Cumulative Incidence Of cGVHD Research Articles

Retrospective analysis of the incidence and outcome of late acute and chronic graft-versus-host disease-an analysis from transplant centers across Europe.

Chronic graft-versus-host disease (cGvHD) is a serious late complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT). This multicenter analysis determined the cumulative incidence (CI) of cGvHD and late acute GvHD (laGvHD) and its impact on transplantation-related mortality (TRM), relapse (R), and overall survival (OS) in 317 patients [296 adults, 21 pediatrics (<12 years of age)] who underwent their first allo-HSCT in 2017. The CI of laGvHD was 10.5% in adults and 4.8% in pediatrics, and the CI of cGvHD was 43.0% in all adult transplant patients and 50.2% in the adult at-risk cohort at the study end. The onset of cGvHD was de novo in 42.0% of patients, quiescent in 52.1%, and progressive in 5.9%. In adults, prophylactic use of antithymocyte globulin or posttransplant cyclophosphamide was associated with a significantly lower incidence of cGvHD (28.7%) vs. standard prophylaxis with calcineurin inhibitors (30.6%) and methotrexate/mycophenolate mofetil (58.4%) (all p < 0.01). TRM was significantly higher in patients with aGvHD (31.8%) vs. cGvHD (12.6%) and no GvHD (6.3%) (all p = 0.0001). OS in the adult at-risk cohort was significantly higher in patients with cGvHD (78.9%) vs. without (66.2%; p = 0.0022; HR 0.48) due to a significantly lower relapse rate (cGvHD: 14.5%; without cGvHD: 27.2%; p = 0.00016, HR 0.41). OS was also significantly higher in patients with mild (80.0%) and moderate (79.2%) cGvHD vs. without cGvHD (66.2%), excluding severe cGvHD (72.7%) (all p = 0.0214). The negative impact of severe cGvHD on OS suggests a focus on prevention of severe forms is warranted to improve survival and quality of life.

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.

Allogenic Stem Cell Transplant in Myelofibrosis: Comparison of Two Tapering Strategies of Immunosuppressive Agents

Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) which can be primary or secondary to Essential Thrombocytopenia (ET) or Polycythemia Vera (PV). Despite all the therapeutic advances in this field over the last decade, allogeneic stem cell transplant (aHSCT) is the only available curative modality. According to literature, the main cause of mortality in the MF patients undergoing aHSCT is relapse (41-61%) and there is currently no standardized strategy to prevent relapse. Studies showed that the presence of GVHD was associated with a lower incidence of relapse. A quicker tapering of immunosuppressive drugs (IS) has been shown to increase the rate of GVHD and in some studies improve patients' outcome in adverse AML. At our center, starting in January 2017 we applied for all patients transplanted for MF a quicker tapering of IS, with all IS being weaned at 3 months instead of 6 months. We report here the outcome of MF patients transplanted with a reduced exposure to IS. Methods This is a retrospective, single center study. All patients transplanted for myelofibrosis between 2010 and 2022 at the university hospital of Nice were included. The indications for allogeneic stem cell transplant were based on the consensus of the EBMT/ELN international working group. We calculated the DIPSS plus score, MTSS score and the MIPSS70 plus score for all patients. In our institution, patients treated before 2017 had a longer immunosuppressive therapy with a duration of IS treatment of 6 months. Since 2017, the immunosuppressants were reduced from Day 60 post allo-HSCT to be weaned at day 100. The statistical study was carried out with SPSS software, Overall and relapse free survival were estimated according to Kaplan Meier and compared according to log rank. Results Forty-one patients have been transplanted and were included. Median age was 60.3 years (42-70). Thirteen are female and 28 are male. Twenty patients (48.8%) had primary MF according to the WHO classification and 21(51.2%) had a transformed MF from another MPN of which: 15 secondary to essential thrombocytopenia, 4 to polycythemia vera and 2 to a MPN not otherwise specified. Twenty-one patients were treated in the 6-month group and 20 patients in the 3-month group. There was no significant difference in terms of cumulative incidence of acute GVHD (p=0.902). Cumulative incidence of cGVHD was significantly higher in the 3-month group (P&amp;lt;0.001) (figure 1). Death has occurred in 15 cases (36.6%) with 10 cases (47.6%) in the 6-month group and 5 cases (25%) in the 3-month group. NRM was not significatively different between the two groups (0.998). 5-year GRFS 41.4% in the 6-month group and 54.1% in the 3-month group (p=0.513). Median follow up was 83.5 months. 5-year OS was 59.5% and 5-year RFS was 60.3%. The presence of chronic GVHD significantly improved OS in our study with a 2-y and a 5-y OS of 83.9% and 77.4% versus 52.9% and 35.3%(p=0.002) (Figure 2). The only score that predicted survival was the MTSS score (P=0.012). Conclusion In this series we found that a shorter course of immunosuppressive treatments resulted in a significantly higher incidence of cGVHD but not of aGVHD. In the entire cohort cGVHD was significantly associated with a better OS. The smaller size of our cohort makes it harder to identify an impact of the 3 months tapering strategy on OS. A larger study is necessary to confirm the impact of a quicker tapering of IS on patients' survival.

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.

