Mild Chronic Graft-versus-host Disease Research Articles

Evaluation of differences in quality of life in patients with chronic graft-versus-host disease

Objective: To evaluate the status of, differences in, and factors influencing quality of life (QoL) in patients with chronic graft-versus-host disease (GVHD). Methods: From September 2021 to February 2023, a cross-sectional study of 140 patients with chronic GVHD was conducted at our center. Symptom burden was assessed by the Lee Symptomatology Scale (LSS), and QoL was assessed by the Medical Outcome Study 36-Item Short-Form Health Survey (SF-36) (version 1) and five-level EuroQoL five-dimensional questionnaire (EQ-5D-5L). Results: Data from 140 respondents, including 32 (22.9%) with mild chronic GVHD, 87 (62.1%) with moderate chronic GVHD, and 21 (15.0%) with severe chronic GVHD, were analyzed. Of the respondents, 61.4% were male, and the median transplantation age was 34 (15-68) years. The primary diagnoses were acute myeloid leukemia (50.0%), acute lymphoblastic leukemia (20.0%), and myelodysplastic syndrome (15.0%). The common chronic GVHD-affected organs included the skin in 74 patients (52.9%), the eyes in 57 patients (40.7%), and the liver in 50 patients (35.7%). Among the whole cohort, the eye (20.48±23.75), psychological (16.13±17.00), and oral (13.66±20.55) scores were highest in the LSS group. The physiological function (36.07±11.13), social function (36.10±10.68), and role-emotional functioning (38.36±11.88) scores were lowest in the SF-36 group. The EQ-5D index was 0.764. The total LSS scores for mild, moderate, and severe chronic GVHD were 6.51±6.15, 10.07±5.61, and 20.90±10.09, respectively. The SF-36 physical component scores (PCSs) were 43.12±6.38, 40.73±7.14, and 36.97±6.97, respectively, and the mental component scores (MCSs) were 43.00±8.47, 38.90±9.52, and 28.96±9.63, respectively. The EQ-5D values were 0.810±0.124, 0.762±0.179, and 0.702±0.198, respectively. The multivariate analysis showed that the overall symptom burden (β=-0.517), oral symptom burden (β=-0.456), National Institute of Health (NIH) criteria for the eyes (β=-0.376), and nutrition-related symptom burden (β=-0.211) were significantly negatively correlated with the PCS. The NIH score (β=-0.260) was negatively correlated with the MCS score. Oral symptom burden (β=-0.400), joint/fascia NIH criteria (β=-0.332), number of involved systems (β=-0.253), overall NIH criteria (β=-0.205), and number of immunosuppressants taken (β=-0.171) were significantly negatively correlated with the EQ-5D score (all P<0.05). Medium to strong correlations were found between the EQ-5D score and the SF-36 score (|r|=0.384-0.571, P<0.001). Conclusions: The QoL of patients with chronic GVHD is impaired, and the more severe the disease, the poorer the QoL. Overall symptom burden, severity of eyes, and oral symptom burden were the most important factors affecting QoL.

Omidubicel-Onlv for Allogeneic Transplantation (allo-HCT) in Patients with Hematologic Malignancies: Results of a Multicenter Open Label Expanded Access Program

Introduction Omidubicel-onlv is a nicotinamide-modified allogeneic hematopoietic progenitor cell therapy donor source derived from umbilical cord blood (UCB). A phase 3 randomized study (NCT02730299) demonstrated improved hematopoietic recovery and decreased infections in patients transplanted with omidubicel compared to UCB. An expanded access program (EAP) was conducted to provide access to omidubicel in advance of commercial availability in the United States (US) in April 2023. Objective This was an open-label, single-arm EAP evaluating clinical outcomes in patients with hematologic malignancies following allo-HCT with omidubicel. Methods Eligible patients (≥12 years) with hematologic malignancies received myeloablative conditioning, prophylactic medications, and supportive care as per institutional guidelines. Patients were monitored for neutrophil and platelet engraftment, infections, graft versus host disease (GVHD), and additional clinical events for up to 2 years post-transplantation. Results were retrospectively compared with previously described outcomes in patients from the phase 3 study comparing transplant with omidubicel (P3-OMI, n=52) and unmanipulated UCB (P3-UCB, n=56). Results Between July 2020 and April 2023, 36 patients were enrolled and 29 (18 males, 11 females) were transplanted at 5 US sites. Median age was 39 years (range: 20-73); 55% were White, 21% Asian, 17% Black, and 7% other. Diagnoses were acute myelogenous leukemia (38%), acute lymphocytic leukemia (28%), myelodysplastic syndrome (21%), and other (14%). All patients received myeloablative conditioning (total body irradiation-based: 58.5%, chemotherapy alone: 34.5%). Median transplanted CD34+ cell dose was 5.6x10 6 cells/kg (range: 1.8-18.7x10 6 cells/kg) and HLA match was 4/6 in 52%, 5/6 in 45%, and 6/6 in 3%. Median follow-up was 6.3 months (range: 0.3-27.7). No infusion reactions were reported. Median time to neutrophil (≥500/µl x3 days) and platelet (&amp;gt;20,000/µl x3 days) engraftment were 13 and 34 days, respectively. Primary graft failure occurred in 2 (6.9%) patients, both alive &amp;gt;100 days after second haploidentical transplant. The incidences of first grade 2-3 bacterial and invasive (grade 3) fungal infection through 100 days post-transplant were 16.9% and 0%, respectively. The incidence of grade 3 viral infections 1-year post-transplant was 13.4%. At 100 and 365 days post-transplant, disease-free survival (DFS) rates were 95.2% and 82.5%, and overall survival (OS) rates were 96.3% and 84.2%, respectively. Acute GVHD was reported in 13 (44.8%) patients (grade 2: 34.5%, grade 3: 10.3%) and mild chronic GVHD in 1 (3.5%) patient. There were 4 deaths (13.8%): 2 due to relapse (Days 275 and 381), 1 due to infection (Day 135) and 1 due to respiratory failure (Day 10). Post-transplant lymphoproliferative disease was reported in 1 patient. Demographic and disease characteristics were similar to those in the phase 3 omidubicel registration trial, including racial and ethnic diversity (&amp;gt;39% minorities). Neutrophil engraftment time in EAP patients was similar to P3-OMI (10 days) and shorter than P3-UCB (20.5 days). Similarly, median platelet recovery was similar to P3-OMI (37 days) and shorter than P3-UCB (50 days). Infection, GVHD, DFS, and OS in EAP were also similar to those observed in P3-OMI (Table 1). Conclusion In a real-world EAP setting, the outcomes of allo-HCT with omidubicel in patients with hematologic malignancies were consistent with those from the phase 3 registration study. These data support the role of omidubicel as a donor source, particularly for patients from diverse racial backgrounds.

