O'Quigley method, except for cryopreserved CD34 and total nucleated cell (TNC) count, whose cutoffs were based on previous findings reported by our group. Pairwise comparisons of the numbers of allele MM showed that receiving units with ≥4 MM had the highest negative impact on OS. Cox and Fine-Gray regression models were built for the different outcomes using the backward elimination method (p<.05 to stay). Results: 963 patients met the eligibility criteria, of which 392 received at least one CB unit with 0-3 allele MM while 571 with ≥4 allele MM. Of those receiving at least one unit with ≥4 allele MM, 18% had a maximum HLA disparity of 5/6 at lower HLA-typing resolution, 69% of 4/6 and 13% of ≤3/6. Median age at dCBT was 49 years old. Acute leukemia and myelodysplastic syndrome (MDS) accounted for 70% of the cases. There was a larger proportion of patients receiving CB units with fewer allele MM after 2012. Other patient-, disease- and CB unit-related characteristics are summarized in Table 1. The day-42 cumulative incidence of neutrophil recovery was 83% (95%CI 81-85). The number of allele MM had no significant impact on neutrophil recovery (≥ 4 MM vs 0-3 MM, multivariate HR 0.94 [0.80-1.11], P=.46). The cumulative incidence of TRM at 4 years was 36% (95% CI 32-40) for patients receiving CB units with ≥4 MM vs. 23% (95% CI 19-28) for those with 0-3 MM (multivariate HR 1.58 [95%CI 1.18-2.11], P=.002] - Fig. 1A). Infectious complications were the most frequent cause of TRM in the group receiving dCBT with ≥ 4 allele MM (40%). Relapse, grade II-IV/III-IV acute and chronic GVHD were not significantly different between the two groups. Patients receiving CB units with 0-3 allele MM had a 4-year survival of 54% (95%CI 49-59) compared to 43% (95%CI 39-47) for those receiving units with ≥4 allele MM (multivariate HR 1.40 [1.11-1.78], P=.005 - Fig. 1B). The inferior OS associated with higher allele HLA disparity was only partially mitigated by increasing the TNC count in multivariate analysis (0-3 MM + TNC ≤ 3.9x10ˆ7/kg vs.0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.50 [0.97-2.32], P=.07; ≥4 MM + TNC > 4.9x10ˆ7/kg vs. 0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.42 [1.06-1.89], P=.02; ≥4 MM + TNC ≤ 4.9x10ˆ7/kg vs. 0-3 MM + TNC > 3.9x10ˆ7/kg, HR 1.66 [1.24-2.22], P=<.001 - Fig. 1C). Discussion: Our results confirm that allele-level HLA typing is a significant factor for OS following dCBT. The inferior OS associated with the increasing number of allele-level MM was driven by higher TRM. Selection of CB units with 0-3 allele-level MM is recommended. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Influence of Conditioning Regimen Intensity on Outcomes Post-Allogeneic Transplantation for AML in Complete Morphological Remission

Introduction: Acute myelogenous leukemia (AML) is a major indication for allogeneic hematopoietic cell transplantation (alloHCT). Myeloablative (MAC) regimens are preferred for their intensity, however, reduced intensity conditioning regimens (RIC) have been increasingly used to permit older patients and patients with comorbidities to undergo transplant. The literature is conflicting regarding the comparison of outcomes between RIC and MAC patients. While MAC regimens are associated with less relapse, non-relapse mortality (NRM) is higher. RIC regimens on the other hand, demonstrate less NRM but higher relapse rates. We sought to compare RIC vs MAC regimens at our centre for alloHCT of AML in complete remission (CR). Methods: We retrospectively analyzed the outcomes of 451 patients that underwent alloHCT for AML at the Princess Margaret Cancer Centre (PMCC) with either RIC or MAC using various donors between the years 2015-2020. Primary endpoint was 2-year overall survival (OS), secondary endpoints included cumulative incidence of relapse (CIR), cumulative NRM, and GVHD free/relapse free survival (GRFS). Conditioning regimen intensity was determined as defined by Bacigalupo et al (BBMT 2009). Of the total cohort 331 patients received RIC and 121 MAC. Among MAC regimens, 59% received FLU(4)Bu(4) (Fludarabine 140mg/m2 + Busulfan 12.8mg/m2). Among RIC patients 71% received Flu(4)Bu(2)TBI(200) (Fludarabine 140mg/m2+ Busulfan 6.4 mg/m2 + TBI 200cGy). Results: Median age at transplant was 48 years (range: 19-67) for MAC recipients and 61 (range: 18-75) for RIC recipients (p<0.001). Other patient characteristics are described in Table 1. For the entire cohort at 2 years, the incidence of NRM was 19.1% for MAC (95% CI: 12.4-26.8) and 22.5% for RIC (95% CI: 18.1-27.1) (p=0.44). Two-year CIR was 19.8% (95% CI: 12.9-27.8) for MAC recipients and 24.5% (95% CI: 20.0-29.4) for RIC recipients (p=0.15). Two-year OS was 61% and 53% for MAC and RIC, respectively (p=0.02). Acute GVHD occurred in 58.3% of MAC recipients versus 46.8% of RIC recipients. Chronic GVHD occurred in 43.3% of the MAC recipients versus 38% of the RIC recipients. At two years GRFS was 40.8% (95% CI: 35.4-46.1) for MAC and 33.7% (95% CI: 25.0-42.6) for RIC, p=0.30. When examining the Disease Risk Index (DRI) for the entire cohort, OS for high risk was 43.3% (95% CI: 32.5-53.5) vs 66.6% (95% CI: 61-71) and 64% (95% CI: 38-80) for intermediate risk and low risk respectively, p<0.001. A propensity score (PS) matched analysis was done matching patients for age, HLA matching (mismatched vs full match), DRI (low, intermediate, high risk) and in vivo T cell depletion (yes vs no). Two-year OS was 67% for the MAC recipients (95% CI: 57-76) and 66% for the RIC recipients (95% CI: 56-75), p=0.95 (Figure 1a). NRM for MAC was 22% (95% CI: 14-30) versus 14% (95% CI: 8-22) for RIC, p=0.19. CIR at 2 years was 18.5% for MAC (95% CI 11-27) and 24.3% for RIC (95% CI: 16-33), p=0.22. GRFS at 2 years was 36% (95% CI: 26.4-45.7) for MAC and 48.3% (95% CI: 38-58) for RIC recipients, p=0.17. In the subgroup analysis examining matched related donor (MRD) recipients in particular, the OS at 2 years was for MAC 83.6% (95% CI: 66.8-91.3) vs 57.3% (95% CI: 45.1-67.7) for RIC, p=0.006 (Figure 1b) Two-year NRM was 10.3% for MAC vs 23.4% for the RIC group, p=0.14. CIR at 2 years was 12.2% for MAC vs 23.4% for RIC in the MRD setting, p=0.11. Conclusions: Our study shows that in the MRD setting there is a statistically significant improved survival, especially in patients with low and intermediate DRI scores. In other donor settings, there is no significant difference in outcomes between patients that undergo alloHCT with MAC vs RIC regimens. MAC conditioning regimens should continue to be the preferred choice of intensity for patients that may tolerate it. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Risk Factors, Prevalence, and Outcomes of Invasive Fungal Disease Post Cellular Therapies: A Real-World Analysis

