Matched Unrelated Donor Transplantation Research Articles

Role of Splenic Irradiation Prior to Transplant for Myelofibrosis: A Global Collaboration

JAK inhibitors and novel agents have shown promising reduction of spleen size in newly diagnosed myelofibrosis. However, not all patients will respond or they eventually progress at some point. Despite hematopoietic cell transplantation (HCT) being the only curative treatment option to date, splenomegaly prior to HCT remains a particular challenge. On the other hand, numbers of patients eligible for HCT continue to increase worldwide, and thus management of splenomegaly becomes more and more relevant. One approach to reduce spleen size prior to HCT could be splenic irradiation. However, evidence on its role remains scarce. We took advantage of a global collaboration between European, US, and Latin American centers to investigate the role of splenic irradiation as part of the HCT platform for patients with myelofibrosis. Radiation therapy had to be given within 3 months prior to or be part of conditioning therapy for HSCT. Detailed information on irradiation as well as post-HCT safety profiles was collected in addition to usual patient-, disease-, and transplant-related variables. This global collaborative study included 52 patients, of whom 71% had primary myelofibrosis, 17% post polycythemia vera and 12% post essential thrombocythemia myelofibrosis. Median age at HCT was 60 years (range, 32-76). Risk category according to DIPSS prior to irradiation was intermediate-1 in 20%, intermediate-2 in 52%, and high in 28%. Driver mutation status was JAK2 in 44%, CALR in 40%, MPL in 4%, and triple negative in 12%. Four patients had portal vein thrombosis before irradiation. Ruxolitinib before irradiation was received by 76% and 4% received fedratinib. Reduced intensity conditioning HCT was received by 73% and 85% were matched related or matched unrelated donor transplants. Median time from irradiation to HCT was 2 weeks (range, 0.9-12 weeks) and median spleen size prior to irradiation was 23 cm (range, 14-35). Spleen size was measured by ultrasound in 70%, CT scan in 20%, and physical examination in 10%. Median total irradiation dose was 7 Gy (range, 3-12), fractionated in a median of 5 administrations (range, 2-12). Splenic irradiation resulted in a significant spleen reduction prior to HCT but was also associated with significant reduction in platelet and leukocyte counts ( Table). Spleen size did not correlate with blood counts prior or after irradiation. Higher platelet count prior to irradiation correlated with higher counts after irradiation (r=0.83; P<0.001). There was no correlation between irradiation dose and post-irradiation hematological toxicities. Only 1 patient had non-hematological adverse events (tumor lysis syndrome). Neutrophil engraftment was achieved by 90% within a median of 18 days after HCT and platelet engraftment was achieved by 81% within a median of 38 days. Median follow-up of the total cohort was 2.7 years and 3-year overall survival was 66% (95% CI, 52-80%; Figure). Non-relapse mortality was 27% (95% CI, 15-39%) and cumulative incidence of relapse was 11% (95% CI, 2-20%; Figure). Incidence of acute GVHD grade II-IV and chronic GVHD was 25% and 38%, respectively. Increased spleen size (as continuous variable) prior to irradiation was associated with worse outcome (P=0.05), showing 3-year survival of 73% for spleen ≤25cm vs 42% for >25cm, and non-relapse mortality of 58% vs 14%, respectively (P=0.02). No effect of spleen size after irradiation on outcomes was observed. All 4 patients with portal vein thrombosis died (2-year survival 25%). A multivariable model showed that larger spleen size before irradiation, lower hemoglobin levels, CALR/MPL-unmuated driver mutation genotype, and presence of portal vein thrombosis were significantly associated with worse survival ( Table). This first international and largest study to date on splenic irradiation as part of the HCT algorithm for patients with myelofibrosis and splenomegaly showed a significant impact of spleen size on overall survival and non-relapse mortality, while relapse rates were low. In addition, lower hemoglobin levels and presence of portal vein thrombosis at time of irradiation predicted worse outcomes.

Allogeneic Hematopoietic Cell Transplantation in the Elderly Results in Similar Survival with Matched Related or Unrelated and Haploidentical Donors: A Report from the Société Francophone De Greffe De Moelle Et De Thérapie Cellulaire (SFGM-TC)

Introduction Higher patient age is no longer considered to be a barrier for allogeneic hematopoietic cell transplantation (HCT). We sought to study the impact of different types of donors on the outcomes of HCT in subjects aged 65 years (y) or more, and to evaluate the determinants of these outcomes. Methods SFGM-TC registry data on first HCTs performed between January 2013 and July 2021 in patients aged 65 y or more, with myeloablative or reduced-intensity conditioning, and a 10/10 human leukocyte antigen (HLA) matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAP) were analyzed. Main exclusion criteria were: MSD/MUD-HCT performed without anti-T lymphocyte globulin (ATG), and HAP-HCT performed without post-transplant cyclophosphamide (PTCY). Univariate analyses according to donor type, as well as multivariable analyses were performed. Results A total of 1176 patients met the eligibility criteria (215 MSD, 721 MUD, 240 HAP). Median follow-up was 2.8 y. In univariate analysis, there was no difference between donor types in terms of 3-y overall survival (OS: MSD 50%, MUD 49%, HAP 49%, p=0.52), progression-free survival (PFS: MSD 41%, MUD 45%, HAP 44%, p=0.51) and graft-versus-host disease-free, relapse-free survival (GRFS: MSD 34%, MUD 32%, HAP 35%, p=0.67). With MSD, the cumulative incidence of progression at 3 y was significantly higher at 47% (MUD 29%, HAP 29%, p<0.001), and non-relapse mortality (NRM) significantly lower at 12% (MUD 26%, HAP 27%, p<0.001). These MSD results were confirmed in multivariable analysis. Incidence of acute graft-versus-host disease (GVHD) at 180 days was lower with MSD: grades II-IV 21% (MUD 35%, HAP 38%, p<0.001) and grade III-IV 8% (MUD 13%, HAP 15%, p=0.05). Incidence of chronic GVHD at 2 y was comparable between MSD, MUD and HAP transplants: moderate to severe 14%, 18% and 15%, respectively, and severe 5%, 6% and 5%, respectively. Conclusions In patients aged 65 y or more, MSD/MUD HCT performed with ATG and HAP HCT performed with PTCY yielded similar survival outcomes. MSD HCT is associated with a lower acute GVHD and NRM but a higher relapse risk. Reducing the toxicity of MUD and HAP HCT may yield better results than with MSD HCT in this population. Acknowledgements: Nicole Raus, Data manager coordinator, SFGM-TC. Viviane Fossat, Secretary, SFGM-TC.

