Alternative Donor Transplantation Research Articles

Alternative donor transplantation for severe aplastic anemia: a comparative study of the SAAWP EBMT

AbstractSelecting the most suitable alternative donor becomes challenging in severe aplastic anemia (SAA) when a matched sibling donor (MSD) is unavailable. We compared outcomes in patients with SAA undergoing stem cell transplantation (SCT) from matched unrelated donors (MUD) (n = 1106), mismatched unrelated donors (MMUD) (n = 340), and haploidentical donors (Haplo) (n = 206) registered in the European Society for Blood and Marrow Transplantation database (2012-2021). For Haplo SCT, only those receiving posttransplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis were included. Median age was 20 years, and the median time from diagnosis to transplantation 8.7 months. Compared with MUD, MMUD (hazard ratio [HR], 2.93; 95% confidence interval [CI], 1.52-5.6) and Haplo (HR, 5.15; 95% CI, 2.5-10.58) showed significantly higher risks of primary graft failure. MUD had lower rates of acute GVHD compared with MMUD and Haplo (grade 2-4: 13%, 22%, and 19%, respectively; P < .001; grade 3-4: 5%, 9%, and 7%, respectively; P = .028). The 3-year nonrelapse mortality rate was 14% for MUD, 19% for MMUD, and 27% for Haplo (P < .001), whereas overall survival and GVHD and relapse-free survival (GRFS) rates were 81% and 73% for MUD, 74% and 65% for MMUD, and 63% and 54% for Haplo, respectively (P < .001). In addition to donor type, multivariable analysis identified other factors associated with GRFS such as patient age, performance status, and interval between diagnosis and transplantation. For patients with SAA lacking an MSD, our findings support MUDs as the preferable alternative donor option. However, selecting between an MMUD and Haplo donor remains uncertain and requires further exploration.

Gender Disparities in Allograft Access Due to HLA-Sensitization in Multiparous Women:Implications for Evaluation of Female Patients for Alternative Donor Transplantation

Gender Disparities in Allograft Access Due to HLA-Sensitization in Multiparous Women:Implications for Evaluation of Female Patients for Alternative Donor Transplantation

Sitagliptin for Prevention of aGVHD in Patients Received Alternative Donor Transplantations: A Prospective, Multicenter, Open-Label, Randomized Controlled Trial

Background： Acute graft versus host disease (aGVHD) remains one of the most frequent complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT) with high mortality. Traditionally, alternative donor transplantation (ADT) from an unrelated donor or a haploidentical family donor has been reported in an increased incidence of aGVHD and severe GvHD. Sitagliptin is a selective inhibitor of dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells which has a costimulatory function in activating T cells. This trial aims to evaluate the safety and efficacy of sitagliptin plus a calcineurin inhibitor, methotrexate (MTX), mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) in the prevention of aGVHD for ADT. Methods： We are performing a prospective, multicenter, open-label, randomized controlled trial (NCT05149365). From 5 HSCT centers in China competitively, patients(pts) who underwent their first allo-HSCT in first or second complete remission (CR) state with hematologic malignancies were received busulfan and cyclophosphamide (Bu/Cy) myeloablative conditioning regimen followed by ADT. 190 eligible pts(18-60 years) were planned randomly assigned in a 1:1 ratio to either a sitagliptin group (600mg sitagliptin taken orally every 12 hours on day -1 to +14, plus conventional prophylaxis including Cyclosporin A(CsA)/ tacrolimus (FK506), MTX, MMF and ATG) and a conventional prophylaxis control group (CsA/FK506, MTX, MMF and ATG). The randomization was based on a computer-generated priori list of 190 binary numbers, with block-balanced with random variable block sizes of two or four pts, without stratification. The primary endpoint was grade II to IV aGvHD by day +100. Key secondary endpoints included severe (grade III or IV) aGvHD by day +100, transplant-related mortality (TRM), relapse-free survival (RFS) and GVHD-free, relapse-free survival (GRFS) from HSCT. At present we have completed pts enrollment and are at the stage of follow-up the study endpoints. Results : From December 2021 to May 2023, a total of 191 pts were enrolled. The ratio of male to female was 113 to 78 with a median age of 38 years (range, 18-60 years). Pts were randomly assigned to the sitagliptin group of 95 and the control group of 96. The clinical and transplantation characteristics at baseline of the intention to treat (ITT) population of the two groups were well balanced (Table1). The last follow-up was on May 30, 2023 and the median follow-up time was 164 (20-512) days. Comparison of the sitagliptin group and the control group by day +100, the cumulative incidence rate of grade II-IV aGVHD was 15.1% and 28.6%, respectively ( P=0.019), and the cumulative incidence rate of grade III or IV aGVHD was 7.6% and 15.9% ( P=0.068); median days of neutrophil engraftment were +11.48 and +11.65 days, respectively (P=0.545); TRM was 3.7% and 7.1% (P=0.454), RFS was 98.7% and 95.9% (P=0.889), respectively and OS of the two groups(96.7% vs 93.6%, P=0.341) was also the same as the RFS. There was no significant difference between the sitagliptin and control groups with regard to cytomegalovirus reactivation, Epstein-Barr virus reactivation, and transplant-related complications (Table 1, Figure 1). The regimen was well tolerated. Only 5(/95) pts discontinued sitagliptin treatment due to adverse events: 4 patients experienced abdominal pain (CTCAE Grade1-2) undergoing sitagliptin therapy 3-7 days and one of them also exhibited hypoglycemia (CTCAE Grade1), which were deemed by clinicians as probable (WHO-UMC) associated with sitagliptin. Symptoms resolved spontaneously within 2 days of cessation. Another patient discontinued treatment due to mild hematemesis initiating sitagliptin therapy only 2 days, which was determined by the clinician as unlikely (WHO-UMC) associated with sitagliptin. Conclusions : Our trial showed sitagliptin combined with conventional prophylaxis (CsA+MTX+MMF+ATG) resulted in a significant reduction of grade II-IV aGVHD in ADT. Furthermore, sitagliptin is ready available, easy of administration, safe, and relatively inexpensive. It remains to be followed up whether it would increase infection and relapse or improve the prognosis of patients after allo-HSCT.

