Cumulative Incidence Of aGVHD Research Articles

Effect of donor and recipient HLA mismatched locus on the prognosis of childhood with leukemia after umbilical cord blood transplantation

Objective: The aim of the study was to investigate the impact of the sites of high-resolution human leukocyte antigen (HLA) mismatch on the prognosis of children with leukemia undergoing umbilical cord blood transplantation (UCBT). Methods: Clinical data and high-resolution HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 locus gene information were collected in the children who underwent the UCBT for the first time at Children's Hospital of Soochow University between January 2016 and June 2023. In each locus, according to whether the two genes were compatible, they were divided into a compatible group (two genes were perfectly matched) and a non-compatible group (one gene was not matched). In different loci, the differences in occurrence, recurrence, non-recurrence death and survival of acute graft versus host disease (aGVHD) were compared between the two groups. Multivariate Cox regression was employed to analyzed the influencing factors for overall survival rate, and Fine-Gray proportional hazards model was employed to analyze the influencing factors of other outcome events. Results: A total of 100 patients were enrolled (55 males and 45 females), whose age [M (Q1, Q3)] at the time of transplantation was 3.9 (2.0, 6.5) years. There were 55 cases in the HLA-A matched group and 45 cases in the mismatched group. The 5-year non-recurrence mortality (NRM) in the HLA-A matched group was lower than that in the mismatched group (P=0.024). The cumulative incidence of aGVHD within 100 days after transplantation in the HLA-A matched group was lower than that in the mismatched group (P=0.017), and there were no statistically significant differences in other outcome events between the groups (all P>0.05). There were 70 cases in the HLA-B matched group and 30 cases in the mismatched group. The 5-year cumulative recurrence rate in the HLA-B matched group was higher than that in the mismatched group (P=0.027). There were 79 cases in the HLA-C matched group and 21 cases in the mismatched group, and there were no statistically difference in the outcome events between the groups (P>0.05). There were 73 cases in HLA-DRB1 matched group and 27 cases in mismatched group. The 5-year overall survival rate in HLA-DRB1 matched group was higher than that in mismatched group (P=0.036), the 5-year cumulative recurrence rate in HLA-DRB1 matched group was higher than that in mismatched group (P=0.028), and the 5-year NRM in HLA-DRB1 matched group was lower than that in mismatched group (P=0.008). The cumulative incidence of aGVHD within 100 days after transplantation in the matched group was lower than that in the mismatched group (P=0.010), and and there were no statistically significant difference in other outcome events between the groups (P>0.05). There were 68 cases in HLA-DQB1 matched group and 32 cases in mismatched group. There was no statistical difference in outcome events between the two groups (all P>0.05). The risk of aGVHD in HLA-A mismatched group was higher than that in HLA-A matched group (HR=1.25, 95%CI: 1.12-1.38). The risk of recurrence in HLA-B mismatched group was lower than that in HLA-B matched group (HR=0.77, 95%CI: 0.63-0.91). Mismatched group at HLA-DRB1 compared with matched group at HLA-DRB1, had a higher risk of aGVHD (HR=1.37, 95%CI: 1.26-1.48), a higher risk of non-recurrence death (HR=1.39, 95%CI: 1.28-1.50), and a higher risk of death (HR=1.27, 95%CI: 1.18-1.36). No association was found between HLA-C and HLA-DQB1 locus with the risk of aGVHD, recurrence, non-recurrence death, and survival (all P>0.05). Conclusions: In UCBT, the risk of aGVHD in children with matching HLA-A sites of donor and recipient is lower than that in children with incompatible HLA-A sites. Compared with children with incompatible HLA-DRB1 sites, children with HLA-DRB1 matched sites has a lower risk of acute GVHD, a lower 5-year NRM, and a higher risk of death. The recurrence rate of children with matching HLA-B loci is higher than that of children without matching HLA-B loci.

Real-World Outcomes of Graft-versus-Host Disease after Allogeneic Hematopoietic Stem Cell Transplantation in Japan: Retrospective Analysis of the Transplant Registry Unified Management Program Registry

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an important therapeutic option for patients with hematological malignancies. However, the development of graft-versus-host disease (GVHD) after allo-HSCT remains a challenge. Although systemic steroid therapy is the established first-line therapy for acute GVHD (aGVHD) and chronic GVHD (cGVHD), many patients are unresponsive or resistant to corticosteroid therapy, and the response is insufficient. To evaluate the clinical characteristics of patients who developed aGVHD and cGVHD after allo-HSCT. This noninterventional, retrospective study used large national registry data from the Transplant Registry Unified Management Program. The study included 29,690 patients with hematological diseases who underwent their first allo-HSCT between January 2010 and December 2019. The primary endpoints of this study were the cumulative incidence of aGVHD and cGVHD. The secondary endpoints were overall survival (OS) and non-relapse mortality (NRM) of patients with aGVHD and cGVHD and OS and NRM of patients who received second-line therapy for aGVHD. Of 29,690 patients who underwent allo-HSCT, 2,807, 6,167, 10,556, 774, and 9,339 patients received related bone marrow (RBM), related peripheral blood (RPB), unrelated bone marrow, unrelated peripheral blood (UPB), and unrelated cord blood, respectively. The cumulative incidence of aGVHD (grades II-IV) at 100 days was high after the related and unrelated mismatched transplantation. Furthermore, response rate for the first- and second-line therapy for aGVHD was low in the RBM/RPB-mismatched (59.6%/61.6%) and UPB-mismatched subgroup (45.5%), respectively. The 3-year NRM in patients with aGVHD was high in the RPB and UPB mismatched subgroups (37.9% and 31.2%, respectively). Developing a novel treatment for steroid-refractory aGVHD is necessary to improve transplant outcomes, particularly for patients undergoing HLA-mismatched transplantation.

Clinical outcomes of patients receiving three versus four doses of methotrexate with concomitant antithymocyte globulin in match unrelated donor allogeneic stem cell transplant: A single-center experience.