Post Transplant Cyclophosphamide (PTCY) in Peripheral Blood Stem Cell Transplant Results in Successful Engraftment and Substantially Low Frequency of Chronic Graft Versus Host Disease (GvHD), without Impaired Cellular Immune Reconstitution

The Post-Transplant Cyclophosphamide (PTCY) approach was first studied in the haploidentical transplant setting, and it resulted in high percentages of engraftment and reduced frequency of acute and mainly chronic GvHD as well as non-relapsed mortality. PTCY is now increasingly being used in HLA-partially and fully matched unrelated, as well as matched related donors. The aim of this study was to investigate the impact of PTCY on the incidence of chronic GvHD, disease relapse and infections because of possible cellular immune impairment. Fifty-one consecutive patients who underwent allogeneic hematopoietic stem cell transplant from an unrelated donor were studied. PTCΥ was administered on days +3 and +4 post-transplant at a dose of 50 mg/kg/day. Additional GvHD prophylaxis included tacrolimus and mycophenolate mofetil starting on day +5. In patients with no evidence of GvHD, immunosuppression was gradually tapered, and eventually stopped by day +90. We evaluated the safety and efficacy of PTCY, focusing on toxicity, engraftment, aGvHD and cGvHD frequency, relapse, non-relapse mortality, survival and immune reconstitution. We performed 51 unrelated donor transplants with PTCY from January 2021 to May 2023 in patients with a median age of 52 (18-69) years. The indication for transplant was AML/MDS (n=36), NHL/CLL, (n=2), pMF (n=2), CML (n=2) και ALL (n=9). Disease risk index (DRI) was intermediate for most patients (34/51), 7 had low and 10 had high DRI. Thirty-seven patients received myeloablative conditioning and 14 reduced-intensity. Overall, three patients were transplanted from a matched sibling, 36 from an 8/8 matched unrelated donor and 12 from an 7/8 HLA-matched unrelated donor. All patients received a peripheral blood graft with a median CD34+ cell dose of 6.97×10e6/kg (3.27-15.82). The most common toxicities observed were mucositis (n=34), diarrhea (n=40), vomit (n=12), liver toxicity (n=3) and acute kidney injury (n=4) - which in all cases were grade Ι-ΙΙ. Engraftment, defined as neutrophils >500/μl, was achieved in 46 cases in a median of 16 (13-27) days. Three patients died before day +28 due to NRM and two additional patients with myelofibrosis and MDS respectively had primary graft failure. The cumulative incidence of aGvHD, grade ΙΙ-IV at 100 days was 46.7% (95%CI: 34.1-63.8). However, aGvHD, grade ΙΙΙ-IV was only 3.9% (95%CI: 1.0-15.5). The cumulative incidence of cGvHD at 18 months was 13,4% (95%CI: 5.8-31.0), with only one case of extensive cGvHD. In a median follow-up of 14.5 (1-28) months, disease free (DFS) was 76,8% (95%CI: 65.5-90.0) at 18 months and overall survival (OS) was 76.3% (95%CI: 64.9-89.8) and 71.6% (95%CI: 58.6-88.3) respectively. There was no statistically significant difference in survival rates for patients who received an HLA mismatched and those who received an HLA-matched unrelated-donor transplant. cGvHD-Relapse-Free Survival was 63.5% (95%CI: 50.3-80.1). Two patients died of their disease and non-relapse mortality was 19.1%. Specifically, 6 patients died of Infections, 1 due to primary graft failure, 1 due to heart failure, and 1 due to Idiopathic Pulmonary Syndrome. Immune reconstitution at month 6 was 420 cells/ul (20-2225) and 179 (13-594) for CD8 and CD4 respectively. At month 12 CD8 and CD4 were 552 (55-3002) and 364 (60-787). 31 viral infections were documented in 28 patients (Respiratory viruses n=13, BKV n=11, CMV n=7). In regard with opportunistic infections, 2 patients had fungal infections and 1 patient atypical mycobacterium. We used PTCY for GvHD prophylaxis in mismatched, full-matched unrelated and matched sibling donor transplants with peripheral blood stem cell graft. This approach was well tolerated. Engraftment was documented in most patients, with a low incidence of grade III-IV aGvHD. Importantly cGvHD, which is the most important barrier in unrelated donor transplant, was substantially low with this method. Cellular immune reconstitution was adequate for CD8 but somewhat impaired for CD4. However, the incidence of viral and opportunistic infections was not increased. Overall, there are implications that PTCY may revert the negative impact of HLA mismatch on the outcomes of unrelated donor transplantation, while it is also a viable option for MUD and MSD transplant.

Alternative Donor Transplantation for Severe Aplastic Anemia: A Comparative Study of the Saawp EBMT

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT INTRODUCTION Allogeneic stem cell transplantation (allo-SCT) from an HLA-matched sibling donor (MSD) is considered the standard of care for younger patients with severe aplastic anemia (SAA). For patients lacking a suitable MSD, matched unrelated donors (MUD) have increasingly been used for SAA patients who do not respond to immunosuppressive therapy. However, a significant number of SAA patients who require allo-SCT are unable to access a fully HLA-matched unrelated donor or experience delays in finding one. In such cases, other alternative options, such as mismatched unrelated donors (MMUD), and haploidentical family donors (Haplo), have been explored. Limited research exists on MUD, MMUD, and Haplo allo-SCT efficacy and safety in SAA. Drawing definitive conclusions for the optimal alternative donor transplant approach remains challenging. This study compares the outcomes of allo-SCT from MUD, MMUD, and Haplo donors in patients with SAA from the SAAWP EBMT. PATIENTS AND METHODS Inclusion criteria All patients diagnosed with SAA who underwent their first allo-SCT between January 2012 and December 2021 from either a MUD, MMUD or Haplo, were included. Only transplants from Haplo donors who received post-transplant cyclophosphamide (PTCy) as prophylaxis for graft-versus-host disease (GVHD) were considered. Statistical Analysis The study utilized statistical methods such as Kaplan-Meier estimation, Log-Rank test, competing risks analysis, and Cox proportional hazards regression. The analyses included OS, EFS, GRFS, NRM, aGVHD, cGVHD, and graft failure. The statistical software R and relevant packages were used. RESULTS Patient and Transplantation Characteristics Table 1 summarizes patient and transplant characteristics for the 1652 participants. Engraftment Neutrophil recovery at 28 days was 85% (95% CI; 83-87) for MUD, 84% (95% CI; 80-88) for MMUD, and 75% (95% CI; 69-81) for Haplo (p = 0.033). Platelet engraftment at 100 days was 88% (95% CI; 86-91) for MUD, 82% (95% CI; 78-87) for MMUD and 72% (95% CI; 65-78) for Haplo (p < 0.001). Graft failure The 1-year cumulative incidence of primary graft failure (PGF) for the MUD, MMUD, and Haplo cohorts was 4% (95% CI; 3-6%), 5% (95% CI; 3-8%) and 16% (95% CI; 11-21%), respectively (p < 0.001). In multivariable analysis, compared with MUD, Haplo (HR, 3.72; 95% CI, 1.97-7.03; p<0.001) was associated with a higher PGF. Other predictors for a higher PGF are shown in Table 2. GVHD The cumulative incidence of aGVHD grades II-IV at 100 days for the MUD, MMUD, and Haplo cohorts was 13% (95% CI; 11-15), 22% (95% CI; 17-26), and 18% (95% CI; 13-24), respectively (p < 0.001). In multivariable analysis, MMUD was associated with an increased risk of aGVHD grades II-IV, when compared with MUD (HR 1.97; 95% CI, 1.4-2.77; p < 0.001). Other predictors associated with a higher risk of aGVHD grades II-IV are shown in Table 2. The 3-year cumulative incidence of cGVHD for the MUD, MMUD, and Haplo cohorts was 18% (95% CI; 15-20), 19% (95% CI; 14-24), and 18% (95% CI; 11-24), respectively (p = 0.9). NRM The 3-year cumulative incidence of NRM was 12% (95% CI; 10-14) for MUD, 17% (95% CI; 13-22) for MMUD, and 22% (95% CI; 15-28) for Haplo (p < 0.001). Survival The 3-year EFS for the MUD, MMUD, and Haplo cohorts was 73% (95% CI; 71-76), 64% (95% CI; 59-70), and 53% (95% CI; 46-61), respectively (p < 0.001), whereas OS was 81% (95% CI; 79-84), 74% (95% CI; 69-79), and 63% (95% CI; 54-71), respectively (p < 0.001). In multivariable analysis, compared to MUD, MMUD (HR, 1.54; 95% CI, 1.12-2.11; p = 0.007) and Haplo (HR, 1.97; 95% CI, 1.35-2.86; p<0.001) were associated with worse survival. Other predictors for a worse OS are shown in Table 2. The 3-year GRFS for the MUD, MMUD, and Haplo cohorts was 71% (95% CI; 68-74), 66% (95% CI; 60-72), and 53% (95% CI; 44-61), respectively (p < 0.001). In multivariable analysis, compared with MUD, MMUD (HR, 1.42; 95% CI, 1.1-1.82; p = 0.006) and Haplo (HR, 1.71; 95% CI, 1.27-2.31; p<0.001) were associated with worse GRFS. Other factors associated with a worse GRFS are shown in Table 2. CONCLUSION In conclusion, our study supports MUD transplantation as the preferred option for SAA patients without a MSD. While MMUD and Haplo transplants are feasible, MMUD appears more favorable than Haplo, even in the era of PTCy.

