Donor Type Does Not Impact Late Graft Failure Following Reduced-Intensity Allogeneic Hematopoietic Cell Transplantation with Post-Transplant Cyclophosphamide-Based Graft-Versus-Host Disease Prophylaxis.

Post-transplant cyclophosphamide (PTCy) is a commonly used graft-vs-host disease (GVHD) prophylaxis, particularly in the setting of haploidentical (haplo) hematopoietic cell transplantation (HCT). The rate of graft failure has been reported to be as high as 12% to 20% in haplo-HCT recipients using PTCy. The objective of this study was to determine whether donor type influenced the risk of late graft failure following reduced-intensity conditioning (RIC) HCT using PTCy-based GVHD prophylaxis. A retrospective cohort analysis using the Center for International Blood and Marrow Transplant Research (CIBMTR) database among adult patients who underwent first RIC haplo or 8/8 matched unrelated donor (MUD) HCT between 2011 and 2018 for acute myeloblastic leukemia (AML), acute lymphoblastic leukemia (ALL) or myelodysplastic syndrome (MDS) with PTCy GVHD prophylaxis. The primary outcome was incidence of late graft failure, defined as secondary graft loss in the absence of relapse or poor graft function requiring a cellular therapy intervention. A total of 1336 patients met the eligibility criteria (1151 haplo, 185 MUD). Patients in the MUD group were older (65 vs. 61 years), less ethnically diverse (95% vs. 72% White), received fewer bone marrow grafts (45% vs. 16%), and had younger donors (median age, 28 vs. 37 years old). Conditioning regimens were predominately fludarabine, cyclophosphamide, and total body irradiation (TBI; 87% haplo and 38% MUD). At 2 years, the adjusted probabilities of late graft failure for the haplo group was 6.5% (95% confidence interval [CI], 5.2-8.0) versus 5.9% (95% CI, 2.7%-10.9%) for the MUD group (P = .79). Multivariate analysis for risk factors associated with late graft failure found associations with a diagnosis of MDS (HR, 1.98; 95% CI, 1.22-3.20; P = .005), and earlier year of HCT (2015-2018 vs. 2011-2014; HR, 0.39; 95% CI, 0.24-0.64; P = .0002). A post-hoc sensitivity analysis was performed to evaluate the effect of donor age and use of peripheral blood stem cell (PBSC) grafts. Graft failure did not differ between haplo and MUD HCT (HR, 1.19; P = .67) when adjusted for donor age nor when restricted to PBSC grafts only (HR, 0.85; P = .70). In this registry-based analysis of patients undergoing RIC HCT for AML, ALL, or MDS using GVHD prophylaxis with PTCy, there was no significant difference in late graft failure rates between haplo and MUD donors. Overall rates of late graft failure were high.

Hickey CL ，Zhang MJ ，Allbee-Johnson M ，Romee R ，Majhail NS ，Malki MMA ，Antin JH ，Benjamin CL ，Bredeson C ，Chhabra S ，Grunwald MR ，Inamoto Y ，Kanakry CG ，Milano F ，Soiffer RJ ，Solomon SR ，Spellman SR ，Brunstein CG ，Cutler C ... -  《-》

Biologically Randomized Comparison of Haploidentical Versus Human Leukocyte Antigen-Matched Related Donor Reduced-Intensity Conditioning Hematopoietic Cell Transplantation.