Graft Versus Host Disease Prophylaxis with Tacrolimus, Sirolimus and MMF in Patients Undergoing Reduced Intensity Conditioning Allogeneic Transplantation

I ntroduction GvHD remains the leading cause of toxic morbidity and mortality (NRM) after allo-HSCT. Different prophylaxis schemes have been developed in the context of reduced intensity conditioning (RIC). In 2019, the multicenter phase 3 trial NCT01231412 compared GvHD prophylaxis based on the calcineurin inhibitor (CNI) CSA plus MMF with (experimental arm) or without (control arm) sirolimus. The triple combination was associated with a lower risk of aGvHD and longer survival and, in the authors' opinion, could constitute a new standard (Sandmaier, Lancet Oncol 2019). We present the largest real-world experience to date with the triple prophylaxis scheme in the context of allo-HSCT with RIC from matched-related (MRD), matched-unrelated (MUD) and mismatched URD (mmURD). Material and Methods Prospective study of 159 consecutive patients receiving an allo-HSCT after RIC between 09/2019 and 12/2022 at two centers using the tacro/siro/MMF as GvHD prophylaxis. The primary endpoint was the cumulative incidence of aGvHD grades 2-4. As secondary variables: cGvHD at 1 and 3 years, NRM at +100, +1 year and overall NRM, OS at 1 and 3 years, PFS at 1 and 3 years and GRFS at 1 and 3 years. Results Baseline characteristics are shown in Table 1. Note the high percentage of patients with high/very high rDRI or HCT-CI of 3+. In 38.4% an URD was used as source of progenitor cells and in 20.8% it was a MMURD. The median follow-up was 20 months (3-40). There were 4 (2.5%) graft failures (2 of them secondary). Median neutrophil and platelet engraftment was 16 days (3-175) and 12 days (7-210). The risk of relapse was 31% and 35% at 1 and 3 years. NRM at day +100, + 1 year and overall NRM was 4.4%, 8.17% and 9.4%. The causes of NRM were GvHD +/- infection in 73%, with other causes being TMA (n=1) and SOS (n=1). The cumulative incidence (CI) of grades 2-4 aGvHD 2-4 at day +100 and +180 was 29.7% and 32.3%, including 40% of upper gastrointestinal tract involvement which resolved with topical treatment. The CI of grades 3-4 aGvHD at day +100 and +180 was 12.8% and 16% (3.14% grade 4). The CI of cGvHD at 1 and 3 years was 21.5% and 51.2% and for moderate/severe it was 13.9% and 36.6%. OS at 1 and 3 years was 70.3% and 61%. Median PFS was 35 months, with 1- and 3-year PFS of 60% and 49%. The GRFS at 1 and 3 years was 44% and 32%. The risk of grades 2-4 aGvHD was significantly higher among patients receiving allo-HSCT from MMURD (at d+100 and +180, 35.4% and 39.9%) vs matched donors (at d+100 and +180, 55.5% and 61%, p=0.04). The same variable also influenced on OS (at 1 and 3 years 73.3% vs 64.6% and 57.6% vs 37.8% for matched vs mismatched donors, respectively; p=0.013) (Figure 1). On the other hand, low and intermediate DRI patients had a significantly better OS as compared to high/very high rDRI patients (at 1 and 3 years 80.8% and 80.8% for low vs 86.7% and 78.3% for intermediate vs 56.9% and 55.1% for high and very high; p=0.013) (Figure 1). Conclusions Triple prophylaxis with Tacro-Siro-MMF shows excelent results in terms of NRM, GvHD and survival in a high-risk and elderly population in the context of allo-HSCT from matched-related (MRD) and matched-unrelated (MUD) donors. The subgroup of patients receiving allo-HSCT from MMURD showed a high incidence of overall and grade 3-4 aGvHD with impact on OS, being a group that will probably benefit from other prophylaxis strategies.

Pilot Study of Donor-Engrafted Clonal Hematopoiesis Evolution and Clinical Outcomes in Allogeneic Hematopoietic Cell Transplantation Recipients Using a National Registry

Improved treatment options, such as reduced-intensity conditioning (RIC), enable older patients to receive potentially curative allogeneic hematopoietic cell transplantation (HCT). This progress has led to increased use of older HLA-matched sibling donors. An unintended potential risk associated with older donors is transplantation of donor cells with clonal hematopoiesis (CH) into patients. We aimed to determine the prevalence of CH in older HLA-matched sibling donors pretransplantation and to assess the clinical impact of donor-engrafted CH on HCT outcomes. This was an observational study using donor peripheral blood samples from the Center for International Blood and Marrow Transplant Research repository, linked with corresponding recipient outcomes. To explore engraftment efficiency and evolution of CH mutations following HCT, recipient follow-up samples available through the Bone Marrow Transplant Clinical Trials Network (Protocol 1202) were included. Older donors and patients (both ≥55 years) receiving first RIC HCT for myeloid malignancies were eligible. DNA from archived donor blood samples was used for targeted deep sequencing to identify CH. The associations between donor CH status and recipient outcomes, including acute graft-versus-host disease (aGVHD), chronic GVHD (cGVHD), overall survival, relapse, nonrelapse mortality, disease-free survival, composite GVHD-free and relapse-free survival, and cGVHD-free and relapse-free survival, were analyzed. A total of 299 donors were successfully sequenced to detect CH. At a variant allele frequency (VAF) ≥2%, there were 44 CH mutations in 13.7% (41 of 299) of HLA-matched sibling donors. CH mostly involved DNMT3A (n=27; 61.4%) and TET2 (n= 9; 20.5%). Post-HCT samples from 13 recipients were also sequenced, of whom 7 had CH+ donors. All of the donor CH mutations (n=7/7; 100%) were detected in recipients at day 56 or day 90 post-HCT. Overall, mutation VAFs remained relatively constant up to day 90 post-HCT (median change, .005; range, -.008 to .024). Doubling time analysis of recipient day 56 and day 90 data showed that donor-engrafted CH mutations initially expand then decrease to a stable VAF; germline mutations had longer doubling times than CH mutations. The cumulative incidence of grade II-IV aGVHD at day 100 was higher in HCT recipients with CH+ donors (37.5% versus 25.1%); however, the risk for aGVHD by donor CH status did not reach statistical significance (hazard ratio, 1.35; 95% confidence interval, .61 to 3.01; P=.47). There were no statistically significant differences in the cumulative incidence of cGVHD or any secondary outcomes by donor CH status. In subset analysis, the incidence of cGVHD was lower in recipients of grafts from DNMT3A CH+ donors versus donors without DNMT3A CH (34.4% versus 57%; P=.035). Donor cell leukemia was not reported in any donor-recipient pairs. CH in older HLA-matched sibling donors is relatively common and successfully engrafts and persists in recipients. In a homogenous population (myeloid malignancies, older donors and recipients, RICr, non-cyclophosphamide-containing GVHD prophylaxis), we did not detect a difference in cGVHD risk or other secondary outcomes by donor CH status. Subgroup analyses suggest potential differential effects by clinical characteristics and CH mutations. Larger prospective studies are needed to robustly determine which subsets of patients and CH mutations elicit meaningful impacts on clinical outcomes.

