Blood Grafts Research Articles

Peripheral Blood Haploidentical Allogeneic Stem Cell Transplantation in Older Adults with Acute Myeloid Leukemia and Myelodysplastic Syndromes Demonstrates Long Term Survival, Results from Australia and New Zealand Transplant and Cellular Therapies

There is a limited body of evidence for haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in older patients. Previous studies have used a high proportion of bone marrow–derived grafts and a variety of conditioning regimens. In Australia and New Zealand, haplo-HCST is predominantly performed using peripheral blood (PB) with universal use of post-transplantation cyclophosphamide (PTCy). To characterize the outcomes of older recipients undergoing haplo-HSCT for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Data were collected through the Australasian Bone Marrow Transplant Recipient Registry (ABMTRR) for patients aged 65 or older receiving a PB haplo-HSCT for AML/MDS between January 2010 and July 2020. A total of 44 patients were included in the analysis. The median follow-up time was 377 days. The median age was 68 (range 65-74) with a median Karnofsky performance status of 90. Thirty patients (68.2%) had AML, whereas 14 (31.8%) had MDS. The median donor age was 40. The most common conditioning regimen was nonmyeloablative fludarabine, cyclophosphamide, and total body irradiation (75%); the remainder of the patients received either melphalan- or busulfan-based regimens, and the majority were reduced intensity, with only 2 patients undergoing myeloablative conditioning. All patients received post-transplantation cyclophosphamide and mycophenolate mofetil, with the majority also receiving tacrolimus (90.5%) and the remainder receiving cyclosporine (9.5%). No patients received anti-thymocyte globulin. Neutrophil engraftment was achieved in 97.6% of patients at a median of 18 days, whereas platelet engraftment was achieved in 92.7% of patients at a median of 28 days. The cumulative incidences of cytomegalovirus (CMV) reactivation and CMV disease were 52.5% and 5.1% at 1 year. The incidence of grade 2-4 acute Graft Versus Host Disease (GVHD) was 18.2%. The incidence of chronic GVHD at 2 years was 40.7%, with extensive chronic GVHD occurring in 17.7% of patients. The incidences of relapse and non-relapse mortality (NRM) at 2 years were 8.8% and 20.7% respectively. The leading causes of death were infection (64.7%) followed by relapse (14.2%). The 2-year overall survival was 74%. Relapse free survival and GVHD free, relapse free survival at 2 years was 70% and 48%. Haplo-HSCT using a peripheral blood graft and PTCy GVHD prophylaxis demonstrates long-term disease control with acceptable rates of NRM for older patients with AML/MDS.

Haploidentical Hematopoietic Cell Transplantation Combined with an Unrelated Cord Blood Unit for Adult Acute Myeloid Leukemia Results in Improved Survival Compared to Haploidentical Hematopoietic Cell Transplantation: Results of a Multicenter, Randomized, Phase III Trial

Introduction Haploidentical hematopoietic cell transplantation (haplo-HCT) is a potent treatment to improve the prognosis of acute myeloid leukemia (AML), but relapse and graft-versus-host disease (GVHD) related to dysregulation of alloreactivity are still the main causes of death posttransplantation. Cord blood graft usually has a promising graft-versus-leukemia effect with a lower cumulative incidence of GVHD. To improve the transplantation strategy, haplo-cord HCT combining haploidentical and unrelated cord blood (UCB) grafts (haplo-cord HCT) has been attempted. Previous studies showed significant improvement in prognosis in B-cell acute lymphoblastic leukemia or refractory acute leukemia patients with haplo-cord HCT compared to haplo-HCT. However, outcomes of haplo-cord HCT for AML patients are not yet clear. This is the first multicentric randomized trial designed specifically for the efficacy and safety of haplo-cord HCT for AML. Methods This is a multicenter, randomized, open-label, phase III study conducted in 5 centers in China (NCT03719534). Patients aged 18-60 years, diagnosed with AML (except for acute promyelocytic leukemia) with measurable residual disease, had an available haploidentical donor and were suitable for allotransplantation were enrolled. Patients were randomized 1:1 to receive UCB and haploidentical grafts infusion after Bu/Cy-based regimen or haploidentical graft infusion only after Bu/Cy-based regimen. The UCB unit, which had at least 3/6 matched HLA loci to the recipient and more than 1×10 4 CD34 + cells/kg of recipient weight, was infused immediately after resuscitation and eight hours before the haploidentical graft infusion. The primary endpoint was 3-year overall survival (OS) and secondary endpoints included progression-free survival (PFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). Results From June 1, 2017, to June 30, 2021, 268 patients were enrolled (Table 1). With a median follow-up of 36.00 months, the 3-year OS was 80.5% (95% CI 73.7-87.9) in the haplo-cord HCT group and 67.8% (95% CI 60.0-76.5) in the haplo-HCT group, respectively (p=0.013, figure 1A). Haplo-cord HCT group showed favorable 3-year PFS and CIR than haplo-HCT group (PFS: 70.3%, 95% CI 62.6-78.8 vs. 57.6%, 95% CI 49.6-67.0, p=0.012; CIR: 12.1%, 95% CI 12.0-12.2 vs. 30.3%, 95% CI 30.1-30.4, p=0.024, figure 1B,C). The 3-year NRM was similar in the two groups (figure 1D). Within two years posttransplantation, the most common grade 3-4 adverse events (AEs) in the haplo-cord HCT and haplo-HCT groups were infections (33.8% and 29.1%), acute GVHD (20.3% and 12.7%) and chronic GVHD (12.0% and 16.4%). AEs leading to death occurred in 8.3% of haplo-cord HCT and 14.9% haplo HCT patients. Post- hoc analysis showed similar median levels of haploidentical chimerism in bone marrow (BM) between the two groups. However, UCB microchimerism was detected in the haplo-cord HCT patients by SNP-NGS in +1m posttransplantation (BM: 0.3%, IQR 0.04-1.6; peripheral blood: 0.06%, IQR 0.03-0.4) and its chimerism percentage decreased with time (figure 1E). Compared to haplo-HCT group, haplo-cord HCT group showed a faster cumulative incidence of neutrophil recovery (p=0.026, figure 1F) and a similar cumulative incidence of platelet recovery. Monitor of immune reconstitution showed a more rapidly increasing rate of T cells in the early period after transplantation in the haplo-cord HCT group (figure 1G). Improved recovery of Th2 (p=0.042), Th17 (p=0.047), Treg (p=0.045), and Tc2 (p=0.045) cells was observed in haplo-HCT group. Conclusions Coinfusion of a UCB unit in haplo-HCT can improve OS in AML patients without excessive AEs, and affect T-cell reconstitution pattern posttransplantation. Haplo-cord HCT could serve as a suitable therapeutic option for this patient population.