Methotrexate (MTX) doses on days +1, +3, +6, and +11 after match unrelated donor allogeneic stem cell transplant (MUD HSCT) is a common graft-versus-host disease (GVHD) prophylaxis regimen. However, the overlapping toxicity of MTX with conditioning chemotherapy sometimes warrants the omission of the fourth dose of MTX. Prior single-institution studies showed conflicting results comparing the outcomes of patients who received three versus four doses of MTX, but to our knowledge, the effect of concomitant antithymocyte globulin (ATG) has not been reported. Charts of patients who underwent MUD HSCT between 2009 and 2023 were reviewed. Patients received rabbit ATG (Thymoglobulin), given at 0.5mg/kg on day -3, 2mg/kg on day -2, and 2.5mg/kg on day -1. MTX is given at 15mg/m2 on day +1 and 10mg/m2 on days +3, +6, and +11. Severe mucositis was the most common indication for day +11 MTX omission (82%). We identified 292 patients (116 in 3 dose cohort and 176 in 4 dose cohort). Median follow-up was 23 months (range 1-151). Patients in the 4 doses cohort were more frequently male (68% vs. 50%, p<0.01), received a reduced intensity conditioning regimen (38.0% vs. 22%, p<0.01), were older (median 58 vs. 54 years, p=0.02), and received a transplant in the earlier era (median HSCT year 2014 vs. 2018, p<0.01). A statistically significant difference was not evidenced between the cohorts for the following outcomes: acute GVHD (aGVHD) (HR 1.1, 95% CI 0.9-1.5), chronic GVHD (cGVHD) (HR 1.3, 95% CI 0.8-1.6), relapse-free survival (RFS) (HR 1.0, 95% CI 0.6-1.5), non-relapse mortality (NRM) (HR 1.4, 95% CI 0.9-2.2), and overall survival (OS) (HR 1.2, 95% CI 0.9-1.7). Both cohorts had similar median time to neutrophil engraftment at 14 days. When ATG is incorporated, omission of day +11 MTX does not significantly impact the rate of engraftment or cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS.

Graft-Versus-Host Disease (GvHD) and Steroid-Refractory GvHD after Allogeneic Hematopoietic Stem Cell Transplantation: A Large Real-World EBMT-Based Epidemiology and Treatment Pattern Study

Introduction: Graft-versus-host disease (GvHD) is a multi-systemic disorder affecting patients who undergo allogenic hematopoietic stem cell transplantation (allo-HSCT) and is associated with considerable morbidity and mortality both in its acute (a) and chronic (c) forms, particularly in patients with steroid-refractory (SR)-GvHD (Flinn AM and Gennery AR. Fac Rev 2023).Given the lack of real-life data on GvHD, this study was conducted using a large European database with the objective to provide evidence on the epidemiology and treatment patterns in patients with aGvHD, cGvHD, and SR-GvHD. Methods: This retrospective, observational cohort study was conducted between July 1, 2014 and December 31, 2020 in allo-HSCT patients registered to the European Society for Blood and Marrow Transplantation (EBMT) database. Male or female patients aged ≥12 years at index (≥18 years for SR-GvHD and ruxolitinib [RUX] cohorts) who had received ≥1 allo-HSCT during this study period (January 1, 2017 to July 1, 2019 for SR-GvHD and RUX cohorts) were included in the study population. The EBMT cohort included all allo-HSCT patients, irrespective of GvHD development post-transplant (Tx). The primary objective was to assess the cumulative incidence of aGvHD and cGvHD in patients from the EBMT cohort who met the inclusion criteria. Overall survival of patients up to 60 months was also assessed in the EBMT cohort. The SR-GvHD cohort comprised a sub-selection of GvHD patients (from selected EBMT centers) who were diagnosed with SR-aGvHD, SR-cGvHD, or both, some receiving RUX as treatment; from the SR-GvHD cohort, a sub-selection of patients who had been treated with RUX for aGvHD and/or cGvHD, irrespective of treatment line, were included in the RUX cohort. Results:In the EBMT database, 60,140 patients had received an allo-HSCT. Most patients (94.5%) underwent 1 allo-HSCT, the remaining had &amp;gt;1 procedure. The EBMT cohort included a higher proportion of male patients between 50 and 69 years (Table 1). The main indication for allo-HSCT was acute leukemia. At the time of Tx, most patients were in their early disease stage and had unrelated donors(Table 1). The cumulative incidence of aGvHD was 27.9% and 27.6%, 4 months after first and second Tx, respectively. The cumulative incidence of cGvHD was 37.4% and 29.7%, 60 months after first and second Tx, respectively. aGvHD was of grade 2-4 in 27.1% of patients, and the most affected organ was skin (33.6%, grade 2-4: 19.5%) followed by liver (4.0%, grade 2-4: 2.3%) and gut (4.6%, grade 2-4: 2.8%); however, organ involvement was not collected in many patients. The cGvHD was limited (13.6%), extensive (14.7%) or of unknown grade (3.1%). Graft failure occurred in 5.9% of patients. The overall survival of EBMT cohort patients at 60 months was 53.1% with a median follow-up time of 32.9 months. The most frequent cause of death was relapse/progression (30.6%) followed by infection (27.1%) and GvHD (19.1%). The EBMT registry contains more SR-GvHD patients but only for subset of 292 SR-GvHD patients, additional information was obtained, of which 37 (34.6%) patients were treated with RUX and 70 (65.4%) with other second-line (2L) treatment for SR-aGvHD. For SR-cGvHD, 59 (31.9%) received RUX and 126 (68.1%) other 2L treatment. Baseline characteristics were comparable between SR-GvHD and the EBMT cohort (Table 1). Within SR-GvHD treatment groups, overall, the baseline characteristics were comparable across RUX and other 2L, and consistent with the EBMT and SR-GvHD cohorts. Compared with other 2L treatment, a slightly higher proportion of RUX-treated patients were females in SR-aGvHD cohort and males in SR-cGvHD cohort. While the most common first-line treatment for aGvHD in both RUX and the other group was methylprednisolone, for SR-cGvHD, it was prednisone+cyclosporine in RUX and prednisone in the other group. Conclusion:This large retrospective real-world evidence study from the EBMT reports on patients with GvHD after allo-HSCT. The cumulative incidence of aGvHD at 4 months post-Tx and cGvHD at 60 months was similar after the first or the second Tx. Though this study provides valuable insights on the epidemiology and treatment patterns of SR-GvHD patients, interpretation of these data is limited due to the small sample size of RUX and other treatment groups compared with the EBMT cohort.

Haploidentical STEM-Cell Transplantation for Children with ACUTE Leukemia and NON-Malignant Disorders, Using ΑΒ + T Cell /CD19 + B-Cell Depletion, a Single Center Experience