Treosulfan Based Haploidentical Αß T Cell Depleted HSCT Represents a Curative Alternative in Pediatric and Adult Patients with Transfusion Dependent Thalassaemia

Background: Quality of life remains severely compromised in patients suffering from Transfusion Dependent Thalassemia (TDT) despite optimal supportive care. HSCT with a MSD, the current curative option, achieving a 92.1% 2y-OS in children and 84.4% in adults (EBMT registry). Unfortunately, availability of MDs is limited, so that haploidentical HSCT is increasingly explored. Methods: 13 TDT patients (median age: 11 years; range: 2-23) received either a CD3 +/CD19 + (n=4; all class II/III) or αß/CD19 + (n=10; 7 class II, II/III) T-haplo-HSCT and were compared with 8 TDT-patients (7 class II, II/III, III) receiving a BM graft from a MSD (median age: 11 years; range: 4-22). Indication for T-haplo HSCT patients was severe iron overload/ transfusion-associated complications. All patients received an identical conditioning regimen consisting of treosulfan, thiotepa, fludarabine (FTT) and ATG-Grafalon, with the only difference in the timing of ATG (upfront in T-haplo-HSCT, prior to d0 in MSD-HSCT). Immunosuppression (IST) was maintained for a minimum of 180 days consisting of calcineurin inhibitors (mainly tacrolimus) and MMF. Results: The OS and DFS for MSD and T-haplo-HSCT was 100%/100% and 100%/92%, respectively (Table 1). The median follow-up was 30 months for MSD (range 4-72) and 38 months for T-haplo-HSCT (range 4-86). Neutrophil engraftment was achieved after a median of 31 days for MSD patients and 17 days for T-haplo-HSCT with a median of 5 x 10 8 TNC/kg (range: 3.28-7.88) and 15 x 10 6 CD3 +/CD19 + or αβ/CD19 + depleted CD34 + cells/kg (range: 9.2-24.2), respectively. One patient received two T-haplo HSCT, due to primary graft failure partly due to a major AB0 incompatibility. A mixed chimerism was observed in 3/7 MSD-HSCT (median 92%; range 27.5-100%) and in T-haplo-HSCT in 2/13 patients (median 99%; range: 45.3 -100%). Transfusion independence was achieved in all MSD and in all but one T-haplo patient. In MSD and in T-haplo-HSCT, IST was terminated after a median of 173 days and 226 days (range: 112-347), respectively. MSD patients reached CD4 counts &amp;gt;50/µl on day +43 (median; range: 25-125) and T-haplo-HSCT patients on day +114 (median; range: 33-173). The treosulfan-based conditioning regimen was well tolerated with no VOD/SOS observed in this high-risk population. No case of acute or chronic Graft-versus-Host disease (GvHD) was observed in the MSD population. In T-haplo-HSCT, 3 patients experienced grade I acute GvHD (skin) which resolved with prednisolone and in 2 cases with additional extracorporeal photopheresis. Only the oldest patient experienced mild chronic skin GvHD, which resolved by day +580. No severe infectious complications occurred despite a prolonged chimerism-triggered weaning of the IST. Conclusions: Independent of donor availability, graft rejection and iron-overload related organ damage (VOD/SOS) are major pitfalls in transplanting advanced stage TDT patients. Treosulfan demonstrated to be an excellent alternative to busulfan in this setting reflected in the safety and efficacy data of this pilot series. Overall, outcomes of T-haplo-HSCT in TDT are very encouraging with a competitive OS, so that a transplant indication in pediatric and AYA TDT patients lacking a MD is feasible.

Phase I Trial of Allogeneic Donor Gamma Delta T Cell Infusion Post-Hematopoietic Cell Transplantation, an Interim Safety Report

Background Patients with 2017 European LeukemiaNet (ELN) adverse risk acute myeloid leukemia (AML) are at 40% risk of relapse leading to poor survival after allogeneic hematopoietic cell transplantation (allo-HCT) (Hansen TCT 2021, Jimenez BMT 2021). Ex vivo donor-derived gamma delta T cells (GDT) expanded with artificial antigen presented calls (aAPC) are a novel therapy with potent MHC-independent antineoplastic cytotoxicity. An ongoing phase 1/1b study is evaluating the safety and potential efficacy of ex vivo expanded donor GDT after reduced-intensity conditioning (RIC) allo-HCT in patients with ELN adverse risk AML ( NCT05015426). We report on manufacturing, safety, and correlative biology of expanded donor GDT after allo-HCT in the first 5 treated patients (Table 1). Methods The primary endpoint is the maximum-tolerated dose (MTD) of allogeneic donor GDT as a single infusion at day 60 after RIC allo-HCT. Next generation sequencing was used for measurable residual disease (MRD) assessment pre-HCT and post-GDT infusion. Donor GDT collected from the same donor of the allo-HCT were enriched from non-mobilized leukapheresis product by stimulation with zoledronic acid and IL-2 for 7 days followed by alpha beta T cell depletion using the Miltenyi CliniMACS. Enriched GDT (&amp;gt;90% TCRVδ2) were then co-cultured with irradiated aAPCs in Wilson Wolf G-Rex 100MCS over 10 days (Boucher J. Immunother 2023). This single center, investigator-initiated phase 1 trial is testing 3 distinct dose cohorts of infused GDT (5 x 10 6 cells/kg, 2.5 x 10 7 cells/kg, and 1 x 10 8 cells/kg) with acceptable range of 25% margin. A Bayesian optimal interval design is used to guide dose escalation/de-escalation decisions. Results First 3 patients enrolled in dose level 1 (DL1) cohort received GDT dose of 6.25 x 10 6 cells/kg, while last 2 patients enrolled in DL2 cohort received 3.13 x 10 7 cells/kg dose. Dose-limiting toxicities (DLT) were evaluated for 42 days following GDT infusion and no DLT were observed. None of the treated patients experienced cytokine release syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) or graft-versus-host disease (GVHD) during DLT period. Among patients treated on DL1, patient #01 had ASXL1 AML with MRD pos (VAF 43.9%) prior to RIC haploidentical (Haplo) HCT. He is in ongoing complete remission (CR) 9 months post-HCT and has had no GVHD. Patient #02 had MRD pos (VAF 61.7%) AML with TP53 mutation/complex karyotype prior to RIC matched sibling donor allo-HCT. He is in CR and has mild chronic GVHD at 7 months post-HCT. Patient #03 with pre-HCT MRD negRUNX1 AML is in ongoing CR 7 months post-RIC Haplo HCT with no GVHD. At day 28 and day 120 post-GDT, all 3 patients were MRD neg in bone marrow and had 100% bone marrow and peripheral blood leukocyte and granulocyte chimerism. In DL2 cohort, patient #04 with RUNX1 AML and patient #05 with t(9;22) AML both were MRD neg prior to RIC Haplo HCT and remain in CR with no GVHD at 5 and 4 months post-HCT, respectively. At day 28 post-GDT, both patients were MRD neg and had 100% chimerism. Patient #05 had a fall during DLT period in a setting of orthostatic hypotension requiring hospitalization for 24 hours for hydration. This was the only grade 3 adverse event observed in this trial. Serum cytokines analyzed included IL2, IL6, IL15, IFNγ, TNFα, Angiopoietin 1&amp;2, and GM-CSF (Figure 1). We compared results prior and up to 90 days post-GDT infusion and found no significant differences, which can explain no CRS or ICANS events yet observed on this trial. Immunophenotype (TCRVδ2, TCRVδ1, PD1, CTLA4, TIGIT and CD28) of GDT was analyzed in samples of donor apheresis, pre- and post-enrichment, infused GDT product and at days 28 and 90 post-infusion. GDT (TCRVδ2) persisted at day 28 and day 90 post-infusion and expressed low levels of cell surface inhibitory receptors. Conclusion This preliminary interim report demonstrates favorable safety and tolerability of donor GDT therapy with no CRS, ICANS or GVHD in first 5 patients treated in this trial. All these patients with adverse risk AML are in ongoing MRD neg CR following RIC allo-HCT, including 2 pre-HCT MRD pos cases with TP53 AML and AXSL1 AML. Early results of this trial are promising, which provides validation for continued testing of adoptive transfer of ex vivo expanded donor GDT. Updated results of this trial will be presented at the annual conference.