Cyclophosphamide with cyclosporine A for graft-versus-host disease prophylaxis in adult patients with acute myeloid leukemia undergoing allogeneic hematopoietic stem cell transplantation from human leucocyte antigen-matched donors

BackgroundGraft-versus-host disease (GVHD) is one of the most severe complications in patients with acute myeloid leukemia (AML) who underwent allogenic hematopoietic stem cell transplantation (HSCT). This study addressed the effectiveness and safety outcomes of high dose post-transplant cyclophosphamide (PT-CY) followed by cyclosporine A (CSA) as a GVHD prophylaxis protocol. Patients and MethodsFrom January 2019 to March 2021, AML patients who underwent HSCT, and received high-dose PT-CY followed by CSA were prospectively recruited, assessed, and followed up for one-year post-transplantation (PT). The cumulative incidences of both acute GVHD (aGVHD) at 100 days PT, and chronic GVHD (cGVHD) at one-year PT were assessed. ResultsThis study included 52 patients. The cumulative incidence (95% CIs) of aGVHD was 2.3% (0.3 – 15.4%), while the cumulative incidence of cGVHD was 23.2% (12.2–41.5%). The cumulative incidence of relapse and non-relapse mortality were 15.6%, and 7.9%, respectively. The median duration to reach neutrophil and platelet engraftment was 17 and 13 days, respectively. The overall, progression-free, and GVHD-free/relapse-free survival rates (95% CIs) were 89.6% (76.6 – 95.6%), 77.7% (62.1–87.5%), and 58.2% (41.6 – 71.7%) respectively. The cumulative incidences of the main transplant-related complications were; neutropenic sepsis (48.3%), cytomegalovirus reactivation (21.7%), pneumonia (13.8%), hemorrhagic cystitis (17.8%), septic shock (4.9%), and CSA toxicity (48.9%). ConclusionPT-CY followed by CSA was associated with low cumulative incidences of both aGVHD and cGVHD without increase in either the relapse or transplant-related complications; so, considered as a promising protocol to be widely applied in the settings of HLA-matched donors.

Haploidentical vs. HLA-matched donor hematopoietic stem-cell transplantation for pediatric patients with acute lymphoblastic leukemia in second remission: A collaborative retrospective study of the Spanish Group for Bone Marrow Transplantation in Children (GETMON/GETH) and the Spanish Childhood Relapsed ALL Board (ReALLNet).

Studies addressing the role of haploidentical as alternative to HLA-matched donors for stem cell transplantation (SCT) often include patients with diverse hematological malignancies in different remission statuses. We compared outcomes of children with acute lymphoblastic leukemia (ALL) undergoing SCT in second complete remission (CR2) from haploidentical (n = 25) versus HLA-matched donor (n = 51). Patients were equally distributed across both groups according to age, immunophenotype, time to and site of relapse, relapse risk-group allocation, and minimal residual disease (MRD) before SCT. Incidence of graft failure, acute graft versus host disease (GVHD), and other early complications did not differ between both groups. We found no differences in overall survival (58.7% versus 59.5%; p = .8), leukemia free survival (LFS) (48% versus 36.4%; p = .5), event free survival (40% versus 34.4%; p = .69), cumulative incidence (CI) of subsequent relapse (28% versus 40.9%; p = .69), treatment related mortality (24% versus 23.6%; p = .83), CI of cGVHD (4.5% versus 18.7%; p = .2), and chronic GVHD-free and leukemia-free survival (44% versus 26.3%; p = .3) after haploidentical donor SCT. Chronic GVHD (HR = 0.09; p=.02) had protective impact, and MRD ≥ 0.01% before SCT (HR = 2.59; p=.01) had unfavorable impact on LFS. These results support the role of haploidentical donor SCT in children with ALL in CR2.

A Multiparameter Prognostic Risk Score of Chronic Graft-versus-Host Disease Based on CXCL10 and Plasmacytoid Dendritic Cell Levels in the Peripheral Blood at 3 Months after Allogeneic Hematopoietic Stem Cell Transplantation