Background: αβ+ T cells/CD19+ B cells depleted haploidentical Hematopoietic stem cell transplantation (αβ+ TCR/ CD19+ depleted haplo-HSCT) is increasingly used in children with acute leukemia (AL) and many non-malignant disorders (NMD) such as severe combined immune deficiency (SCID), inborn errors of immunity (IEI), bone marrow failure (BMF, acquired/congenital) and familial Hemophagocytic lymphohistiocytosis (HLH), in need of a transplant and not having a matched related donor. Within this heterogenous group of patients, it is important to try to define introductory requirements for successful outcomes, and to identify risk factors for transplant related complications. Methods: Data was collected retrospectively regarding children age &amp;lt;21 years with AL or NMD who underwent αβ+ TCR/ CD19+ depleted haplo-HSCT at Sheba Medical Center between the years 2012-2021. Results: Seventy-four children underwent αβ+ TCR/ CD19+ depleted haplo-HSCT, for AL and NMD. Acute Leukemia subgroup Thirty-eight children had AL of them 34 patients engrafted successfully. The median time for neutrophil and platelet engraftment was 10 (range 9-17) and 13 (range 10-22) days, respectively. We observed 5-years overall survival (OS) and event free survival of 51% and 42%, respectively for the whole cohort. There were no cases of grade 3-4 acute graft versus host disease and only two patients had chronic graft versus host disease. EFS was higher in patients with graft composition of γδ+ T cells greater than the median value (MV) of 9.5X10^6 cells/kg than in patients who recieved cell dose lower than MV (54% vs 26%, P=0.04). Non-malignant Disorders Thirty-six children had NMD. Twenty-six of them (72%) engrafted and ten did not (did not achieved neutrophil count above 500 cells/uL at day 30). Engraftment kinetics was similar to AL subgroup. Secondary rejection was observed in two patients. Conditioning regimen varied within this subgroup. For patients with BMF, busulfan or treosulfan/fludarabine was administrated. All patients with HLH conditioned with treosulfan/fludarabine/thiotepa regimen. Patients with SCID, either did not recieved conditioning or received fludarabine/thiotepa/melphalan or treosulfan/fludarabin conditioning. For patients with IEI the protocol was based on treosulfan/fludarabin/thiotepa. Full donor chimerism was observed at day 30 in all patients who engrafted. Five-year OS was 56% for the whole cohort. OS was higher for patients without active infection at the day of transplant compared to patients with active infection (91.7% vs 33%, respectively, p=6.4X10-4). Mortality was high with thirteen patients dying from infection and one from veno-occlusive disease. Cumulative incidence of aGVHD was 30% with the majority were no greater than grade 2 and for cGVHD was 19%. Conclusions: αβ+/CD19+ haploidentical Hematopoietic stem cell transplantation can offer long-term survival for children with acute leukemia and NMD. For children with AL, we observed a presumed protective role for higher content of γδ+ T cell in the graft which need to be evaluate prospectively in a larger cohort. There were no cases of severe GVHD and the rate of grade 1-2 GVHD was low. For children with NMD αβ+ TCR/CD19+ depleted haplo-HSCT is feasible and effective. Children with active infections at day 0 had poorer outcomes whereas children without an active infection had excellent outcomes. Thus, patients who have a clear indication for transplant should be evaluated for transplant as early as possible.

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

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

Clinical Outcomes of Patients Receiving 3 Versus 4 Doses of Methotrexate with Concomitant Anti-Thymocyte Globulin; A Single Center Experience

Background: Four doses of methotrexate (MTX) given on day +1, +3, +6, and +11 after allogeneic stem cell transplant (HSCT) is considered one of the most common graft-versus-host disease (GVHD) prophylaxis regimen. However, mucositis and occasionally transaminitis prohibit safe delivery of the fourth dose of MTX. Prior single institution studies showed conflicting results comparing the outcomes of patients who received 3 vs 4 doses of MTX but to our knowledge, the effect of concomitant anti-thymocyte globulin (ATG) use has not been reported. As both ATG and MTX synergistically prevent GVHD via suppressive effects on T-cells. Our institution uniquely incorporates ATG as part of the conditioning regimen for patients receiving HSCT from 10/10 loci match unrelated donors (MUD) and here we report the clinical outcomes between patients who received 3 versus (vs) 4 doses of MTX. Methods: We retrospectively reviewed the charts of patients who underwent HSCT from MUD between 2009 to 2023 at the University of Iowa Hospital and Clinics. We use rabbit ATG (Thymoglobulin R), given at 0.5 mg/kg on day -3, 2 mg/kg on day -2, and 2.5 mg/kg on day -1. MTX is given at 15 mg/m 2 on day +1 and 10 mg/m 2 on day +3, +6 and +11 per institutional protocol. Statistical Analysis: Time was calculated from transplant to recurrence or death for recurrence-free survival (RFS) and overall survival (OS), respectively. For acute and chronic GVHD (aGVHD and cGVHD), time was calculated from transplant to onset of acute and chronic GVHD. Relapse and death were considered as competing events. For non-relapse mortality (NRM), time was calculated from transplant to death; relapse was considered a competing event. Cox regression and Fine-Gray competing risk models were used to estimate the effect of patient, disease, and treatment characteristics on outcomes Results: We identified 296 patients with various indications of HSCT; the most common was acute myeloid leukemia (45.3%). There were 117 and 179 patients who received 3 doses and 4 doses of MTX respectively. Patients characteristics reported in table 1. Median follow-up was 21.9 months (range 0.6 to 150.8). Patients who received 4 doses of MTX were more frequently male (68.2% vs 49.6%, p&amp;lt;0.01), received a reduced intensity (compared to myeloablative) preparative regimen (38.0% vs 23.1%, p&amp;lt;0.01), were older (median 58 vs 54 years, p=0.01), and underwent transplant at an earlier year (median year of transplant 2014 vs 2018, p&amp;lt;0.01). Severe mucositis was the most common reason for omission of the 4 th dose of MTX. Maximum grade of aGVHD was similar between cohorts (p=0.83). A statistically significant difference was not evidenced between patients receiving 4 versus 3 doses of MTX for the following outcomes: aGVHD (HR 1.11, 95% CI 0.84-1.46), grade 3-4 aGVHD (HR 1.41, 95% CI 0.77-2.60), RFS (HR 1.01, 95% CI 0.66-1.56), NRM (HR 1.33, 95% CI 0.84-2.10) and OS (HR 1.21, 95% CI 0.87-1.69). While significant on univariate analysis, MTX dose was not significantly associated with extensive cGVHD (HR 1.44, 95% CI 0.92-2.26) after adjustment for transplant year. Additionally, the median time to neutrophil engraftment was 14 days in both cohorts. Conclusion: When ATG is used concomitantly, omission of the 4 th dose of MTX does not significantly impact the rate of neutrophil engraftment, cumulative incidence of aGVHD, cGVHD, RFS, NRM, and OS after HSCT from MUD. However, a small sample size and non-randomized nature of this study prompts further confirmation study from a large prospective multicenter randomized control trial.

Reaching the cyclosporine a level target slowly in four weeks correlates with better prognosis for Chinese patients after allogeneic haematopoietic cell transplantation

ABSTRACTObjectivesThis study investigated the impact of early cyclosporin A (CsA) initiation (day −5) on the risk of acute graft versus host disease (aGvHD) after allogeneic haematopoietic cell transplantation (allo-HSCT).MethodsSixty-seven leukaemia patients who underwent allo-HSCT were investigated. The correlation between the CsA level in the first four weeks and the following indices was examined: GvHD, cumulative incidence (CI) of GvHD, CI of relapse at month 18, and non-relapse mortality (NRM) at month 18.ResultsA significant association between aGvHD and CsA level in the fourth week after allo-HSCT was observed, with the incidence of aGvHD in the fourth week in the lower level group being higher than that in the higher level group (p = 0.044). The CI of aGvHD was 30.1% and 9.8% at day +90 and 42.3% and 17.1% at day +180 in the lower level and higher level groups, respectively.ConclusionFor Chinese patients, early introduction and reaching the target CsA concentration within four weeks after allo-HSCT have a positive effect on preventing GvHD, especially in the fourth week after HSCT. Compared to the Western population, the target CsA concentration is lower and the time required to reach the target (within 4 weeks) is longer in the Chinese population (274.75 ng/mL).