Longitudinal Blood Count Analysis Reveals That Poor Graft Function after Pediatric Hematopoietic Cell Transplantation Is a Common Complication Associated with Poor Outcome

Background Poor graft function (PGF) is an important complication of allogeneic hematopoietic cell transplantation (allo-HCT), predisposing to infections, bleeding complications and mortality. The reported incidence and outcome of PGF differ between studies, which may partially be explained by differences in patient cohorts and HCT strategies. Pediatric HCT differs from the adults setting in several aspects, such as the underlying disease and use of relatively young donors, including cord blood. To date, however, information on the incidence and outcome of PGF in pediatric HCT recipients is limited. Aim To determine the incidence, risk factors and outcome of poor graft function in pediatric HCT recipients. Methods Longitudinal blood count and transfusion data from 63.219 measurements were retrieved from the Utrecht Patient Oriented Database (ten Berg et al., Clin Chem Lab Med, 2007) to investigate PGF in pediatric recipients of a first HCT. Patients with less than 5 measurements within the first 30 days or 10 measurements within the first 100 days post-HCT were excluded. In line with published definitions, PGF was defined as cytopenia and/or transfusion dependence for 3 consecutive days after day 28 in ≥2 lineages simultaneously, and patients with relapse, grade III-IV GvHD and/or rejection were excluded (Müskens et al., Blood Reviews, 2023). Cytopenias were defined as thrombocytes <20x10 9/L, neutrophils <0.5x10 9/L and hemoglobin <7 g/dL (Kong et al., Biol Blood Marrow Transplant, 2013). Individual and cohort-wide reconstitution patterns of thrombocytes, neutrophils, and hemoglobin after HCT were analyzed and used to identify patients with PGF. Cumulative incidence and survival analyses were conducted using the {survival} R package. Probability of overall survival (OS) and event-free survival (EFS), defined as retransplantation-free, stem-cell-boost free survival, were calculated using the Kaplan-Meier estimate and compared at one year using the log-rank test. Risk factors for PGF and EFS were assessed in univariable and multivariable Cox proportional hazard models. Results Among 348 pediatric recipients who met the inclusion criteria, we identified 53 patients that fulfilled the criteria for PGF, resulting in a cumulative incidence of 0.15 (95% confidence interval (CI): 0.11-0.18). Risk factors for PGF included HCT for hematological disease (p = 0.03) and from an HLA-mismatched donor (p < 0.01). No difference in PGF incidence was observed between recipients of cord blood and bone marrow donors. The one-year OS (1Y OS) of patients in the PGF group was 71% (95% CI: 59-85%), compared to 91% (95% CI: 87-94%) in the good graft function (GGF) group (p < 0.0001, Figure 1A). Infectious disease was the cause of death in 47% in the PGF group, compared to 27% in the GGF group (p = 0.21). The 1Y EFS was 53% (95% CI: 41-68%) in the PGF group, compared to 90% (95% CI: 86-93%) in the GGF group (p < 0.0001, Figure 1B). Conclusion PGF is a common complication in pediatric HCT recipients. No difference in PGF incidence was observed between bone marrow and cord blood grafts. Both patient-specific (underlying disease) and donor-specific (HLA-matching) may contribute to its pathophysiology. PGF patients show a marked reduction in overall and event-free survival, highlighting the need for therapeutic strategies to prevent and/or treat PGF after HCT.

Clonal Hematopoiesis Is Common in Long-Term Survivors of Pediatric Hematopoietic Cell Transplantation, Including Umbilical Cord Blood Transplantation

Background 1. Approximately 20.000 to 200.000 hematopoietic stem and progenitor cells (HSPCs) contribute to steady-state adult hematopoiesis. During ageing, the overall diversity of the HSPC pool decreases, which is in part driven by the selective expansion of HSPC clones with driver mutations, a process called clonal hematopoiesis (CH). CH is an age-related condition that predisposes to hematologic malignancy, cardiovascular disease, and all-cause mortality. Hematopoietic stem cell transplantation (HCT) recipients are at increased risk of CH, but the mechanisms driving the emergence and expansion of CH clones are largely unknown. Furthermore, the prevalence of CH in pediatric HCT recipients, in whom the long-term consequences of CH are particularly relevant, remains to be defined. Aim To determine the prevalence and risk factors of CH in long-term survivors of HCT at pediatric age. Methods We included survivors of HCT at pediatric age, with a minimum survival of 5 years after HCT. CH was assessed by targeted, error-corrected sequencing of mutations in 27 cancer driver genes in whole blood, at a variant allele frequency detection threshold of 1%. HSC age was calculated by the sum of the age of the donor and the interval after HCT. In case the age of a donor was unknown (n=53), the median age for donors of the same donor relation were used (i.e., 12.6 years for sibling donors and 28.7 for matched unrelated donors). Clinical characteristics were compared using the Wilcoxon signed ranked test for continuous variables and Chi-squared or Fisher's exact test for categorical variables. Results Here, we report the interim results of the first 120 HCT survivors in this study. The median age of the survivors was 20.4 years (range 6.7-51.8), and the median interval after HCT was 11.8 years (range 5.2-38.2). Indications for HCT were hemato-oncology (n=95), bone marrow failure (n=22), or immune deficiency (n=3). The median calculated age of the HSCs was 31 years (range 5.2-61.8). CH was present in 13.3% of survivors (n=16). Mutated genes were DNMT3A (n=15), TET2 (n=4) and MPL (n=1), with three individuals having more than one driver mutation. The median variant allele frequency of the CH clones was 2.2%, but allele frequencies up to 30% were found. No differences were observed in recipient age or interval after HCT between individuals with or without CH (Figure 1A). However, the age of the HSCs was significantly higher in individuals with CH compared to those without (38.6 versus 26.3 years, p = 0.01, Figure 1B). Surprisingly, we detected CH in two recipients of umbilical cord blood grafts, at an interval of 11 and 15 years after HCT. Conclusion Clonal hematopoiesis is common in long-term survivors of pediatric HCT. After HCT, the prevalence of CH is related to the age of the transplanted HSCs, rather than the age of the survivor. The presence of CH in cord blood HSCs within two decades after HCT suggests that HCT-related factors may drive the de novo emergence and/or outgrowth of donor-derived CH. Ongoing research is aimed at investigating how factors such as stem cell source and post-transplant complications affect clonal expansion after HCT. Furthermore, we are investigating the prevalence of CH in an age-matched control cohort using the same detection pipeline, enabling direct comparison of the prevalence of CH in HCT survivors compared to the general population.