Chronic GVHD (cGVHD) is the major cause of long-term morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). There are no biomarkers that can consistently predict its occurrence. We aimed to evaluate whether numbers of antigen-presenting cell subsets in peripheral blood (PB) or serum chemokine concentrations are biomarkers of cGVHD occurrence. The study cohort comprised 101 consecutive patients undergoing allogeneic HSCT between January 2007 and 2011. cGVHD was diagnosed by both modified Seattle criteria and National Institutes of Health (NIH) criteria. Multicolor flow cytometry was used to determine the number of PB myeloid dendritic cells (DCs), plasmacytoid DCs, CD16+ DCs, and CD16+ and CD16- monocytes, as well as CD4+ and CD8+ T cells, CD56+ natural killer cells, and CD19+ B cells. Serum concentrations of CXCL8, CXCL10, CCL2, CCL3, CCL4, and CCL5 were measured by a cytometry bead array assay. At a median of 60 days after enrollment, 37 patients had developed cGVHD. Patients with cGVHD and those without cGVHD had comparable clinical characteristics. However, previous acute GVHD (aGVHD) was strongly correlated with later cGVHD (57% versus 24%, respectively; P=.0024). Each potential biomarker was screened for its association with cGVHD using the Mann-Whitney U test. Biomarkers that differed significantly (P < .05) between patients with cGVHD and those without cGVHD were analyzed by receiver operating characteristic (ROC) curve analysis to select the variables predicting cGVHD with an area under the ROC curve (AUC) >.5 and a P value <.05. A multivariate Fine-Gray model identified the following variables as independently associated with the risk of cGVHD: CXCL10 ≥592.650 pg/mL (hazard ratio [HR], 2.655; 95% confidence interval [CI], 1.298 to 5.433; P=.008), pDC ≥2.448/μL (HR, .286; 95% CI, .142 to .577; P < .001) and previous aGVHD (HR, 2.635; 95% CI, 1.298 to 5.347; P=.007). A risk score was derived based on the weighted coefficients of each variable (2 points each), resulting in the identification of 4 cohorts of patients (scores of 0, 2, 4, and 6). In a competing risk analysis to stratify patients at differing risk levels of cGVHD, the cumulative incidence of cGVHD was 9.7%, 34.3%, 57.7%, and 100% in patients with scores of 0, 2, 4, and 6, respectively (P < .0001). The score could nicely stratify the patients based on the risk of extensive cGVHD as well as NIH-based global and moderate to severe cGVHD. Based on ROC analysis, the score could predict the occurrence of cGVHD with an AUC of .791 (95% CI, .703 to .880; P < .001). Finally, a cutoff score ≥4 was identified as the optimal cutoff by Youden J index with a sensitivity of 57.1% and a specificity of 85.0%. A multiparameter score including a history of previous aGVHD, serum CXCL10 concentration, and number of pDCs in the PB at 3 months post-HSCT stratify patients at varying risk levels of cGVHD. However, the score needs to be validated in a much larger independent and possibly multicenter cohort of patients undergoing transplantation from different donor types and with distinct GVHD prophylaxis regimens.

Long-Term Analysis of an Open-Label, Multicentre, Randomized Phase 3 Trial Comparing Busulfan Plus Cyclophosphamide Versus Busulfan Plus Fludarabine As a Preparative Regimen for Allogeneic Stem-Cell Transplantation in Patients with Acute Myeloid Leukemia

Background In a previous randomized trial performed by the Gruppo Italiano Trapianto di Midollo Osseo in AML patients (GITMO, AML-R2 study, Clinical Trial.gov number NCT01191957, Rambaldi A et al.: Lancet Oncology, 2015), we compared the combination of busulfan (3.2 mg/kg/die for four days) and fludarabine (160 mg/sqm) (BuFlu) with the conventional combination of busulfan and cyclophosphamide (120 mg/kg) (BuCy2). In this study, 252 AML patients with a median age of 52, undergoing allogeneic transplantation in first (n=213) or second (n=37) remission, from a sibling (n=114) or unrelated (n=138) donor were randomly assigned 1:1 to BuCy2 (n=125) or BuFlu (n=127). GvHD prophylaxis was based on cyclosporine-A and methotrexate; in case of unrelated donors, anti Thymocyte Globulin was given at a total dose of 5 mg/kg (or 7.5 mg/kg in case of HLA acceptable disparity). The 1-year non-relapse mortality (NRM) (primary endpoint of the study) of patients assigned to BuFlu proved significantly lower (7.9% in the BuFlu arm vs. 17.2% in BuCy2 arm, Gray's test p=0.026). There was no difference between the two arms in terms of cumulative incidence of relapse (CIR), leukemia free survival (LFS), overall survival (OS) at 1 and 2 years after transplant. Grade III-IV acute graft versus host disease (GvHD) was significantly higher in BuCy2 group (12 patients [10%]) than BuFlu group (3 patients [2%]). Hereby we present the long-term analysis of this clinical trial. Methods We collected data about the last follow up (dead/alive), the causes of death (NRM/disease relapse), the incidence of chronic GvHD (cGvHD) and current cGvHD therapy, the occurrence of disease relapse with the type of subsequent treatment including a second allogeneic transplant. We also searched for long-term side effects including cardiovascular events, secondary malignancies, other relevant medical events (i.e. infections, neurological or pulmonary events etc.). The Endpoints of the current analysis were NRM, CIR, LFS, OS, cumulative incidence of cGvHD, cumulative incidence of moderate/severe cGvHD, cGvHD and leukemia-free survival (GLFS). Results With a median follow up time for the whole study population of 6 years (range 0.03-13), the 4-years NRM is 10% in BuFlu arm vs 20% in BuCy2 arm (P= 0.0388). The 4 and 10-years CIR was not statistically different in both arms (36% vs. 33% in in BuFlu and BuCy2, and 39% vs 37% in BuFlu vs. BuCy2 arm). Similarly, we did not observe any difference in terms of 4-years LFS (53% vs 47% in BuFlu and BuCy2 arm, respectively), OS (56% in both arms) and cumulative incidence of moderate/severe cGvHD (14% in BuFlu arm vs 19% in BuCy2 arm). The 4-years GLFS was 35% in BuFlu arm vs 24% in BuCy2 (P= 0.0602). The incidence of secondary malignancies was not different in the two study groups (16 events, 7 in BuCy2 arm and 9 in BuFlu arm). Conclusion: This long-term analysis confirms the benefit in terms of NRM associated with the BuFlu conditioning which was not associated to a higher incidence of late leukemia relapse. We found a better trend in GLFS in BuFlu arm, most likely due to a lower rate of grade III/IV acute GvHD in the experimental arm. Although we did not observe any difference between the two arms, CIR was stable and high (40% in both arms at 10 years) throughout the observation period. Therefore, AML relapse remains the major concern, urging the development of new therapeutic interventions driven by post-transplant MRD monitoring and pre-emptive therapies in high-risk patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Favorable outcomes of allogeneic hematopoietic stem cell transplantation with fludarabine-bendamustine conditioning and posttransplantation cyclophosphamide in classical Hodgkin lymphoma.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment for patients with relapsed and refractory classic Hodgkin lymphoma (rrHL). However, the optimal conditioning regimen and GVHD prophylaxis for rrHL remain undetermined. The aim of this study was to investigate outcomes of allo-HSCT with a fludarabine plus bendamustine (FluBe) conditioning regimen and GVHD prophylaxis with posttransplantation cyclophosphamide (PTCY) in patients with rrHL. Allo-HSCT results in 58 adult patients with rrHL were analyzed retrospectively. Three-year overall survival and event-free survival were 81% (95% CI 65-91) and 55% (95% CI 38-72), respectively. The cumulative incidence of relapse (CIR) at 3years was 33% (95% CI 13-51). The cumulative incidence of aGVHD grade II-IV and severe aGVHD grade III-IV was 36% (95% CI 22-48) and 22% (95% CI 9-33), respectively. The cumulative incidence of cGVHD was 32% (95% CI 17-45), including moderate or severe cGVHD in 17% (95% CI 4-28). Patients who developed aGVHD after allo-HSCT had significantly lower CIR (24% vs 49%, p = 0.004). The use of PBSC as a graft source also significantly reduced CIR (4% vs 61%, p = 0.002). FluBe-PTCY allo-HSCT facilitates favorable outcomes, low toxicity, and mortality in rrHL.