Allogeneic Hematopoietic Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia - Retrospective Dual-Center Study

Background: Adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) are treated with various chemotherapy regimens. Some patients undergo allogeneic hematopoietic stem cell transplantation (HCT) due to high-risk genetic characteristics, chemo-resistant disease (failure to achieve timely measurable residual disease (MRD) negative remissions, or relapse or refractory disease. There is paucity of data on outcomes of AYA ALL patients receiving HCT. Methods: We performed a dual-center analysis of data from MD Anderson Cancer Center (MDACC) and Dana-Farber Cancer Institute (DFCI) to evaluate outcomes of AYA patients who received HCT for Philadelphia-negative (Ph neg) ALL and examined variables that might have an impact on these outcomes. We included all patients who received their first HCT between the ages of 15-40 years between the years 2010-2022. MRD status was evaluated using flow cytometry with a sensitivity of 0.01%. Acute and chronic graft versus host disease (GvHD) were classified according to consensus criteria. The primary endpoint was overall survival (OS), and secondary endpoints included progression rate and non-relapse mortality (NRM). Cox proportional hazards regression analysis was used to evaluate predictors of OS, and Fine and Gray regression for predictors of relapse and NRM. Competing risks were accounted for in analyses pertaining to progression and NRM. Results: A total of 376 Ph neg ALL AYA patients were included in the analysis, 247 from MDACC and 129 from DFCI. The median age at transplant was 25 (range 15-40) years, 39 patients (10%) were aged ≤18 years at time of HCT and 251 (67%) were males.The majority had B-ALL (n=282, 75%), 42 (11%) had complex karyotype and 28 patients (7%) had translocation (4:11). Most patients received either pediatric-inspired (48%) or hyper- cyclophosphamide, vincristine sulfate, doxorubicin, dexamethasone (CVAD) based (42%) frontline induction regimens, and the median time from diagnosis to HCT was 11 (range 2-283) months. At transplant, most patients were in CR1 or CR2 (44% each); 63% of patients achieved MRD negativity prior to HCT. Most patients received an HCT from a matched unrelated donor (MUD) (33%) or a matched sibling donor (MSD) (32%), and most patients received myeloablative conditioning (MAC) (79%) ( Table 1). The cumulative incidence of grade 2-4 acute GvHD and grade 3-4 acute GvHD at 6 months was 37% (95% CI 33%-42%) and 13% (95% CI 10%-17%), respectively. The cumulative incidence of chronic GvHD at 3 years was 28% (95% CI 23%-33%), with most patients experiencing either mild (39%) or moderate (36%) chronic GvHD, and 25% had severe chronic GvHD. For patients transplanted in CR1, CR2 and CR3/PD the estimated 3-year OS was 69% (95% CI 61%-77%), 53% (95% CI 44%-61%) and 29% (95% CI 16%-43%), respectively; the 3-year NRM rate was 9% (95% CI 5%-15%), 18% (95% CI 13%-25%) and 27% (95% CI 16%-43%), respectively; and the 3-year progression rate was 27% (95% CI 20%-35%), 36% (95% CI 29%-45%) and 48% (95% CI 36%-65%), respectively. In multivariate analysis, HCT in CR3/PD was associated with inferior OS (HR 4.3, p&amp;lt;0.001) and higher NRM (HR 2.3, p=0.04, Table 2), however there was no difference in survival between HCT at CR1 vs. CR2 (p=0.3); &amp;gt;2 lines of therapy prior to HCT was associated with inferior OS (HR 1.8, p=0.004) and higher rate of progression (HR 1.9, p=0.008); HCT-CI&amp;gt;3 was associated with inferior OS (HR 1.6, p=0.01) and higher NRM (2.3, p=0.004); positive MRD status prior to HCT was associated with inferior OS (HR 1.9, p=0.004) and higher rate of progression (HR 3.3, p&amp;lt;0.001); use of bone marrow graft was associated with lower rate of progression (HR 0.6, p=0.02) and use of a matched donor (MSD/MUD) was associated with lower NRM (HR 0.5, p=0.01). Conclusions: In this analysis of a large dual-center cohort of AYA Ph -ALL patients that received HCT, we found that patients transplanted in CR1 had the most favorable outcomes with 69% 3-year OS. Patients not in CR1/CR2, patients who received HCT after &amp;gt;2 lines of therapy and those with positive MRD pre-HCT had inferior OS on MVA. Although patients who received HCT at CR3/PD had inferior OS, an estimated one-third of patients were still alive at 3 years after HCT.

A Novel Protocol Improves Engraftment in Tαβ + Cell Depleted Haplo-HSCT for Patients with Thalassemia Major

Background: Hematopoietic stem cell transplantation (HSCT) remains a proven curative approach for patients with thalassemia major (TM) over long-term practice. However, achieving successful engraftment and managing graft-versus-host disease (GVHD) continue to pose significant challenges. While low incidence of GVHD has been observed in Tαβ + cell-depleted HSCT (TDH) from haploidentical donors, graft failure (GF) remains a considerable concern, particularly in patients with TM. To enhance the engraftment in TM-TDH, we conducted this prospective/retrospective single-center clinical study. Method: A total of 137 patients diagnosed with TM received TDH at the BMT-center, Taixin Hospital, between March 2021 and April 2023. The median age of the patients was 7 years (ranging from 2 to 19 years), with 89 males and 48 females. The median follow-up time was 408 days (ranging from 99 to 857 days). The conditioning regimen consisted of Thymoglobulin on -day 21, followed by 3-Gy total body irradiation on -day 11. On -day 10, the patients received an infusion of donor lymphocytes (2*10 8/kg), followed by cyclophosphamide (Cy) at a dose of 50mg/kg on days -8, -7, and -2, and 25mg/kg on day -1. Additionally, blood-concentration adjusted busulfan was administered on days -6 to -4, fludarabine at a dose of 40mg/kg on days -6 to -2, and thiotepa at 10mg/kg on day -3. For GVHD prophylaxis, short-term (&amp;lt; 6 months) low-dose tacrolimus or sirolimus with or without mycophenolate mofetil was used. The mean infused CD34+ cells were 31.09 (ranging from 14.25 to 61.12) *10 6/kg, TCRγδ+ cells were 39.49 (ranging from 5.18 to 140.39) *10 6/kg, and NK cells were 109.18 (ranging from 27.52 to 309.41) *10 6/kg, respectively. The targeted infusion of TCRαβ+ cells was aimed at 1.5-2.0*10 5/kg. Results: Out of the 137 patients, 133 achieved successful engraftment (97.1%) with median engraftment times of 16 days (ranging from 9 to 48 days) for ANC to reach 0.5x10 9/L, 11 days (ranging from 1 to 23 days) for HB to reach 80g/L, and 10 days (ranging from 5 to 22 days) for platelets to reach 20x10 9/L, respectively. GF was observed in four patients. Among them, two patients with GF underwent salvage alternative donor second HSCT on +day 19 and +day 32, respectively, and are currently thalassemia-free. One patient received infusion of cryopreserved auto-peripheral blood stem cell and continues to live with TM. Unfortunately, four patients passed away, with one GF patient dying from suspected virus myocarditis on +day 11, one potentially due to virus hepatitis or hepatic GVHD on day +188, and the remaining two from virus bronchiolitis obliterans on +day 211 and +day 254, respectively. The overall survival (OS) and thalassemia-free survival (TFS) rates were 96.5% and 94.3%, respectively. The incidence of GF and transplant-related mortality (TRM) were 2.9% and 3.5%, respectively (Fig.). Acute GVHD of grade I-II and grade III-IV was observed in 10.53% and 9.02% of patients, respectively, while mild and moderate chronic GVHD occurred in 7(5.1%) and 1(0.7%) patient(s), respectively. The incidence of veno-occlusive disease was mild and limited. C onc lusion: The current study demonstrates the efficacy of a novel protocol in enhancing engraftment in TDH for patients with TM and with low incidence of both acute GvHD and chronic GvHD. This approach represents a significant advancement in the field of TM-TDH. Fig.1 Curve of OS, TFS, TRM and Rejection in TM-TDH

Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide Expedites Donor-Derived Immune Reconstitution in a Pediatric Severe Aplastic Anemia Cohort

Severe aplastic anemia (SAA) is a life-threatening, idiopathic process involving the immune-mediated destruction of hematopoietic stem cells. Treatment involves immunosuppressive therapy (IST) and/or allogeneic hematopoietic cell transplantation (HCT). The latter has recently been optimized with use of a post-transplant cyclophosphamide (PTCy) based graft-versus-host disease (GvHD) platform, permitting successful HCT with only half-HLA-matched haploidentical donors. In pediatrics, this platform results in &amp;gt;90% overall survival with low rates of GvHD and graft failure. However, reports on donor chimerism and immune reconstitution are limited. We hypothesized that a PTCy platform would expedite CD3 donor engraftment and CD4 T cell recovery. In a phase III clinical trial, we treated three cohorts of pediatric (age &amp;lt;/=25 years) patients with SAA requiring alloHCT: MUD, MSD, and HAPLO. The MUD cohort included n=15 recipients of 7-8/8 HLA-matched unrelated donor grafts (n=5 7/8, n=10 8/8) with median age 14 years (range 2-17 years), following cyclophosphamide (Cy) 50 mg/kg, fludarabine (Flu) 200 mg/m 2, rabbit anti-thymocyte globulin (rATG) 9 mg/kg total dose rabbit and low dose total body irradiation (TBI) at 200 cGy. The MSD cohort included n=9 recipients of 8/8 HLA-matched sibling donor grafts with median age 15 years (range 12-24 years), following Cy 200 mg/kg and 9 mg/kg rATG. The HAPLO cohort included n=4 recipients of 4/8 HLA-matched related donor grafts with median age 8.5 years (range 2-21 years) following Cy 29 mg/kg, Flu 150 mg/m 2, 9 mg/kg rATG, and low dose TBI at 200 cGy. GvHD prophylaxis consisted of 30 days of mycophenolate mofetil, and 100 days of a calcineurin inhibitor (followed by an 8-10 week taper), with the HAPLO cohort additionally receiving post-transplant Cy (PTCy) 50 mg/kg/day on days +3 and +4. Peripheral blood lymphocyte counts and peripheral blood and bone marrow donor chimerism were evaluated on days +100, +180 and +365. Recipient characteristics were largely equivalent between cohorts, with 43% receiving IST prior to HCT. Clonality was overrepresented in the HAPLO cohort (2 of 4, 1 with monosomy 7 myelodysplastic syndrome and 1 with a large PNH clone), with only 2 of 15 in the MUD and none in the MSD cohorts. Active controlled infections at the time of HCT were additionally overrepresented in the HAPLO cohort, with disseminated pseudomonas in 1. The MUD cohort had 1 with Rhizopus invasive sinusitis (none in the MSD cohort). Achievement of neutrophil engraftment was statistically significantly delayed in the HAPLO cohort at a median of 17 days compared to 12 for MSD and 14 for MUD, p=0.004), however there were no episodes of primary or secondary graft failure. With only a single late death from intracranial hemorrhage in the MUD cohort, OS was equivalent at 2 years (100% in MSD and HAPLO cohorts, 93.3% in MUD). GvHD rates were low with only 1 (MUD) experiencing grade II acute GvHD, and 1 (MUD) experiencing mild chronic GvHD. Immune reconstitution varied by cohort with statistically significantly greater CD3 peripheral blood donor chimerism (p&amp;lt;0.001) as well as CD4 (p=0.04) and CD8 (p=0.03) T cell counts over time for the HAPLO recipients (CD3 chimerism in Fig 1, CD4 count in Fig 2; 2-way ANOVA fixed effects model). Considering a CD4 &amp;gt;200 cell/uL as clinically meaningful, we assessed the proportion of each cohort achieving this milestone at each timepoint. While each cohort had an increase in proportion achieving CD4&amp;gt;200 over time, the HAPLO cohort reached 50% with CD4 &amp;gt;200 at day +100, compared to 11% MUD and 0% MSD (p=0.09). At day +180, the proportion with CD4 &amp;gt;200 were 36% MUD, 25% MSD and 75% HAPLO (1 yr: 90% MUD, 100% MSD and HAPLO). Donor availability remains a challenge to successful transplant for patients with SAA, and haploidentical matches overcome donor limited accessibility. PTCy as GvHD prophylaxis is associated with low incidences of graft failure and severe GvHD. While PTCy might be anticipated to inhibit donor T cells and immune reconstitution, our data, albeit limited by small cohorts, demonstrates superior and more efficient CD3 donor engraftment and CD4 T cell count recovery following HAPLO HCT with PTCy compared to non-PTCy based MUD and MSD cohorts.

