Early Mixed Donor Chimerism is a Strong Negative Prognostic Indicator in Allogeneic Stem Cell Transplant for AML and MDS.

Allogeneic bone marrow transplantation remains the most potent curative therapy for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) due to the graft-versus-tumor effect provided by donor cells. Donor chimerism is utilized early after transplantation to evaluate engraftment and to monitor the persistence of donor hematopoiesis. Literature is conflicting regarding to the prognostic utility of early mixed donor chimerism, chimerism kinetic patterns as well as factors associated with it and we sought to clarify this uncertainty. In this single-centre retrospective analysis, 141 adults aged 18 years of age or older with AML (n = 104) and MDS (n = 37) who received their first transplant from HLA matched related, matched unrelated or mismatched related (haploidentical) donors between 2016 and 2022 and had at least day 30 chimerism measured were included. Approximately 30% received post-transplant cyclophosphamide for graft-versus-host disease (GVHD) prophylaxis and 67% of subjects received reduced-intensity conditioning. Chimerism was measured using STR-PCR from unfractionated peripheral blood mononuclear cells (whole blood; WB) and CD3+ (T cell; TC) compartment at each time point. Complete donor chimerism was defined as ≥95% whereas <95% defined as mixed. Competing risk analysis was used to estimate cumulative incidence of relapse with kinetic calculations completed using an increment factor. Kaplan-Meier was used for overall survival (OS) and relapse-free survival (RFS). Cox proportional hazards regression was used to explore prognostic factors for OS and RFS. Both day 30 mixed WB and TC donor chimerism were individually associated with an increased risk of relapse and worse overall and relapse-free survival at days 30, 60 and 90 post-transplant. Day 30 mixed WB was more specific for relapse (86%), while mixed TC was more sensitive (67%). Complete day 30 chimerism had a negative predictive value of 63% and 70% and positive predictive value of 57% and 67% for WB and TC, respectively. Day 30 WB and TC donor chimerism of <88.92% and 89.29% had specificities of 79.17% and 82.19% although sensitivities only approximated 50%. Evaluating the kinetics of chimerism over the first 90 days provided additional information for prognosticating relapse than absolute chimerism values at individual time points in both WB day 30 to 90 [HR, 1.75 (95% CI, 1.04 to 2.94); P < .035] and TC day 60 to 90 [HR, 1.32 (95% CI, 1.03, 1.69); P < .29]. Twice as many patients with complete chimerism developed acute GVHD compared to those with mixed chimerism. Factors that were found to be associated with day 30 mixed TC chimerism were donor source, ATG GVHD prophylaxis, myeloablative conditioning and female sex, while only donor source was associated with mixed WB. Both TC and WB day 30 mixed chimerism were associated with an increased risk of relapse. Early mixed WB and TC chimerism is strongly associated with a worse overall and relapse-free survival. The serial measurement of chimerism early post-transplant for monitoring chimerism kinetics provides additional prognostic information beyond the absolute donor chimerism value at a single time point. Haploidentical stem cell transplants were associated with a lower likelihood of mixed chimerism than other donor sources.

Radford M ，Garcia-Horton A ，Badami R ，Jin E ，Usmani N ，Grafodatskaya D ，McCready E ，Khalaf D ，Walker I ，Leber B ，Lepic K ，Pond G ，Berg T ... -  《-》

Allogeneic Hematopoietic Cell Transplant For Bone Marrow Failure or Myelodysplastic Syndrome in Dyskeratosis Congenita/Telomere Biology Disorders: Single-Center, Single-Arm, Open-Label Trial of Reduced-Intensity Conditioning Without Radiation.

Dyskeratosis congenita/telomere biology disorders (DC/TBD) often manifest as bone marrow failure (BMF) or myelodysplastic syndrome (MDS). Allogeneic hematopoietic cell transplant (alloHCT) rescues hematologic complications, but radiation and alkylator-based conditioning regimens cause diffuse whole-body toxicity and may expedite DC/TBD-specific non-hematopoietic complications. Optimization of conditioning intensity in DC/TBD to allow for donor hematopoietic cell engraftment with the least amount of toxicity remains a critical goal of the alloHCT field. We report prospectively collected standard alloHCT outcomes from a single-center, single-arm, open-label clinical trial of bone marrow or peripheral blood stem cell alloHCT for DC/TBD-associated BMF or MDS. Conditioning was reduced intensity (RIC), including alemtuzumab 1 mg/kg, fludarabine 200 mg/m2, and cyclophosphamide 50 mg/kg. A previous single-arm, open-label phase II clinical trial for the same patient population conducted at the same center, differing only by inclusion of 200 cGy of total body irradiation (TBI), served as a control cohort. The non-TBI cohort included 10 patients (ages 1.7-65.9 years, median follow-up of 3.9 years) compared with the control TBI cohort, which included 12 patients (ages 2.2-52.2 years, median follow-up of 10.5 years). Baseline characteristics differed only in total CD34+ cells received, with a median of 5.6 (non-TBI) compared with 2.6 (TBI) x 106/kg (P = .02; no difference in total nucleated cells). The cumulative incidence of day +100 grade II-IV acute and 4-year chronic graft-versus-host disease (GvHD) were low at 0% and 10% (non-TBI) and 8% and 17% (TBI), respectively (acute, P = .36; chronic, P = .72). Primary graft failure was absent. Secondary non-neutropenic graft failure occurred in one (non-TBI cohort). The non-TBI cohort demonstrated delayed achievement of full donor chimerism but superior lymphocyte recovery. There was no difference in 4-year overall survival at 80% (non-TBI) and 75% (TBI; P = .78). MDS as an indication for alloHCT was uncommon but overall associated with poor outcomes. There were 3 MDS patients in the non-TBI cohort: 1 relapsed and died at day +387; 1 relapsed at day +500 and is alive 5.5 years later following salvage with a second alloHCT; 1 relapsed at day +1093 and is alive at day +100 after a second alloHCT. There was 1 MDS patient in the TBI cohort who achieved 100% donor myeloid engraftment without relapse but died at day +827 from a bacterial infection in the setting of immune-mediated cytopenia. Elimination of TBI from the RIC regimen for DC/TBD was not associated with significant changes in rates of graft failure, GvHD, and overall survival but was associated with delayed achievement of full donor chimerism and improved lymphocyte reconstitution. For DC/TBD-associated BMF, TBI appears to be dispensable. Optimal approaches to DC/TBD-associated MDS remain unclear. Larger cohorts are needed to better assess the unique contribution of TBI and donor CD34+ cell dose. Longer follow-up is required to assess differences in DC/TBD complications and late effects.

Dimitrov M ，Merkle S ，Cao Q ，Tryon RK ，Vercellotti GM ，Holtan SG ，Kao RL ，Srikanthan M ，Terezakis SA ，Tolar J ，Ebens CL ... -  《-》

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 ... -  《-》

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 ... -  《-》

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 ... -  《-》