Using haploidentical donors for allogeneic hematopoietic cell transplantation (HCT) broadens transplant accessibility to a growing number of patients with hematologic disorders. Moreover, haploidentical HCT with post-transplant cyclophosphamide (PTCy) has become widespread practice due to accumulating evidence demonstrating favorable rates of survival and graft-versus-host disease (GvHD). Most studies comparing outcomes by donor sources have been confounded by variability in conditioning regimens, graft type (peripheral blood [PB] or bone marrow), and post-transplant GvHD prophylaxis (PTCy or non-PTCy), making it difficult to define the effect of donor source on outcomes. Levine Cancer Institute started a transplant and cellular therapy program in 2014, with both haploidentical and matched related donor (MRD) transplants initially performed using a uniform reduced-intensity conditioning (RIC) regimen, PB grafts, and PTCy-based GvHD prophylaxis. This retrospective observational study was conducted to compare the clinical outcomes associated with RIC haploidentical HCT and MRD HCT in patients receiving identical conditioning regimens, graft types, and supportive care. Our transplant database was queried to evaluate demographic characteristics, clinical features, and outcomes of RIC HCT for consecutive patients with hematologic malignancies who received haploidentical or MRD grafts between March 2014 and December 2017. An MRD was the preferred donor source; when unavailable, a haploidentical donor was used. Sixty-seven patients underwent haploidentical HCT and 25 MRD HCT. Overall, characteristics of transplant recipients were similar for the haploidentical and MRD groups; however, haploidentical donors were younger than MRDs (median 36 yr versus 57 yr, P < .0001). Results of univariable analysis showed similar overall survival (OS) for haploidentical and MRD HCT (hazard ratio [HR], 1.15; 95% CI, 0.61 to 2.15; P = .669). One-year, 1-yr, and 5-yr OS were 80.2%, 54.7%, and 41.2% for haploidentical HCT and 76.0%, 55.7%, and 51.1% for MRD HCT, respectively. With a median follow-up of 81.90 months, results of multivariable analysis revealed that donor source (haploidentical versus MRD) was not significantly associated with OS (HR, 0.97; 95% CI, 0.51 to 1.87; P = .933), relapse-free survival (HR, 0.75; 95% CI, 0.42 to 1.35; P = .337), cumulative incidence of relapse (HR, 0.81; 95% CI, 0.39 to 1.70; P = .579), or non-relapse mortality (HR, 1.12; 95% CI, 0.40 to 3.14; P = .827). Cumulative incidences of acute GvHD (aGvHD) and chronic GvHD (cGvHD) were not significantly different for haploidentical and MRD HCT (grades II to IV aGvHD: HR, 1.78; 95% CI, 0.72 to 4.37; P = .210; grades III to IV aGvHD: HR, 2.84; 95% CI, 0.34 to 23.63; P = .335; cGvHD: HR, 1.00; 95% CI 0.36 to 2.76; P = .995). With care that was homogenous in terms of conditioning regimens, graft type, GvHD prophylaxis, and supportive care, 92 patients who were biologically randomized to either haploidentical HCT or MRD HCT after RIC with PTCy had comparable outcomes.

Grunwald MR ，Sha W ，He J ，Sanikommu S ，Gerber JM ，Ai J ，Knight TG ，Fasan O ，Boseman V ，Kaizen W ，Chojecki A ，Ragon BK ，Symanowski J ，Avalos B ，Copelan E ，Ghosh N ... -  《-》

Total Body Irradiation and Fludarabine with Post-Transplantation Cyclophosphamide for Mismatched Related or Unrelated Donor Hematopoietic Cell Transplantation.

Allogeneic hematopoietic cell transplantation (HCT) remains the sole curative treatment for most patients with hematologic malignancies. A well-matched donor (related or unrelated) remains the preferred donor for patients undergoing allogeneic HCT; however, a large number of patients rely on alternative donor choices of mismatched related (haploidentical) or unrelated donors to access HCT. In this retrospective study, we investigated outcomes of patients who underwent mismatched donor (related or unrelated) HCT with a radiation-based myeloablative conditioning MAC regimen in combination with fludarabine, and post-transplantation cyclophosphamide (PTCy) as higher-intensity graft-versus-host disease (GVHD) prophylaxis. We retrospectively assessed HCT outcomes in 155 patients who underwent mismatched donor HCT (related/haploidentical versus unrelated [MMUD]) with fractionated-total body irradiation (fTBI) plus fludarabine and PTCy as GVHD prophylaxis at City of Hope from 2015 to 2021. Diagnoses included acute lymphoblastic leukemia (46.5%), acute myelogenous leukemia (36.1%), and myelodysplastic syndrome (6.5%). The median age at HCT was 38 years, and 126 patients (81.3%) were an ethnic minority. The Hematopoietic Stem Cell Transplantation Comorbidity Index was ≥3 in 36.1% of the patients, and 29% had a Disease Risk Index (DRI) of high/very high. The donor type was haploidentical in 67.1% of cases and MMUD in 32.9%. At 2 years post-HCT, disease-free survival (DFS) was 75.4% and overall survival (OS) was 80.6% for all subjects. Donor type did not impact OS (hazard ratio [HR], .72; 95% confidence interval [CI], .35 to 1.49; P = .37) and DFS (HR, .78; 95% CI, .41 to 1.48; P = .44), but younger donors was associated with less grade III-IV acute GVHD (HR, 6.60; 95% CI, 1.80 to 24.19; P = .004) and less moderate or severe chronic GVHD (HR, 3.53; 95% CI, 1.70 to 7.34; P < .001), with a trend toward better survival (P = .099). The use of an MMUD was associated with significantly faster neutrophil recovery (median, 15 days versus 16 days; P = .014) and platelet recovery (median, 18 days versus 24 days; P = .029); however, there was no difference in GVHD outcomes between the haploidentical donor and MMUD groups. Nonrelapse mortality (HR, .86; 95% CI, .34 to 2.20; P = .76) and relapse risk (HR, .78; 95% CI, .33 to 1.85; P = .57) were comparable in the 2 groups. Patient age <40 years and low-intermediate DRI showed a DFS benefit (P = .004 and .029, respectively). High or very high DRI was the only predictor of increased relapse (HR, 2.89; 95% CI, 1.32 to 6.34; P = .008). In conclusion, fludarabine/fTBI with PTCy was well-tolerated in mismatched donor HCT, regardless of donor relationship to the patient, provided promising results, and increased access to HCT for patients without a matched donor, especially patients from ethnic minorities and patients of mixed race.