Clinical Outcomes of Image-Guided Volumetric Modulated Arc Therapy for Total Body Irradiation

Volumetric modulated arc therapy (VMAT)-based total body irradiation (TBI) with image guidance is a novel technique that is increasing in implementation. Compared to conventional TBI, VMAT-TBI offers favorable dose homogeneity, better organ-at-risk sparing, and enhanced patient comfort. However, whether these dosimetric advantages translate to improved clinical outcomes that justify the increased planning and delivery burden is not well understood. Only a single study of clinical outcomes of VMAT-TBI exists in the literature. We present the largest study to date of clinical outcomes of VMAT-TBI. In this IRB-approved retrospective single-institution study, all patients treated with VMAT-TBI conditioning for allogeneic stem cell transplant, per the institution's published protocol, were identified. Dosimetric data were abstracted from the radiation oncology treatment planning system. Clinical data were abstracted from the electronic medical record. The primary outcome was six-month overall survival (6M OS) from the last day of TBI by Kaplan-Meier method. Fifty-five patients (47 adult and 8 pediatric) were treated with VMAT-TBI between June 2020 and December 2022. All patients received conditioning chemotherapy with standard-dose TBI of 12 or 13.2 Gy in 8 twice-daily fractions. The PTV coverage (V95%) mean was 95.3% ± 1.2%. Mean lung dose was 9.5 Gy ± 0.6 for adult patients and 8.4 Gy ± 0.9 for pediatric patients. Mean lung dose rate was 18.0 cGy/min ± 4.4. Mean kidney dose was 5.9 Gy ± 0.6. Mean skin dose measured by MOSFET was 12.7 Gy ± 1.2. Median treatment time was 63 minutes (range: 53-104). Median follow-up was 7.7 months. At most recent follow-up, 78% of patients were alive. 6M OS was 82%. Common acute toxicities were fatigue (90.9% of patients, all grade 1-2), diarrhea (70.9%, all grade 1-2), nausea (76.4%, all grade 1-2), mucositis (60% grade 1-2, 12.7% grade 3, 1.8% grade 4, no grade 5), and xerostomia (54.5%, all grade 1). Mean pretreatment FEV1 was 98.3 percent of predicted (%p) ± 11.9%p and mean posttreatment FEV1 was 94.7%p ± 13.8%p. Mean pretreatment GFR was 101.4mL/min/1.73m² ± 17.4, mean 3-month posttreatment GFR was 92.4 ± 20.0, and mean 6-month posttreatment GFR was 97.5 ± 26.48. One patient experienced grade 2 pneumonitis; there were no other cases of pneumonitis. There were no acute grade 3+ toxicities aside from mucositis. Observed late toxicities were cataracts (7.3%, all grades 1-3) and hypothyroidism (12.7%, all grades 1-2). There were no grade 3+ late toxicities. Mild acute graft-versus-host disease (GVHD) was noted in 27.2% of patients and mild chronic GVHD was noted in 14.5% of patients, with no other cases of GVHD. In the largest series to date, VMAT-TBI had excellent oncologic and toxicity outcomes. A randomized trial of VMAT-TBI versus standard TBI is warranted.

Abstract 2 Results of an Open Label Expanded Access Study of Omidubicel-onlv for Allogeneic Transplantation (allo-HCT) in Patients with Hematologic Malignancies

Abstract Introduction Omidubicel, a nicotinamide expanded allogeneic hematopoietic progenitor cell therapy derived from umbilical cord blood (UCB) was recently FDA approved for use as a sole donor source in allo-HCT based on phase III study results showing improved hematopoietic recovery and decreased infection rate compared to standard UCB. Objectives Open label, single arm expanded access program (EAP) evaluating clinical outcomes for patients with hematologic malignancies following omidubicel allo-HCT. Methods Eligible patients (&amp;gt;12 years) received myeloablative conditioning with supportive care per institutional guidelines. Patients were followed for engraftment, infections, graft versus host disease (GVHD), and two year post-transplantation outcomes. Results Between July 2020 and April 2023, 36 patients were enrolled at 5 US centers, and 29 (18 male, 11 female) were transplanted; median age was 38 years (range: 20-73); 55.2% white, 17.2% Black, 20.7% Asian, 10.3% other. Diagnoses included AML (37.9%), ALL (27.6%), MDS (20.7%) and other (13.8%). Median transplanted CD34+ cell dose was 5.6x106 cells/kg and HLA match was 4/6 in 51.7%, 5/6 in 44.8%, and 6/6 in 3.5%. Median follow-up was 6.25 months (range 0.33-27.7). At 100 and 365 days post-transplant, PFS rates were 95.5% and 82.9%, and OS rates were 96.3% and 84.4%, respectively. No infusion reactions were reported. Median neutrophil (&amp;gt;500/µl x3 days) and platelets (&amp;gt;20,000/µl x7 days) engraftment times were 12 and 33 days, respectively. Primary graft failure occurred in 2 (6.9%) patients, both alive &amp;gt;100 days after second transplant. Incidence of first grade 2 or 3 bacterial, viral, or invasive fungal infections through 100 days post-transplantation were 13.8%, 24.1% and 0%, respectively. Acute GVHD was reported in 13 (44.8%) patients (grade II: 34.5%, grade III: 10.3%) and mild chronic GVHD in 1 (3.5%). There were 4 deaths (13.8%): 2 due to relapse @275 and 381 days, 1 due to infection (day 135) and 1 due to pulmonary failure on day 10. Post-transplant lymphoproliferative disease was reported in one. Discussio In this real-world EAP setting, allo-HCT with omidubicel was well tolerated, and observed engraftment and infections consistent with published Phase 3 data. These data further support the role of omidubicel particularly for patients from diverse racial backgrounds.

Human leucocyte antigen-matched related haematopoietic stem cell transplantation using low-dose cyclophosphamide, fludarabine and thymoglobulin in children with severe aplastic anaemia.

When human leucocyte antigen-matched related donors are available, haematopoietic stem cell transplantation (HSCT) in children with severe aplastic anaemia (SAA) represents the standard of care. Cyclophosphamide (Cy) 200 mg/kg and anti-thymocyte globulin (ATG) are frequently administered, but to-date, no standard conditioning regimen exists. In this study, we investigated the efficacy of a unified HSCT conditioning protocol consisting of low-dose Cy 80 mg/kg, fludarabine and ATG. Data were reviewed from children aged ≤14 years with either acquired SAA or non-Fanconi anaemia inherited bone marrow failure syndrome (IBMFS) between 2011 and 2022 at various Saudi institutions. Graft-versus-host disease (GVHD) prophylaxis included mycophenolate mofetil and calcineurin inhibitors. HSCT was performed in 32 children (17 females and 15 males). Nine patients had deleterious mutations (two ERCC6L2, two ANKRD26, two TINF2, one LZTFL1, one RTEL1 and one DNAJC21). Four patients had short telomeres. All 32 patients engrafted successfully. At 3 years post-transplant, the event-free survival was 93% and overall survival was 95%. Two patients experienced secondary graft failure or myelodysplastic syndrome. A low probability of GVHD was observed (one acute GVHD II and one mild chronic GVHD). These data highlight how HSCT using low-dose Cy as part of a fludarabine-based regimen is safe and effective in SAA/non-Fanconi anaemia IBMFS.

Humoral response and safety of the BNT162b2 and mRNA-1273 COVID-19 vaccines in allogeneic hematopoietic stem cell transplant recipients: An observational study

BackgroundThe effectiveness of mRNA COVID-19 vaccines and the optimal timing of vaccine administration in allogeneic hematopoietic stem cell transplantation (Allo-HSCT) recipients remains inadequately investigated. We examine the effectiveness and safety of mRNA COVID-19 vaccines in allo-HSCT recipients. MethodThis prospective observational study included 44 allo-HSCT recipients and 38 healthy volunteers. The proportion of subjects acquiring anti-S1 IgG antibodies were considered as the primary endpoint. The occurrence of adverse events after vaccination and objective deterioration of chronic graft-versus-host disease (GVHD) were defined as secondary endpoints. In addition, we compared the geometric mean titers (GMT) of anti-S1 antibody titers in subgroups based on time interval between transplantation and vaccination. ResultsA humoral response to the vaccine was evident in 40 (91%) patients and all 38 healthy controls. The GMT of anti-S1 titers in patients and healthy controls were 277 (95% confidence interval [CI]: 120–643) BAU/mL and 532 (95% CI 400–708) BAU/mL, respectively. (p = 0.603). A short time interval between transplantation and vaccination (≤6 months) was associated with low anti-S1 IgG antibody titers. No serious adverse events and deterioration of chronic GVHD were observed. Only one case of new development of mild chronic GVHD was recorded. ConclusionMessenger RNA COVID-19 vaccines induce humoral responses in allo-HSCT recipients and can be administered safely.