Selecting the Right Alternative Donor: Comparison of Outcomes of HLA-Mismatched Alternative Donor Hematopoietic Cell Transplantations in Adult Patients with Acute Lymphoblastic Leukemia Regarding KIR-Ligand Mismatch

Background: Allogeneic hematopoietic cell transplantation from cord blood (CBT) or haploidentical donor (HIDT) has proved to be a viable option for patients unable to find a human leukocyte antigen (HLA)-matched conventional donor. However, few single-centered studies have compared outcomes of the two alternative donor transplantations in adult acute lymphoblastic leukemia (ALL). Aim: Our aim is to compare outcomes of adult ALL patients treated with CBT with those treated with HIDT. Secondly, we tried to find out factor that could be considered in selecting donor for alternative donor transplantation to improve clinical outcomes. Methods: We compare outcomes of adult ALL patients treated with CBT (n=134) between 2008 and 2022 with those treated with HIDT (n=47) between 2018 and 2022.Conditioning regimen for CBT consisted of total body irradiation (12Gy) plus cytarabine (9g/m 2) plus fludarabine (150mg/m 2). Graft-versus-host disease (GVHD) prophylaxis was attempted using tacrolimus and mycophenolate mofetil. For HIDT, we used reduced toxicity conditioning (RTC) regimen including fludarabine (150mg/m 2) plus busulfan (6.4mg/kg). GVHD prophylaxis was done with ATG 1.5mg for 4 days plus short course methotrexate (MTX) (15mg/m 2) plus tacrolimus. Killer cell immunoglobulin-like receptor (KIR) ligand mismatch was calculated in both GVH and HVG direction using HLA-KIR ligand database, and its effect on clinical outcomes of alternative donor transplantation was investigated. Results: In HIDT, CD34+ cell count (´10 6/kg) was significantly higher (7.4 vs. 0.1, P&amp;lt;0.001), and the patients were older (49 vs. 33.5, P&amp;lt;0.001) compared to CBT. Other characteristics, such as cytogenetic risk and leukocyte count at diagnosis, did not show significant difference between the two groups. Incidence of acute GVHD II-IV (51.1% vs. 50.0%), III-IV (25.5% vs. 17.9%), and moderate to severe chronic GVHD (10.8% vs. 11.0%) between HIDT vs. CBT were similar. After median follow-up of 39.4 months (range: 5.5-167.4), HIDT showed higher cumulative incidence of relapse (CIR) compared to CBT (47.9% vs. 18.9%, P&amp;lt;0.001), which remained true even after stratifying by age subgroup (Age&amp;lt;40: P=0.033, Age≥40: P=0.002). Conversely, CBT showed higher non-relapse mortality (NRM) than HIDT (22.8% vs. 9.0%, P=0.038), but the same was true only in the older age subgroup (Age&amp;lt;40: P=0.484, Age≥40: P=0.002). These effects summed up to produce comparable results in estimated 3-year disease-free survival (DFS) of CBT and HIDT (58.4% vs. 43.5%, P=0.103), especially in the older subgroup (38.7% vs. 40.7%, P=0.897). Multivariate analysis also revealed that HIDT was related with higher relapse (HR 3.47; 95%CI 1.92-6.27, P&amp;lt;0.001), and CBT with higher NRM (HR 4.18; 95%CI 1.42-12.3, P=0.009). GVH direction KIR ligand mismatching worked for lower 3-year DFS in CBT (40.3% vs. 74.4%, P=0.007), although CIR and NRM did not show significant difference (27.8% vs. 15.6%, P=0.178; 35.0% vs 18.4%, P=0.057, respectively). On the other hand, the mismatch resulted in lower incidence of acute GVHD II-IV (32.0% vs. 54.2%, P=0.011). The trend remained when such effect was investigated separately in CBT and HIDT, but it was not statistically significant (33.3% vs. 53.1%, P=0.082; 28.6% vs. 57.6%, P=0.053, respectively). Conclusions: Our data shows higher NRM in CBT, and unexpected higher relapse rate in HIDT. Age of the patient should be considered when choosing CBT, because in older patients CBT showed notably worse NRM compared to HIDT. Higher incidence of relapse in HIDT may be attributable to ALL disease characteristics itself or insufficient elimination of leukemic cells by RTC regimen with stronger GVHD prophylaxis. Similar to what is known in acute myeloid leukemia, GVH direction KIR incompatibility showed protective effect against acute GVHD in ALL. However, the mismatch resulted in worse DFS in ALL patients treated with CBT, but not in those treated with HIDT. Possible explanation to this phenomenon is that the number of NK cells in cord blood was insufficient for mismatch-induced graft-versus-leukemia effect, while its immune response against infected cells was suppressed by the same mechanism that resulted in lower acute GVHD. Keywords: Acute lymphoblastic leukemia, Cord blood transplantation, Haploidentical donor transplantation, HLA-mismatched transplantation, Killer-cell immunoglobulin like receptor