The Two-Step Allogeneic Stem Cell Transplantation Approach Results in Rapid Engraftment and Excellent Outcomes in Patients with Lymphoid Malignancies

The 2-step graft engineering approach has been the main platform for allogeneic hematopoietic cell transplantation (allo-HCT) at Thomas Jefferson University since 2005. We have previously described separating donor lymphocyte infusion followed by cyclophosphamide for bidirectional tolerization from CD34-selected hematopoietic grafts in haploidentical and matched related donors. Here we analyzed 60 patients with high-risk lymphoid malignancies who underwent a 2-step allo-HCT between 2008 and 2020. The majority of patients received haploidentical stem cell grafts (82%), and 20% of patients received matched related donor stem cell grafts. The patients underwent allo-HCT for diffuse large C cell lymphoma (n=17; 28%), chronic lymphoblastic leukemia (n=10; 17%), follicular lymphoma (n=8; 13%), and Hodgkin lymphoma (n=7; 12%). Eight patients (13%) had received prior high-dose chemotherapy. Thirty patients (50%) had a Hematopoietic Cell Transplantation Comorbidity Index ≥3, and 20 patients (33%) had a Center for International Blood & Marrow Transplant Research Revised Disease Risk Index of high risk or very high risk. The median patient age was 56 years (range, 24 to 75 years). Neutrophils engrafted at a median of 11 days (range, 9 to 16 days), and platelets engrafted at a median of 16 days (range, 13 to 37 days). With a median follow-up of 6 years, the 3-year probability of overall survival was 62.9% (95% confidence interval [CI], 49.3% to 73.8%), and that of disease-free survival was 60.2% (95% CI, 46.4% to 71.6%). The cumulative incidence of relapse at 3 years was 11.9% (95% CI, 5.2% to 21.6%). The cumulative incidence of nonrelapse mortality at 3 years was 30.1% (95% CI, 1.91% to 42.0%). The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) at 1 year was 45% (95% CI, 32.2% to 57.0%), and that of grade III-IV acute GVHD at 1 year was 5% (95% CI, 1.3% to 12.6%). The cumulative incidence of cGVHD at 3 years was 15.2% (95% CI, 7.5% to 25.4%). The 2-step approach achieved excellent outcomes in high-risk lymphoid malignancies, with rapid neutrophil and platelet recovery.

Outcome of Haploidentical Peripheral Blood Allografts Using Post-Transplantation Cyclophosphamide Compared to Matched Sibling and Unrelated Donor Bone Marrow Allografts in Pediatric Patients with Hematologic Malignancies: A Single-Center Analysis

The introduction of post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis has made haploidentical (haplo) hematopoietic stem cell transplantation (HSCT) a common approach in adults, but pediatric experience is limited. Based on the encouraging adult data and with the aim of decreasing the risk of graft failure, our center is increasingly using peripheral blood stem cells (PBSCs) from haplo donors with PTCy. Here we compare outcomes of bone marrow (BM) transplantation with traditional donor choices, including matched sibling donors (MSDs) and 10/10 HLA matched unrelated donors (MUDs), with those of haplo PBSC grafts in pediatric patients with hematologic malignancies. In this retrospective single-center study, the primary endpoint was the comparison of GVHD-free relapse-free survival (GRFS; defined as absence of acute GVHD [aGVHD] grade III-IV, relapse, death, or chronic GVHD [cGVHD] requiring systemic therapy) for the 3 cohorts. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), nonrelapse mortality (NRM), and incidence of aGVHD and cGVHD). A total of 104 consecutive patients underwent first allogeneic (allo)-HSCT for a hematologic malignancy or myelodysplastic syndrome between January 2014 and December 2020 using a haplo family donor (PBSCs; n=26), an MSD (BM; n=31), or an MUD (BM; n=47). Patient demographic and transplantation characteristics were not significantly different across the cohorts, apart from remission status, with the haplo cohort having more patients in third or later complete remission before HSCT (P < .01). The median duration of follow-up for the entire cohort was 573 days. The cumulative incidence of aGVHD (grade II-IV or grade III-IV) was not significantly different among the cohorts; however, the cumulative incidence of cGVHD at 18 months was highest in the MUD cohort (31.7%, versus 10.0% in the MSD cohort and 9.2% in the haplo cohort; P=.02). There were no differences in the 18-month cumulative incidence of relapse or NRM. OS and RFS at 18 months were 80.7% (95% confidence interval [CI], 61.7% to 100%) and 73.8% (95% CI, 55.5% to 98.1%) for the haplo cohort, 83.4% (95% CI, 72.8% to 95.5%) and 70.3% (95% CI, 57.9% to 85.3%) for the MUD cohort, and 80.9% (95% CI, 66.9% to 97.7%) and 66.5% (95% CI, 50.5% to 87.5%) for the MSD cohort, with no statistically significant differences among the cohorts. GRFS at 18 months was 61% (95% CI, 43.3% to 85.9%) for the haplo cohort, 44.6% (95% CI, 31.8% to 62.5%) for the MUD cohort, and 62.1% (95% CI, 45.7% to 84.3%) for the MSD cohort (P=.26). Haploidentical PBSC HSCT with PTCy had comparable outcomes to MSD and MUD BM HSCT and less cGVHD compared with MUD BM HSCT in children. The logistical advantages and lower resource burden of haplo HSCT with PBSCs make it a feasible alternative to MUD HSCT in children with hematologic malignancies. Given that this is a retrospective comparison of transplantation platforms rather than donor types, further prospective studies are warranted. © 2021 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