Value of blood lipid in predicting graft dysfunction after organ and tissue transplantation: A study of Mendelian randomization

BackgroundWhile immunosuppressive regimens have improved outcomes in solid organ transplantation, non-immune factors have also been identified as contributors to graft prognosis. Age, gender, hormones, heredity, and other diseases have been recognized to affect organ transplantation. However, the causal relationship between blood lipids and graft dysfunction remains unverified in human clinical investigations. In this study, we employed two-sample Mendelian randomization (MR) to examine the causality between different types of blood lipids and graft dysfunction following organ and tissue transplantation. MethodsWe conducted a two-sample MR study using available genome-wide association summary data from the online database MRBASE (http://app.mrbase.org/), which encompasses over 11 billion associations between genetic factors and health-related outcomes, enabling researchers to explore various potential determinants of poor health. The exposure factors included four types of blood lipids: high-density lipoprotein, low-density lipoprotein, cholesterol, and triglycerides. For each exposure factor, three databases were selected for analysis. The outcome factor was the failure and rejection of transplanted organs and tissues. All databases consisted of European population samples, without specific subgroups. The related studies were conducted between 2016 and 2022, and the "TwoSampleMR" R package was employed for variant selection. ResultsA total of 13 sample groups were collected and analyzed. The results revealed a causal association between blood lipids and graft dysfunction following organ and tissue transplantation. Specifically, the two-sample MR analysis confirmed that low-density lipoprotein and cholesterol levels were significant risk factors for increased graft dysfunction risk after transplantation. Moreover, high-density lipoprotein potentially reduced the risk of allograft dysfunction, while triglycerides possibly elevated the risk. ConclusionsOur recent study provides the initial confirmation that blood lipids may initiate causal pathological processes leading to graft dysfunction after organ and tissue transplantation.

Loss of CD34+ Cells and Effect of the Number of Viable Cryopreserved CD34+ Cells in the Infused Blood Grafts on Hematologic Recovery, Progression-Free Survival and Overall Survival in NHL Patients After Autologous Stem Cell Transplantation

PatientsThis post-hoc study aimed to find out factors affecting graft viable CD34+ cell loss during processing and cryopreservation in 129 non-Hodgkin lymphoma (NHL) patients receiving autologous stem cell transplantation (auto-SCT) and the impact of a low (< 2.0 × 106/kg, group A) and a decent number (≥ 2 × 106/kg, group B) of viable CD34+ cells infused on the hematologic recovery, progression-free survival (PFS) and overall survival (OS) after auto-SCT. ResultsThe median loss of viable CD34+ cells during cryopreservation was higher in group A (47% vs. 19%, p < .001). A higher yield of CD34+ cells at the first apheresis in group B (p = .002) was linked with greater loss of viable graft CD34+ cells after cryopreservation. Filgrastim (FIL) use for mobilization seemed to associate with higher viable CD34+ cell loss compared to pegfilgrastim (PEG) or lipegfilgrastim (LIPEG) in both groups (in group A FIL 66 vs. PEG 35%, p = .006; in group B FIL 37 vs. PEG 15 vs. LIPEG 13%, p < .001). Hematologic recovery after auto-SCT was faster in group B. Neither viable CD34+ cell loss during storage nor viable CD34+ cell number < 2.0 × 106/kg infused affected on PFS or OS. ConclusionsG-CSF type used in mobilization and mobilization capacity were found to correlate with viable CD34+ cell loss during processing and storage. Most importantly, low infused viable CD34+ cell count did not seem to impact on PFS or OS.

Excellent leukemia control after second hematopoietic cell transplants with unrelated cord blood grafts for post-transplant relapse in pediatric patients.

Patients with leukemia relapse after allogeneic hematopoietic cell transplant (HCT) have poor survival due to toxicity and disease progression. A second HCT often offers the only curative treatment. We retrospectively reviewed our bi-institutional experience (MSKCC-USA; Utrecht-NL) with unrelated cord blood transplantation (CBT) for treatment of post-transplant relapse. Overall survival (OS) and event-free survival (EFS) were evaluated using the Kaplan-Meier method, treatment-related mortality (TRM) and relapse were evaluated using the competing risk method by Fine-Gray. Twenty-six patients age < 21 years received a second (n=24) or third (n=2) HCT with CB grafts during the period 2009-2021. Median age at first HCT (HCT1) was 11.5 (range: 0.9-17.7) years and all patients received myeloablative cytoreduction. Median time from HCT1 to relapse was 12.8 (range 5.5-189) months. At CBT, median patient age was 13.5 (range 1.4-19.1) years. Diagnoses were AML: 13; ALL: 4, MDS: 5, JMML: 2; CML: 1; mixed phenotype acute leukemia: 1. Sixteen patients (62%) were in advanced stage, either CR>2 or with active disease. Median time from HCT1 to CBT was 22.2 (range 7-63.2) months. All patients engrafted after CBT. Thirteen patients developed acute GvHD; 7 had grade III or IV. With a median survivor follow-up of 46.6 (range 17.4-155) months, 3-year OS was 69.2% (95% CI 53.6-89.5%) and 3-year EFS was 64.9% (95% CI 48.8-86.4%). Eight patients died, 3 of AML relapse and 5 due to toxicity (respiratory failure [n=4], GvHD [n=1]) at a median time of 7.7 (range 5.9-14.4) months after CBT. Cumulative incidence of TRM at 3 years was 19.2% (95% CI 4.1-34.4%). Notably, all TRM events occurred in patients transplanted up to 2015; no toxicity-related deaths were seen in the 16 patients who received CBT after 2015. Cumulative incidence of relapse was 15.9% (95% CI 1.6-30.2%) at 3 years, remarkably low for these very high-risk patients. Survival was very encouraging following CB transplants in pediatric patients with recurrent leukemia after first HCT, and TRM has been low over the last decade. CBT needs to be strongly considered as a relatively safe salvage therapy option for post-transplant relapse.

Evaluation of effectiveness of advanced platelet rich fibrin (A-PRF) with demineralized freeze-dried bone allograft (DFDBA) placed into fresh extraction sockets with immediate implant placement: A clinical and radiographic study

Background: Dental implant placement has evolved over time with the introduction of numerous novel protocols. Following tooth extraction throughout the healing phase, alveolar ridge resorption is a potential issue that can be mitigated by the utilisation of a variety of techniques, one of which is the placement of immediate implants. The immediate implant treatment protocol offers numerous benefits, such as minimal surgical procedures, which thereby reduce overall treatment time, preserve bone height, and produce better aesthetic results, particularly in the anterior region. Such protocols have made implant insertion so much easier that results can now be anticipated more precisely. The distance between the lateral surface of an implant and surrounding alveolus is known as the jumping gap distance (JGD). JGD of &gt;1.5 mm affects spontaneous bone healing. Research incorporating biomaterials such as membranes produced from blood and bone grafts has significantly contributed to the success of this therapy. Methods: This research will be carried out over the course of a year. Twelve implants will be placed in systemically healthy individuals with one tooth/teeth in the maxilla and/or mandible indicated for extraction. Using a two-stage protocol, implant placement will be done simultaneously after extraction along with augmentation with A-PRF and DFDBA. The second stage surgery will be conducted three months after implant placement. Within 3-6 weeks, abutments will be connected and the final prosthesis will be placed. Expected results: Crestal bone changes and implant stability after using of A-PRF and DFDBA will serve as indicators to determine the implant's success after 6 months. Conclusion: The augmentation procedures have shown to be successful in obtaining bone fill and in resolving bone defects that are present in proximity with implants. An immediate implant placement along with bone augmentation may decrease resorption of horizontal bone. Trial registration: REF/2023/03/064371.