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 &amp;lt; 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 &amp;lt; 0.001). In multivariable analysis, compared with MUD, Haplo (HR, 3.72; 95% CI, 1.97-7.03; p&amp;lt;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 &amp;lt; 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 &amp;lt; 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 &amp;lt; 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 &amp;lt; 0.001), whereas OS was 81% (95% CI; 79-84), 74% (95% CI; 69-79), and 63% (95% CI; 54-71), respectively (p &amp;lt; 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&amp;lt;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 &amp;lt; 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&amp;lt;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.

Gender Disparities in Allograft Access Due to HLA-Sensitization in Multiparous Women: Implications for Evaluation of Female Patients for Alternative Donor Transplantation

Introduction: The relationship between allograft patient (pt) demographics &amp; HLA-antibody (HLA-Ab) burden, &amp; the degree to which HLA-Ab burden impacts donor type received in the current era of “donors for all”, is not established. Methods: We examined associations between pt sex/ parity, ancestry, &amp; HLA-Ab burden in consecutive adult allograft recipients (excluding HLA-identical siblings) with acute leukemia, MDS, or MPN, transplanted 1/2018-12/2022. We also assessed the impact of HLA-Ab burden on donor type received. We classified HLA-Ab burden by the number &amp; intensity of class I (HLA-A, B, -C) &amp; II (HLA-DR, -DQ, -DP) HLA-Abs. A mean fluorescence intensity (MFI) &amp;gt; 1,000 defined a positive HLA-Ab. Pts were classified as broadly sensitized (more than the median number of class I/ II HLA-Abs among Ab positive pts) &amp;/or highly sensitized (MFI &amp;gt; 10,000 for ≥ 1 HLA-Ab). For pts with &amp;gt; 1 screen, the one closest to transplant was used. We hypothesized that multiparous females have the greatest HLA-Ab burden, limiting provision of haploidentical (haplo) grafts in these pts due to the rejection risk. Results: Of 672 pts [median age 60 yrs (range 29-79), 419/672 (62%) with acute leukemia, 472/672 (70%) with European ancestry], 278/672 (41%) were female of whom 54/278 (19%) were nulliparous, 52/278 (19%) uniparous &amp; 172/278 (62%) multiparous. Overall, 367/672 (55%) received 8/8 unrelated donor (URD) &amp; 305/672 (45%) HLA-disparate grafts [137 cord blood (CB), 88 haplo, &amp; 80 5-7/8 URD (mmURD)]. As expected, non-European pts received 2x the proportion of HLA-disparate grafts [165/472 (35%) vs 141/200 (70%), p &amp;lt; .001]. Pt ancestry was not associated with HLA-Ab burden. Pt sex/ parity &amp; HLA-Ab burden associations are shown in Table 1A &amp; Fig. 1. Over one third [254/672 (38%)] of pts had a positive screen for class I/ II HLA-abs (median of 8 HLA-Abs of positive pts, range 1-113). In the 254 positive pts, 3,563 Abs were detected with the MFI distribution being 1,001-4,000 in 1,340/3,563 (38%), 4,001-10,000 in 874/3,563 (25%) &amp; &amp;gt; 10,000 in 1,349/3,563 (38%). Of the total pt cohort, 140/672 (21%) pts were broadly &amp;/or highly sensitized with 90/672 (13%) being both broadly &amp; highly sensitized. Compared with males &amp; nulliparous females, uni- &amp; multi-parous female pts had over 2x the proportion of positive screens [117/448 (26%) vs 137/224 (61%), p &amp;lt; .001]. They also had more than 8x the proportion broadly &amp; highly sensitized [17/448 (4%) vs 73/224 (33%), p &amp;lt; .001]. HLA-Ab burden by donor type is shown in Table 1B. Among HLA-disparate graft recipients, compared with recipients of CB &amp; mmURDs, fewer haplo recipients had positive screens [96/217 (44%)CB/ mmURD vs 27/88 (31%) haplo, p = .029]. Less than half the proportion were broadly &amp; highly sensitized [37/217 (17%) CB/ mmURD vs 7/88 (8%) haplo, p = .041]. Also, haplo recipients included the fewest multiparous females [16/88 (18%)] compared with making up over one quarter of 8/8 URD [98/367 (27%)], CB [36/137 (26%)], or mmURD [22/80 (28%)] transplants. Conclusion: Over 10% of transplanted pts were broadly &amp; highly sensitized to HLA. The HLA-Ab burden was predominantly in parous females (33% of our pt cohort), most of whom had HLA-Abs with one-third of this group being both broadly &amp; highly sensitized. Moreover, pts with a high HLA-Ab burden were the least likely to receive haplos, &amp; thus these transplants were less common in multiparous females. These data have immediate implications for alternative donor transplant evaluations of female patients: given that HLA-Abs should be expected among parous females, in the absence of a matched adult donor, mmURD or CB may need to be considered over haplo grafts. This could compound allograft access for multiparous female pts of non-European heritage, given many will lack a fully matched adult donor &amp; non-European pts have greatly decreased URD availability (Fingrut et al., ASH 2023). These challenges are under-appreciated in the transplant field. At initial allograft evaluation, transplant centers should obtain ancestry &amp; parity histories &amp; screen for HLA-Abs. In the absence of a suitable HLA-identical sibling donor, this information, together with the URD search prognosis (ie Davis et al., TCT 2023), should then guide triage to alternative donor allografts. Finally, prospective analysis of the impact of donor-specific HLA-Abs on donor selection &amp; transplant outcomes as well as development of effective HLA de-sensitization strategies are urgently needed.