Effect of Age on Outcomes of Allogeneic Transplantation in Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome

Background: Allogeneic stem cell transplantation (allo-SCT) has become an increasingly important consolidation treatment option for patients with acute myeloid leukemia (AML) and as upfront therapy for patients with high-risk myelodysplastic syndrome (MDS). Although the median age at diagnosis for both diseases is above 65 years, studies evaluating allo-SCT as treatment option for patients aged 65 years or older are limited. Further, as the population ages, the number of patients above 65 years considered for allo-SCT will continue to rise. Thus, the aim of our current investigation was to analyze outcomes based on age in AML/MDS patients <65 years old and ≥65 years old who received allo-SCT at the Ohio State University.Methods: A retrospective analysis was performed for all AML/MDS patients who received allo-SCT between January 1984 and December 2018 at our institution. Primary endpoints included progression free survival (PFS) and overall survival (OS). PFS was counted from the day of transplantation to relapse or death. OS was defined as survival from the day of allo-SCT until death from any cause, with censoring of patients known to be alive at the time of last follow-up. PFS and OS were calculated using Kaplan Meier Curves. Secondary endpoints included cumulative incidences of grade II-IV and III-IV acute GVHD (aGVHD), chronic GVHD (cGVHD), relapse, and non-relapse mortality (NRM). Cumulative incidence rates of aGVHD, cGVHD, relapse, NRM were estimated and compared using Gray's test accounting for competing risks.Results: The cohort consisted of 900 AML/MDS patients, with 150 patients ≥65 years and 750 patients <65 years. The median age at transplant for the <65 years group was 49 years (range: 18-64 years) and 68 years (range: 65-76 years) for the ≥65 years group. Gender, race, Karnofsky score, and comorbidity index were similar between the two groups. A higher proportion of patients received myeloablative (MA) conditioning (65.1%) in the <65 years of age compared to 20% in the ≥65 years of age (p<0.01). A higher proportion of older patients had matched unrelated donors (57.3%), and reduced intensity conditioning (RIC) regimens (80%).The median time from diagnosis to transplantation was 176 days (range: 55-4920) for age <65 years and 168 days (range: 34-6079 days) for age ≥65 years. Median follow-up from allo-SCT was 5.9 years (range 0.8-35.9 years) and 3.4 years (range: 1.0-9.6 years) from transplantation among survivors. Neutrophil and platelet engraftment were similar among the groups (p=0.35; 0.11). 3 year OS of 42.3% (95% CI: 38.7-45.8%) and PFS of 38.3% (95% CI: 34.8%-41.9%) were observed for age <65 years. The corresponding OS and PFS for age ≥65 years was 46.3% (95% CI: 37.9%-54.3%) and 43.0% (95% CI: 34.7%-51.0%), respectively (Figure 1a & 1b). Cumulative incidences of relapse at 1 year in <65 and ≥65 years were 26.4% and 25.3%, respectively (p=0.43). The cumulative incidence of NRM at 1 year in <65 and ≥65 years was 23.2% and 17.3%, respectively (p=0.12; Figures 1c and d). The incidences of acute and chronic GVHD were similar in the two age groups. The cumulative incidence of aGVHD at day 100 in <65 and ≥65 years was 40.3% (95% CI: 36.4%-44.2%) and 43.0% (95% CI: 34.9%-50.7%), respectively. The cumulative incidence of cGVHD at day 365 in <65 and ≥65 years was 40.8% (95% CI: 36.9%-44.6%) and 41.6% (95% CI: 33.6%-49.4%), respectively.Conclusion: Overall, our study suggests similar outcomes for elderly patients undergoing allo-HCT as compared to their counterparts, which is in line with prior studies. This likely is due to advancements in the transplant field, including the development of RIC and alternative donors, which have allowed greater access to transplant for older adults. Utilization of allo-HCT is feasible and should be considered for AML/MDS patients ≥65 years. Further research is underway to evaluate the important determinants of health status in older patients undergoing allo-HCT and to ultimately help predict NRM (BMT CTN 1704). [Display omitted] DisclosuresBumma: Amgen, Sanofi: Speakers Bureau; Janssen, Oncopeptides, Sanofi: Consultancy. Vasu: Seattle Genetics: Other: travel support; Boehringer Ingelheim: Other: Travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy; Novartis: Consultancy, Research Funding. Mims: Syndax Pharmaceuticals: Consultancy; BMS: Consultancy; Jazz Pharmaceuticals: Consultancy; Abbvie: Consultancy; Genentech: Consultancy; Kura Oncology: Consultancy; Leukemia and Lymphoma Society: Consultancy; Glycomemetics: Research Funding; Aptevo: Research Funding; Xencor: Research Funding; Daiichi-Saynko: Consultancy. Brammer: Celgene: Research Funding; Seattle Genetics: Speakers Bureau; Kymera Therapeutics: Consultancy. Saad: Incyte Pharmaceuticals: Consultancy; careDx: Consultancy; Amgen: Research Funding; Kadmon: Research Funding; OrcaBio: Research Funding; Magenta Therapeutics: Consultancy. de Lima: Miltenyi Biotec: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

Gvhd after PBSC-Haploidentical Stem Cell Transplantation (Haplo-SCT) with Post Transplantation-Cyclophosphamide (PT-Cy)