Clinical Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation Using Busulfan/Cyclophosphamide and Melphalan or Thiotepa As Conditioning Regimen in 37 Patients with Acute Megakaryoblastic Leukemia

Background Acute megakaryoblastic leukemia (AMKL) is a rare and heterogeneous subtype of acute myeloid leukemia (AML), which accounts for approximately 10% of childhood AML and about 1% of adult AML. Patients with non-Down's syndrome AMKL (non-DS-AMKL) are often associated with a poor prognosis with a 3-year overall survival (OS) rate of less than 40%. Currently, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potential curative therapy for AMKL. However, the long-term survival post-transplant needs to be improved. Here we conducted a single-center study to evaluate the long-term efficacy and safety of allo-HSCT in 37 non-DS-AMKL patients using an innovative conditioning regimen of Busulfan/Cyclophosphamide (Bu/Cy) and Melphalan (MEL) or Thiotepa (TT). Methods From August 2015 to July 2023, a total of 37 non-DS-AMKL patients (M/F 21:16) were treated consecutively in our hospital (Hebei Yanda Lu Daopei Hospital). The median age was 2 years (range 1-9 years). Chromosomal abnormalities were present in 24 cases, with fusion genes as follows CBFA2T3/GLIS2 (5 cases) 13.5%, NUP98-KDM5A (2 cases) 5.4%, MLL-AF10 (3 cases) 8.1%, MLL-AF9 (1 case) 2.7%. Gene mutations: WT1 (10 cases) 27%, JAK2 (7 cases) 18.9%, EVI1 (6 cases) 16.2%, TET2 (4 cases) 10.8%, ASXL1 (4 cases) 10.8%, PTPN11 (4 cases) 10.8%, NRAS (3 cases) 8.1%, GATA1 (2 cases) 5.4%. Before transplantation, in bone marrow (BM), 29 patients were in complete remission (CR), 3 were in partial remission (PR) and the rest 5 were in non-remission (NR). Thirty-three patients received the haploidentical transplantation (donors from parents n=31, siblings n=2) including 1 with the 3 rd transplant, and 4 received matched-unrelated donor transplantation. The stem cell sources were from BM and peripheral blood stem cells (PBSCs) among the 33 related donors, and PBSCs for the 4 unrelated donors. Patients received a median cell number of total mononuclear cells 20.15×10 8/kg (10.7-32.85), CD34+ cells 12×10 6/kg(4.05-27.14) and CD3+ cells 4.66×10 8/kg(1.81-19.38). The conditioning regimens administered were modified Bu/Cy (fludarabine 30 mg/m 2/d×5d; cytarabine 2g/m 2/d×5d; Bu 3.2 mg/kg/d×4d, Cy 1.8g/m 2/d×2d; etoposide 100mg/m 2/d×2d; antithymocyte globulin 1.5mg/kg/d×5d) in 2 patients, Bu/Cy+MEL (MEL 55mg/m 2/d×2d) in 31 patients, and Bu/Cy+TT (TT 2.5mg/kg/d×2d) in the rest 4 patients. Cyclosporine A (CSA)+ mycophenolate mofetil (MMF)+ short methotrexate (sMTX) were used as graft-versus-host disease (GVHD) prophylaxis. Results The median follow-up time was 24 months (2-84 months), and all 37 cases survived the graft, with a median leukocyte engraftment of +13 days (9-21 days), and a median platelet engraftment of +9 days (4-38 days). BM was assessed one month after transplantation, with all grafts fully donor-type. The 5-year OS was 54.1% (Figure 1). There was a significantly higher OS in the CR group (5-year OS 69%) than the PR or NR groups (P<0.001) (Figure 2). Among the CR patients, no significant difference was observed in the 3 different condition regimen groups with modified BU/CY group OS of 50%, BU/CY+MEL group OS of 69.6% and BU/CY+TT group OS of 75% (P=0.869) (Figure 3). After transplantation, 17 patients died including 11 from relapse, 4 from GVHD, 1 from gastrointestinal bleeding and 1from cerebral hemorrhage. The cumulative recurrence rate (CIR) was 29.7%, among which the CIR of the CR group was 17.2%, the PR group of 66.7% and the NR group of 80% (P<0.001). Post-transplant, the incidence of acute GVHD (aGVHD) was 35.13% (Grade II-IV), and severe aGVHD (Grade III-IV) incidence was 18.91%. And 51.35% of patients developed chronic GVHD. Other complication incidences were cystitis at 16.21%, cytomegalovirus at 5.94%, Epstein-Barr viremia at 13.5% and infections at 21.62%. Conclusions Our study indicates that the use of modified Bu/Cy +MEL or +TT conditioning regimens in allo-HSCT procedures presents a feasible and effective approach, demonstrating an improvement in overall survival for non-Down Syndrome AMKL patients. Crucially, it was observed that achieving CR prior to transplantation significantly contributes to better outcomes. Therefore, it is strongly recommended that allo-HSCT is performed in CR status. However, to corroborate these findings, it is essential to conduct long-term, large-scale clinical research across multiple centers.

Choosing Between Older Matched Sibling Donor and Younger Matched Unrelated Donor in Allogeneic Hematopoietic Cell Transplantation: Comparison of Clinical Outcomes in Acute Myeloid Leukemia and Myelodysplastic Syndrome

The choice between an older matched sibling donor (MSD) and a younger matched unrelated donor (MUD) in allogeneic hematopoietic cell transplantation (HCT) remains a subject of ongoing debate. In this single-center retrospective study of 377 patients who received peripheral blood stem cell (PBSC) transplants for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS), we compared outcomes of 85 patients who received grafts from MSDs age >60 years and 292 patients who received grafts from MUDs age <30 years. Compared to recipients of MSD transplants, recipients of MUD transplants were younger and more likely to receive dual T cell depletion (TCD), a higher CD34+ cell dose, and a fresh graft. Recipients of MSD transplants were maintained on immunosuppressive therapy longer than those who received MUD grafts. We found no differences in overall survival, relapse-free survival, graft-versus-host disease (GVHD)-free and relapse-free survival, nonrelapse mortality, relapse, engraftment, graft failure, and acute GVHD between recipients of MSD grafts and recipients of MUD grafts. We report a higher 30-day incidence, but not 1-year incidence, of bloodstream infections among recipients of MUD transplants compared to subjects who received their grafts from a MSD. The incidence of moderate-severe chronic GVHD was higher in MSD graft recipients compared with MUD graft recipients in univariate analysis, but not in multivariate analysis. Although this difference could reflect the greater use of dual TCD, known to be associated with very low rates of chronic GVHD in MUD transplant recipients, the incidence of moderate-severe chronic GVHD was no different between MSD and MUD transplant recipients following propensity score matching, suggesting that other variables could be responsible. Taken together, our data suggest that in patients with AML or MDS who receive PBSC transplants, such factors as convenience, ease of access, and costs should be considered when selecting an older MSD over a younger MUD.