Comparison of Haploidentical Stem Cell Transplantation with Post-Transplantation Cyclophosphamide versus Umbilical Cord Blood Transplantation in Adult Patients with Aplastic Anemia

Aplastic anemia patients who are refractory to immunosuppressive therapy or with very low neutrophil counts require allogeneic hematopoietic stem cell transplantation (HSCT). Umbilical cord blood transplantation (UCBT) has been a treatment option when an HLA-matched donor is not available, and HSCT from a related haploidentical donor using post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis (PTCy-haplo) recently became another important approach. We aimed to compare the outcomes of PTCy-haplo and UCBT in adult patients with aplastic anemia to identify more effective and safer approaches for alternative donor transplantation. Data in a nationwide registry were analyzed retrospectively to assess the outcomes of aplastic anemia patients age ≥16 years who underwent PTCy-haplo or UCBT as their first HSCT between 2016 and 2020. The primary endpoint was 1-year overall survival (OS) after HSCT. Secondary endpoints included 1-year failure-free survival (FFS), neutrophil and platelet engraftment, and acute and chronic GVHD. Eighty-three patients who underwent PTCy-haplo (n=24) or UCBT (n=59) were eligible. The 1-year OS rate was 78.5% (95% confidence interval [CI], 55.7% to 90.5%) in the PTCy-haplo group and 77.5% (95% CI, 64.5% to 86.3%; P=.895) in the UCBT group. The 1-year FFS rate was 78.7% (95% CI, 56.1% to 90.6%) in the PTCy-haplo group and 62.2% (95% CI, 48.5% to 73.3%; P=.212) in the UCBT group. Among patients age <40 years, the PTCy-haplo group had a significantly higher FFS rate (92.9% [95% CI, 59.1% to 99.0%]) vs 63.9% [95% CI, 43.2% to 78.7%]; P=.047). Neutrophil engraftment and platelet engraftment rates were significantly higher in the PTCy-haplo group compared with the UCBT group: 95.8% (95% CI, 73.9% to 99.4%) vs 78.0% (95% CI, 65.1% to 86.6%, P < .001) and 83.3% (95% CI, 61.5% to 93.4%) vs 72.9% (95% CI, 59.6% to 82.4%; P=.025). No significant difference was observed in the cumulative incidence of grade II-IV acute GVHD and chronic GVHD between the 2 groups. Aplastic anemia patients achieved significantly higher neutrophil and platelet engraftment rates with PTCy-haplo than with UCBT. OS and the incidences of acute and chronic GVHD were similar between the 2 groups. In patients age <40 years, the FFS rate was higher in the PTCy-haplo group. PTCy-haplo is promising for alternative donor transplantation in adult patients with aplastic anemia.

An Optimized Search Prognosis Tool to Predict 8/8 HLA Allele-Matched Unrelated Donor Procurement

For patients in need of allogeneic transplantation who lack an HLA-identical sibling, an 8/8 HLA allele-matched unrelated donor (URD) is a standard alternative. However, delays in URD procurement can adversely impact patient care. Recipient genotype and search assessment (MSKv1.0)-based tools can predict search prognosis for many, but both tools have lower performance in non-European ancestry patients. Using the MSKv1.0 tool, we analyzed searches from 1530 potential allograft recipients (including 863 who underwent transplantation) with the aim of creating an optimized MSKv2.0 search prognosis tool that can classify a URD search as either Good or Poor with a high level of accuracy while also limiting an ambiguous Fair search prognosis regardless of patient ancestry. By MSKv2.0, the 8/8 URD search prognosis distribution was 57% Good, 21% Fair, and 22% Poor in Europeans and 15% Good, 21% Fair, and 63% Poor in non-Europeans. Importantly, compared to MSKv1.0, the likelihood of Fair categorization was reduced to <25% with comparable Fair rates (P=.847) in both European and non-European groups. Moreover, all patients with an MSKv2.0 Good prognosis had an 8/8 URD identified, and almost all of those who underwent transplantation had an 8/8 URD (Europeans, 99%; non-Europeans, 98%; P=.504). The MSKv2.0 tool also was highly accurate at classifying Poor searches, with <10% identifying an 8/8 URD, and almost all patients who underwent transplantation (Europeans, 95%; non-Europeans, 96%) receiving an alternative donor. Using preliminary search results, MSKv2.0 accurately classifies patients by likelihood of 8/8 URD procurement, greatly facilitating triage to 8/8 URD (Good prognosis) or alternative donor (Poor prognosis) transplantations.