Objective: Cellular therapies, including CAR-T cell, gene therapy, autologous and allogeneic hematopoietic cell transplantation (HCT), remain a cornerstone in management of various benign and malignant disorders. Despite intensified efforts to improve strategies, invasive fungal infections (IFD) remain an important cause of morbidity and mortality. Therefore, we investigated risk factors, prevalence, and outcome of IFD in the era of novel anti-fungal prophylaxis. Methods: We retrospectively enrolled consecutive adult patients that underwent cellular therapies at our JACIE-accredited center according to standard operating procedures (2013-2022). We defined IFD according to current consensus (2020) and guidance on imaging (2021, EORTC). We analyzed the following factors: age, disease, donor, HLA matching, conditioning, graft, severe acute and moderate/severe chronic GVHD, antifungal prophylaxis, immunosuppressants, IFD type (according to current consensus), galactomannan/β-D-glucan, cultures, imaging, bacterial/viral infections, IFD treatment, relapse, and overall survival (OS). Results: We studied 950 recipients of cellular therapies (19 CAR-T cell and 2 gene therapies, 456 autologous and 473 allogeneic HCT). No CAR-T cell and gene therapy patient developed IFD; while 3/456 autologous HCT recipients who suffered from primary refractory/relapsed lymphomas presented with probable IFD. Further analysis was performed only in allogeneic HCT recipients. Possible IFD was documented in 31/473 at a median of 112 (range 7-1353) post-transplant day, probable in 11/473 (5: positive galactomannan, 6: positive cultures) at 154 (12-469), proven in 10/473 (3: positive galactomannan, 7: positive cultures) at 226 (25-1146) day. Concurrence of bacterial or viral infection was documented in 20/52 and 17/52 patients respectively. Second IFD episode occurred in 3 patients (1: probable, 2: proven IFD), that succumbed to TRM (1) and relapse (2). Candida species were isolated in 9 patients, Fusarium in 2 and Aspergillus in 2. Mucormycosis was diagnosed in 2 patients, while the remaining IFD were attributed to aspergillosis. During the aplastic period, caspofungin had been administered as primary prophylaxis (41/52) and amphotericin as secondary prophylaxis (11/52), which were then changed to posaconazole and isavuconazole respectively for the immunosuppression period. Independent risk factors for IFD were type of donor (20% in alternative, 12% in unrelated, and 5% in sibling donors, p=0.006) and moderate/severe chronic GVHD (15% versus 8%, p=0.029). Five-year OS was significantly lower in patients with IFD, especially those with proven IFD (p=0.041). IFD remained a predictor of OS (p=0.044) independently of donor type and chronic GVHD. Conclusions: Our large real-world cohort indicates the relatively low prevalence of proven IFD in the era of novel antifungal prophylaxis, which is however associated with poor outcomes in allogeneic HCT recipients. Possible IFD, assessed by host and clinical factors including updated documentation of imaging, has shown similar outcomes to probable IFD. Therefore, wider application of sensitive mycological testing is needed for high-risk populations, such as alternative alloHCT recipients or chronic GVHD patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Why Are Patients Not Getting a Graft? an Intent-to-Transplant Analysis in the Times of Universal Coverage and Haploidentical Donors