Improved outcomes of UM171–expanded cord blood transplantation compared with other graft sources: real-world evidence

AbstractCord blood (CB) transplantation is hampered by low cell dose and high nonrelapse mortality (NRM). A phase 1-2 trial of UM171-expanded CB transplants demonstrated safety and favorable preliminary efficacy. The aim of the current analysis was to retrospectively compare results of the phase 1-2 trial with those after unmanipulated CB and matched-unrelated donor (MUD) transplants. Data from recipients of CB and MUD transplants were obtained from the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Patients were directly matched for the number of previous allogeneic hematopoietic stem cell transplants (alloHCT), disease and refined Disease Risk Index. Patients were further matched by propensity score for age, comorbidity index, and performance status. Primary end points included NRM, progression-free survival (PFS), overall survival (OS), and graft-versus-host disease (GVHD)-free relapse-free survival (GRFS) at 1 and 2 years after alloHCT. Overall, 137 patients from CIBMTR (67 CB, 70 MUD) and 22 with UM171-expanded CB were included. NRM at 1 and 2 years was lower, PFS and GRFS at 2 years and OS at 1 year were improved for UM171-expanded CBs compared with CB controls. Compared with MUD controls, UM171 recipients had lower 1- and 2-year NRM, higher 2-year PFS, and higher 1- and 2-year GRFS. Furthermore, UM171-expanded CB recipients experienced less grades 3-4 acute GVHD and chronic GVHD compared with MUD graft recipients. Compared with real-world evidence with CB and MUD alloHCT, this study suggests that UM171-expanded CB recipients may benefit from lower NRM and higher GRFS. This trial was registered at www.clinicaltrials.gov as #NCT02668315.

Haploidentical transplant with posttransplant cyclophosphamide vs matched related and unrelated donor transplant in acute myeloid leukemia and myelodysplastic neoplasm

Hematopoietic cell transplantation from haploidentical donors (haploHCT) has facilitated treatment of AML and MDS by increasing donor availability and became more feasible since the introduction of post-transplant cyclophosphamide (ptCY). In our single-center retrospective analysis including 213 patients with AML or MDS, we compare the outcome of haploHCT (n = 40) with ptCY with HCT from HLA-identical MRD (n = 105) and MUD (n = 68). At 2 years after transplantation, overall survival (OS) after haploHCT was not significantly different (0.59; 95% confidence interval 0.44–0.79) compared to MRD (0.77; 0.67–0.88) and MUD transplantation (0.72; 0.64–0.82, p = 0.51). While progression-free survival (PFS) was also not significantly different (haploHCT: 0.60; 0.46–0.78, MRD: 0.55; 0.44–0.69, MUD: 0.64; 0.55–0.74, p = 0.64), non-relapse mortality (NRM) was significantly higher after haploHCT (0.18; 0.08–0.33) vs. MRD (0.029; 0.005–0.09) and MUD (0.06; 0.02–0.12, p < 0.05). Higher NRM was mainly caused by a higher rate of fatal infections, while deaths related to GvHD or other non-relapse reasons were rare in all groups. As most fatal infections occurred early and were bacterial related, one potential risk factor among many was identified in the significantly longer time to neutrophil engraftment after haploHCT with a median of 16 days (interquartile range; 14.8–20.0) vs. 12 days (10.0–13.0) for MRD and 11 days (10.0–13.0) for MUD (p = 0.01).

Incidence of cutaneous graft-versus-host disease in a Singapore academic medical centre - A retrospective cohort study.

Cutaneous graft-versus-host disease (GVHD) is common in allogeneic haematopoietic stem cell transplantation. HLA mismatch is the most significant determinant of GVHD. Our study aimed to compare the incidence of cutaneous GVHD haploidentical (Haplo) and matched donors in an Asian population. Retrospective cohort study of the 2015-2019 bone marrow transplant registry was conducted in a transplant centre. We compared the incidence of cutaneous GVHD in Haplo with allogeneic matched unrelated donor (MUD) and matched-sibling donor (MSD) transplant recipients. Secondary objectives include acute and chronic GVHD incidence, dermatology referrals, and histological findings. One hundred and seventy-nine out of 203 cases were reviewed; 17 (9.5%) Haplo, 80 (44.7%) MUDs and 82 (45.8%) MSDs. The median follow-up for Haplo, MUD and MSD was 15.2, 34.2 and 35.7months, respectively. Haplo had a higher cumulative incidence of cutaneous GVHD than MUD and MSD (p=0.053). Chronic GVHD was only reported in MSD. The most common histology was vacuolar interface changes (13 [44.8%]) with a wide range of onset post-transplant (19-456 days). Haplo donors may have a higher GVHD incidence than MUD and MSD in our predominantly Asian cohort. This information may be helpful when counselling patients pre-transplant. Further prospective studies are required.

Donor Genetic Predisposition to High Interleukin-10 Production Appears Protective against Acute Graft-Versus-Host Disease.

The persistence of graft-versus-host disease (GVHD) as the principal complication of allogeneic hematopoietic cell transplantation (HCT) demonstrates that HLA matching alone is insufficient to prevent alloreactivity. We performed molecular and functional characterization of 22 candidate cytokine genes for their potential to improve matching in 315 myeloablative, 10/10 HLA-matched donor−recipient pairs. Recipients of a graft carrying the -1082GG IL10 gene promoter region variant had a three-fold lower incidence of grade II−IV acute GVHD compared to IL10-1082AA graft recipients (SHR = 0.25, p = 0.005). This was most evident in matched unrelated donor (MUD) transplants, where the greatest alloreactivity is expected. IL10-1082GG transplants did not experience an increased incidence of relapse, and, consequently, overall survival was two-fold higher in IL10-1082GG MUD transplants (HR = 0.17, p = 0.023). Longitudinal post-transplant measurements demonstrated that -1082GG is a high-IL10-producing and -expressing genotype with attenuated CD8+ T-cell reconstitution. High post-transplant donor chimerism in T- and myeloid-cells (>95%) confirmed a predominant donor, rather than recipient, genotype effect on immune function and aGVHD. To date, this is the first study to report corroborating genome-to-cellular evidence for a non-HLA donor immunogenetic variant that appears to be protective against GVHD. The incorporation of IL10 variants in donor selection criteria and clinical-management decisions has the potential to improve patient outcomes.

Post-Transplant Cyclophosphamide, Abatacept and Short Course of Tacrolimus (CAST) for Graft-Versus-Host Disease Prevention Following Haploidentical Peripheral Blood Stem Cell Transplantation