Safety and Efficacy of Extracorporeal Photopheresis for Acute and Chronic Graft-Versus-Host-Disease

Introduction Graft-versus-host disease(GVHD) is a severe complication of allogeneic hematopoietic cell transplantation(alloHCT), directly linked to increased morbidity and mortality. Despite novel biologic agents under study or commercial use in this field, corticosteroids and conventional intensified immunosuppressive therapy remain the cornerstone of treatment. Extracorporeal photopheresis (ECP) has been used as an alternative treatment. We studied the safety and efficacy of ECP in a large real-world cohort of GVHD patients. Methods We enrolled consecutive patients, of our JACIE-accredited center, that received ECP post alloHCT over the last 2 decades for cGVHD and over the last decade for steroid-dependent or refractory grade II-IV aGVHD. All patients with unrelated or haploidentical donors received thymoglobulin (ATG) 5mg/kg as prophylaxis. GVHD prophylaxis included cyclosporine-methotrexate in myeloablative and cyclosporine-MMF in reduced toxicity/intensity regimens. Before ruxolitinib or ibrutinib availability, MMF, cyclosporine or ATG were commenced as second line treatment in steroid-refractory patients, depending on previous prophylaxis. ECP was mostly administered as third line treatment for cGVHD and after assessment of response of 5 days of steroid treatment according to our protocol: 1 session/week for the 1 st month for cGVHD and 2sessions/week for aGVHD, 1 session/2 weeks for 3 months, evaluation of response and 1 session/month for 6 months. Before Ruxolitinib's availability, ATG was commenced simultaneously with ECP initiation in steroid-refractory aGVHD patients. Results We studied 112 patients with moderate or severe cGVHD. Only 13 received 4 or less ECP sessions because of severe GVHD-related morbidity and were excluded from further analysis. Median ECP sessions were 17(6-49). There were no ECP-related adverse events. 67 patients presented with cutaneous sclerosis manifestations, 73 mucocutaneous disease, 36 liver, 42 visceral and 27 lung involvement. ECP was commenced as second line in 35 patients. Ruxolitinib was administered in combination with ECP in 19 patients, while ibrutinib in 2. Bacterial infections were observed in 43 patients, viral in 38 and fungal in 11 patients. Only 19 patients did not show response. Significantly lower rates of response presented in patients with visceral involvement(p=0.037) and earlier post-transplant GVHD diagnosis (p=0.001). With a follow-up of 45.2 (5.6-345.1) months, 5-year CI of cGVHD-related mortality was 21.2% and was significantly reduced in patients with ECP response (p&amp;lt;0.001). 5-year OS was 65.3% and was independently associated with HLA matching (p=0.011), higher number of ECP sessions(p&amp;lt;0.001), later initiation of ECP (p=0.002), response to ECP (p=0.036) and no relapse(p=0.001). Regarding aGVHD, we studied 28 patients, aged 45 (18-67), with myeloablative (16), reduced toxicity (8) and intensity (4) conditioning, from sibling (4), matched (11) or one locus mismatched (12) volunteer unrelated and haploidentical (1) donors. Disease risk index was very high (1), high (11), intermediate (14) and low (2). aGVHD was observed at day +17(8-50). Skin, intestine and liver involvement was evident in 9 patients, skin and intestine in 13 and skin only in 6 patients. 13 patients were steroid-dependent and 15 steroid-refractory. ECP was commenced at day +18 (8-56) for 15 (4-20) sessions. The majority of patients (19/27) presented partial (7), very good (11) or complete (1) response. With 9.9 (1.7-113) months of follow-up, immunosuppression was reduced in 12/27 and ceased in 1 patient. Clinically significant bacterial infections were found in 19 patients, fungal in 3, CMV and EBV reactivation in 19 and 12 respectively and other viral in 6 patients. Cumulative incidence of aGVHD was 56.4 at 1-year.Five-year overall survival (OS) was 34%. Reduction of immunosuppression(p=0.026) and number of ECP sessions(p&amp;lt;0.001) were associated with improved OS, irrespectively of other factors. In particular, optimal OS was observed in patients that received more than 19 ECP sessions (Figure). Conclusion Our data confirm that ECP is safe and effective for GVHD. Even in the era of novel biologics, ECP should be considered early in the course of GVHD, before irreversible end organ damage has been established. Combination with other treatments and individualized treatment algorithms remain important unanswered questions.

Evaluation of the Use of Post-Transplant Cyclophosphamide in Patients Diagnosed of Myelodysplastic Syndrome Who Undergo Allogenic Hematopoietic Cell Transplantation