Introduction: allogeneic hematopoietic stem cell transplantation (alloHSCT) is a potentially curable option for patients with hematologic diseases. When considered candidates, patients face barriers to receive a transplant such as disease activity, education, financial constraints, donor availability, among others. These factors are particularly harder to overcome for patients in low- and middle-income countries. Therefore, we aimed to analyze factors that limit or favor access to an alloHSCT in a population that has been HLA typed and therefore with a potential intent-to-transplant. Methods: we retrospectively reviewed records from 2015 until the start of the COVID19 pandemic in two of the largest Mexican government-funded transplant centers in two geographic regions in Mexico with in-house HLA typing, in one of them, an outpatient transplant strategy is followed for most patients. HLA-typed patients who were potentially eligible for transplantation were included and their outcomes were assessed in an intent-to-transplant basis. We compared the outcomes of patients who underwent transplantation to those who did not and evaluated contributing barriers to access alloHSCT with multivariate logistic regression. This study was performed on behalf of the TCTMX working group. Results: we screened 391 patients, 42 were excluded as they had no indication for alloHSCT with a total of n=349 patients analyzed. The median age at HLA-typing was 34 years (IQR 22-46); n=211 (60.5%) had acute leukemia (AL), n=61 (17.5%) bone marrow failure (BMF), n=45 (12.9%) lymphoma, n=25 (7.2%) myeloproliferative neoplasms (MPN), n=4 (1.1%) chronic lymphocytic leukemia (CLL) and n=3 (0.9%) multiple myeloma (MM). Most patients (n=209, 59.9%) had government insurance coverage. Median time from diagnosis to HLA-typing was 8 months (IQR 3-19). The majority had a potential donor (95.1%): n=191 haploidentical (54.7%), n=139 a matched sibling donor (39.8%) and 2 an unrelated donor (0.6%). Almost half of them eventually received a transplant (n=170, 48.7%), the median time to HLA-typing to alloHSCT was 3 months (IQR 1-6). Sex, age and diagnoses were similar between transplanted and non-transplanted patients, while non-transplanted patients had a higher proportion of not compatible and haploidentical donors. Disease activity or progression was the biggest barrier for transplantation, followed by waiting for a hospital bed and comorbidities (Table 1). Donor availability limited transplant access for only 11.7% of patients. Access to transplantation was favored by private/out-of-pocket payment (OR 2.1 95% CI 1.3-3.4), and receiving care in the outpatient center (OR 6.4 95% CI 4-10.5), while HLA matching was not (OR 1.1 95% CI 0.8-1.7). Non-relapse mortality (NRM) in alloHSCT was 22.3%. Median overall survival (OS) from the intent-to-transplant cohort was 15 months (CI 95% 11.4-18.5). An OS landmark analysis for patients alive at or beyond 3 months (the median time from HLA-typing to alloHSCT) showed prolonged survival in alloHSCT (35 vs 13 months, p <.001), figure 1. By the time of the analysis 139 patients (39.8%) were still alive and 132 (37.8%) were event-free. Conclusion: the most frequent barrier to transplantation was the disease itself, followed by the transplant waiting list and comorbidities. Access to out-of-pocket resources and an outpatient strategy or center effect favored alloHSCT. In the era of haploidentical transplantation, donor availability was a smaller issue. An approach to overcome barriers could be to implement outpatient transplantation and eliminate the waiting list barrier without increasing NRM, to improve the health policy in the direction of more patients get coverage, patient education to diminish the rates of rejection and improve their comorbidities. To our knowledge, this is the largest intent-to-transplant analysis in a population that has been HLA-typed. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Basiliximab in the Prevention of aGVHD for Unrelated Donor Hematopoietic Stem Cell Transplantation in Patients with Thalassemia Major: A Prospective, Multicenter, Open-Label, Randomized Controlled Study