Impact of Donor Age in Haploidentical-Post-Transplantation Cyclophosphamide versus Matched Unrelated Donor Post-Transplantation Cyclophosphamide Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

Haploidentical hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis is associated with inferior overall survival (OS) compared to HLA-matched unrelated donor (MUD) HCT with PTCy prophylaxis in patients receiving reduced-intensity conditioning (RIC). Given prognostic implications of donor age, we investigated the differences in outcomes of patients with acute myeloid leukemia (AML; n=775) undergoing RIC-HCT with a younger MUD (age <35 years; n=84) versus a younger haploidentical donor (age <35 years; n=302) versus an older haploidentical donor (age ≥35 years; n=389). The older MUD group was excluded from the analysis because of small numbers. The younger haploidentical donor group (median age, 59.5 years) was somewhat younger than the younger MUD group (median age, 66.8 years) and the older haploidentical donor group (median age, 64.7 years). More patients in the MUD group received peripheral blood grafts (82%) compared to the haploidentical donor groups (55% to 56%). In multivariate analysis, compared to the younger MUD group, the younger haploidentical donor group (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.12; P=.005) and the older haploidentical donor group (HR, 2.36; 95% CI, 1.50 to 3.71; P < .001) had a significantly inferior OS, and the younger haploidentical donor group (HR, 3.72; 95% CI, 1.39 to 9.93; P=.009) and older haploidentical donor group (HR, 6.91; 95% CI, 2.75 to 17.39; P < .001) had a significantly higher risk of nonrelapse mortality. The older haploidentical group had a significantly higher risk of grade II-IV acute GVHD (HR, 2.29; 95% CI, 1.38 to 3.80; P=.001) and grade III-IV acute GVHD (HR, 2.70; 95% CI, 1.09 to 6.71; P=.03). There were no significant differences across the groups in the incidence of chronic GVHD or relapse. Among adult AML patients in CR undergoing RIC-HCT with PTCy prophylaxis, a young MUD may be preferred over a young haploidentical donor.

Cord blood grafts for patients with HIV?

Since CCR5 is a key co-receptor for HIV entry into cells, replacing an HIV patient's cells with CCR5-deficient cells is thought to protect the new hematopoietic/immune system from infection. In this issue of Cell, Hsuetal. show that transplanting a cord blood graft carrying the CCR5Δ32 mutation led to a durable HIV remission in a patient with HIV and leukemia.

41 - A Pilot Study of UM171 Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Stem Cell Transplant in High and Very High-Risk Myeloma Patients

41 - A Pilot Study of UM171 Expanded Cord Blood Grafts for Tandem Auto/Allogeneic Stem Cell Transplant in High and Very High-Risk Myeloma Patients

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., &amp;lt;7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (&amp;lt;6/8) HCT recipients (75% vs. 76%, respectively; P &amp;gt;0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = &amp;gt;0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.

Effector Memory-Expressing CD45RA (TEMRA) CD8+ T Cells from Kidney Transplant Recipients Exhibit Enhanced Purinergic P2X4 Receptor-Dependent Proinflammatory and Migratory Responses.

The mechanisms regulating CD8+ T cell migration to nonlymphoid tissue during inflammation have not been fully elucidated, and the migratory properties of effector memory CD8+ T cells that re-express CD45RA (TEMRA CD8+ T cells) remain unclear, despite their roles in autoimmune diseases and allotransplant rejection. We used single-cell proteomic profiling and functional testing of CD8+ T cell subsets to characterize their effector functions and migratory properties in healthy volunteers and kidney transplant recipients with stable or humoral rejection. We showed that humoral rejection of a kidney allograft is associated with an accumulation of cytolytic TEMRA CD8+ T cells in blood and kidney graft biopsies. TEMRA CD8+ T cells from kidney transplant recipients exhibited enhanced migratory properties compared with effector memory (EM) CD8+ T cells, with enhanced adhesion to activated endothelium and transmigration in response to the chemokine CXCL12. CXCL12 directly triggers a purinergic P2×4 receptor-dependent proinflammatory response of TEMRA CD8+ T cells from transplant recipients. The stimulation with IL-15 promotes the CXCL12-induced migration of TEMRA and EM CD8+ T cells and promotes the generation of functional PSGL1, which interacts with the cell adhesion molecule P-selectin and adhesion of these cells to activated endothelium. Although disruption of the interaction between functional PSGL1 and P-selectin prevents the adhesion and transmigration of both TEMRA and EM CD8+ T cells, targeting VLA-4 or LFA-1 (integrins involved in T cell migration) specifically inhibited the migration of TEMRA CD8+ T cells from kidney transplant recipients. Our findings highlight the active role of TEMRA CD8+ T cells in humoral transplant rejection and suggest that kidney transplant recipients may benefit from therapeutics targeting these cells.

Phase II Study of Myeloablative 8/8- or 7/8-Matched Allotransplantation with Post-Transplant Cyclophosphamide, Tacrolimus, and Mycophenolate Mofetil: Marked Reduction in Gvhd Risk without Increased Relapse Risk Compared to Historical Cyclosporine/Methotrexate