INTRODUCTION Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative strategy for patients with MDS. Although the outcomes of allo-HCT performed in MDS patients have improved, transplant toxicity remains a relevant limitation for determining this patient's eligibility and transplant success. The use of PTCY for GVHD prevention is becoming a common practice in the allo-HCT community. At our institution, as in many others, PTCY-based prophylaxis has been progressively used, irrespective of the selected donor type. PTCY effectively prevents the onset of GVHD. However, its use is also associated with increased infectious complications, delayed engraftment, and specific organ toxicities. Little is known, however, about the efficacy and safety of using PTCY in patients with MDS undergoing allo-HCT. This study reports the results of comparing the outcomes of PTCY-based versus (vs.) conventional prophylaxis in a cohort of MDS patients undergoing allo-HCT. METHODS This study includes the 69 patients with MDS who underwent their first allo-HCT at our institution in the years 2010 to 2022. Retrospective data were updated in June 2023. The study cohort was divided into two groups according to the GVHD prophylaxis used in the transplant platform (PTCY-based vs. other prophylaxis) in order to compare their respective outcomes. RESULTS The baseline characteristics of the study cohort according to the GVHD prophylaxis are shown in Table 1. Overall, the median age was 59, with 17 (24.6%) patients older than 65. According to the IPSS-R score, 11 (15.95%) patients were classified into the high-risk group, and 20 (29%) into the very-high-risk group. Fifteen (21.7%) adults underwent allo-HCT upfront, and 54 (78.3%) received prior treatment with either chemotherapy-based 7 (10.1%) or HMA-based regimens 49 (71%). Most of the baseline characteristics were balanced between the two study groups, except for the proportion of allo-HCT using 9/10 mismatched unrelated and haploidentical donors, which was higher in the PTCY group (50.0% vs. 10.3%, p&amp;lt;0.001). Post-transplant results are shown in Table 1. All patients engrafted. The medians of days to neutrophil (20 vs. 16, p&amp;lt;0.01) and platelet (15 vs. 12, p&amp;lt;0.01) engraftment were longer in patients who received PTCY. The use of PTCY resulted in similar rates of grades II-IV (Day +100 cumulative incidence (CI): 40.0% vs. 30.8%, p=0.56), in higher incidence of III-IV aGVHD (20.0% vs. 5.1%, p=0.052), and in lower rates of moderate/severe cGVHD (0% vs. 37.0%, p&amp;lt;0.001). Post-transplant outcomes were similar in patients who received PTCY and in those who did not. The 2-years OS, RFS, NRM, CIR and GRFS of patients who received PTCY were 44.2%, 42.7%, 35.5%, 21.8% and 40.4%; for those patients that did not receive these numbers were 64.1%, 61.5%, 15.4%, 23.1% and 30.8% ( Table 1). A multivariate analysis was performed to compare the effects of PTCY in post-transplant results (aGVHD CI, OS and NRM), controlling for covariates whose omission could bias the results of the univariate comparisons. As shown in Table 2 when controlled by donor type, patients who underwent allo-HCT with PTCY had comparable risk for presenting grades II-IV (HR 0.94, P=0.89) and III-IV aGVHD (HR 2.57, P=0.20) than patients without PTCY. The null hypothesis that patients with MDS and PTCY prophylaxis had similar transplant outcomes than those with conventional prophylaxis was not rejected: OS (HR 1.36, p=0.45), NRM (HR 2.28, p=0.21) and CIR (HR 0.39, p=0.27). The multivariate analysis also revealed that older patients (HR 1.11, p=0.01) and patients transplanted in a worse performance status (KPS&amp;lt;90) (HR 3.40, p=0.006) had worse OS secondary to higher risk for NRM. In addition, patients classified into the very-high-risk group (HR 10.88, p&amp;lt;0.001), and patients with a higher number of blasts prior to allo-HCT (HR 1.26, p=0.06) all had a higher risk for disease relapse. CONCLUSION The use of PTCY in adults undergoing allo-HCT for MDS resulted in comparable post-transplant outcomes than the use of more conventional prophylaxis but lowered the rates of moderate/severe cGHVD. Higher risk for NRM was documented in older adults and in patients with worse performance status. Furthermore, patients with a very-high-risk MDS, according to R-IPSS, were exposed to higher risk for relapse irrespective of the intensity of the conditioning regimen used as part of the transplant platform.

Efficacy and safety of allogeneic hematopoietic stem cell transplantation in the treatment of 28 patients with hepatitis-related aplastic anemia

Objective: To evaluate the efficacy and safety of HLA-haploidentical hematopoietic stem cell transplantation (allo-HSCT) for hepatitis-related aplastic anemia (HRAA) patients. Methods: Retrospective analysis was performed on hepatitis-associated aplastic anemia patients who received haplo-HSCT at our center between January 2012 and June 2022. October 30, 2022 was the final date of follow-up. Results: This study included 28 HRAA patients receiving allo-HSCT, including 18 males (64.3% ) and 10 females (35.7% ), with a median age of 25.5 (9-44) years. About 17 cases of severe aplastic anemia (SAA), 10 cases of very severe aplastic anemia (VSAA), and 1 case of transfusion-dependent aplastic anemia (TD-NSAA) were identified. Among 28 patients, 15 patients received haplo-HSCT, and 13 received MSD-HSCT. The 2-year overall survival (OS) rate, the 2-year failure-free survival (FFS) rate, the 2-year transplant-related mortality (TRM) rate, the 100-day grade Ⅱ-Ⅳ acute graft-versus-host disease (aGVHD) cumulative incidence rate, and the 2-year chronic graft-versus-host disease (cGVHD) cumulative incidence rate were 81.4%, 81.4% (95% CI 10.5% -20.6% ), 14.6% (95% CI 5.7% -34.3% ), 25.0% (95% CI 12.8% -45.4% ), and 4.2% (95% CI 0.6% -25.4% ), respectively. After transplantation, all patients had no significant liver function damage. Compared with the MSD-HSCT group, only the incidence of cytomegaloviremia was significantly higher in the haplo-HSCT group [60.0% (95% CI 35.2% -84.8% ) vs 7.7% (95% CI 0-22.2% ), P=0.004]. No statistically significant difference in the Epstein-Barr virus was found in the 2-year OS, 2-year FFS, 2-year TRM, and 100-day grade Ⅱ-Ⅳ aGVHD cumulative incidence rates and 2-year cGVHD cumulative incidence rate. Conclusion: Allo-HSCT is safe and effective for HRAA, and haplo-HSCT can be used as a safe and effective alternative for newly diagnosed HRAA patients who cannot obtain HLA-matched sibling donors.

Effect and safety of 10-day decitabine-containing conditioning regimen for allogeneic hematopoietic stem cell transplantation in 31 patients with acute myeloid leukemia/myelodysplastic syndrome

Objective: To investigate the early effect and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a 10-day decitabine-containing conditioning regimen in the treatment of acute myeloid leukemia (AML) /myelodysplastic syndrome (MDS) . Methods: From April 2021 to May 2022, 31 AML/MDS patients who received allo-HSCT with a 10-day decitabine-containing conditioning regimen were analyzed. Results: AML (n=10), MDS-AML (n=6), CMML-AML (n=1), and MDS (n=14) were identified in 31 patients, 16 males, and 15 females, with a median age of 41 (20-55) yr. Neutrophils and platelets were successfully implanted in 31 patients (100%), with a median implantation duration of 12 (9-30) and 14 (9-42) days, respectively. During the preconditioning period, 16 patients (51.6%) developed oral mucositis, with 15 cases of Ⅰ/Ⅱ grade (48.4%) and one case of Ⅲ grade (3.2%). After transplantation, 13 patients (41.9%) developed CMV viremia, six patients (19.4%) developed hemorrhagic cystitis, and four patients (12.9%) developed a local infection. The median time of acute graft versus host disease (aGVHD) following transplantation was 33 (12-111) days. The cumulative incidence of aGVHD and Ⅲ/Ⅳ grade aGVHD was 41.9% (95% CI 26.9%-61.0%) and 22.9% (95% CI 13.5%-47.5%), respectively. There was no severe cGVHD, and mild and moderate chronic GVHD (cGVHD) incidence was 23.5% (95% CI 12.1%-43.6%). As of November 30, 2022, only one of the 31 patients had relapsed, with a 1-yr cumulative relapse rate (CIR) of 3.2% (95% CI 0.5%-20.7%). There was only one relapse patient death and no non-relapse deaths. The 1-yr overall survival (OS) and disease-free survival (DFS) rates were 92.9% (95% CI 80.3%-100%) and 96.8% (95% CI 90.8%-100%), respectively. Conclusions: A 10-day decitabine-containing conditioning regimen for allo-HSCT reduced relapse and was safe and feasible in treating AML/MDS.