Mismatched donor transplantation with post-transplantation cyclophosphamide for advanced cutaneous T-cell lymphoma: A single-center experience.

e19045 Background: Mismatched blood or marrow transplantation (BMT) using post-transplantation cyclophosphamide (PTCy) for graft-versus-host disease (GvHD) prophylaxis has not been well-studied in CTCL. Methods: We analyzed all patients above 18 years old with relapsed/refractory CTCL undergoing mismatched alloBMT. Primary endpoints included disease-free survival (DFS) and overall survival (OS). Secondary endpoints included time to neutrophil and platelet recovery, GvHD outcomes, and day +30 and day +60 donor chimerism. Results: From 2003-2020, 8 patients with relapsed CTCL underwent mismatched related (n=7) or mismatched unrelated (n=1) BMT. Mean age was 50 years (range 30-62); median time from diagnosis was 2 years (range 1.3-11.4). All had received prior treatment for their disease; two (25%) had received immune checkpoint inhibitors. Four (50%) were in partial response and 4 (50%) were in complete remission prior to BMT. Six received bone marrow grafts. Two received mobilized peripheral blood. Five (62.5%) achieved full donor chimerism by day 30 after BMT; 6 (75%) had achieved full donor chimerism by day 60 after BMT. One patient failed to engraft. Mean time to neutrophil recovery was 17.3 days (range 17-45); mean time to platelet recovery was 28.4 days (range 11-69). Median DFS was 11.3 months (95% confidence interval 2.6 months-not reached). Median OS was not reached. One patient developed grade 1 acute GvHD, and 2 patients developed mild chronic GvHD. There were no instances of transplantation-related mortality (TRM). At 1 year post-BMT, 4 patients had relapsed (50%), and no patients had died. At 3 years post-BMT, 7 patients had relapsed (87.5%), and 1 patient had died (12.5%). Conclusions: In our preliminary retrospective study, partially mismatched BMT with PTCy-based GVHD prophylaxis for advanced-stage CTCL was associated with minimal GvHD, no TRM, and good long-term survival. Investigation into relapse reduction is warranted.[Table: see text]

Abatacept-based Graft-Versus-Host Disease Prophylaxis in Haplo-identical Hematopoietic Cell Transplant in a High-risk Cohort.

There is insufficient guidance in using posttransplant cyclophosphamide in patients with organ dysfunctions. Abatacept (Aba), a T cell costimulation blockade, has recently been shown to prevent severe acute graft-versus-host disease (GVHD). We report adding Aba as GVHD prophylaxis in 4 pediatrics patients who received haplo-hematopoietic cell transplantation. Two patients had grade 2 acute GVHD and 2 had mild chronic GVHD. All 4 patients are alive with full donor chimerism, and 3 are off immunosuppressants. An Aba-based regimen can result in reliable engraftment and acceptable GVHD when concerns of organ dysfunction prevents the use of posttransplant cyclophosphamide in haplo-hematopoietic cell transplantation.

Nonmyeloablative, HLA-Mismatched Unrelated Peripheral Blood Transplantation with High-Dose Post-Transplantation Cyclophosphamide

High-dose post-transplantation cyclophosphamide (PTCy) is an effective platform for prevention of severe graft-versus-host disease (GVHD) after allogeneic bone marrow (BM) transplantation with mismatched unrelated donors (mMUDs). Previous studies evaluating PTCy with mMUDs favored BM allografts over peripheral blood stem cell transplantation (PBSCT) due to concerns that PBSCT may be associated with an increased risk of acute and chronic GVHD. In addition, haploidentical PBSCT is associated with high rates of cytokine release syndrome (CRS), which is another concern with mMUD PBSCT. This study was conducted to determine the feasibility and safety of using mMUD PBSCT with PTCy as GVHD prophylaxis. Patients who received mMUD PBSCT using a PTCy-based GVHD prophylaxis at Johns Hopkins Hospital as part of a prospective clinical trial of mMUD and non-first-degree relative haploidentical transplantation with PTCy (ClinicalTrials.gov identifier NCT01203722) were included. All patients underwent T cell-replete PBSCT between November 2012 and August 2020. Statistical analyses were performed using the Kaplan-Meier method and proportional subdistribution hazard regression model for competing risks. The 29 patients in the study had a median age of 54 years, with 10 patients (34%) age ≥60 years. Nineteen grafts (66%) were matched for 9/10 HLA loci, 6 (21%) were match for 8/10, and 4 (14%) were matched for 7/10. No primary or secondary graft failure occurred. The median time to neutrophil recovery (≥500/µL) was 17 days, and that to platelet recovery (≥20,000/µL) was 28 days. Full donor chimerism was achieved in all patients by day +60. The cumulative incidence (CuI) of grade II-IV acute GVHD at 180 days was 15% (90% confidence interval [CI], 3% to 26%). There were no cases of severe chronic GVHD, 3 cases of mild chronic GVHD, and 1 case of moderate chronic GVHD. The CuI of nonrelapse mortality (NRM) was 7% (90% CI, NA to 18%) at 1 year. Eighteen patients (62%) experienced mild CRS (grade 1-2), and 1 patient (3%) experienced severe CRS (grade 3-5). At 1 year, the CuI of relapse was 29% (90% CI, 8% to 50%), overall survival was 93% (90% CI, 85% to 100%), progression-free survival was 64% (90% CI, 46% to 88%), GVHD-free relapse-free survival was 41% (90% CI, 23% to 73%), and chronic GVHD-free relapse-free survival was 64% (90% CI, 46% to 88%). Our data indicate that mMUD PBSCT using PTCy-based GVHD prophylaxis is safe and feasible. All patients engrafted, and rates of NRM (7%) and acute GVHD (15%) at 1 year were low. There was only 1 case (3%) of severe CRS. Compared with previously published outcomes, mMUD PBSCT using PTCy-based GVHD prophylaxis has a safety and efficacy profile that may not be different from that of PBSCT from matched donors. These results further solidify that all patients who require blood or BM transplantation should be able to find an acceptable donor.