Introduction Allogeneic hematopoietic cell transplantation (HCT) is the only potentially curative treatment for many high-risk hematologic malignancies. Myeloablative conditioning (MAC) is currently the standard of care for young and fit patients; however, graft-versus host disease (GVHD) continues to be a major limitation to the success of HCT, increasing post-transplant morbidity and mortality. An ideal HCT is one that combines strategies to reduce the incidence and severity of GVHD, without compromising graft versus-tumor effect. We hypothesized that the GVHD prophylaxis regimen consisting of post-transplant cyclophosphamide (PTCy), tacrolimus (Tac) and mycophenolate mofetil (MMF) would reduce the incidence of chronic GVHD in patients receiving a standard MAC HCT without an increase in risk of malignant relapse. Methods This is an analysis of a phase II study at the University of Minnesota using a MAC regimen of either: 1. total body irradiation (TBI, total dose 1320 cGy administered twice a day from days -4 to -1) or 2. Busulfan 3.2mg/kg daily (cumulative AUC 19,000 - 21,000 μmol/min/L) plus fludarabine 160mg/m2 days -5 to -2 for patients unable to receive further radiation, followed by a GVHD prophylaxis regimen of PTCy (50mg/kg days +3 and +4), Tac and MMF (beginning day +5). The primary endpoint is cumulative incidence of chronic GVHD requiring systemic immunosuppressive treatment at 1 year post-transplant. Eligibility included: age ≤ 60 years, malignant or non-malignant diagnosis, matched related (MRD) or unrelated (MUD) donor with either a bone marrow (BM) or filgrastim-mobilized peripheral blood (PB) graft. We compared those results to our previous MAC protocol which utilized a regimen of either cyclophosphamide (60mg/kg days -6 and -5)/TBI (1320 cGy administered twice a day from days -4 to -1) or busulfan (0.8 mg/kg/dose IV in 4 daily doses days -9 to -6 [total 12.8 mg/kg])/ cyclophosphamide (50 mg/kg days -5 to -2) and GVHD prophylaxis consisted of cyclosporine and methotrexate. Results Through June 2022, we treated 125 patients with a median follow up of 472 days post-transplant. Of those, 48% were female and 22 (17.6%) were ≤ 18 years old with median age at HCT of 38 years (range, 1-59 yrs; Interquartile range [IQR], 22-50 yrs). Donor source was 8/8 MRD in 69 patients (55.2%), 8/8 MUD in 44 (35.2%), and 7/8 MUD in 12 (9.6%). Graft source was bone marrow in 43 patients (34.4%) and PB in 82 (65.6%). Preparative regimen was TBI in 89.6% of patients. 124 of 125 patients achieved primary neutrophil engraftment by 42 days, median 16 days (range, 13-30). 119 of 125 achieved platelet engraftment by 6 months, median 25.5 days (range, 14-98). 91 patients (72.8%) required total parenteral nutrition (TPN) for oral mucositis and regimen-related toxicities during their initial transplant admission. Cumulative incidence of Grade II-IV acute GVHD by day +100 was 16% (95% confidence interval (CI): 9-23%); Grade III-IV acute GVHD was 4% (CI: 0-8%). No patients experienced grade IV GVHD and there were no deaths due to GVHD. At 1 year, only 3 of 105 patients developed chronic GVHD requiring immune suppression, for a cumulative incidence of 4% (CI: 0-8%). Two-year cumulative incidence of relapse was 25% (CI: 15-36%). Two-year overall survival was 80% (CI: 69-87%) and two-year GVHD-free relapse free survival (GRFS) was 57% (CI: 45-67%). Kaplan-Meier curves comparing overall survival and GRFS between this cohort and our previous MAC protocol without PTCy are shown in Figure 1. Figure 2 shows the comparison between these two consecutive cohorts in incidence of acute and chronic GVHD, transplant-related mortality (TRM) and relapse. Discussion Myeloablative HCT with a TBI or Busulfan/Fludarabine-based preparative regimen, followed by a GVHD prophylaxis regimen of PTCy, Tac, and MMF results in extremely low incidence of chronic GVHD, the primary objective of this clinical trial. Importantly, this regimen is feasible and effective for pediatric and adult patients. Further improvement in outcomes could potentially be achieved by incorporating post-transplant relapse mitigating strategies as well as supportive care measures to decrease regimen-related toxicities. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Artificial Intelligence Methods to Estimate Overall Mortality and Non-Relapse Mortality Following Allogeneic Hematopoietic Cell Transplantation in the Modern Era: An EBMT Transplant Complications Working Party Study

Introduction Allogeneic hematopoietic cell transplantation (alloHCT) is a life-saving procedures for many hematological diseases. However, its toxicity counterbalances its curative potential. Several prognostic scores have been created in the last two decades. Most scores derive from small sized and monocentric cohorts of patients. Also, contemporary patients and alternative donors are usually excluded from these scores. Methods We selected patients from the EBMT registry with the following characteristics: age > 18 years old; allogeneic hematopoietic cell transplantation (alloHCT) performed between 2010 and 2019; hematological disease diagnosis (AML/ALL; MDS/MPN; NHL/HL; plasma cell dyscrasias); any disease status at transplant; use of HLA-matched (familiar or unrelated) or haploidentical donor; myeloablative or RIC/NMA conditioning regimen; peripheral blood or bone marrow graft source. The primary objective was to create a prognostic score able to predict overall mortality (OM) at +2 years. The secondary objective was to predict non-relapse mortality (NRM) at 2 years. To create a newer prognostic score, we explored the following statistic and machine-learning techniques: step-wise logistic regression, support vector machine with linear and radial kernels, random forest, gradient boosting, elasticnet. We also tested simple fully connected neural network. The score included all the pre-transplant variables with a well-known prognostic role in terms of NRM related to disease (disease type) patient (age, gender, Karnofsky score, body mass index, presence of significant comorbidities, CMV status) transplant (time from diagnosis to transplant, donor type, GVHD prophylaxis, conditioning intensity, graft type) and transplant center characteristics (JACIE accreditation, > 20 alloHCT/year). OM model development was made on 70% of the data set, optimized on 15% and validated on the 15% of remaining data. Models with the best accuracy were selected to build the prognostic score. Results A total of 48984 patients were included into the analysis (Table 1). Median follow-up time for survivors was 38.4 months. Overall mortality and NRM at +2 years were 39.5% (95% CI=39.0-40.0%) and 19.0% (95% CI=18.5-19.5%), respectively. The 5 models predicted 2-year OM and NRM with similar AUC values. Best models were, for OM, gradient boosting (XGBoost) with AUC=0.64 (95% CI 0.630-0.655) and for NRM, elasticnet with AUC=0.58 (0.566-0.594). Neural networks had slightly higher performance for NRM but has limitations regarding the explicability of results. Same results were observed also when performing the analysis with the haploidentical cohort (n=5.934, AUC 0.66 for OM and 0.57 for NRM). In the final prognostic score including all the variables, gradient boosting was used to predict OM and elasticnet to predict NRM. The score was able to furnish a personalized prediction for each patient with continuous values. Patients with the lowest score had a 2-year OM and NRM of 22.2% and 8.7%, respectively. Patients with the highest score had a 2-year OM and NRM of 81.2% and 87.1%, respectively. A visual representation of the score prediction distribution was made on the validation cohort grouping the potential results into 4 groups (figure 1). Conclusion Our score showed to be useful in improving risk stratification of OM and NRM in the current era, including haploidentical transplants and post-transplant cyclophosphamide GVHD prophylaxis which were not included in previous scores. However, a generally poor accuracy despite the robust methodology confirms previous observations highlighting that the results of a prognostic score itself should not be used to exclude patients from a life-saving procedure. In such high-risk cases, more comprehensive evaluations (e.g. geriatric scores), biological scores (e.g. EASIX scores) and the overall patient's clinical phenotype should be evaluated to establish the actual transplantation risk and help in this difficult therapeutic choice Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Blood or Marrow Transplantation (alloBMT) Using Haploidentical Grandchildren Donors and Post-Transplant Cyclophosphamide (PTCy) -Based Gvhd Prophylaxis