197 - Contemporary Comparison of Alternative Donor Transplantation Sources with Matched Related Donors for Pediatric Severe Aplastic Anemia Demonstrates Non-Inferior Outcomes: A Single Center Experience

197 - Contemporary Comparison of Alternative Donor Transplantation Sources with Matched Related Donors for Pediatric Severe Aplastic Anemia Demonstrates Non-Inferior Outcomes: A Single Center Experience

Outcomes associated with allogeneic hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma in the era of novel agents.

Relapsed or refractory Hodgkin lymphoma (R/R HL) is a challenging disease with limited treatment options beyond brentuximab vedotin and checkpoint inhibitors. Herein we present the time-trend analysis of R/R HL patients who received allogeneic hematopoietic cell transplantation (allo-HCT) at our center from 2001-2017. The patients were divided into two distinct treatment cohorts: era1 (2001-2010), and era2 (2011-2017). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic graft versus host disease (GVHD). Among the 51 patients included in the study, 29 were in era1, and 22 were in era2. There was decreased use of myeloablative conditioning in era2 (18% vs. 31%) compared to era1 and 95% of patients in era2 previously received brentuximab Vedotin (BV). Haploidentical donors were seen exclusively in era2 (0% vs. 14%) and more patients received alternative donor transplants (7% vs. 32%) in era2. The 4-year OS (34% vs. 83%, p< 0.001) and 4-year PFS (28% vs. 62%, p= 0.001) were significantly inferior in era1 compared to era2. The incidence of 1-year NRM was lower in era2 compared to era1 (5% vs. 34%, p= 0.06). The cumulative incidence of acute GVHD at day 100 was similar in both eras (p= 0.50), but the incidence of chronic GVHD at 1year was higher in era2 compared to era1 (55% vs. 21%, p= 0.03). Despite the advent of novel therapies, allo-HCT remains an important therapeutic option for patients with R/R HL.

In 2022, which is preferred: haploidentical or cord transplant?

Allogeneic hematopoietic stem cell transplantation is the treatment of choice for high-risk hematological malignancies such as acute myeloid and lymphocytic leukemia, myelodysplastic syndrome, and myeloproliferative disorders. Alternative donor transplantation from either haploidentical (haplo-SCT) or cord blood donor (CBT) is an established therapeutic alternative for patients who need transplants but lack a human leukocyte antigen-matched donor. Although haplo-SCT (mainly non-T-cell-depleted haplo-SCT with posttransplant cyclophosphamide) is increasing while CBT is decreasing worldwide (Figure 1), recent developments in CBT, especially cord blood expansion and other strategies to improve engraftment and immune reconstitution post-CBT, make CBT still a valuable option. This article discusses the 2 options based on the currently available data, focusing on adults, and tries to give some clues to help the transplant physician choose a haploidentical vs a cord blood donor. Given the limited numbers of published or ongoing well-designed randomized controlled trials comparing haplo-SCT to CBT and the overall similar clinical results in the available, mostly registry-based, and single-center studies, with substantial heterogeneity and variability, the decision to perform haplo-SCT or CBT in a given patient depends not only on the patient, disease, and donor characteristics and donor availability (although most if not all patients should have in principle an alternative donor) but also on the transplant physician's discretion and, most importantly, the center's experience and preference and ongoing protocols and strategies.

Two decades of stem cell transplantation in patients with Fanconi anemia: Analysis of factors affecting transplant outcomes.

Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for the hematological complications of patients with Fanconi anemia (FA). Over the last two decades, HSCT outcomes have improved dramatically following the development of regimens tailored for FA patients. In this study, we analyzed genetic, clinical, and transplant data of 41 patients with FA who underwent HSCT at Hadassah Medical Center between November 1996 and September 2020. Overall survival (OS) was 82.9% with a median follow-up time of 2.11-years (95% CI, .48-16.56). Thirteen patients (31.7%) developed acute graft-versus-host disease (GVHD), three of them with grades 3-4. Nine patients developed chronic GVHD, five had extensive disease. Twelve patients (29.3%) developed stable mixed-chimerism with complete resolution of bone marrow failure (BMF); none of them had acute nor chronic GVHD. Significantly higher GVHD rates were observed in transplants from peripheral blood stem cell grafts as compared to other stem cell sources (p=.002 for acute and p=.004 for chronic GVHD). Outcome parameters were comparable between HSCT from matched-sibling (n=20) to other donors (n=21), including survival rates (p=.1), time to engraftment (p=.69 and p=.14 for neutrophil and platelet engraftment time, respectively), chimerism status (p=.36 and p=.83 for full-donor and mixed chimerism, respectively), and GVHD prevalence (p=1). Our results demonstrate the vast improvements in HSCT outcomes of patients with FA, narrowing the gap between matched-sibling versus alternative donor transplantations. Our data identifies factors that may significantly affect transplant outcomes such as graft source and chimerism status.