T-cell replete Haplo-SCT using PT-Cy as GVHD part of prophylaxis has become a valid option to perform allogeneic transplantation in patients without an available HLA-matched donor. The absence of additional ex vivo procedure has participated to its increasing use in the field of transplantation. Because of HLA disparity, bone marrow (BM) was initially chosen as stem cell source, based on previous observations of lower incidences of GVHD after HLA-matched donor transplantation, when using BM graft as compared with G-CSF mobilized peripheral blood stem cells (PBSC). In contrast, use of PBSC may improve engraftment and disease control favoring larger adoption of the procedure. However, the use of PBSC graft for Haplo-SCT remains controversial. We here report our experience of PBSC Haplo-SCT using PT-Cy for hematological malignancies.We selected patients (pts) with hematological malignancies who underwent Haplo-SCT using PT-Cy at 2 transplant centers from March 2012 to June 2016, using the following criteria: PBSC as graft source; first allogeneic transplantation; PT-Cy as part of GVHD prophylaxis. Patients with refractory acute leukemia who received sequential conditioning regimens were excluded. GVHD prophylaxis included PT-Cy (D+3 and D+4) in association with calcineurin inhibitors and MMF started from D+5.The aim of this retrospective study was to provide a comprehensive description of GVHD following PBSC Haplo-SCT with PT-Cy. Beyond calculation of the cumulative incidence of both acute and chronic GVHD, we precisely describe GVHD features by grading organ involvement and severity. In addition, we assess the prevalence of GVHD and immunosuppressive treatment (IST) at 3, 6, 9, 12, 15, 18, 21 and 24 months after Haplo-SCT in disease free patients, as well as quality of life.We retrospectively analyzed 181 consecutive pts with a median age of 60 years (19-73). Ninety-seven (54%) pts were affected by myeloid diseases, mostly (29%) AML. Disease risk index was high or very high in 47 pts (26%). Non-myeloablative conditioning regimen (low dose TBI + cyclophosphamide and fludarabine) was used in 92 pts (51%), while the remaining patiens received busulfan-based conditioning regimen, with reduced and myeloablative doses in 67 pts (38%) and 21 (12%) pts, respectively.The median CD34+ and CD3+ cells infused were 5.3 x 10^6/kg (range, 1.5-18.1) and 280 (range, 38-704), respectively.Median time to neutrophil recovery (ANC >500 x106/L) was 21 days (range, 17-112) and 30 days (range, 10-394) to platelet recovery (PLT > 20 G x 109/L).Between 24-48 hours after donor stem cells infusion, 88% of recipients experienced fever with chills (median temperature = 40,1°C). No microbiological proof of infection was found in most pts, while bacterial infection was identified in bloodstream culture in 9 % of pts.Fever completely disappeared the day after the last PT-Cy infused dose in 79% of patients.The incidence of grade II-IV and III-IV aGVHD was 23% and 8% at 100 days, respectively. Among patiens who developed aGVHD, 58 (82%) presented with isolated skin involvement, while gut GVHD was responsible for most grade III-IV GVHD (16/20, 80%).The cumulative incidence of cGVHD was 18% at 2 years. According to NIH classification, half of the patients who developed cGVHD presented with mild forms, without needing systemic treatment (mostly skin and mucosa involvement), while severe forms occurred in 3% of GVHD cases.As shown in Figure 1, at 6 months post Haplo-SCT, IST was discontinued in 40% of disease-free patients. In addition, most patients who were disease-free at 2 years were living with no immunosuppressive treatment (98%) and no GVHD (94%).At 2 years, NRM, relapse, PFS, OS and GRFS were 21%, 17%, 62%, 66% and 50%, respectivelyWe conclude that PBSC Haplo-SCT using PT-Cy is a feasible procedure, with low incidences of severe forms of both acute and chronic GVHD. In addition, we pointed out that almost all surviving patients were living without GVHD and IST at 2 years, suggesting a preserved quality of life. Thus, as previously shown using BM as graft source, PT-Cy allows performing T-replete Haplo-SCT with low incidence of GVHD also using PBSC, with very low long term GVHD-related morbidity. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

The Minnesota Refined Acute GVHD Score Predicts Response to Initial Therapy, Survival and Non-Relapse Mortality after Haploidentical Transplantation with Post-Transplant Cyclophosphamide