Background: High dose PT-Cy allows the safe and effective use of haploidentical relatives as an allograft source. This platform increased the pool of related donors to include haploidentical siblings, parents, and children; more recently, second-and third-degree relatives have also been shown to be safe allograft donors. There is no consensus on the ideal donor; our standard practice is to prioritize young relatives such as siblings, children, or rarely parents- is safe and feasible. AlloBMT using nonmyeloablative (NMA) conditioning is safe and feasible in select patients aged 70 and above, a large group with hematologic malignancies. An increasing number of older patients have been treated with allogeneic blood or marrow transplantation (alloBMT) using related haploidentical donors. Older patients are more likely to have older siblings and children, and recent reports associated older donor age with worse outcomes. Therefore, we report the safety and utility of grandchildren (GC) as haploidentical donors and compare outcomes to patients with children donors. Methods: We reviewed records of patients at Johns Hopkins Hospital who received T-cell replete related allogeneic haploidentical donor blood or marrow grafts. We identified eight hundred and seven consecutive adults (≥18 years) between May 1, 2016, to October 1, 2021. Patients with aggressive myeloid and lymphoid malignancies were included. Only the first transplant was included for patients who received more than one transplant. All patients received NMA conditioning consisting of fludarabine, cyclophosphamide, and total body irradiation at 200 or 400 cGy. GVHD prophylaxis consisted of PT-Cy on days 3 and 4, followed by mycophenolate mofetil and either tacrolimus or sirolimus starting on day 5. Statistical analysis was performed using t-test, Wilcoxon rank sum test, or Chi-square test. Overall survival (OS), progression-free survival (PFS), relapse and non-relapse mortality (NRM) were estimated using Kaplan-Meier methods. Additionally, propensity score matching analysis (PSMA) for patient's age, BMT year, and graft source was performed. Results: Analysis was done on four hundred and sixty patients who received grafts from children donors and twenty-nine grandchildren donors. The median follow-up for patients was 28.8 (range 0.2 - 70.8) and 30 (range 0.8-50.4) months in children and GC, respectively. The most common diagnosis in both groups was acute leukemia compromising about a third of the patients, followed by myelodysplastic syndrome/ myeloproliferative disorders and Non-Hodgkin's (Table 1). Median age of patients in the GC group was 11 years older, 73 years (range 57-78) compared to 62 years (range 36 - 78) in the children group. The median age of children donors was 30 years (range 12-52), and 21 years (range 14-34) in the GC group. Patients in the GC group had higher comorbidities compared to patients in the children group, with a median hematopoietic cell transplantation comorbidity index (HCT-CI) of 2 (range 1-5) and 1 (range 0-7) respectively, (P=0.001). There was almost twice as many patients with HCT-CI of ≥3 in the GC compared to the children group, 38% and 21% respectively. The use of marrow vs PBSC as the graft source was not significantly different between the two groups (table 1). The two-year cumulative incidence of NRM was statistically significant higher for the GC group at 27% compared to 12% in the children group (P= 0.02). Since NRM is more likely in older patients, and older patients were more likely to be in GC group, we performed a PSMA. When matched for age, BMT-year and HCT-CI, PSMA did not show significant differences in NRM (HR 1.49, 95% 0.7-3.4, P=0.35). Similarly, OS, relapse and PFS did not show differences before or after PSMA. The two-year OS was 58% and 64% for children and GC, respectively (HR 0.82, 95% CI 0.36-1.88, P=0.63). Two-year relapse cumulative incidence was 24% and 7% for children and grandchildren, respectively (HR 0.45, 95% CI 0.15-1.34, P=0.15). Two-year PFS was comparable 52% and 56% for children and GC groups, respectively (HR 0.93, 95% CI 0.5-1.73, P=0.82) (fig. 1). Conclusions: Despite older age and comorbidities, the outcomes of alloBMT from grandchildren were at least as good as those from children, with 2-year OS of 64% and 58%, respectively. Choosing grandchildren as donors was associated with promising outcomes and should be examined further. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Allogeneic Hematopoietic Cell Transplant Yields Long Term Disease Free Survival in a Significant Number of Patients with Classic Hodgkin Lymphoma

Background: Classic Hodgkin's lymphoma (cHL) is a highly curable disease. A minority of patients, however, will have relapse/refractory (RR) disease and these patients are challenging to manage especially those who relapse after autologous hematopoietic cell transplant (auto-HCT). Even though a number of salvage options are available for these patients none of them is considered curative except allogeneic hematopoietic cell transplant (allo-HCT). Design and Methods: Retrospective analysis of 33 patients who had allo-HCT using matched family donors for cHL between January 2007 and December 2021. Continuous variables were summarized using medians and ranges. Categorical variables were summarized using frequencies and percentages. Probabilities of overall survival (OS) and disease free survival (DFS) were calculated using Kaplan-Meier estimate. Statistical analysis was conducted sing R studio (version 1.3.959 © 2009-2020 RStudio, PBC). Results: The median patient age at allo-HCT was 27 years. Seventeen patients were males and 16 were females. Five patients had early stage disease (Ann Arbor stage I, II) and 28 had advanced stage disease (Ann Arbor III, IV). Regarding the histologic type of cHL, eighteen had nodular sclerosis (NS), eight had mixed cellularity (MC), one had lymphocyte rich (LR), one had lymphocyte depleted (LD) and five cases were labeled as classic HL without further classification. Seventeen patients received brentuximab vedotin and fourteen patients received check point inhibitors prior to allo-HCT. The median number of chemotherapy lines prior to allo-HCT was 4 (range: 2-8). Twenty seven patients had chemosensitive disease (complete or partial remission) while 6 patients had chemoresistant disease (stable or progressive) prior to allo-HCT. Twenty seven patients had undergone auto-HCT prior to allo-HCT. Eighteen patients had elevated (>50) erythrocyte sedimentation rate (ESR) while 15 had normal ESR prior to allo-HCT. The majority of patients were conditioned with a reduced intensity regimen (29 patients versus 4 patients conditioned with myeloablative regimen). Twenty five patients received non-TBI (total body irradiation) based conditioning while 8 patients had TBI based regimen. The most frequently used conditioning regimen was fludarabine + melphalan. Nine patients received ATG (anti thymoglobulin) as a part of the conditioning while 24 patients did not. Thirty one patients received peripheral blood graft while 2 patients received bone marrow graft. The five years DFS was 37.5%. Twenty seven % of patients had acute GVHD (graft versus host disease) and 48% had chronic GVHD. The effect of a number of variables (number of chemotherapy lines, pre-allo-HCT ESR, conditioning intensity, ATG vs no ATG, receipt of pre-allo-HCT brentuximab or check point inhibitors, prior auto-HCT, chemosensitivity pre-allo-HCT and histologic subtype) was tested on the DFS. The only two variable that were statistically associated with a better DFS were pre-allo-HCT chemosensitivity (P=0.006) and non-NS histologic subtype (P=0.027). (Figure 1 and 2). Conclusions: Allogeneic stem cell transplantation can result in long-term progression-free survival in heavily pre-treated patients with Hodgkin's lymphoma. Patients with no response to salvage chemotherapy pre-allo-HCT and patients with NS subtype had detrimental outcomes. Better selection of patients before allo-HCT can result in a higher cure rates. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long Term Outcomes of Patients with Chronic Myeloid Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation in the Era of Oral Tyrosine Kinase Inhibitors