Busulfan, fludarabine, and melphalan are effective conditioning for pediatric and young adult patients with myeloid malignancies underdoing matched sibling or alternative donor transplantation.

Allogeneic hematopoietic cell transplantation (allo-HCT) remains a curative option for patients with high-risk myeloid malignancies. We present our 10-year experience (October 2012 to October 2021) of consecutive allo-HCT in patients with myeloid malignancies treated on the pediatric HCT service and conditioned with myeloablative targeted dose-busulfan (BU), fludarabine (FLU), and melphalan (MEL). Twenty-three children, adolescents, and young adult patients (CAYA) (median age 15.4years) with acute myeloid leukemia (AML, n = 17), myelodysplastic syndrome (MDS, n = 4), or chronic myeloid leukemia (CML, n = 2) underwent allo-HCT post-BU-FLU-MEL. Four patients had treatment-related AML/MDS. Donor/stem cell source was matched sibling donor (MSD) PBSC (n = 7), matched unrelated donor (MUD) PBSC (n = 2), umbilical cord blood (UCB) (n = 3), or haploidentical-BMT (n = 11). Risk stratification was low (n = 2), intermediate (n = 15), high (n = 3), and very high risk (n = 1). The two patients with CML had failed tyrosine kinase inhibitor therapies. With a median follow-up of 41.6months, the relapse rate is only 4.5% with an overall survival (OS) 100%, progression-free survival (PFS) 95.5%, and graft-versus-host-free-relapse-free survival (GRFS) 67.8%. The donor source and the acute graft-versus-host disease (GvHD) prophylaxis regimen significantly impacted grade II-IV aGvHD 66.7% versus 19.2% (p = .039) and chronic graft-versus-host-disease (cGvHD) 66.7% versus 0% (p = .002) in the patients receiving MSD or MUD PBSC compared to haplo-BMT, respectively, resulting in improved GRFS in haplo-BMT, 83.3% compared to 40% matched donor peripheral blood stem cell transplant (PBSCT) (p = .025). Our results demonstrate that BU-FLU-MEL is efficacious conditioning for disease control in young patients with myeloid malignancies undergoing MSD or alternative donor allo-HCT, but in the setting of PBSC grafts with cyclosporine A-methotrexate (CSA-MTX) GvHD prophylaxis, it results in an unacceptably high incidence of GvHD.

Outcomes for Acute Myeloid Leukemia Relapse after Allogeneic Hematopoietic Cell Transplantation Remain Poor in the Modern Era

Background: Relapse of acute myeloid leukemia (AML) following allogeneic hematopoietic cell transplantation (allo-HCT) has historically been associated with dismal prognosis with most patients failing to achieve subsequent remission and estimated 2-year overall survival (OS) of <15 %. Rapid progress in the understanding of AML biology and genomics resulted in recent FDA approval of several novel small molecules and immunotherapies for the treatment of front-line and relapsed/refractory AML, as early as 2017. We hypothesized that the availability of novel therapies for AML relapsing after allo-HCT has resulted in an improved OS in recent years. Methods: Patients with AML ≥18 years old who underwent allo-HCT at Stanford University between the years 2010 and 2021 and subsequently relapsed were included in this study. Patients were divided into two eras based on year of relapse: 2010-2016 (early era) and 2017- 2022 (later era). Descriptive statistics were used to characterize patients across the two cohorts; Kaplan Meier method was used to evaluate OS. Results: A total of 258 adults with AML relapsed following allo-HCT; 142 (55%) transplanted in the early era and 116 (45%) in the later era. Relative to the early era, patients who relapsed in the later era were more likely to be Hispanic (19.8% vs. 8.5%, P=0.01), have adverse risk leukemia (64.7% vs 52.1%, P=0.039), poorer performance status as defined by KPS <90 (46.6% vs. 16.9%, p<0.001), an HCT-comorbidity index of ≥ 3 (43.1% vs. 28.2%, P=0.012), and receive alternative donor transplant (haploidentical donors 11.2% vs 3.5%, P=0.002; umbilical cord blood 9.5% vs. 4.2%, P=0.002). Post-HCT maintenance therapy was used more frequently in the later era (16.4% vs. 2.1%, P=0.002). Median age, sex, and conditioning intensity did not significantly differ between the two cohorts. The median time to AML relapse post-HCT was similar in the early vs late era (149 days vs. 172 days, P=0.003). The management of relapse differed significantly across eras (Figure 1), as expected, with patients in the later era more commonly receiving targeted therapy with FLT3 inhibitors and IDH1/2 inhibitors (25% vs. 7.7%), hypomethylating agents (HMA) (51.7% vs. 35.2%) and BCL2 inhibitors (32.8% vs 3.5%) and less likely receiving cytotoxic chemotherapy (21.6% vs 34.5%). The use of donor lymphocyte infusion increased over time (16.9% vs. 12.1%) as did second allo-HCT (10.3% vs. 7%). Despite increased use of novel therapies in the later era, there was no improvement in median OS compared to the early era (5.1 months versus 4.5 months, p=0.43) or 2-year OS following post-HCT relapse (19.1% vs. 12.4%, P=0.26), (Figure 2). Across both eras, relapsed AML was the most common cause of death in this cohort, attributed to 83.7% of all deaths. Conclusion: Despite the greater use of novel therapies to treat post-HCT relapse of AML in recent years, OS remains poor and has not improved. Relapsed AML following allo-HCT remains a significant clinical challenge despite advances in modern AML therapeutics. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pediatric-Specific Patterns of Clonal Evolution Arising from Acquired Aplastic Anemia