Background: Hematopoietic stem cell transplantation (HSCT) is currently the only clinical cure for thalassemia major (TM). Graft-versus-host disease (GVHD) and transplant-related mortality (TRM) remain major barriers to clinical outcomes in TM-unrelated donor transplantation (MUD-HSCT). Aims: The role of Basiliximab in preventing acute graft-versus-host disease (aGVHD) after MUD-HSCT in thalassemia major (TM) is still unknown. We performed a prospective, multicenter, open-label, randomized controlled trial (RCT). The study is registered at www.clinicaltrials.gov as #NCT02342145. PATIENTS AND METHODS: Patients with TM with unrelated donor were randomly assigned to a basiliximab group (20 mg/kg basiliximab on days 0 and +4, respectively, plus tacrolimus [FK506], methotrexate [MTX], and mycophenolate mofetil [MMF]) and a control group (FK506, MTX, and MMF). The primary end point of this study was grade 2-4 aGVHD on day 100. Results: From April 2015 and September 2021, a total of 205 TM patients were enrolled. The ratio of male to female was 123 to 82 with a median age of 7 years (range, 2-19 years). Patients were randomly assigned to the basiliximab group of 102 and the control group of 103. Comparison of the basiliximab group and the control group, the cumulative incidence rate of grade 2-4 aGVHD was 24.5% and 29.1%, respectively (P=0.456), and the cumulative incidence rate of grade 3-4 aGVHD was 8.8% and 14.6% (P=0.201); the cumulative incidence rate of moderate or severe chronic GVHD was both 2.9%; median days of neutrophil engraftment were +11.8 and +11.6 days, respectively (P=0.701), platelets Implantation days were +15.4 and +13.5 days (P=0.126); TRM was 3.6% and 7.1% (P=0.249), over survival (OS) was 96.4% and 92.0% (P=0.188), respectively and thalassemia-free survival (TFS) of the two groups was also the same as the OS. There was no significant difference between the basiliximab and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, and transplant-related complications. Subgroup analysis according to the degree of HLA matching showed that the 9/10 mismatch group had significantly lower OS and TFS than the 10/10 matched group (both 82.6% v 96.5%, P=0.004). The 3-year OS and TFS of the entire cohort (205 TM patients ) were 94.1% and 94.0%, respectively(Table 1, Fig 1). CONCLUSION: This first prospective randomized study showed basiliximab at a dose of 20 mg on day 0 and day+ 4 did not reduced the incidence of both aGVHD and cGVHD in patients with TM after MUD-HSCT. The incidence of aGVHD in unrelated donor transplants for TM patients is still high, 9/10 mismatched unrelated donor transplants had poor result when comparing 10/10 matched donor transplants for TM patients. Unrelated donors are still a very good alternative source of donors. The TFS of TM patients treated by unrelated donor transplantation can reach 94.0%. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Innate Cell Engager AFM13 Combined with Preactivated and Expanded Cord Blood-Derived NK Cells for Patients with Double Refractory CD30+ Lymphoma

Patients with multiple relapsed or refractory (R/R) Hodgkin lymphoma (HL) and other CD30+ lymphoma have few effective therapies available and targeted adoptive natural killer (NK) cell immunotherapy is an active area of investigation. Transfer of non-targeted NK cells has shown limited clinical benefit as target recognition of cancers by NK cells remains a substantial barrier. The innate cell engager (ICE®) construct, AFM13, is a first-in-class CD30/CD16A bispecific antibody construct that induces specific and selective killing of CD30+ tumor cells by engaging and activating NK cells. As a single agent, AFM13 has limited clinical activity against HL, likely due to the reduced effector function of autologous NK cells in these patients, which provides the rationale for the combination of AFM13 with allogeneic NK cells. Our prior preclinical work identified a promising combination of cord blood (CB)-derived NK cells that were first IL-12/IL-15/IL-18-preactivated followed by expansion (P+E) with engineered K562 feeder cells expressing membrane-bound IL-21, 4-1BB ligand and CD48 ex vivo, and subsequently complexed with AFM13 just prior to infusion (Kerbauy et al, Clin Cancer Res 2021; 27:3744-56). These cytokine-induced memory-like CB-derived NK cells precomplexed with AFM13 (AFM13-NK) presented chimeric antigen receptor (CAR)-NK cell-like features and showed an increased in vitro and in vivo antitumor activity compared to either P+E NK or AFM13 alone. Building on this work we wished to clinically study adoptive AFM13-NK cell therapy in pts with R/R CD30+ lymphomas. METHODS: This single-center phase I-II trial (NCT04074746) evaluates the safety and activity of AFM13-NK, followed by AFM13 monotherapy. Patients aged 15-75 years with R/R CD30+ lymphomas refractory to brentuximab vedotin are enrolled. The trial goals are to identify the recommended phase 2 dose (RP2D) of AFM13-NK cells, estimate the overall (ORR) and complete response (CR) rates, event-free (EFS) and overall survival (OS) rates, and studies of NK cell activation and persistence. Each treatment cycle consisted of fludarabine/cyclophosphamide (days −5 to −3), followed by infusion of the AFM13-NK cells, cultured for 14 days as described above (day 0), and three weekly IV infusions of AFM13 (200 mg, days 7, 14 and 21). Two cycles were administered to patients 1-19 and 4 cycles were given starting with patient 20. Response was evaluated on day 28 of each cycle. Patients were enrolled at 3 dose levels: DL1 (106 NK/Kg), DL2 (107NK/Kg) and DL3 (108 NK/Kg). Each patient received the same NK dose in all cycles. RESULTS: As of 7/31/22, 30 pts have been enrolled and treated (Table) at DL1 (N=3), DL2 (N=3) and DL3 (N=24), with 1 (N=1), 2 (N=24), 3 (N=3) or 4 cycles (N=3). All patients had active progressive disease at enrollment and no bridging therapy was given. The cords used for each of the 69 cycles were selected with no consideration for HLA match, which was 0/6 (N=31), 1/6 (N=31), 2/6 (N=5), 3/6 (N=1) and 4/6 (N=1). The product infused consisted of >99% NK cells (expanded >2,700 fold), with only 0.02% T cells. The NK cells were >98% viable and 92% of them were bound to AFM13. The products were infused fresh. There were no infusion-related reactions (IRR) after infusing AFM13-NK and 11 IRR in 182 infusions of AFM13 alone (6%) (1 grade 3, 10 grade 2). We saw no cases of CRS, ICANS or GVHD of any grade. DL3 (108 NK/Kg) was established as the RP2D. The ORR in the entire study is 97% with 63% CRs. All 24 patients treated at the RP2D responded (100% ORR) with 70.8% (17/24) CRs. Five patients had a response consolidated with a SCT. At median follow-up of 8 (range 1-23) months, the EFS and OS rates of all 30 patients are 57% and 83%, respectively. AFM-NK cells were detected in serum from day 1 post infusion and persisted for 3-4 weeks. Donor NK levels followed similar patterns after each cycle, which argues against a sensitization effect in the patient after the first NK infusion. Donor NK cells showed by CyTOF increased binding to AFM13 and expression of activation markers. CONCLUSIONS: This is the first clinical trial to date using an ICE® construct precomplexed with cytokine-induced memory-like CB-NK cells to treat patients with CD30+ R/R HL and NHL. Our preliminary results indicate that this ICE® precomplexed CB-NK cell therapy has an excellent tolerability profile and is highly active in patients with heavily pretreated R/R CD30+ lymphomas and warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