Background: Haploidentical blood and marrow transplantation (BMT) substantially expands the pool of potential hematopoietic stem cell donors, including for minority groups. However, the outcomes of haploidentical transplantation remain inferior to matched unrelated donor (MUD) transplants when a standard post-transplant cyclophosphamide (PTCy)-based graft versus host disease (GvHD) prophylaxis regimen is employed in both settings. To address this issue, we sought to develop a more effective GvHD prevention regimen in haploidentical transplantation. While abatacept (Aba) seems to decrease the incidence of acute GvHD, PTCy is particularly effective in the prevention of chronic GvHD. Therefore, we designed a regimen that combines the merits of both agents and examined whether such approach can allow early withdrawal of tacrolimus (Tac). Methods: We enrolled 46 adult patients with hematological malignancies receiving haploidentical transplantation from a relative in a prospective single center pilot phase Ib-II clinical trial. Patients received non-myeloablative, reduced-intensity or myeloablative preparative regimens followed by G-CSF mobilized peripheral blood transplants and a combination of PTCy (50mg/kg on days +3 and +4), Aba (10mg/kg on days +5, +14 and +28) and Tac at a dose adjusted based on blood level. Tac taper was initiated on day +60 and completed by day +90. After treating 30 patients, the study was amended to administer an additional dose of Aba on day +56 based on the noted timing of acute GvHD development and Aba terminal ½ life. Patients received standard supportive care by institutional practice including G-CSF and anti-microbial prophylaxis. Serologically CMV positive patients also received letermovir prophylaxis. Results: Patient characteristics are summarized in table 1. Importantly, 19 out of 46 (41.3%) patients were from racial or ethnic minorities. The data cutoff date was July 29th, 2022. Three patients were excluded from this analysis due to short follow-up. For the remaining patients, median follow-up was 8.9 months. Median time to neutrophil engraftment was 18 days (13-30). One patient died before achieving platelet (plt) engraftment and 2 patients have not yet achieved plt engraftment. For the remaining 40 patients, median time to plt engraftment was 29 days (16-52). All patients achieved full donor chimerism at the time of count recovery. Tac was successfully tapered off as planned in all but 5 patients. Cumulative incidence of acute GvHD grades II-IV, III-IV and IV with death as competing event was 12.8%, 5.1% and 0%, respectively. One-year (y) cumulative incidence of moderate to severe chronic GvHD was 17.1%. All cases of acute GvHD except 1 grade II acute GvHD were observed in the first 30 patients. Cases of chronic GvHD included 2 cases of overlap syndrome. There was no case of steroid-refractory acute GvHD or GvHD-related death. One-y cumulative incidence of relapse (non-relapse mortality as competing event) was 8.3% (95% CI 0%-17.1%). KM estimates of 1-year relapse-free survival (RFS), overall survival (OS) and GRFS (composite end point of grade III-IV acute GvHD-, chronic GvHD requiring systemic therapy- and relapse-free survival) were 91.7% (95% CI 83%-100%), 90.6% (95% CI 80.9%-100%) and 71.8% (95% CI 57.2%-90%), respectively. None of the safety stopping rules was triggered. There was 1 case of thrombotic microangiopathy due to Tac and 2 cases of sinusoidal occlusive disease, 1 requiring treatment with defibrotide; all 3 patients recovered. There were 2 cases of respiratory failure of undetermined etiology. One-y cumulative incidence of non-relapse mortality (relapse as competing event) was 2.6% (95% CI 0%-7.8%). The incidence of CMV and EBV reactivation was 39.5% and 2.3%, respectively. There was no case of adenovirus or HHV-6 virus reactivation. BK viruria occurred in 27.9% of patients with limited symptomatology (1 patient required treatment with cidofovir). Immune reconstitution results are summarized in figure 1. Conclusion: CAST is a new GvHD prevention regimen that seems safe and effective, yielding excellent outcomes. CAST also allows early discontinuation of Tac. Outcomes with longer follow-up will be presented at the meeting. If the results are confirmed, CAST might be a step forward toward closing an important health disparity gap in BMT, equalizing the outcomes of haploidentical transplantation and MUD transplants. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Reduced Toxicity FluBu3 Regimen Showed a Comparable Post-Transplant Outcomes to a Myeloablative BuCy Conditioing in Acute Myeloid Leukemia Patients Receiving First Allogeneic Hematopoietic Stem Cell Transplantation in MRD Negative CR1

Introduction: In a previous report, we found that post-transplant clinical outcomes were not significantly different between MAC (BuCy, CyTBI) and RIC (FluBu2TBI400) groups in AML CR1 with pre-transplant low WT1 expression. Based on this result, we expanded the use of conditioning regimen with reduced dose intensity for patients achieving deep response by minimal residual disease (MRD) assessment with available assays. FluBu3 regimen, consisting of fludarabine for 5 days (30mg/m2/day, D-6 to D-2) and busulfan for 3 days (3.2mg/kg/day, D-5 to D-3), was chosen and applied as reduced toxicity conditioning (RTC) in our institution since Jan 2017. Method: In this analysis, we compared MAC and RTC regimens; BuCy (busulfan 3.2 mg/kg/day for 4 days from D-7 to D-4 and cyclophosphamide 60 mg/kg/day for 2 days from D-3 to D-2) and FluBu3 protocols were used as MAC and RTC regimen, respectively. The inclusion criteria were set as follows: (1) adult (age ≥ 18 years) AML patients who were registered in a prospective cohort study; (2) receiving first allogeneic hematopoietic stem cell transplantation (HSCT) in CR1 between Aug 2017 and Nov 2021; (3) MRD negative at pre-transplant; (4) transplantation from either HLA-matched (8/8) sibling donor (MSD), matched unrelated donor (MUD) or 1-locus mismatched (7/8) unrelated donor (MMUD); (5) the use of either BuCy or FluBu3 conditioning. MRD negativity was defined by the absence of abnormalities in the following order; (i) <3 log reduction in RUNX1-RUNX1T1 and CBFB-MYH11, (ii) <4 log reduction of NPM1 level from diagnosis, and (iii) pre-transplant WT1 levels ≥ 250 copies for RUNX1-RUNX1T1, CBFB-MYH11, or NPM1 mutation negative AML. Peripheral blood was used as the source of stem cells in all patients, and the data was analyzed based on information available as of Jun 2022. Results: A total of 124 patients met the inclusion criteria, and 78 (62.9%) and 46 (37.1%) patients received BuCy and FluBu3 conditioning, respectively. The median age was 45 years and the patients with intermediate cytogenetics comprised the majority (71.8%). By the donor type, 64 (51.6%), 48 (38.7%) and 12 (9.7%) patients underwent MSD, MUD and MMUD transplantation. Between the two conditioning groups, patients receiving FluBu3 were older (median 39.5 vs 53 years, p<0.001) and significantly more patients in the FluBu3 group had received ATG (37.9% vs 93.5%, p<0.001). In each of the BuCy and FluBu3 groups, after median follow up of 39.5 and 53 months (p<0.001), the 2-year overall survival (OS) of 78.3% and 84.5% (p=0.358), relapse free survival (RFS) of 78.0% and 76.3% (p=0.806), cumulative incidence of relapse (CIR) of 7.7% and 21.5% (p=0.074) and non-relapse mortality (NRM) of 14.3% and 2.2% (p=0.0324) were observed. In addition, the probabilities of grade II-IV acute graft versus host disease (aGVHD) and cGVHD of moderated to severe at 2-year for BuCy and FluBu3 were 46.2% and 39.2% (p=0.306), and 59.5% and 36.0% (p=0.008), respectively. At the time of data cut-off, relapse was the main cause of HSCT failure in FluBu3 group (n=8) while NRM contributes most to HSCT failure in BuCy group (n=11). Six of 8 relapsed patients receiving FluBu3, compared to 1 out of 6 in BuCy group, had high-risk features of either poor cytogenetics or FLT3-ITD mutation. The majority of NRM in the BuCy group, 8 out of 11 cases, was due to GVHD and 4 of them received transplantation from MMUD. Conclusion: Among the AML patients in MRD negative CR1, the FluBu3 RTC regimen showed a comparable post-HSCT outcomes to a BuCy conditioing in terms of similar OS and RFS, while associated with significant reduced NRM that was offset by trend towards higher risk of relapse.