Arslan S ，Desai A ，Yang D ，Mokhtari S ，Tiemann K ，Otoukesh S ，Samara Y ，Blackmon A ，Agrawal V ，Pourhassan H ，Amanam I ，Ball B ，Koller P ，Salhotra A ，Aribi A ，Becker P ，Curtin P ，Artz A ，Aldoss I ，Ali H ，Stewart F ，Smith E ，Stein A ，Marcucci G ，Forman SJ ，Nakamura R ，Al Malki MM ... -  《-》

Incidence, Risk Factors, and Outcomes of BK Hemorrhagic Cystitis in Hematopoietic Stem Cell Transplantation From HLA-Matched and Haploidentical Donors With Post-Transplant Cyclophosphamide.

BK hemorrhagic cystitis (BK-HC) is a common complication following hematopoietic stem cell transplantation (HSCT), particularly when posttransplant cyclophosphamide (PTCy) is used as graft-versus-host disease (GVHD) prophylaxis. However, comparative studies of BK-HC incidence in matched sibling donors (MSD) and unrelated donors (MUD) often include small haploidentical (HAPLO) donor cohorts and usually lack detailed information on disease evolution, coinfections, management and impact on outcomes. This study aimed to evaluate the incidence, risk factors, and outcomes in patients with hematologic malignancies undergoing HSCT from MSD, MUD, HAPLO donors using PTCy as GVHD prophylaxis. Furthermore, we analyze risk factors for BK-HC and its impact on renal function and transplant outcomes. Retrospective analysis of BK-HC episodes in patients undergoing HSCT from 167 MSD, 129 MUD and 103 HAPLO from a single institution. Uniform GVHD prophylaxis with PTCy, sirolimus and mycophenolate mofetil was given, irrespective of donor type or conditioning intensity, and mesna was used prophylactically with PTCy. The incidence of grade 2-4 BK-HC was 23%, with a higher prevalence of grades 3-4 in HAPLO (19%), compared to MSD (11%) and MUD (8%) recipients (P = .02). BK-HC was diagnosed at a median of 29 days after HSCT and symp toms persisted for a median of 27 days, with longer duration in grade 3-4 cases (P = .02). Additionally, higher grades were associated with a greater transfusion burden (P < .001). JC virus coinfection was detected in 24%, and cytomegalovirus viruria in 17%, which was not treated. BK antiviral treatment beyond supportive care was used in only two patients, while antibacterial treatments were prescribed in 28% for urinary symptoms and in 57% for concomitant infections in other sites. Younger age and HAPLO donors were significant risk factors for developing higher-grade BK-HC. No interaction was seen between age and conditioning intensity. Importantly, BK-HC did not significantly impact overall survival or graft-versus-host disease-free relapse-free survival as a time-dependent variable, as well as non-relapse mortality. Furthermore, BK-HC patients maintained stable creatinine renal clearance at 1-year post-transplant. BK-HC is a relatively early frequent complication in allogeneic HSCT with PTCy, especially in HAPLO recipients, with symptoms typically lasting a median of three weeks. Supportive care remains the mainstay of treatment, while specific antiviral treatments are rarely needed. The role of cidofovir and concomitant CMV viruria treatment are yet to be established. Our findings suggest that BK-HC does not significantly impact transplant outcomes and renal function.