Introduction. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm (MPN) that without therapy is a uniformly lethal disease. Historically allogenic stem cell transplant (HCT) was the only curative therapy. In 2001 imatinib was the first CML specific oral tyrosine kinase inhibitor (TKI) approved and since then the treatment of CML has dramatically improved. Subsequently, 2nd and 3rd generation TKIs were developed and have been shown to be superior to imatinib either as initial therapy in certain high-risk patients and in other patients that fail imatinib. However, despite the advances in therapy, patients still die of CML, in fact, in 2020 it is estimated that 8,450 patients will be diagnosed with CML and 1,130 patients will die of CML. HCT remains a curative option for patients with CML. As the safety and availability of HCT improve, we aimed to describe the role of transplant in the modern era of CML therapy. Methods. We performed a retrospective chart review of patients who underwent their first HCT between June 28, 2006 and December 31, 2021 for CML in either chronic or accelerated phase at the time of transplant. Results. A total of 122 patients were identified. Patient and HCT characteristics are shown in Table 1. The median age at time of transplant was 45 (8-67), 72 (59%) are male. Fifty-four (44.3%) of patients received their transplant between 2006-2012 and 68 (55.7%) of patients received their transplants between 2013-2021. Fourteen (11.5%) patients were in accelerated phase CML at the time of HCT and the rest were in chronic phase. The median time from diagnosis to transplant was 23 months (1.8-307). Ninety-seven patients (79.5%) received ablative conditioning regimens. A total of 46 patients (37.7%) had matched related donors, 54 patients (44.3%) had matched unrelated donors, 14 patients (11.5%) had haploidentical donors, and 8 patients (6.7%) had a cord blood graft. 102 patients (83.6%) received peripheral blood stem cell grafts. GVHD prophylaxis always included a calcineurin inhibitor with the addition of methotrexate in 36 (29.5%) of patients, sirolimus in 60 (49.2%), Mycophenolate in 7 (5.7%), and post-transplant cyclophosphamide in 19 (15.6%) patients. Sixty-one patients (50%) had grade 2 or higher acute GVHD, and 19 (15.6%) had grade 3-4 acute GVHD. Extensive chronic GVHD was present in 81 (66.4%) of patients. Median follow-up of surviving patients was 59.3 months (3.3, 183.8) and overall the median follow-up was 30 months (0.55, 183.8). The estimated 12, 36, and 60-month Overall Survival (OS) of the cohort was 76.9% (95%CI 69.7-85), 66.1% (95% CI 57.7-75.6), and 58.4% (95% CI 49.4-69). Progression free survival (PFS) of the cohort at 12, 36, and 60 months was 71% (95% CI 63.2-79.7), 62% (95% CI 53.6-71.7) and 54.1% (45.1-65%) respectively. The median OS and PFS was not reached (Figure 1a,b). Fifty-two patients in the cohort died, 31 (59.6%) died of complications of treatment, 12 (23.1%) died of progression of disease, and 9 (17.3%) died of unknown causes. The day 100 cumulative incidence of non-relapse mortality (NRM) was 4.1% (1.7-9.7%) and the 1-year NRM was 17.2% (11.5-25.7%). Conclusion. This study shows excellent long term survival in patients who received an allo HCT for CML. And while, the modern treatment of CML largely relies on oral TKIs, in those patients who do not tolerate TKIs or fail available TKIs, allogeneic transplant remains an active, potentially curable therapy and should be considered. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Patients with TP53-Mutated Myeloid Neoplasms (TP53-MN) and the Role of Allogenic Blood or Marrow Transplantation (alloBMT)