Differences in Patterns of Infections Among Allogeneic Hematopoietic Cell Transplant Patients Receiving Letermovir Prophylaxis for Cytomegalovirus

Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic- cell transplantation (HCT) with a significant increase in morbidity and mortality among patients who acquire such infection. Pre-emptive prophylaxis in which antiviral agents are started based on detection of CMV in the blood to prevent clinical disease has been the standard practice for many years. This approach was limited by the toxicity of available anti-CMV medications and increased complications among patients who activate CMV(1, 2). Letermovir, an antiviral agent that inhibits replication by binding to components of the terminase complex (UL51, UL56, or both) was approved in 2017 for prevention of CMV infection and disease among HCT recipients(3). Letermovir has been shown to delay polyfunctional CMV-specific cellular immune reconstitution as well as cause a decrease in absolute polyfunctional CD8+ T cell responses(4). The impact of such delayed immune reconstitution on infections other than CMV has not been widely described especially in the setting of post-transplant cyclophosphamide as GVHD prophylaxis. To study the impact of Letermovir on non-CMV infections during the first 6 months post HCT and to assess its effect on other transplant endpoints including OS, DFS, NRM, relapse, acute and chronic GVHD, we analyzed 409 consecutive patients who received their HCT at our center between 2016 and June of 2021. Letermovir prophylaxis was started at our center in January 2018 and is given to patients receiving MUD or haploidentical transplant and are either CMV+ or donor is CMV+. The final dataset included 321 subjects with the following characteristics: Median age 54 years (19-80); disease AML/ALL/MDS 81%, NHL/HD/Other 19%; donor type haplo (69%), MUD 31%; Cell Source PBSC 88%; Myeloablative conditioning 38% ; Donor/Recipient +/+ 50%, +/- 12%, -/+ 38% . The median follow up for survivors was 31.2 (11.5-52.6) months for letermovir group versus 66.2 (53.1-76.9) months for no letermovir group. Patients in the letermovir group were less likely to have received a reduced intensity regimen (22% vs 33%, p=0.05) and to have received a marrow graft (8% vs 16%, p=0.02). The survival endpoints at 3 years were OS (72.7% vs 68.8% p=0.5), DFS (64.4% vs 58.0% p=0.27), relapse (21.2% vs 28.6% p=0.08) and non-relapse mortality NRM (14.5% vs 13.5% p=0.5) for letermovir compared to no letermovir . The cumulative incidences for grade II-IV acute and moderate-severe chronic GVHD were 50.7% vs 40.2%, p=0.08 and 24.3% vs 24.1%, p=0.85 for Letermovir and no letermovir respectively The cumulative incidence of CMV reactivation was significantly lower for letermovir 24.4% compared to 57.1% for letermovir (p<0.001) figure 1, whereas non-CMV infections were similar between both groups with a trend towards lower infections for letermovir recipients 75.2% vs 83% p=0.07, figure 1. When assessing the difference in non-CMV infections per infection, there was no difference in the mean number of infections at 6 months post-HCT where patients in both groups had a mean of 2.5 infections. When looking at different types of infections between Letermovir and no letermovir groups, there was no difference in mean number of bacterial infections (1.58 vs 1.43), viral infections (0.90 vs 0.95) and fungal infections (0.16 vs 0.22), P =NS for all. Our data shows that in a large cohort of allogeneic HCT recipients, mostly haploidentical with Post-transplant cyclophosphamide, letermovir significantly decreases CMV reactivation without changing the pattern or incidence of non-CMV infections. 1. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38. 2. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711-9. 3. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. The New England journal of medicine. 2017;377(25):2433-44. 4. Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood. 2021;138(1):34-43. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Late Graft Failure in MDS and Acute Leukemia Patients Receiving Allogenic Hematopoietic Cell Transplantation with Post Transplant Cyclophosphamide As Gvhd Prophylaxis

Introduction: Post-transplant cyclophosphamide (PTCy) is a commonly used prophylactic therapy for graft-vs-host disease (GVHD), particularly in the setting of haploidentical (haplo) transplantation. Despite prior studies showing comparable survival outcomes when compared to HLA matched unrelated donor transplantation (MUD-HCT) using traditional calcineurin inhibitor based GVHD prophylaxis, the rate of graft failure has been reported to be as high as 12-20% in haplo-HCT recipients. In the current study, we report the impact of PTCy on engraftment failure and overall mortality in AML, ALL and MDS patients after haplo vs MUD HCT receiving a uniform PTCy GVHD prophylaxis to determine if excess late graft failure is due to PTCy, donor source or a combination of both factors. Methods: We performed a retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research database among adult patients who underwent first reduced intensity conditioning (RIC) haplo or 8/8 MUD allogeneic HCT between 2011 and 2018 for AML, ALL or MDS with PTCy GVHD prophylaxis previously described by Gooptu et al (Blood 2021). The two comparative cohorts were: 1.) haplo recipients receiving GVHD prophylaxis with PTCy, calcineurin inhibitor/mTOR inhibitor and mycophenolate, and 2.) MUD-HCT recipients receiving GVHD prophylaxis with PTCy, calcineurin inhibitor/mTOR inhibitor and mycophenolate. The population was restricted to patients that initially engrafted after transplant. The primary outcome was incidence of late graft failure, defined as any graft failure following primary neutrophil engraftment. We sought to identify risk factors for graft failure in the two cohorts. Secondary outcomes were overall mortality and its associated risk factors in the haplo vs. MUD-HCT cohorts. Results: A total of 1336 patients met the eligibility criteria (N=60 haplo and N=2 MUD excluded due to a lack of initial engraftment). Of these, 1151 patients received a haplo-HCT and 185 received a MUD-HCT. Patients in the Haplo group were older (61 vs 65), more ethnically diverse (28% vs 5% non-Caucasian), received more bone marrow grafts (45% vs 16%), had older donors (median age 37 vs 28 years old), received predominately TBI/Cy/Flu regimens (86% vs. 32%) and had longer median follow-up (29 vs 25 months) (Table 1). At 2 years, the adjusted probabilities of late graft failure for the haplo-HCT group was 6.5% (95% CI 5.2-8.0) vs 5.9% (95% CI 2.7-10.9) for the MUD (p = 0.785). The 2-year overall survival, however, was significantly lower for the haplo-HCT cohort, 56% (95% CI 53-39) vs 69% (95% CI 61-75) for the MUD-HCT group (p=0.001). Multivariate analysis to factors associated with increased risk of graft failure demonstrated that a diagnosis of MDS, HR 1.98 (95% CI 1.22-3.20, p=0.005), and being transplanted in the earlier time period (2015-2018 vs 2011-2014 HR 0.39, 95% CI 0.24-0.64, p =0.0002). Multivariate analysis to evaluate risk factors associated with overall mortality demonstrated that haplo-HCT, HR 1.46 (95% CI 1.11-1.91, p-value = 0.007), high risk disease, HR 2.31 (95% CI 1.87-2.84, p=<0.0001), HCT comorbidity score of >/= 3, HR 1.34 (95%CI 1.13-1.58, p=0.0007), and a diagnosis of ALL, HR 0.51 (95%CI 0.39-0.67, p=<0.001) were all significantly associated with increased risk. A post-hoc sensitivity analysis to evaluate the effect donor age between donor types on graft failure was performed. Cases and controls were selected where donor age was between 18-49 years old, resulting in a sub-cohort of 1078 patients (898 haplo and 180 MUD). When adjusted for donor age, graft failure did not differ between haplo and MUD HCT HR 1.19(95% CI 0.53 - 2.69, p=0.6731) (Figure 1). Conclusion: In this registry-based analysis of patients undergoing reduced intensity transplant for AML, ALL or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates when utilizing a haplo vs. MUD-HCT with PTCy for GVHD prophylaxis. Overall mortality, however, was significantly higher in the haploidentical donor cohort, as previously reported. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Outcomes of Matched Unrelated Donor Allogeneic Stem Cell Transplants with High CD34-Positive Cell Dose: A Single Center Experience