Circulating extracellular vesicles as a predictive biomarker for acute graft-versus-host disease

The diagnosis and management of graft-versus-host disease (GVHD) have remained important challenges in allogeneic stem cell transplantation (allo-SCT). Novel diagnostic methods and therapeutic interventions are needed to further improve on patient outcomes. Extracellular vesicles (EV) are microvesicles formed by the inversion of the phospholipid bilayer of different cellular subtypes and have been described as biomarkers of cellular damage, activation, and intercellular signaling in numerous clinical scenarios. We studied the association between the levels of EV and the incidence of acute GVHD (aGVHD). Forty patients undergoing allo-SCT for hematological malignancies had their plasma collected at neutrophil engraftment. Using flow cytometry combined with fluorescent beads, the total circulating EV count (TEV) was established with annexin V positivity; CD61 positivity was used for platelet-derived EV (PEV), and CD235 positivity, for erythrocyte-derived EV (EryEV). TEV counts greater than 516/μL were associated with a higher cumulative incidence (CI) of grade II to IV aGVHD (54% vs. 21%; p=0.02), as were EryEV counts above 357 /μL (CI of aGVHD: 59% vs. 26%; p=0.04). In patients who are exposed to reduced intensity conditioning (RIC), stronger associations of both high TEV and EryEV counts with aGVHD were observed (77% vs. 22%; p=0.003 and 89% vs. 27%; p=0.002, respectively). PEV levels were not associated with the risk of aGVHD. Our data suggest that the measurement of cell-derived EV at engraftment can be used as a preemptive biomarker for acute GVHD.

Early Use of Antibiotics and Unfavorable Results after Allogeneic Hematopoietic Stem Cell Transplantation, a Competing Risk Analysis in a Cohort of 274 Patients

The use of empiric broad-spectrum antibiotics for the treatment of febrile episodes during the first weeks of allogeneic transplant has been associated with an increase in the incidence of acute Graft versus Host Disease (aGVHD) and transplant-related mortality (TRM). However, there are several confounding factors; age, donor source, conditioning, GVHD prophylaxis, disease index risk, comorbidities, and the time of initiation of antibiotics that can preclude strong conclusion regarding the importance of this association. We present the outcomes of a cohort of 274 patients whose received or not antibiotics in the early phase of transplant after adjustment for confounding factors and competing risks Methods and patients. Retrospective cohort study from a single cancer center. All consecutive patients older than 15 years and transplanted with bone marrow or peripheral stem cell, from Jan 2003 to Dec 2019, were included. The cohort who was exposed was composed of the patients that received IV antibiotics between day - 7 and + 7 and it was compared with the group that did not. TRM was defined as death due to any transplantation-related cause other than disease relapse from day 0 until + 365, aGVHD was diagnosed and classified according to MAGIC criteria and it was measured until d + 100. For statistical porpoises univariable and multivariate survival analyses were conducted, and Fine-Gray models were fitted to account for competing risks, also, an exploratory subgroups analysis was conducted according to the type of antibiotic received. The study was approved by Institutional Ethic Committee Results. The main characteristics of the patients are summarized in table 1. Briefly: the whole group consisted of 274 patients; median age 36.6 years, 244 had malignancies, 185 acute leukemia. The disease index risk was intermediate or higher in 250, 109 underwent to haplo transplant, and 150 received cyclophosphamide pos transplantation. 154 (56%) received early antibiotic and 119 (44%) did not. The median follow-up for the entire group was 560 days, the cumulative incidence (CI) of TRM at 1 year was 21% in the exposed group vs. 9% in the non-exposed p: 0.007. Without adjustment, early use of antibiotics was associated with a significant increase in the TRM risk (sHR 2.49, 95%CI: 1.26-4.9; p=0.008), and after adjustment, it continued to be an independent risk factor for TRM (sHR 2.48, 95%CI: 1.25-4.90; p=0.009) (table 2). The CI of aGVHD was 24% in the exposed patients vs.15% in the other group; p=0.049). Without adjusting, the early use of antibiotics was associated with an increase in the risk (sHR 1.74, 95%CI: 1.00-3.03; p=0.05), however, after adjusting in multivariate analysis, this effect did not persist (sHR 1.49, 95%CI: 0.818-2.73; p=0.19). Regarding the antibiotic administered it was meropenem in 60% of the cases, cefepime in 30%, and vancomycin was added in 18%. When comparing each antibiotic with the non-early use of them, both, cefepime and meropenem were associated with increased risk of TRM (p=0.008 and p=0.003, respectively) while no differences were found between the use of vancomycin and the non-use of antibiotics (p:0.615) Conclusion. This study shows that, after adjusting for several confounding factors and competing risk, the early use of antibiotics during allogeneic transplant increases the risk of TRM. This result is in concordance with those obtained by other groups which studied the effect of them in late periods of the transplant. However, our finding, in terms of aGVHD, is different from those which have been published, this is difficult to explain, and it is hypothesis generating; we can speculate that the use of post-transplant cyclophosphamide in an important part of our cohort, including sibling donors, and the low incidence of this complication in the whole cohort can be part of the explanation. Understanding whether GVHD is a mediator between antibiotic use and mortality requires further investigation. For a while, the results of this and other studies demand to be cautious with the use of empiric antibiotics during the early period of the allogeneic transplantation Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Microbial Bile Acid Metabolism Shapes Effector T Cell Responses during Inflammation in Mouse and Human