ABO-incompatible Pediatric Liver Transplantation With Antibody and B-cell Depletion-free Immunosuppressive Protocol in High Consanguinity Communities.

From November 2010 to June 2015, 176 children aged 0.2-to18 y were transplanted in the King Faisal Specialist Hospital and Research Center. Out of those, 19 children were transplanted across blood group barriers (ABO incompatible). The underlying diseases were biliary atresia (n = 6); progressive familial intrahepatic cholestasis type 2 (n = 4); Crigler-Najjar syndrome (n = 3); hepatoblastoma (n = 2); and urea cycle disorder, Caroli disease, cryptogenic cirrhosis, and neonatal sclerosing cholangitis (n = 1 each). Immunosuppression consisted of basiliximab, mycophenolate, tacrolimus, and steroids. Pretransplant prophylactic plasmapheresis, high-dose immunoglobulins, and rituximab were not administered. The grafts were from living donors (n = 17) and deceased donors (n = 2). Living donor morbidity was nil. The recipient median age was 21 mo (5-70 mo). After a median follow-up of 44 mo, 2 recipients (10%) died because of sepsis, 1 because of uncontrolled acute myeloid leukemia. The overall rejection rate was 7%, and no grafts were lost because of antibody-mediated rejection (AMR). HLA matching was 3.8 of 6 (A, B, DR), and there were 2 patients presented with acute cellular rejection, 1 patient with AMR, and 1 patient with biliary strictures. ABO incompatible liver transplantation is a feasible and life-saving option even with antibody and B-cell depletion-free protocol without increasing the risks for AMR. We speculate that this excellent result is most likely because of presence of relatively low titer ABO isoagglutinins and the high HLA match compatibility caused by habit of longstanding interfamilial marriages as typical of Saudi Arabia.

Blood donor biobank and HLA imputation as a resource for HLA homozygous cells for therapeutic and research use

BackgroundAllogeneic therapeutic cells may be rejected if they express HLA alleles not found in the recipient. As finding cell donors with a full HLA match to a recipient requires vast donor pools, the use of HLA homozygous cells has been suggested as an alternative. HLA homozygous cells should be well tolerated by those who carry at least one copy of donor HLA alleles. HLA-A-B homozygotes could be valuable for HLA-matched thrombocyte products. We evaluated the feasibility of blood donor biobank and HLA imputation for the identification of potential cell donors homozygous for HLA alleles.MethodsWe imputed HLA-A, -B, -C, -DRB1, -DQA1, -DQB1 and -DPB1 alleles from genotypes of 20,737 Finnish blood donors in the Blood Service Biobank. We confirmed homozygosity by sequencing HLA alleles in 30 samples and by examining 36,161 MHC-located polymorphic DNA markers.ResultsThree hundred and seventeen individuals (1.5%), representing 41 different haplotypes, were found to be homozygous for HLA-A, -B, -C, -DRB1, -DQA1 and -DQB1 alleles. Ten most frequent haplotypes homozygous for HLA-A to -DQB1 were HLA-compatible with 49.5%, and three most frequent homozygotes to 30.4% of the Finnish population. Ten most frequent HLA-A-B homozygotes were compatible with 75.3%, and three most frequent haplotypes to 42.6% of the Finnish population. HLA homozygotes had a low level of heterozygosity in MHC-located DNA markers, in particular in HLA haplotypes enriched in Finland.ConclusionsThe present study shows that HLA imputation in a blood donor biobank of reasonable size can be used to identify HLA homozygous blood donors suitable for cell therapy, HLA-typed thrombocytes and research. The homozygotes were HLA-compatible with a large fraction of the Finnish population. Regular blood donors reported to have positive attitude to research donation appear a good option for these purposes. Differences in population frequencies of HLA haplotypes emphasize the need for population-specific collections of HLA homozygous samples.