Haploidentical Hematopoietic Stem Cell Transplantation With Reduced Intensity Conditioning, T-Cell Replete Grafts and Post-Transplant Cyclophosphamide In Pediatrics

Hematopoietic stem cell transplants (HSCT) may be curative in the treatment of many hematological diseases. However, most patients do not have an HLA- matched sibling donor and an unrelated donor search may be a long process, during which the patients' disease may relapse or progress. Haploidentical transplants with in vitro T-cell depletion have been used in Pediatrics. However, it requires specialized laboratory infra-structure to manipulate the graft, increases the chances of graft failure and relapse. In vivo T-cell depletion can be achieved with the use of post-transplant cyclophosphamide, as reported by the Johns Hopkins and other groups. The results in adults are very promising and comparable to unrelated double cord blood transplants. Children, however, have not been included in any of the reported protocols. Our objective is to report the institutional experience with five consecutive children who received Haploidentical HSCT with reduced intensity conditioning, T-cell replete grafts and post transplant cyclophosphamide. MethodsChildren with clear indication to be treated with HSCT and no HLA-matched related or unrelated donor available were offered compassionate haploidentical transplants. Conditioning comprised cyclophosphamide 14.5 mg/kg/day on days -6 and -5, fludarabine 30 mg/m2/day for five consecutive days starting on day -6, and 2Gy total body irradiation given in a single fraction on day -1. Bone marrow was harvested from donors and infused into recipients on day 0. The target nucleated cell dose was 5 x10(8) mononuclear marrow cells/kg (i.e., peripheral blood count was substracted from the marrow cell count). There was no graft manipulation. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg IV on days +3 and +4 with 140% Mesna divided on hours 0, 4, 8 and 12 after each dose, Mycophenolate mofetil 15 mg/kg po every 8 hours (maximum 3 g/day) from day +5 to day +35, and tacrolimus from day + 5 to day +180 to keep levels between 5 and 10ng/ml. Prophylactic antimicrobial therapy was started on day +1 and included fluconazole and acyclovir. ResultsFive children with AML and T-ALL (three in CR2; one induction failure and one 4th relapse) were offered haploidentical transplants as the first HSCT. They had a median age of 10 years (4-16) and weight 41 kg (14-67), 2 girls. One graft was a peripheral blood stem cell collection per physician preference. The median total nucleated cell count was 12x10(8)/kg (10-27) with 10x10(6) CD34/kg (5-15). Mucositis was mild in three patients and none of them had sinusoidal obstruction syndrome. All patients engrafted after a median 14 days (13-17) but one of them, in 4th relapse of acute promyelocytic leukemia (APL), rejected the graft. Two of four evaluable patients had mild acute graft versus host disease (GVHD), and one mild chronic GVHD. The patient with APL died of two graft rejections on day+125, one T-ALL relapsed on day+180 and three children are disease-free with excellent clinical status one month to 1.7 years after transplant. We conclude that haploidentical HSCT with post-transplant cyclophosphamide is feasible to treat children without an available matched related or unrelated donor and should be prospectively studied. Disclosures:No relevant conflicts of interest to declare.

Carfilzomib in Addition to Standard Cyclosporine/Methotrexate Combination Effectively Prevents Acute Graft-Versus-Host Disease after Allogeneic Stem Cell Transplantation from Unrelated Donors

Background: Acute graft-versus-host disease (GVHD) remains a major obstacle for successful allogeneic stem cell transplantation (HSCT) from unrelated donors. Novel preventive regimens are thus needed. The proteasom inhibitor bortesomib has immune modulatory effects that were shown to be beneficial in several studies adding a short treatment course to the standard calcineurin/ methotrexate regimen in matched and mismatched unrelated donor transplant. Carfilzomib is a second generation irreversible proteasome inhibitor. It is more selective than bortesomib and was shown to be more effective in relapsed refractory multiple myeloma. However, there is no data on the effect of carfilzomib in GVHD prevention. We explored a novel regimen consisting of 2 doses of carfilzomib at 20 mg/m2, given on days 1 and 2 after HSCT combined with standard anti GVHD prophylaxis regimen of cyclosporine/ methotrexate. The study enrolled patients with acute myeloid leukemia (AML) in remission (CR) or patients with myelodysolastic syndrome (MDS) with less than 10% blasts, given a 10/10 or 9/10 matched unrelated donor transplant with fludarabine-based reduced-intensity or reduced-toxicity conditioning.Patients and Methods: 20 patients, 8 male, 12 female, median age 63 years (range, 30-72) were recruited to the study. Fifteen patients had AML and 5 had MDS. Ten patients were in CR1, 5 in CR2 and 5 were previously untreated at the time of transplantation. The conditioning regimen included fludarabine combined with intravenous busulfan at reduced doses (n=6) or myeloablative doses (n=11) or with treosulfan (n=3). All patients were also given antithymocyte globulin (ATLG ,Grafalon ,Neovii, total dose 15 mg/kg). The donors were all unrelated donors and were 10/10 HLA matched (n=10) or 9/10 matched (n=5). Transplantation outcomes were compared to a historical group of 100 patients with similar patient and transplant characteristics given unrelated donor transplant with a standard anti GVHD cyclosporine/ methotrexate GVHD prevention regimen.Results: Eighteen patients completed the planned two days of carfilzomib on day 1 and 2 post-transplant. One patient had only one dose and one none of the doses due to adverse events that dictated stopping treatment by protocol. The median follow-up is 11 months (range 1-29). All patients engrafted with a median of 15 days (range, 10-31) compared with 14 days (range, 9-23) in the control group (P=0.14). Mucositis grade ≥3 occurred in 60% and 24% of the study patients and historical controls, respectively (P=0.001). There was no difference in the rate of all other grade ≥3 organ toxicities, 20% and 30%, respectively (P=0.36). Acute GVHD grade II-IV occurred in only one patient in the study group, a cumulative incidence of 5% (95%CI, 1-34) compared with 39% (95%CI, 30-50) in the control group (P=0.007). Chronic GVHD occurred in 5 patients in the study group , a cumulative incidence of 58% (95%CI, 30-100) compared with an incidence of 41% in the historical controls (95%CI, 33-52) (P=0.58). Notably, all study pts had mild chronic GVHD while, the incidence of moderate to severe chronic GVHD was 0% and 18% (95%CI, 11-30), respectively (P=0.17). Non-relapse mortality (NRM) occurred in 2 patients on study, one died of acute GVHD and the other of multi-organ failure. The cumulative incidence of NRM was 11% (95%CI, 3-39) and 22% (95%CI, 15-32), in the study and control group, respectively (P=0.68). Finally, only one study patient relapsed, cumulative incidence 8% (95%CI, 1-53), compared to 26% (95%CI, 18-36) in the historical controls (P=0.310). In all, 17/20 study patients are alive with an estimated 2-year survival of 81% (95%CI, 68-100) compared to 56% (95%CI, 46-66) in the control group, respectively (Figure, P=0.31).Conclusions: Carfilzomib in addition to standard cyclosporine/ methotrexate as anti GVHD prophylaxis after unrelated- donor transplant is safe and allows better prevention of acute GVHD without compromising the graft-versus-leukemia effect. The add on of carfilzomib results in favorable outcome. Larger studies with longer follow-up are required to confirm these initial promising results. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Consolidative CD8+ Memory T-Cell Donor Lymphocyte Infusion Augments Donor Chimerism with a Low Risk of Gvhd Following Matched Related Donor Hematopoietic Cell Transplantation