Microbial transformation of bile acids (BAs) regulates intestinal immune homeostasis but their effect on T cell-driven pathologies is unknown. We previously reported that gut dysbiosis in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT) is associated with increased graft-versus-host disease (GVHD), in which graft-derived T cells recognize the host as foreign. We hypothesized that the dramatic changes in intestinal microbiome composition during GVHD would lead to changes in the BA pool, which would alter immunoregulatory mechanisms governing T cell responses. Using a preclinical MHC-disparate GVHD model (B6 into BALB/c) and quantifying BAs with liquid chromatography-mass spectrometry, we found that GVHD was associated with a significant decrease in total BA concentration with a preferential loss of microbiota-dependent unconjugated primary BA (PBAs) and secondary BA (SBAs) (p=0.0002 and p<0.001, n=10/group). Metagenomic sequencing revealed changes in microbiota composition, including reduced abundance of Lactobacillus johnsonii and expansion of Enterococcus faecalis in GVHD mice (FDR=0.03, n=5/group) as previously reported. These changes were accompanied by a reduction in the abundance of bile salt hydrolase (BSH) genes (p=0.008) encoded by the gut microbiome (mainly Lactobacillus johnsonii). BSH catalyzes the deconjugation of PBAs, which is the gateway reaction leading to SBAs formation, suggesting that GVHD affects the BA pool by compromising early steps in microbial BA metabolism. To investigate the effects of GVHD on host metabolism, we profiled the liver transcriptome by bulk RNA-sequencing analysis. Pathways involved in BA metabolism were reduced in the livers of GVHD mice, which was associated with reduced levels of transcripts for genes involved in BA synthesis (Abcd3, Hsd17b11, Cyp7b1, Hsd17b6) and secretion (Abcg8, Slc22a18). As BAs regulate their synthesis via farnesoid X receptor (FXR) in a negative feedback loop, these results suggested that FXR activation may be increased because of loss of SBAs. Indeed, SBAs counteracted the activation of FXR by the natural agonist chenodeoxycholic acid, in FXR reporter assay and FXR TR-FRET coactivator assay, suggesting that bacterial transformation of BAs generally decreases FXR activity in vivo. Pharmacological activation of FXR (B6 into BALB/c, treatment with selective FXR agonist GW4064 day -1 to day 7, p<0.0001, n=20/group) showed increased mortality, whereas genetic ablation of FXR in donor T cells decreased GVHD and improved OS in two preclinical models (B6 into BALB/c, p<0.0001, n=30/group, Fig. 1a and B6 into 129, p<0.0001, n=20/group). Mice transplanted with TΔFXRcells had reduced GVHD-related pathology compared to recipients of TWT on day 28 post allo-HCT (p=0.006, n=10/group). Furthermore, we found reduced IFNγ production by CD4+ and CD8+ TΔFXR cells in the lamina propria of the large intestine on day 14 post-transplant (p=0.01 and p=0.02, n=10/group). Finally, we set out to corroborate our preclinical findings in allo-HCT patients. We compared 63 fecal samples from allo-HCT patients with lower gastrointestinal GVHD obtained at peri-GVHD onset (+/- 10 days) with 61 samples from control allo-HCT patients without GVHD, who were matched for age, graft type and HLA compatibility. Samples from controls were selected +/-10 days from pseudo-GVHD day that was assigned based on their paired GVHD patient. Most of the samples were exposed to the SBA ursodeoxycholic acid (UDCA, 93%). Similar to our findings in mice, we found that SBAs (non-UDCA, Fig. 1b) and unconjugated PBAs, as well as BSH abundances were decreased in GVHD patients compared to controls (p=0.007, p=0.008, and p=0.02 respectively). Notably, we found that important immunomodulatory SBAs were reduced in GVHD patients compared to controls, including 3-oxolithocholic acid, isolithocholic acid and ω-muricholic acid (p=0.01, p=0.004, and p<0.001). Lastly, in 747 allo-HCT recipients, we found that UDCA exposure was associated with a lower incidence of Enterococcus sp. domination (p=0.001), lower aGVHD cumulative incidence (p=0.005) and improved OS (p=0.017) as previously reported. Our results in mice and humans suggest that loss of SBA and increased FXR activation may amplify T-cell driven disease such as GVHD and provide a rationale to target the host-microbiota BA network to improve clinical outcomes in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Donor lymphocyte infusions after haploidentical stem cell transplantation with PTCY: A study on behalf of the EBMT cellular therapy & immunobiology working party.

Donor lymphocyte infusion (DLI) is a treatment option to prevent or treat relapse after allogeneic hematopoietic cell transplantation (HCT). We here report data for 173 patients who received one or multiple DLIs after haploidentical-HCT with post-transplant cyclophosphamide (PTCY) at 47 EBMT centers from 2009 to 2018. Indication for DLI was: prophylactic for 59 (34.3%), preemptive for 20(11.6%), and therapeutic for 93(54.1%). For the prophylactic group, the median number of DLIs was 1 (IQR:1-2.5) with a median first dose of 0.1 × 106 CD3+ T cell/kg, for the preemptive 2 (IQR:1-3) with 0.5 × 106 CD3+ T cell/kg, for the therapeutic 1 (IQR:1-3) with 1 × 106CD3+ Tcell/kg, respectively. OS after first DLI was 61% (46-75%) for prophylactic, 40% (19-61%) for preemptive, and 22% (13-31%) for therapeutic. CI of II-IV aGVHD and cGVHD was 17% (7-27%) and 53% (40-67%) for the prophylactic, 20% (2-38%) and 21% (3-39%) for the preemptive, 17% (9-24%) and 24% (15-33%) for the therapeutic group, respectively. Our data show great variability in the indications and modalities of DLI across responding EBMT centers. Survival rates remain relatively low in patients with active disease. While the cumulative incidence of aGVHD appears acceptable, we showed a high incidence of cGVHD in the prophylactic group, compared with preemptive and therapeutic DLI. These data should be investigated further in prospective clinical trials.

CT-275 Incidence and Characteristics of Chronic GVHD in Haploidentical Stem-Cell Transplantation With Post-Transplantation Cyclophosfamide: Experience of the Spanish Group of Hematopoietic Transplantation and Cell Therapy (GETH-TC)

Chronic graft-versus-host-disease (cGVHD) is a relevant cause of late morbidity and mortality related to allogenic-stem-cell transplantation in long-term survivors. GVHD prophylaxis using post-transplantation cyclophosphamide (PTCy) has improved haploidentical stem-cell transplantation (haplo-HSCT) outcomes; however, data related to characteristics, risk factors, or cGVHD outcomes are limited. In this study, we analyze the incidence, risk factors and disability related to cGVHD in patients undergoing haplo-HSCT PTCy. Retrospective multicenter analysis of 389 consecutive patients that underwent haplo-HSCT-PTCy at 7 Spanish transplant centers from 2007 to 2020. cGVHD diagnosis was made following the NIH criteria and Disability related to cGVHD was defined as Fatobene et al criteria. Median age was 48 years (5-74), and 62% were males. AML and HL were the most common indications for transplantation (37%, 22%). 36% received a previous transplant. The median follow-up was 35 months (3-102). Cumulative incidence of aGVHD and aGVHD III-IV at day +180 was 66% and 20%. The 2-year OS was 59%, 2-year PFS 54%, 2 year-GRFS was 45%. 95 patients developed cGVHD, cumulative incidence of cGVHD and cGVHD moderate-severe was 34% and 10% at 3 years. 42 patients required systemic treatment. In the univariate analysis of risk factors for cGVHD in patients alive on day +100, female donor (p=0.034), female donor and male recipient (p=0.041), DRI low (p=0.026), myeloablative conditioning (p=0-047), previous aGVHD (p=0.014), and the use of radiotherapy in conditioning (p=0.004) were identified. Busulfan conditioning was identified as a protective factor (p=0.036). In multivariate analysis, the presence of previous GVHD (p=0.031) and the protective power of conditioning with busulfan (p=0.036) remains statistically significant. cGVHD according to NIH at 3 years, moderate cGVHD showed a higher OS (p=0.054), higher PFS (p=0.004) and lower relapse than the rest of the groups (p=0.035). Receiving one line of treatment (p=0.043) and use of bone marrow were the only risk factors identified for these patients. Haplo-HPT with Cy-post shows a low, but not negligible incidence of cGVHD, and its use represents an alternative for some patients. The development of moderate cGVHD is a protective factor in this transplant modality. The characterization of predictive factors of this subgroup is relevant given the results.

The impact of Rituximab administered before transplantation in patients undergoing allogeneic hematopoietic stem cell transplantation: A real-world study.