CT-025 Impact of Stem Cell Source on Outcome of Allogeneic Stem Cell Transplantation in Pediatric Cancer

Allogeneic hematopoietic stem cell transplantation is an established option of therapy for many malignant and non-malignant diseases which involve the hematopoietic and immune systems. The numbers of patients who are eligible for this procedure are continuously increasing due to the better supportive care and the developments in the use of alternative donors and stem cell sources. A retrospective study included 159 patients transplanted at bone marrow transplantation unit, children cancer hospital Egypt (CCHE) 57357. All patients with high risk hematological malignancy were considered eligible. Stem cell source obtained for these patients was either bone marrow (BM) or peripheral blood (PB). HLA matching was either matched related donor (MRD) or haploidentical transplant. Impact of stem cell source on the outcome of these patients was analyzed. BM was the most commonly used graft source in 92.5% of cases with OS of 81.9% and EFS of 70.9%. PB was only used in 7.5% with 50% OS and 33.3% EFS (P value =0.021). MRD was used in 86% of patients, while 10.1% received their allograft from haploidentical donors. At the end of the study 64.8% of the patients were alive, 34.6% died while only one patient lost follow up. With median duration of follow up of 64 months, the 3-year overall survival of the whole patients was 64% Conclusions: Bone marrow has a better survival outcome as a source of stem cell in allogeneic SCT than peripheral blood. However, it should be noted than PB SCT was used in Juvenile myelomonocytic leukemia patients which is known to have the worst outcome when transplanted.

CML-006 CML Blastic Crisis Diagnosis Based on a Lymph Node Biopsy in an Egyptian Male Patient: A Rare Case Report

Chronic myeloid leukemia (CML) is a clonal myeloproliferative triphasic clinical disorder characterized by a distinct genetic abnormality: the BCR-ABL fusion gene (Philadelphia chromosome). The presence of blasts in the lymph node (LN) is enough for a diagnosis of blast-phase CML. The case study herein is a very rare presentation. A case report of a 53-year-old Egyptian male patient who presented in 2020 with night fever and sweats. Oncology Center Mansoura University. Examination revealed firm, non-tender, generalized cervical and bilateral axillary lymphadenopathy. The patient's abdominal examination revealed moderate, firm, and non-tender splenomegaly. Complete blood count: white blood cell count 239 k/µL, normocytic normochromic anemia with hemoglobin 11 g/dL, and platelet count 321 k/µL. Differential leukocyte count revealed blasts (1%), myelocytes (12%), metamyelocytes (25%), polymorphonuclear leukocytes (50%), eosinophils (2%), basophils (3%), and lymphocytes (2%). Bone marrow (BM) examination was hypercellular; 70% of the total BM cellularity was replaced by myeloid series highlighted by myeloperoxidase, and few blasts (<1%) were CD34+, suggesting chronic-phase CML. BCR-ABL1 gene rearrangement by Q RT-PCR was 65.9% IS. The patient started imatinib 400 mg/d. LNs were suspicious, and excisional biopsy showed multiple fatty nodules -3.5×3 cm; the cut section was firm, grayish white, partially effaced, and replaced by infiltrate of myeloid series (MPO+, CD3-, CD30-, and CD79a) with a high Ki67 proliferation index. LN infiltration suggested a CML blastic crisis despite the fact that repeated BM aspirate samples revealed no increase in blasts. However, the new BM biopsy (BMB) revealed that most of the cellularity was replaced by myeloid series with CD117+ (15%) and CD34+. Acute leukemia risk assessment revealed FLT3- and inv(16)+, and FISH analysis indicated t(9:22). The patient was refractory to ICT and imatinib and was shifted to salvage. Complete remission was confirmed by PET/CT scan and BMB; however, he did not achieve a molecular response (Q RT-PCR for BCR-ABL1 15% IS). He was switched to dasatinib with consolidation chemotherapy, and HLA matching was done for results. This case report highlights the importance of a rare CML presentation with extramedullary infiltrates. A myeloid sarcoma should be excluded before setting the treatment plan.

Clinical Efficacy and Survival Analysis of Adult Patients with Acute Myeloid Leukemia after Microtransplantation