IntroductionMixed chimerism (MC) after allogeneic hematopoietic cell transplantation (HCT) is associated with an increased risk of disease relapse. An unmanipulated donor lymphocyte infusion (DLI) can convert MC to full donor chimerism (FC) but can also precipitate severe acute graft-versus-host disease (GVHD). We recently showed in a phase I trial that a subset of purified CD8+CD44hi memory T cells derived from HLA-matched sibling donors may induce graft-versus-tumor reactions in patients with relapsed hematologic malignancies following allogeneic HCT with objective responses in 25% of patients and a low incidence of GVHD (Muffly et al, 2016 ASH Abstract #4615). Here we report on the preliminary results of a phase II study using CD8+ memory T-cell DLI as consolidative therapy early after transplant for patients with MC to assess the rate of conversion to FC, the risk of GVHD, and the prevention of disease relapse.MethodsPatients: Eligible patients were 18-75 years of age with a high-risk or refractory hematologic malignancy who underwent nonmyeloablative allogeneic HCT from a matched sibling donor using total lymphoid irradiation and antithymocyte globulin conditioning, and who had MC (<95% donor CD3+ cells) at day +30. Patients were without acute GVHD at the time of the CD8+ memory T-cell DLI and were on tacrolimus or cyclosporine monotherapy for GVHD prophylaxis at the time of DLI.CD8+ memory T cells: Phenotypic CD8+ memory T cells were isolated from matched sibling donors following two days of unmobilized apheresis using a tandem immunomagnetic selection strategy including CD45RA depletion followed by CD8+ enrichment on the CliniMACS Plus instrument. Cell purity was determined by flow cytometry analysis. CD8+ memory T cells were infused between day +30 and day +70 at a dose of 5 x 106 cells/kg, which was determined in the prior phase I trial to be the maximum dose that could be collected from two apheresis products.Study Endpoints: Following DLI, patients were assessed for the development of acute and chronic GVHD, conversion from MC to FC (≥95% donor CD3+ chimerism) within three months, and for disease relapse. Secondary outcomes included the incidence of adverse events, invasive infections, non-relapse mortality, overall survival, and disease-free survival.ResultsPatient characteristics and outcomes after DLI are summarized in Table 1. Nine patients received CD8+ memory T-cell DLI at a median of 42 days post-HCT (range 33-62 days). The cell product was highly enriched for CD8+/CD45RA-/CD45RO+ cells, and flow analysis confirmed the selected cells were phenotypically consistent with the CD8+ T effector memory subset with a post enrichment purity of ≥96% (range 96.4-98.8%) in all patients. Median age of the patients was 60 years (range 30-71 years) with a median follow up of 306 days post-HCT (range 131-747 days). Diagnoses included non-Hodgkin lymphoma (n=5), acute myeloid leukemia (n=2), myelodysplastic syndrome (n=1), and Hodgkin lymphoma (n=1). Median donor CD3+ chimerism at day +30 was 88% (range 23-93%).CD8+ memory T-cell DLI was well tolerated with no adverse events. Six of the nine patients (67%) converted from MC to FC within three months post-DLI with a median donor CD3+ chimerism of 97% (range 95-100%). Two patients developed grade II acute GVHD (skin only) that was treated to resolution. One patient developed mild chronic GVHD. No patients developed severe acute GVHD (grade III-IV) or extensive chronic GVHD. No patients developed invasive infections, and non-relapse mortality was 0%. Of the three patients who failed to convert from MC to FC, two had residual disease at the time of transplant, one of whom had early disease relapse at day +88. Four of the six patients who converted to FC were in complete remission (CR) at the last follow up. One of the three patients with persistent MC was in CR at the last follow up. For the entire study cohort, the median disease-free survival is 1.1 years and the median overall survival is not yet reached.ConclusionsConsolidative CD8+ memory T-cell DLI following nonmyeloablative matched related donor HCT is well tolerated, converted six of nine patients (67%) with MC to FC, and was associated with a low rate of GVHD with no cases of severe acute or extensive chronic GVHD in this study. Patients continue to accrue to trial, and further accrual and longer follow up are needed to determine if this strategy will reduce relapse rates for high-risk patients with MC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Haploidentical Peripheral Stem Cell Transplantation for Young Patients with Severe Aplastic Anemia Using Post-Transplantation Cyclophosphamide and Methotrexate

Severe aplastic anemia (SAA) is a serious bone marrow failure disorder that is often cured with hematopoietic stem cell transplantation (HSCT). The absence of a matched related donor is common, however, and thus novel approaches are needed to safely expand the donor pool to include alternative donors, especially haploidentical related donors, for patients with SAA. This study aimed to explore a novel approach to HSCT for patients with SAA without an available HLA-identical sibling or a matched unrelated donor, termed haploidentical peripheral blood stem cell transplantation (haplo-PBSCT), using a conditioning regimen comprising cyclophosphamide, busulfan, and fludarabine (CBF) and a graft-versus-host disease (GVHD) prophylaxis regimen with post-transplantation cyclophosphamide (PTCy), low-dose methotrexate (LD-MTX), and calcineurin inhibitors. This prospectively designed nonrandomized study included 29 patients with SAA who underwent haplo-PBSCT between November 2017 and May 2020. The median patient age was 17 years (range, 14 to 30 years), and the median time to neutrophil recovery was 13 days (range, 13 to 15 days). There was 1 primary graft failure (GF) in the group receiving PTCy at a dose of 50 mg/kg and no GFs in the group receiving PTCy at a dose of 100 mg/kg. The median duration of follow-up was 736 days (95% confidence interval, 512 to 879 days). The estimated 1-year overall survival and disease-free survival were 91.7 ± 5.7% and 89.7 ± 5.7%, respectively. Only 1 of the 27 patients developed grade II acute GVHD. Four patients developed limited and mild chronic GVHD, involving only the skin or/and oral mucosa. Haplo-PBSCT following CBF and followed by PTCy and LD-MTX represents a novel approach for safely expanding the donor pool to include alternative donors for young patients with SAA.

Charlson comorbidity index predicts outcomes of elderly after allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the curative therapy for acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS), but advanced age with multiple comorbidities limits the eligibility for allo-HSCT. We conducted a retrospective study to investigate the comorbidities assessments and prognostic factors that predict outcomes for these patients. Clinical data of patients older than 50 years who had received diagnoses of AML or MDS and underwent allo-HSCT were obtained. Information on patient characteristics, including age, gender, allogeneic transplant type, conditioning regimens, Charlson comorbidity index (CCI), and presence of acute graft-versus-host disease (GVHD) or chronic GVHD, were collected and analyzed. Two hundred fifty-five elderly patients with a median age at allo-HSCT of 57 years were included. The significant prognostic factors associated with worse overall survival (OS) were CCI ≥3 (hazard ratio: 1.88) and grade III-IV acute GVHD (3.18). Similar findings were noted in the non-relapse mortality analysis. To investigate the effects of chronic GVHD on patient outcomes, OS analysis was performed for those with survival >100 days after transplantation. The results revealed CCI ≥3 (1.88) and grade III-IV acute GVHD (2.73) remained poor prognostic factors for OS, whereas mild chronic GVHD (0.43) was associated with better OS. This cohort study suggests that CCI ≥3 predicts poor outcomes, primarily due to a higher NRM risk. Careful management of GVHD after transplantation could improve outcomes in elderly patients with AML or MDS after allo-HSCT.

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma

A Phase 2 Trial of Ibrutinib and Nivolumab in Patients with Relapsed or Refractory Classical Hodgkin's Lymphoma