Rituximab is used to eliminate B cells as a chimeric monoclonal antibody directed against CD20, a B-cell antigen expressed on B cells. To explore the impact of rituximab administered before transplantation, we implemented a retrospective, monocentric study and utilized real-world data collected at our center between January 2018 and December 2020, and then followed until December 2021. Based on whether a dose of 375mg/m2 rituximab was used at least once within two weeks before transplantation, patients undergoing allo-HSCT were classified into two groups: rituximab (N=176) and non-rituximab (N=344) group. Amongst all the patients, the application of rituximab decreased EBV reactivation (P<0.01) and rituximab was an independent factor in the prevention of EBV reactivation by both univariate and multivariate analyses (HR 0.56, 95%CI 0.33-0.97, P=0.04). In AML patients, there were significant differences in the cumulative incidence of aGVHD between the two groups (P=0.04). Our data showed that rituximab was association with a decreased incidence of aGVHD in AML patients according to both univariate and multivariate analyses. There was no difference between the two groups in other sets of populations. Thus, our study indicated that rituximab administered before transplantation may help prevent EBV reactivation in all allo-HSCT patients, as well as prevent aGVHD in AML patients after allo-HSCT.

S241: NON-RESTRICTIVE DIET DOES NOT INCREASE GASTROINTESTINAL INFECTIONS AND FEBRILE NEUTROPENIA IN PATIENTS WITH NEUTROPENIA AFTER STEM CELL TRANSPLANTATION: DATA FROM A MULTICENTRE, RANDOMIZED TRIAL

Background: Infections represent a major cause of morbidity and mortality during neutropenia, especially after hematopoietic stem cell transplantation (HSCT). Multiple preventive measures, including low microbial diet, have been adopted to reduce these complications. However, the effect of a protective diet (PD) in this setting has never been explored prospectively and evidence-based results lack. Conversely, there is evidence that PD could negatively affect the quality of life and that a prolonged fasting duration can increase the incidence of acute gastrointestinal graft-versus-host disease (aGVHD) in allo-HSCT recipients. Aims: To prospectively compare infection and aGVHD rates in patients receiving a non-restrictive diet (NRD) compared to PD after HSCT. Methods: Since July 2016 we conducted a multicentre randomized interventional study comparing the use of a PD (Arm A) vs NRD (Arm B) in hematological patients aged≥18 years hospitalized to receive autologous or allogenic HSCT. Stratification for allo-HSCT patients was planned. Patients received the assigned diet during the entire period of neutropenia. For PD, foods cooked >80°C and/or thick peel fruit were considered diet-specific. For the NRD, raw fruit and vegetables (adherent to hospital hygiene standards) were considered diet-specific. The primary objective was to demonstrate the lack of significant differences in incidence of infections grade >2 (according to CTCAE 4.0) and deaths during neutropenia between the two arms. Secondary endpoints included assessment of gastrointestinal infections and fever of undetermined origin (FUO), change in body weight, length of hospitalization, overall survival estimated at 30 days and cumulative incidence of aGVHD within 100 days after allo-HSCT. Results: Overall, 162 patients were analyzed at interim analysis, 80 patients in PD group and 82 in NRD group. The two arms were well balanced in terms of: sex, age, disease type, number of previous therapeutic lines, disease status at enrollment, antimicrobial prophylaxis, and reason for hospital admission. Moreover, 32 patients received an allo-HSCT, 17 in the PD and 15 in the NRD group respectively. Detailed patients’ characteristics are summarized in Table 1. We did not observe a significant difference in terms of infections in the two randomized arms; infections grade >2 or death were reported in 35 (43.7%) patients in arm A and in 34 (41.5%) patients in arm B [relative risk RR=1.05, confidence interval (CI)95%=0.76-1.4]. The number of patients developing gastrointestinal infections and FUO during hospitalization was 8 (10%) vs 8 (9.8%) [RR=1.01, CI95%=0.57-1.53] and 32 (40%) vs 28 (34.1%) [RR=1.13, CI95%=0.82-1.54] in arm A and arm B, respectively. No differences in weight variations from admission to discharge were observed comparing arm A and arm B (mean 4.15kg vs 3.66kg, p=0.3). Average hospitalization length in the two arms was respectively 20.6 vs 21.5 days (p=0.4). No deaths were reported at day+30. For 32 allo-HSCT recipients, aGVHD grade ≥2 incidence at day +100 was 5% vs 1.2% in arm A and arm B, respectively (RR 1.65, CI95%=0.77-2.19). Image:Summary/Conclusion: Results of this multicentre prospective trial show similar rate of infections and deaths between patients receiving a PD versus a NRD during neutropenia after HSCT. These data suggest that the use of NRD could be considered for transplanted patients without risks of more infective events.

Haploidentical Stem Cell Transplantation After TCR-αβ+ and CD19+ Cells Depletion In Children With Congenital Non-Malignant Disease

Haploidentical hematopoietic stem cell transplantation (haplo-HSCT) represents a valuable alternative for children with nonmalignant disease and ex vivo negative selection of TCR-αβ+ cells is an emerging graft manipulation option that carries several potential advantages in terms of reduced risk of graft-versus-host disease (GvHD) and improved immune reconstitution. We report all consecutive patients with a diagnosis of nonmalignant disease who received a TCR-αβ+ and CD19+depleted haplo-HSCT at "IRCCS Istituto Giannina Gaslini" from 2013 to 2019; the conditioning regimen was myeloablative or non-myeloablative, depending on underlying disease; all patients received antithymocyte globulin and rituximab. No post-transplantation GvHD prophylaxis was given in presence of a TCR-αβ+ cell dose in the graft lower than the threshold of 1×105/kg of the recipient's weight. Among 20 HSCTs, engraftment occurred in 17 (85%) after a median of 14 and 12 days from graft infusion for neutrophils and platelets, respectively. Primary graft failure was diagnosed in 3 (15%) patients, and 2 (10%) experienced secondary rejection; all of these patients underwent a second HSCT. The cumulative incidence of a-GvHD and c-GvHD was 15% (2=grade 1, 1=grade 4) at 90 days and 5% (1=grade 1) at 7 months, respectively. Cytomegalovirus reactivation requiring pre-emptive treatment was observed in 9 patients (45%). One patient developed a JC virus-related progressive multifocal leukoencephalopathy, successfully managed with donor-derived virus-specific T-cell infusions. A complete immunological recovery was reached in most patients within 6 months. After a median follow-up of 4 years, 18 patients are alive, with a cumulative survival probability of 90%. Haplo-HSCT after ex vivo TCR-αβ+/CD19+ negative selection may be considered a good option for children with nonmalignant diseases because it ensures a high engraftment rate with an acceptable risk of graft failure, very low incidence of significant GvHD, and good immune reconstitution with low frequency of severe virus-related disease. However, the control of viral infection/reactivation should be kept high to promptly provide pre-emptive treatments and approaches of antiviral adoptive immunotherapy.