Introduction Acquired aplastic anemia (aAA) occurs in both children and adults, though pathophysiology and clinical outcomes differ significantly by age. While clinical testing for paroxysmal nocturnal hemoglobinuria (PNH) clones is routine, targeted next generation sequencing (NGS) for myelodysplastic syndrome (MDS) associated variants has only recently been implemented. Furthermore, single nucleotide polymorphism array (SNP-A) assessing for copy neutral loss of heterozygosity in the human leukocyte antigen (HLA) region on chromosome 6p (6p CN-LOH) and HLA NGS assessing for allele specific loss of function (LoF) mutations, which together are seen in up to 25% of aAA cases, are only now being considered for clinical use. Recent studies have reported on the frequency and overlap of these 3 types of clonal evolution (PNH, MDS-associated, HLA-targeting) in adult aAA cohorts, but none focus specifically on pediatric patients, whose MDS-associated clonal evolution patterns are distinct. Delineating patterns of clonal hematopoiesis in pediatric aAA to determine whether evolution driven by immune escape (PNH and HLA loss) affects likelihood of MDS development is critical for personalizing therapeutic options. Thus, we aimed to describe the frequency, clinical significance, and overlap of clonal evolution including PNH, HLA loss, and MDS-associated gene mutations in a pediatric cohort of aAA patients. Methods This study identified 85 pediatric aAA patients treated at Children's Hospital of Philadelphia (CHOP) and enrolled on the IRB-approved CHOP/Penn BMF Registry and Repository in whom clinical testing for all patterns of clonal hematopoiesis was available or could be performed with biorepository samples. PNH flow cytometry was performed clinically in all cases; subjects with PNH > 0.05% in the granulocyte fraction were considered as having a PNH clone. Peripheral blood and bone marrow samples were used for SNP-A, HLA-NGS, and an institutional somatic mutation NGS panel for hematological malignancies encompassing 118 genes. Descriptive and contingency statistical analyses along with Fisher's Exact Test were performed using SAS (Cary, NC). Results Demographic composition of the 85 pediatric subjects with aAA included a median age of 10.7 years (1.7-20.8), male/female ratio of 59%/41%, and a representative race/ethnicity distribution (Table 1). In total, 66% displayed at least one clonal event. As expected, PNH clones were most common, present in 45% (38/85) of the cohort. An additional 16 (19%) exhibited acquired HLA loss by 6p CN-LOH (n=6), allele specific LoF mutations (n=6), or both (n=4). Fifteen (18%) had clonal hematopoiesis associated with MDS, of whom 3 had cytogenetic lesions that progressed to clinical MDS (3.5%), and 12 developed no morphologic features of MDS but demonstrated a total of 14 mutations in MDS-associated genes (BCOR/BCORL1 n=6, KMT2C/KMT2D n=3, RUNX1 n=1, ASXL1 n=1, SRSF2 n=1, PRPF8 n=1, CALR n=1). Critically, pediatric subjects with aAA who developed HLA loss did not develop MDS-associated mutations, with no patient demonstrating both subtypes of clonal events (Figure 1). In contrast, PNH and MDS-associated clonal events overlapped in 11% of the overall cohort. In total, 60% of patients with MDS-associated clonal hematopoiesis also possessed PNH clones, and 23% of patients with detectable PNH clones demonstrated at least one MDS-associated clonal event. Only 3.53% (n=3) of the cohort demonstrated both PNH and HLA loss, and PNH clone size was < 1% in all 3 patients. Furthermore, patients with HLA loss were significantly less likely to have PNH clones than those without HLA somatic alterations (19% vs 51%, p = 0.026). Correlations between patterns of clonal hematopoiesis and clinical outcomes will be presented. Concalusions Pediatric aAA patients treated with IST are at risk for developing MDS and hemolytic PNH. Presence and evolution of clonal hematopoiesis influenced decisions to pursue IST versus alternative donor transplant. Importantly, our study demonstrates that occurrence of clonal hematopoiesis by HLA loss does not increase and may even decrease the risk of developing MDS-associated or PNH clones. This finding strongly suggests that treatment decisions for aAA patients whose only clonal event is HLA loss need not be considered distinctly from patients with no clonal changes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Universal posttransplant cyclophosphamide after allogeneic transplant, a retrospective single institution study

BackgroundThe excellent results of posttransplant cyclophosphamide in decreasing graft-versus-host disease (GVHD) after haploidentical (HI) allogeneic transplant have challenged current donor selection algorithms. Patients and methodsWe compared outcomes after matched sibling (MSD) versus alternative donor transplant using identical graft-versus-host disease (GVHD) prophylaxis including posttransplant cyclophosphamide (PTCy. Endpoints included engraftment, time outside of the hospital in the first 100 days after transplant, overall survival (OS), non-relapse mortality (NRM) and percentage of patients disease-free and off immunosuppression (DFOI) at one year and at the last follow-up. ResultsThere were significant differences at baseline between matched donor versus HI donor transplants with higher disease-risk index (DRI), more female-to-male donor recipient pairs and a higher percentage of Black patients in the HI group. Engraftment and time out of the hospital favored MSD and matched unrelated donor transplants. Multivariate analysis showed that high DRI and Black race were associated with decreased survival and Black race was associated with a higher NRM. ConclusionsWith the use of PTCy, our results support current donor selection algorithms. The finding of decreased survival and increased NRM in Black patients requires confirmation in a larger number of patients as well as the development of mitigation strategies.