To investigate the clinical efficacy and survival factors of microtransplantation (MST) in adult patients with acute myeloid leukemia (AML). For a retrospective analysis of 27 adult patients with AML receiving MST from July 2014 to October 2021, the median age was 59(29-77) years old, 13 cases were ≥60 years old, 14 case were <60 years old, 13 cases were male and 14 cases were female. Classification by FAB: AML-M2 6 cases, AML-M4 6 cases, AML-M5 2 cases, AML-M6 2 cases, AML（Undivided type） 9 cases, AML myeloid sarcoma 2 cases (primary AML 21 cases, AML secondary to MDS 6 cases). Cytogenetic analysis showed 25 patients with a normal karyotype, 2 patients with an abnormal karyotype, and 20 patients with an abnormal molecular biology. Induction chemotherapy regimens mainly include: IA, DA, MA or HA regimen, including CAG or CIG in combination with decitabine, and single-agent decitabine. 17 patients achieved complete remission (CR) after 1 course of induction chemotherapy and 4 patients achieved CR after 2 courses of induction chemotherapy. 3 patients received CR by four courses of decitabine, 2 patients received no remission, and 1 patient underwent no induction chemotherapy and were treated direct MST. There were 16 patients with pretransplant CR and 11 patients were not in remission before transplantation. Follow-up mainly used consult patient's medical records and telephone inquiry to observe the adverse effects and efficacy of MST treatment. Survival analysis was performed by Kaplan-Meier method, with the main observation indicators overall survival(OS) and leukemia-free survival(LFS), and performed with the Log-rank test. Multivariate analysis was performed by the Cox regression model. A total of 79 MST were performed in 27 AML patients with good overall safety and no special serious adverse effects. The median time of leukocyte recovery was 13(4-28) days, and the median time of platelet recovery was 13(4-30) days. There were 50 cases of infection, 5 cases of abnormal liver function and 3 cases of abnormal cardiac function. Except for abnormal cardiac function, all other complications did not affect the treatment and were cure. Acute or chronic GVHD, renal insufficiency, abnormal coagulation function, and severe bleeding were not observed during treatment or during follow-up. As of the follow-up date, the median follow-up time of the 27 patients was 79(14-171) months, the median OS time was 62(1-171) months, and the median LFS time was 15(0-171) months. The 2-year OS rate was 65.7%（17/27）, and the 2-year LFS rate was 47.4%（12/27） . The complete response rate of 27 patients treated with MST was 48.1% (13/27). 8 patients relapsed during MST treatment, including 7 patients after the completion of the first MST course and 1 patient after the completion of the second MST course. 2 patients relapsed after the end of the course of MST. 13 patients died, including 10 patients because of disease progression, two patients from severe infection, and one patient from cardiac damage. MST has the advantages of small toxic side effects, complete compatibility of HLA matching is not required, effective avoidance of GVHD and rapid hematopoietic recovery, which can improve OS and LFS in elderly AML and young AML patients, and is one of the treatment options for patients without HLA matching.

Eplet matching in pediatric heart transplantation: The SickKids experience.

Epitope-based tissue matching may be superior to HLA antigen matching. We compared antigen to molecular-level HLA matching on outcomes following pediatric heart transplantation (HTx). This is a retrospective, single centre cohort study (2013-2020). HLA antigen and eplet mismatch analyses were performed in HTx patients <18 years old. Primary endpoint was graft loss; secondary endpoints were rejection and cardiac allograft vasculopathy (CAV). A multivariable Cox regression analysis was used to examine associations between eplet or antigen mismatching and outcomes. A logistic regression analysis was performed to examine associations between eplet or antigen mismatching and outcomes. Seventy-seven patients (40% males) were included, with a median age at HTx 4.3 years [range 0.05-18]. Median HLA class I and II eplet mismatches were 10 (1-22) and 11 (1-23). Median class I and II antigen mismatches were 5 (1-6) and 4 (0-6). 9 patients (11.7%) died [median time 4 months (range 0.1-46)]. Eight (10.4%) patients developed AMR [median time 22 days (IQR=168)]. Twenty-one patients (27.3%) had acute cellular rejection [median time 40 days (IQR=85.5)]. In univariate analysis, patients with HLA Class II DPB eplet mismatches above the median for this cohort had an increased risk of graft loss (OR 5.3 [95%CI: 1.03-27.5], p=0.039). HLA eplet mismatching was not associated with rejection; antigen mismatching was not associated with either graft loss or rejection. In multivariable analysis, patients with HLA Class II DPB eplet mismatches above the median had an increased risk of graft loss (HR 8.14 [95% CI: 1.26-49], p=0.02). HLA eplet mismatching was not associated with rejection; antigen mismatching was not associated with graft loss or rejection. A logistic regression analysis including 'number of HLA Class II DPB eplet mismatches' correctly predicted 95.8% of the outcomes. In our cohort of pediatric heart transplant recipients, the number of HLA Class II DPB eplet mismatches was associated with graft loss. Molecular-level HLA matching is an emerging tool for graft loss risk stratification, but further study is required.

Comparable survival outcomes with haploidentical stem cell transplantation and unrelated bone marrow transplantation.

We retrospectively compared outcomes of unrelated donor bone marrow transplant (UBMT) and HLA-haploidentical peripheral blood stem cell transplantation using post-transplant cyclophosphamide (PTCy-haploPBSCT) using the Japanese registry data. Recipients of first HCT for acute leukemia and myelodysplastic syndromes between 2012 and 2015 were included. The analyzed subjects comprised UBMT recipients with 8/8 matched HLA alleles (n = 1470), 7/8 matched alleles (n = 859), 6/8 matched alleles (n = 186), and recipients of PTCy-haploPBSCT (n = 133). In multivariate analyses with 8/8 matched UBMT as the reference, PTCy-haploPBSCT showed similar overall mortality, decreased risk of non-relapse mortality (NRM), increased risk of relapse, and decreased risk of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD. Adjusted probabilities for 8/8 matched UBMT, PTCy-haploPBSCT, and 7/8 and 6/8 matched UBMT groups at 2 years post-transplant were 61%, 60%, 58%, and 52% for overall survival, 23%, 28%, 21%, and 19% for relapse, and 20%, 7%, 24%, and 33% for NRM. PTCy-haploPBSCT was associated with remarkably low NRM, contributing to survival outcomes that were comparable to 8/8 matched UBMT. The higher relapse rate in the PTCy-haploPBSCT group might be associated with the higher proportion of high-risk patients. PTCy-haploPBSCT may be a viable alternative when HLA-matched related donors are not available.