Introduction: CD34+ peripheral blood stem cells serve as the primary source for the majority of allogeneic stem cell transplants for hematologic malignancy, and adequate cell numbers must be infused to ensure engraftment. While the target dose is typically 5x106 cells/kg, there have been conflicting data on the effect of higher doses on outcomes. Due to concern for adverse effects, such as graft-versus-host disease (GVHD), some groups have suggested capping the CD34+ cell dose; however, various levels have been recommended, and the majority of studies have only small numbers of patients at very high cell doses where any effects may be most evident. In addition, manipulation of grafts can be time-consuming and lead to an increased risk of contamination. To better assess the effect of high cell dose on outcomes, we reviewed patients at our center who received matched unrelated donor (MUD) transplants with CD34+ dose in the highest quintile. Methods: We performed a single-center retrospective analysis of adult patients with hematologic malignancy who received a MUD allogeneic stem cell transplant with CD34+ cell dose in the highest quintile (>13x106 cells/kg) from 2005 to 2021. Data were collected on patient and donor demographics, disease and transplant characteristics, and CIBMTR risk index. Outcomes were compared with the remaining MUD transplant patients during the same time period, including overall survival (OS), relapse-free survival (RFS), transplant-related mortality (TRM), GVHD rates and severity, and engraftment kinetics, with survival data censored at 10 years. Patients who received multiple transplants or had cryopreserved grafts were excluded. Neutrophil (PMN) engraftment was defined as the first of 3 consecutive days with absolute neutrophil count >500 cells/µL, and platelet (PLT) engraftment defined as the first of 3 consecutive days with PLT count >20x103 cells/µL and at least 7 days after most recent transfusion. Demographic data and GVHD rates were compared by Fisher's exact test or chi-squared test; age by Welch's t-test; engraftment kinetics medians by Mann-Whitney U test; and OS, RFS, and TRM by Kaplan-Meier analysis with log-rank (Mantel-Cox) test for significance. Results: 36 patients were identified in the highest quintile with a median CD34+ dose of 16.83x106 cells/kg (range: 13.02-39.02) compared to 139 control patients with median dose of 7.74x106 cells/kg (2.72-12.99). Patients in the high-dose group were more likely to be female (58.3% vs 38.8%, p=.04), with no other statistically significant differences in donor, recipient, or disease characteristics (Table 1). There was a trend toward faster PLT engraftment in the CD34-high group (median 16 vs 16.5 days, p=.058), but there was no effect on PMN engraftment time (14 vs 14, p=.78). There was no difference in incidence of acute GVHD, either grade 2 or above (33.3% vs 36.0%, p=.85) or grade 3 or above (19.4% vs 15.8%, p=.62), and the groups showed similar incidence of chronic GVHD both overall (38.9% vs 48.2%, p=.35) and for severe disease (13.9% vs 11.5%, p=.77). There was no significant difference in OS between the two groups by Kaplan-Meier analysis (Figure 1, p=.44). Comparing the CD34-high group to the control group, the estimated 2-year survival was 47.2% vs 55.7%, and the estimated 5-year survival was 37.3% vs 45.2%. There was similarly no difference in RFS or TRM (p=.34 and p=.55, data not shown). Conclusions: Previous studies of the effect of CD34+ cell dose on transplant outcomes have been limited by small numbers of patients at the highest doses. In this single-center study using one of the highest dose cutoffs in the literature (>13x106 cells/kg), we showed a trend toward faster PLT engraftment with no difference in GVHD incidence or mortality. As a retrospective study, a major limitation is possible confounding, and we plan to include other potential factors, such as GVHD prophylaxis, in multivariate analysis, though our initial results did not show major differences in baseline characteristics. In this cohort, patients receiving very high CD34+ cell doses had similar outcomes to those receiving standard doses. These data do not support the routine use of graft reduction by CD34+ cell number, which may help guide future practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Impact of FLT3 Inhibitor-Based Therapies on Outcomes of Acute Myeloid Leukemia (AML) Patients Receiving Allogenic Stem Cell Transplantation: A Retrospective Study

Background The FMS-like tyrosine kinase 3 (FLT3) mutation affects approximately 30% of patients with acute myeloid leukemia (AML) and is associated with increased relapse and mortality. FLT3 inhibitors are known to improve survival when used in the induction, consolidation and relapsed/refractory phases of AML. However, due to their novelty, little is known about the impact of FLT3 inhibitors on graft-versus-host disease (GVHD), relapse and survival after hematopoietic stem cell transplantation (HSCT). Methods We retrospectively analyzed adult patients treated at the University of Southern California Norris Comprehensive Cancer Center between May 2017 and July 2022. All patients had an AML diagnosis with either a FLT3-ITD or FLT3-TKD mutation, received a FLT3 inhibitor at one or more time points during their treatment course, and underwent HSCT. Our primary endpoint was graft-versus-host disease-free, relapse-free survival (GRFS). Secondary endpoints included 2-year overall survival (OS), 2-year relapse-free survival (RFS), and FLT3 inhibitor discontinuation due to adverse side effects. Acute GVHD was defined per the 2018 MAGIC criteria and chronic GVHD was defined per the 2014 NIH criteria. Results Of the 40 patients included in this study, 30 (75%) had the FLT3-ITD mutation, and 10 (25%) had the FLT3-TKD mutation. Age at time of HSCT ranged from 30-69 years old (median= 47). Males and females were evenly represented, and most patients were Hispanic (55%). The majority of patients (67.5%) were in first complete remission (CR1) at the time of HSCT. ELN 2022 genetic risk stratification was mainly intermediate (77.5%) and adverse (15%). All patients received peripheral blood stem cells, and most (70%) underwent myeloablative conditioning regimens. All patients received a FLT3 inhibitor before HSCT, during the induction/consolidation phase or relapsed/refractory phase before achieving CR. Of the 29 patients who used maintenance therapy after HSCT, 18 (62%) received gilteritinib while 11 (38%) received midostaurin. Using Cox survival analysis, univariate predictors of adverse events in GRFS were matched unrelated donor (MUD) when compared to haploidentical-HSCT (HR = 4.77, p=0.023), pre-transplant ATG (HR =3.99, p=0.049), and lack of maintenance FLT3 inhibitors (HR = 3.03, p = 0.034). On bivariate analysis, MUD HSCT continued to be predictive when controlling for time from induction to HSCT (Table 1, Model 2) and age at HSCT (Table 1, Model 3). Patients who received a FLT3 inhibitor for post-HSCT maintenance therapy had significantly improved OS (p = 0.033) and RFS (p=0.016) on Kaplan-Meier survival analysis, with an OS of 96.2% and RFS of 89.7% at 24 months, and an OS of 90.1% and RFS of 82.8% at 36 months. Eight patients discontinued FLT3 inhibitors at maintenance due to side effects, having a shorter length of FLT3 inhibitor use, 116 days vs. 230 days (p = 0.005). Discussion Our results found multiple factors were associated with worsened GRFS, including MUD transplant, pre-transplant ATG and lack of maintenance FLT3 inhibitors. Post-HSCT maintenance, primarily with gilteritinib, resulted in improved OS and RFS in our patients, similar to the findings of prior studies with other FLT3 inhibitors. Amongst our patients receiving FLT3 inhibitors for maintenance, OS at 24 months was 96.2% compared to prior reports of 90.5% with sorafenib and 85% with midostaurin. RFS in our FLT3 inhibitor maintenance group was 89.7% at 24 months, compared to prior reports of 85% with sorafenib and midostaurin. OS and RFS for our FLT3 inhibitor maintenance group remained high at 36 months. Additional studies, such as the ongoing phase III clinical trial BMT CTN Protocol 1506, can be used to confirm our findings. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intensified conditioning regimens improved disease-free survival and engraftment after unrelated single-unit cord blood transplantation but not after matched sibling or matched unrelated donor allogeneic hematopoietic cell transplantation.