Background: TP53 mutations are present in up to 20% of patients with myeloid malignancies and are frequently associated with a complex karyotype (CK) and poor responses to therapy. Even though overall response rates have improved significantly with less intensive induction modalities such as hypomethylating (HMA) agents alone or in combination with venetoclax, most patients succumb to their disease. AlloBMT remains the only curative option and even though the outcomes after alloBMT are disappointing, some patients achieve long-term survival. In the current study, we aimed to determine the clinical outcome of patients with TP53-MN and the impact of therapies including alloHCT on outcomes. Methods: We performed a single-center retrospective review of adult patients with TP53-MN evaluated at Johns Hopkins between November 2015 and February 2020. The analysis of somatic mutations was performed using a 59-gene targeted next-generation sequencing (NGS) assay. Cytogenetic analysis was performed on bone marrow or peripheral blood using standard methods including G-banding by trypsin with Giemsa staining. Results: We identified a total of 93 patients with TP53-MN. Disease subtypes included de novo AML (n = 22), AML arising from MDS/MPN (n = 15), MDS (n = 23), therapy-related myeloid neoplasm (n = 29), MDS/MPN overlap syndrome (n = 2) and MPN (n = 2). The median (Q1, Q3) age was 67 years (59 - 73 years). Cytogenetics was available for 89/93 (95.7%) patients. Of those, 73 (82.0%) patients had complex karyotype (CK). The median maximum TP53 variant allele frequency (VAF) per patient was 42.5%. Sixty-two (66.6%) patients had TP53 null phenotype: 14 (15.1%) patients had multiple TP53 mutations, 37 (41.6%) had deletion 17p and 11 (12.0%) had copy-neutral loss-of-heterozygosity (CnLOH). Overall, 79/93 (85%) patients received therapy: 20 (25.3%) were treated with HMA alone, 30 (38.0%) with HMA+venetoclax, 10 (12.7%) with HMA+others, 15 (19.0%) with intensive chemotherapy, 2 (2.5%) with an immunomodulatory drug, 1 (1.3%) with ivosidenib and 1 (1.3%) with a JAK2 inhibitor. Of those, 29 (36.7%) patients received non-myeloablative alloBMT with post-transplant cyclophosphamide (10 (34.5%) bone marrow and 19 (65.5%) mobilized peripheral blood grafts (PBSCT)). Median overall survival (OS) in patients receiving alloBMT, any therapy, or supportive care was 18.9, 4.1, and 2.5 months respectively (p < 0.001, Figure 1). Among patients in the alloBMT group, there was a significant OS difference between TP53-MN CK vs. non-CK (median OS 13.7 months vs not reached, p = 0.01, Figure 2). Also, patients with TP53-MN CK demonstrated better OS when treated with alloBMT compared to any therapy or supportive care. However, most TP53-MN CK patients ultimately succumbed to their disease regardless of the therapeutic modality. Therapeutic modalities prior to alloBMT did not appear to affect post-alloBMT outcomes but among patients who received PBSCT, OS was significantly better in patients receiving 400cGy vs 200 cGy total body irradiation (median OS 8.9 vs. 21 months, p=0.01). Conclusions: TP53-MN appears to be a heterogeneous disease with a variable prognosis. While OS of patients with TP53 mutations and non-CK who underwent alloBMT resembled that of intermediate-risk AML, patients with TP53 null phenotype associated with CK had a worse outcome. Even though OS appears to be significantly improved with alloBMT, particularly patients receiving PBSCT+400cGy TBI, most patients eventually relapse. Novel therapeutic strategies are urgently needed to improve the outcomes of TP53 CK patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abatacept/Tacrolimus or Abatacept/Tacrolimus/Post-Transplant Cyclophosphamide Are Safe and Highly Effective in Preventing Graft-Versus-Host Disease in Matched or Mismatched Donor Peripheral Blood Stem Cell Transplantation

Background: Abatacept blocks CD28-CD80/86 axis and prevents T-cell co-stimulation. In early studies, abatacept has shown promising results when added to methotrexate and tacrolimus in matched and mismatched donor SCT. Further promising results have been demonstrated with a combination of post-transplant cyclophosphamide (PTCy), abatacept, and a short course of tacrolimus to improve the results of GvHD prevention in the setting of haploidentical SCT. Based on this data we initiated a phase Ib-II clinical trial of the efficacy and toxicity of the Abatacept/Tacrolimus/PTCy combination for patients who received HLA-mismatched grafts and Abatacept/Tacrolimus combination for patients who received HLA-matched grafts. Aim: assess the frequency of acute and chronic GVHD grade II-IV. Patients received G-CSF mobilized peripheral blood grafts from related and unrelated donors. GvHD prevention consisted of PTCy 50mg/kg IV on day +3 and +4, abatacept 10mg/kg IV on day -1, +5, +14 and +28 and tacrolimus. Tacrolimus was started on day -1 at 0.02 mg/kg/day by continuous IV and adjusted thereafter to maintain a trough level of 5-12 ng/mL. Tacrolimus taper was planned to begin on day +90 and complete by day +120 in the absence of GvHD. All patients received standard supportive care including acyclovir and co-trimoxazole until CD4-count >200 cells/muL, posaconazole/voriconazole until day +60, and if CMV positive by serology, ganciclovir 5 mg/kg per day until day +100. G-CSF was administered routinely until neutrophil engraftment. From Oct 2020 to Jul 2022, 51 patients were enrolled. The median age was 44 years (23-64) M/F 49%/51%. Diagnosis: AML 23,5% (12/51), B-NHL 17,6% (9/51), HD 17,6% (9/51), ALL 15,6% (8/51), MDS 9,8% (5/51), MF 5,9% (3/51), CLL 4% (2/51), MM 4% (2/51), AA 2% (1/51). Disease status before conditioning: 30/51 had CR, 15/51 - PR, 6/51- active disease. Conditioning regimens: Treo/Flu for AML, ALL, MDS and MF (28/51, 55%), Benda/Flu for B-NHL, HD, CLL and MM (22/51, 43%), Flu/Cy/ATG for AA (1/51, 2%). RIC/MAC: 65%/35%. 29,4% (15/51) of patients received cryopreserved products. Median times to ANC and platelet engraftment were 15 (8-60) and 18 days. 2 patients had primary graft failure (absence of engraftment > 28 days, non-response MDS before SCT and B-NHL, both 5/10, both older than 60). In both cases, a second HSCT was performed from the same donors. In the first case (non-response MDS), repeated HSCT without any effect and the patient died, in the second case, there was graft engraftment with the restoration of blood parameters. 1 patient (ETP ALL, mismatched related donor 5/10) had poor graft function. Transfusion of purified CD34+ cells (Miltenyi Biotec) from the same donor was accompanied by restoration of hematopoiesis. With a median follow-up was 154 days (25-641) with 34 patients having >120 days, 23 >180 days, and 7 >365 days of follow-up, 13,7% (7/51) patients developed acute GvHD grade II-IV (mostly skin, gut, liver). 9,8% (5/51) of patients developed chronic GvHD grade II-IV (skin, lungs, mucous eyes, liver, joints). 47% (24/51) completed tacrolimus taper by day +120. 3 patients switched from tacrolimus to sirolimus and one to prednisone due to intolerance or toxicity. 3 patients with MF received ruxolitinib from day +30 as a treatment for MF (no signs of GVHD of any grade). All patients with GvHD grade II-IV received systemic steroids. 7 patients received ruxolitinib, 3 - MMF, 4 - rituximab, 1 - daratumumab, 2 - ibrutinib, 1 - acalabrutinib and 2 - imatinib. CMV activation rate was 35,3%. There were 1 case of BK virus and 1 case of JC virus (patient with HD after aGVHD and cGVHD). 2 patients developed thrombotic microangiopathy (one received tacrolimus, one did not). During the observation period, 25,5% (13/51) patients died: 3 due to COVID-19, 4 due to relapse/progression, 3 from infectious complications (2 sepsis and 1 PML due to JCPyV), 1 from non-engraftment, and 1 due to uncontrolled AIHA. Summary: our preliminary results suggest that Abatacept/Tacrolimus +- PTCy is feasible and seems to offer very promising outcomes with low rates of acute and chronic GvHD grade II-VI. Based on this and previous trials we need a phase III clinical trial to evaluate abatacept. In our practice, abatacept-based immunosuppressive therapy has become routine. Additional reducing mortality is possible due to the widespread use of anti-covid antibodies and the exclusion of patients with a lack of response to disease therapy.