Letermovir vs. high-dose valacyclovir for cytomegalovirus prophylaxis following haploidentical or mismatched unrelated donor allogeneic hematopoietic cell transplantation receiving post-transplant cyclophosphamide

Patients undergoing haploidentical or mismatched unrelated donor (haplo/MMUD) allogeneic hematopoietic cell transplantation (alloHCT) receiving post-transplant cyclophosphamide (PTCy) are at high risk of cytomegalovirus (CMV) infection. Experience with letermovir (LET) in this population is limited. This single center retrospective cohort study compared CMV and transplant outcomes between LET and a historical control with high-dose valacyclovir (HDV) prophylaxis in adults undergoing haplo/MMUD alloHCT. Thirty-eight CMV seropositive patients were included, 19 in each arm. LET reduced the incidence of CMV infection (5% vs. 53%, RR 0.01, 95% CI 0.014–0.71, p = .001) and need for CMV treatment by day +100 (5% vs. 37%, RR 0.14, 95% CI 0.18–0.99, p = .017) compared to HDV. Median CMV event-free-survival was improved with LET (not reached vs. 80 days, HR 0.114, 95% CI 0.07–0.61, p = .004). These data support the efficacy of LET in alternative donor transplants.

Pediatric immune deficiencies: current treatment approaches.

To summarize the currently available definitive therapies for patients with inborn errors of immunity (IEIs) with a strong focus on recent advances in allogeneic hematopoietic cell transplantation (HCT) and gene therapy, including the use of alternative donors, graft manipulation techniques, less toxic approaches for pretransplant conditioning and gene transfer using autologous hematopoietic stem cells. In the absence of a matched sibling or a matched related donor, therapeutic alternatives for patients with IEIs include alternative donor transplantation or autologous gene therapy, which is only available for selected IEIs. In recent years, several groups have published their experience with haploidentical hematopoietic cell transplantation (HHCT) using different T-cell depletion strategies. Overall survival and event free survival results, although variable among centers, are encouraging. Preliminary results from autologous gene therapy trials with safer vectors and low-dose busulfan conditioning have shown reproducible and successful results. Both strategies have become valid therapeutic options for patients with IEIs. A new promising and less toxic conditioning regimen strategy is also discussed. Definitive therapies for IEIs with HCT and gene therapy are in stage of evolution, not only to refine their efficacy and safety but also their reach to a larger number of patients.

Clinical Features, Cancer Biology, Transplant Approach and Other Integrated Management Strategies for Wiskott-Aldrich Syndrome.

Wiskott–Aldrich syndrome (WAS) is a rare X-linked recessive inborn error of immunity (IEI) first described in 1937. Classic WAS is characterized by the triad of thrombocytopenia with small platelets, recurrent infections due to combined immunodeficiency, and eczema. Hematopoietic stem cell transplantation (HSCT) was the only curative option available for five decades, with excellent outcomes reported for matched sibling donors (MSD) and matched unrelated donors (MUD). More recently, alternative donor transplants such as umbilical cord blood (UCB) and haploidentical transplant have emerged as viable options due to improvements in better graft selection, cell dosing, and effective allograft manipulation measures. Gene therapy is another potential curative option with promising results, yet currently is offered only as part of a clinical trial.

Comparing cord blood transplantation and matched related donor transplantation in non-remission acute myeloid leukemia.

Cord blood transplantation (CBT) is an alternative donor transplantation method and has the advantages of rapid availability and the possibility of inducing a more potent graft-versus-leukemia effect, leading to a lower relapse rate for patients with non-remission relapse and refractory acute myeloid leukemia (R/R AML). This study aimed to investigate the impact of CBT, compared to human leukocyte antigen-matched related donor transplantation (MRDT). This study included 2451 adult patients with non-remission R/R AML who received CBT (1738 patients) or MRDT (713 patients) between January 2009 and December 2018. Five-year progression-free survival (PFS) and the prognostic impact of CBT were evaluated using a propensity score (PS) matching analysis. After PS matching, the patient characteristics were well balanced between the groups. The five-year PFS was 25.2% (95% confidence interval [CI]: 21.2-29.5%) in the CBT group and 18.1% (95% CI: 14.5-22.0%) in the MRDT group (P = 0.009). The adjusted hazard ratio (HR) was 0.83 (95% CI: 0.69-1.00, P = 0.045); this was due to a more pronounced decrease in the relapse rate (HR: 0.78, 95% CI: 0.69-0.89, P < 0.001) than an increase in the NRM (1.42, 1.15-1.76, P = 0.001). In this population, CBT was associated with a better 5-year PFS than MRDT after allogeneic HSCT.