Abstract 30 Should Cord Blood Unit Distribution Patterns Impact Collection Strategies?

IntroductionThe National Cord Blood Program has a large inventory of clinical cord blood units (CBUs) available for transplant (more than 60,000). As a small proportion is distributed each year, new collections should theoretically replenish the inventory, but it is unclear which characteristics should be prioritized for banking.ObjectiveOur goal was to characterize distributed CBUs (in terms of cellularity, race/ethnicity, and match), compare them with the inventory, and devise a collection strategy.MethodsShipments from January 2015 to March 2022 were reviewed (n = 1,046). Race/ethnicity information on CBUs was obtained at the time of collection and was available for 55,934 stored CBUs and 1,020 distributed CBUs. It was also obtained for 394 recipients. HLA match was determined as HLA-A and B antigens and DRB1 allele match (/6), and allelic match as HLA-A, B, C, DRB1 allele match (/8). Total nucleated cells (TNC) and CD34 cells were counted at banking of the CBU, and cell doses (per kg of recipient’s weight) were calculated at shipment.ResultsThe proportion of White Non-Hispanic (WNH) CBUs distributed (38%) was lower than what is present in the inventory (46%), but match levels were higher among these units (Figure 1A and 1B), with 55% of WNH CBUs being 5/8 or higher, vs 40% for minorities’ CBUs. Race match between CBU and recipient led to higher matched transplants, but 41% of race mismatched CBUs still reached 6/8 or higher allele match. The median TNC was 102 × 107 for stored CBUs and 167 × 107 for distributed CBUs (Figure 1C). Better matched units have been selected with lower cell contents (Figure 1D).Figure 1.Distribution characteristics.DiscussionCBUs broaden transplant options across ethnic groups, and much focus has been placed on collecting minorities’ CBUs. However, our analysis showed that WNH CBUs are still the largest distributed population, with higher allele match to the recipient (predicting better transplant outcomes), so these CBUs should not be excluded from collection strategies. From the data presented here, the goal for new collections should be to obtain CBUs with higher TNC and CD34 (spreading across all races and ethnicities). These would replenish the pool of high cellularity CBUs that are more often selected for transplant.

P8.052: Long-term Outcomes and Predictors of Graft Function in Living-Donor Preemptive Kidney Transplants

Background: Beyond the new strategies for dialysis treatment, kidney transplantation has already been associated with better outcomes for patients with advanced kidney chronic disease (CKD), and a preemptive kidney transplant seems to be the preferred option for those patients. Thus, this study purposed to evaluate predictors of long-term graft function and unfavorable outcomes in living-donor preemptive kidney transplant recipients. Methods: Single-center cohort study enrolled 222 living-donor preemptive kidney transplant recipients transplanted between 2011 and 2016 and followed up to 2021. Five-year graft function was estimated by CKD-Epi (5-year-eGFR). The primary outcome was composed of death, graft loss, acute rejection, and 5-year-eGFR < 30 mL/min/1.73m2. The multivariable analysis for 5-year-eGFR was performed by linear regression and logistic regression for the primary outcome. Results: Recipients were 40 (31; 48) years old, 59.9% were male, and 35.1% had CKD due to chronic glomerulonephritis. Donors were 48.5 (41.0; 55.2) years old, being most frequently siblings (50%) or parents (28/8%). One-third of patients received ATG as an induction strategy (30.2%), followed by Tacrolimus + azathioprine (59.5%) or cyclosporin + azathioprine (14.4%) or tacrolimus + mycophenolate (11.3%) as the maintenance immunosuppression. The overall incidence of acute rejection, graft loss, and death was 20.3%, 6.3%, and 0.5%, respectively. The median follow-up time was 88.9 months, and the median 5-year-eGFR was 54.7 mL/min. Sixty-five patients presented the primary outcome (29.2%), significantly associated with the HLA compatibility, not using induction therapy and CMV-related event. Compared with identical HLA matches, the OR was 6.81 for haploidentical (P=0.001) and 11.2 for distinct (P<0.001) HLA matches. In addition, the probability for the primary outcome was reduced by 81% (OR= 0.19, p<0.001) for patients who received ATG as induction therapy and 4-fold higher in those who had CMV-related events (OR=4.09; p=0.001). In the linear regression, the association with 5-yr-eGFR was less evident with HLA matches and AR than donor age. Thus, the identical HLA (B= +6.04; p=0.09) match and AR (B=-6.34; p=0.07) tend to be associated with 5-year-eGFR in the linear regression, while donor age (B= -0,69 per year old; p<0.001) presented a significant and inverse association. Conclusion: In recipients of living-donor preemptive kidney transplants, the HLA matches, thymoglobulin induction therapy, and CMV-related events were predictors of composite outcomes of long-term death, graft loss, acute rejection, and low grade of graft function. In addition, only donor age was independently associated with long-term graft function.