The impact of conditioning intensity on different donor groups has been unclear in allogeneic transplantation. The objective of this study was to clarify the effect of conditioning intensity on disease-free survival (DFS), relapse, non-relapse mortality (NRM), neutrophil engraftment, and graft-versus-host disease for each donor type. We retrospectively evaluated the effect of conditioning intensity on transplant outcomes for patients with acute leukemia or myelodysplastic syndrome aged between 16 and 60years in Japan using the transplant conditioning intensity (TCI) scoring system. A total of 8526 patients who received first allogeneic transplantation from 6/6 antigen-matched sibling donor (MSD, n=2768), 8/8 allele-matched unrelated donor (MUD, n=2357), and unrelated single-cord blood (UCB, n=3401) were eligible for the analyses. Compared to conditioning with TCI score 4.0, which was corresponds to conventional myeloablative conditioning, including cyclophosphamide with total body irradiation 12Gy or busulfan 12.8mg, and was considered as the reference group in the multivariate analyses, intensified conditioning with TCI score ≥4.5 improved DFS (hazard ratio [HR],0.81, P<0.001) and relapse rate (HR, 0.70, P<0.001) but only after UCB transplants and not MSD and MUD transplants. In contrast, NRM was higher after intensified conditioning with TCI score ≥4.5 for MSD (HR, 1.39, P=0.008) and MUD (HR, 1.47, P=0.002) transplants but not UCB transplants (HR, 1.12, P=0.240). Neutrophil engraftment was also significantly higher after intensified conditioning with TCI score ≥4.5 but only for UCB transplants (HR, 1.24, P<0.001), whereas it was significantly lower after reduced-intensity conditioning with TCI score ≤3.5 for MSD transplants only (HR, 0.82, P<0.001). These data demonstrated that an intensified conditioning regimen improved survival and engraftment rate only after a UCB transplants. Therefore, TCI scoring system could enable the optimization of conditioning intensity according to donor type, particularly in terms of survival and engraftment.

Analysis of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies: A Single-center Study

To analyze the survival, prognostic factors, and prevention of relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with hematological malignancies, and explore the relationship between immune reconstruction, loss of human leukocyte antigen (HLA-loss) and relapse after transplantation. From July 2012 to June 2020, 47 patients with hematological malignancies who relapsed after allo-HSCT were retrospectively analyzed, including 20 cases undergoing matched-sibling donor transplantation (MSD), 26 cases undergoing haploidentical transplantation (HID), and 1 case undergoing matched-unrelated donor transplantation (MUD). Multivariate analysis was used to analyze the risk factors related to post-relapse overall survival (PROS). All the 47 patients were implanted successfully. The cumulative incidence of grade Ⅱ-Ⅳ, Ⅲ/Ⅳ acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 40.4%, 10.6%, and 31.9%, respectively. The incidence of grade Ⅱ-Ⅳ and Ⅲ/Ⅳ aGVHD in HID group was 42.3% and 11.5%, while in MD group was 38.1% and 9.5% (P=0.579, P=1.000), and the incidence of cGVHD in the two groups was 34.6% and 28.6% (P=0.659). The PROS of patients with NK cell absolute count > 190 cells/μl 30 days after transplantation was higher than that of patients with NK cell absolute count ≤190 cells/μl (P=0.021). The 1-year and 3-year PROS of all the patients was 68.1% and 28.4%, respectively, while in the HID group was 78.9% and 40.3%, in the MD group was 54.4% and 14% (P=0.048). Multivariate analysis showed that grade Ⅱ-Ⅳ aGVHD and time of relapse < 3 months were independent risk factors of PROS (P<0.05). The therapeutic effect of haploidentical transplantation in patients with relapsed hematological malignancies after allo-HSCT is better than that of matched donor transplantation. The high absolute count of NK cells 30 days after transplantation can increase PROS. Grade Ⅱ-Ⅳ aGVHD and time of relapse < 3 months have prognostic significance for long-term survival of patients with relapsed hematological malignancies after transplantation.

Characteristics of Graft-Versus-Host Disease (GvHD) After Post-Transplantation Cyclophosphamide Versus Conventional GvHD Prophylaxis

Post-transplantation cyclophosphamide (PTCy) has been shown to effectively control graft-versus-host disease (GvHD) in haploidentical (Haplo) transplantations. In this retrospective registry study, we compared GvHD organ distribution, severity, and outcomes in patients with GvHD occurring after Haplo transplantation with PTCy GvHD prophylaxis (Haplo/PTCy) versus HLA-matched unrelated donor transplantation with conventional prophylaxis (MUD/conventional). We evaluated 2 cohorts: patients with grade 2 to 4 acute GvHD (aGvHD) including 264 and 1163 recipients of Haplo and MUD transplants; and patients with any chronic GvHD (cGvHD) including 206 and 1018 recipients of Haplo and MUD transplants, respectively. In comparison with MUD/conventional transplantation ± antithymocyte globulin (ATG), grade 3-4 aGvHD (28% versus 39%, P=.001), stage 3-4 lower gastrointestinal (GI) tract aGvHD (14% versus 21%, P=.01), and chronic GI GvHD (21% versus 31%, P=.006) were less common after Haplo/PTCy transplantation. In patients with grade 2-4 aGvHD, cGvHD rate after Haplo/PTCY was also lower (hazard ratio [HR]=.4, P < .001) in comparison with MUD/conventional transplantation without ATG in the nonmyeloablative conditioning setting. Irrespective of the use of ATG, non-relapse mortality rate was lower (HR=.6, P=.01) after Haplo/PTCy transplantation, except for transplants that were from a female donor into a male recipient. In patients with cGvHD, irrespective of ATG use, Haplo/PTCy transplantation had lower non-relapse mortality rates (HR=.6, P=.04). Mortality rate was higher (HR=1.6, P=.03) during, but not after (HR=.9, P=.6) the first 6 months after cGvHD diagnosis. Our results suggest that PTCy-based GvHD prophylaxis mitigates the development of GI GvHD and may translate into lower GvHD-related non-relapse mortality rate.

Defibrotide Prophylaxis of Sinusoidal Obstruction Syndrome in Adults Treated With Inotuzumab Ozogamicin Prior to Hematopoietic Stem Cell Transplantation.

Sinusoidal Obstruction Syndrome (SOS) is a life threatening HSCT complication and it can rapidly evolve in Multiple Organ Dysfunction Syndrome, with a mortality exceeding 80%. Early treatment with defibrotide is the leading factor for efficacy. Its prophylactic use is recommended in the pediatric setting, but its value isn’t validated for adults, although factors for individual risk assessment are debated. We here present a real-world experience of Defibrotide prophylaxis in adults at very high risk of SOS. We treated with prophylactic Defibrotide and Ursodeoxycholic Acid seven patients receiving allogeneic HSCT for high risk B-ALL, previously treated with single agent Inotuzomab-Ozogamicin. They all had other high risk factors for SOS such as previous hepatotoxicity, previous allo-HSCT, double alkylating conditioning. All patients received Treosulfan-Fludarabine conditioning, Thiotepa was added in 4 patients and 4GyTBI in 2 patients. GvHD prophylaxis included post-transplant cyclophosphamide, rapamycin and mycophenolate. Donor source was PBSC. Five patients received family MMRD transplant, 1 patient a MRD transplant and 1 patient a MUD transplant. Non-severe gastrointestinal bleeding occurred in two patients requiring defibrotide temporarily discontinuation. SOS occurred in 3/7 cases within 21 days after HSCT and no late-onset SOS were diagnosed. SOS caused death in all cases. All three patients were characterized by a common pattern of very high risk factors by prior HSCT, they all received a myeloablative conditioning with Treosulfan-Thiotepa and a MMRD transplant. Defibrotide prophylaxis apparently failed to protect against the development of SOS in those patients treated with a double alkylator-based conditioning regimen, while a possible efficacy for the other high-risk patients is debatable.