Chorão P ，Villalba M ，Balaguer-Roselló A ，Montoro J ，Granados P ，Gilabert C ，Panadero F ，Pardal AA ，González EM ，de Cossio S ，Benavente R ，Gómez MD ，Gómez I ，Solves P ，Santiago M ，Asensi P ，Lloret P ，Eiris J ，Martínez D ，Louro A ，Rebollar P ，Perla A ，Salavert M ，Rubia J ，Sanz MÁ ，Sanz J ... -  《-》

Uniform Graft-versus-Host Disease Prophylaxis using Post-Transplantation Cyclophosphamide, Methotrexate, and Cyclosporine following Peripheral Blood Hematopoietic Stem Cell Transplantation from Matched and Haploidentical Donors for Transfusion-Dependent T

Although the survival of patients with transfusion-dependent thalassemia (TD-TM) is reportedly inferior after haploidentical hematopoietic stem cell transplantation (HSCT), the heterogeneity of transplantation approaches in studies suggests the need to assess the effect of conditioning regimen on matched and haploidentical transplantation outcomes. A novel post-transplantation cyclophosphamide (PTCy)-based approach for patients with TD-TM undergoing haploidentical HSCT was reported in our prior study. Here we aimed to retrospectively evaluate the real-world efficacy and safety of graft-versus-host disease (GVHD) prophylaxis in patients with TD-TM after HSCT from matched donors and haploidentical donors (HIDs). In this retrospective multicenter study, among 238 patients with TD-TM who underwent HSCT, 160 underwent peripheral blood HSCT, using uniform GVHD prophylaxis with PTCy, methotrexate, and cyclosporine, at member centers of the Bone Marrow Failure Working Group of Hunan Province between 2019 and 2023. The median age of the cohort at transplantation was 6 years (95% confidence interval [CI], 6 to 7 years). The 160 donors included 99 (61.9%) haploidentical family members, 13 matched sibling donors, and 48 matched or mismatched unrelated donors. The engraftment rate was 98.8% (95% CI, 96.1% to 97.7%). HSCT from HIDs had a lower risk of mixed chimerism (HR, .078; P = .022). Within 100 days after transplantation, 31 patients (19.6%; 95% CI, 14.0% to 26.3%) had grade II-IV acute GVHD (aGVHD), 9 of whom had grade III-IV aGVHD (5.7%; 95% CI, 2.9% to 10.1%). HIDs were significantly associated with a higher risk of grade II-IV aGVHD (HR, 3.973; P = .009). Nineteen patients (11.9%; 95% CI, 7.6% to 17.6%) developed late aGVHD after a median of 516 days (95% CI, 407 to 709 days). Twenty-six patients (16.5%; 95% CI, 11.3% to 22.8%) exhibited any 1 of the diagnostic, distinctive, or atypical features of chronic GVHD (cGVHD) according to the 2014 National Institutes of Health (NIH) criteria after a median of 690 days (95% CI, 496 to 902 days). Among these 26 patients, 7 had NIH-defined cGVHD, 14 had only 1 distinctive sign with no histologic evidence, and 5 had only atypical cGVHD signs. Of the 26 patients, 5 were classified with overlap syndrome. Of 21 patients classified with NIH-defined and potential cGVHD, 3 had moderate cGVHD and 1 had severe cGVHD. Logistic regression analyses identified that grade II-IV aGVHD independently predicted subsequent cGVHD (HR, 3.920; P = .006). The rates of cGVHD were similar in the matched donor and HID groups. Thalassemia-free survival (TFS) and event-free survival (EFS) were 97.5% (95% CI, 94.2% to 99.2%) and 90.6% (95% CI, 85.4% to 94.4%), respectively, after a median of 690 days (95% CI, 496 to 902 days). TFS rates were similar in the matched donor and HID groups (P = .549). The EFS rate was significantly higher in the matched donor group compared to the HID group (P = .033). Our study suggests that when PTCy-based uniform GVHD prophylaxis is administered, HSCT from matched donors and HIDs results in a low incidence of severe GVHD and treatment-related mortality with satisfactory survival.

Gong S ，Tian X ，Yang R ，Yang L ，Wang Z ，Yang K ，Chen K ，He X ，Deng W ，Yang X ，Lei M ，Fu B ... -  《-》