Background: Despite prophylactic treatments with immunosuppressive agents, approximately 50% of transplant recipients develop acute GVHD (aGVHD) with an overall response rate (ORR) to steroid front-line therapy of approximately 64% and a 6-month overall survival (OS) of 66% (Martin PJ, BBMT 2012;18:1150-63). Recently, the University of Minnesota (MN) identified a new clinical refined risk score that was more powerful than the IMBTR score to predict response and survival of patients with aGVHD (MacMillan ML et al, BBMT 2015;21:761-7). In particular, at aGVHD onset patients at standard (SR) and high-risk were characterized by opposite outcomes in terms of ORR (69% vs 43%), non-relapse mortality (NRM; 22% vs 44%) and OS (71% vs 52%). This score was mainly based on patients receiving a transplant either from a matched-related-donor or a matched or mismatched unrelated donor. Because haploidentical transplant (Haplo-SCT) with post-transplant cyclophosphamide (PT-Cy) is becoming a widespread option for patients lacking a HLA identical donor, we set to identify whether the refined MN aGVHD risk score is useful in the setting of Haplo-SCT in order to early identify which patients are at higher risk of death for aGVHD and may benefit from upfront, intensified treatments.Methods: Between 2011 and 2016, 318 patients received a Haplo-SCT with PT-Cy. 87 patients (27%) developed aGVHD of grade 2-4. Median age was 56 year old (20-72), 56 were male and 18 (21%) of them received a transplant from a female donor. Graft source comprised peripheral blood stem cells (PBSC) in 64 (73%) and bone marrow (BM) in 23 (37%), 56% of the patients received a reduced intensity (RIC) and 38% a non-myeloablative (NMA) conditioning, 53% had a HCT-CI>3 and 14% an unfavorable (D/R: Neg/Pos) CMV serostatus. Acute GVHD characteristics were as follows: 61 (70%) had grade 2 and 26 (30%) grade 3-4 according to Glucksberg staging, 25 (29%) had a grade A-B and 62 (71%) a grade C-D according to IMBTR index, 63 (72%) had only skin and 24 (28%) also visceral involvement, 65 (75%) were classified as standard risk (SR) and 22 (28%) as high-risk according to the MN risk score2. Front line therapy consisted of steroid in 59% of the subjects and steroid combined with extracorporeal photochemotherapy in 41%.Results: Day 28 cumulative incidence (CI) of non-responder (NR) was 21% (95% CI: 12-29) and CI of aGVHD relapse within 6 months was 8% (95% CI: 1-14). CI of cGVHD was 16% (95% CI: 9-25). 3y-OS was 55% (95% CI: 43-66) and 1y-NRM 23% (95% CI: 15-32). CI of CMV reactivation after aGVHD onset was 40% (95% CI: 29-50). Patients' outcome according to the main variables is summarized in Table I. Day 28 CI of of NR differed between MN SR and high-risk patients: 15% vs 36%, p=0.09. Glucksberg, IMBTR and visceral/non visceral grading had a similar capacity to identify patients with different chance of response. On multivariate analysis no variable was independently associated with day 28 probability of NR: of note, the MN high-risk group had a hazard ratio (HR) of 1.7 (95% CI: 0,2-12,6). Relative to 1y-NRM and 3y-OS rates, patients with high risk MN score were at higher risk od death: relative to SR, 1y-NRM was 50% vs 14% (p=0.0002) and a 3y-OS was 42% vs 60% (p=0.04). The IMBTR score was not capable to distinguish different groups in terms of NRM and OS, while stage 3-4 aGVHD according to Glucksberg grading was associated with a worse NRM, but not OS. Only the distinction between visceral and no-visceral aGVHD yielded results similar to the MN risk score (Table I). On multivariate analysis no variable was an independent predictor of NRM or OS due to the small patients number. Of note, in terms of NRM, high-risk MN group had a HR of 2.7 (95% CI: 0,2-26,8) and visceral GVHD had a HR of 1.5 (95% CI: 0.2-10.2). Relative to OS, high-risk MN group had a HR of 2.0 (95% CI: 0,3-11,3), while visceral GVHD had a HR of 1.7 (95% CI: 0.3-8.7).Conclusion: The refined MN aGVHD risk score is useful to identify at aGVHD onset patients at higher risk of non-response and mortality also in the contest of Haplo-SCT with PT-Cy. This score appears more powerful than the IBMTR, but similar to Glucksberg grading, to identify patients at higher risk. These preliminary observations need to be validated on a larger number of patients in order to identify whether the MN risk score may be useful to orient treatment decisions for aGVHD occurring after Haplo-SCT with PT-Cy. [Display omitted] DisclosuresCarlo-Stella:Rhizen Pharmaceuticals: Research Funding; Boehringer Ingelheim: Consultancy, Honoraria; ADC Therapeutics: Research Funding. Santoro:Merck: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Hematopoietic stem cell transplantation for inherited bone marrow failure syndromes: alternative donor and disease-specific conditioning regimen with unmanipulated grafts

ABSTRACT Objective: The outcomes of alternative donor hematopoietic stem cell transplantation (HSCT) with unmanipulated grafts for Inherited bone marrow failure syndromes (IBMFS) are discouraging. Our study is to demonstrate that IBMFS with disease-specific characteristics requires a tailored conditioning regimens to enhance engraftment and reduce regimen related toxicities. Methods: We retrospectively analyzed 42 patients diagnosed with IBMFS and transplanted with an alternative donor graft at our center from November 2012 to August 2018. Twenty-seven patients had Fanconi anemia (FA), 7 had dyskeratosis congenita (DC), and 8 had severe congenital neutropenia (SCN). Patients received ex-vivo unmanipulated alternative donor grafts from a matched unrelated donor (MUD) (n = 22), haploidentical donor (HID) (n = 17) and unrelated cord blood donor (UCBD) (n = 3). FA and DC patient subgroups received reduce intensified conditioning (RIC), while SCN patients received a myeloablative conditioning (MAC) regimen. Results: The median follow-up time for the surviving patients was 38 months (range: 9–63 months). The failure-free survival (FFS) for entire cohort was 76.1%, and was 72.4%, 100% and 56.2% for patients with FA, DC and SCN, respectively. There were no primary graft failures. The cumulative incidence of aGVHD at day 100 was 48.1%. The cumulative incidence of cGVHD at 1 and 3 years was 35.0% and 69.3%, respectively. Conclusion: HSCT using alternative donors with unmanipulated grafts and disease-specific conditioning regimens for IBMFS patients shows promising survival.

36. Safety and Reactogenicity of the Adjuvanted Recombinant Zoster Vaccine after Allogeneic Hematopoietic Stem Cell Transplantation

BackgroundHerpes zoster (HZ) is common after allogeneic hematopoietic stem cell transplantation (HCT) and associated with high morbidity. While antiviral prophylaxis reduces incidence, increased risk remains after discontinuation and vaccination strategies are needed. A non-live adjuvanted recombinant zoster vaccine (RZV) has been developed but not yet studied in this population.MethodsIn this single center prospective observational cohort study, allogeneic HCT recipients ³18 years old and 9–24 months from HCT were eligible to receive 2 doses of RZV separated by ³8 weeks as part of revised institutional vaccination guidelines. The primary endpoint was safety and reactogenicity in the total vaccinated cohort (TVC). The secondary endpoints were incidence and severity of chronic graft versus host disease (cGVHD) in the TVC compared to historical controls and incidence rates of HZ in the TVC and modified total vaccinated cohort (mTVC).ResultsOf the 158 participants (mean age 55 years, 91 [58%] male) in the TVC, 150 (95%) received second vaccine. 92.1% had solicited reactions with 87.3% injection site reactions (18.7% grade 3) and 82.8% general reactions (26.5% grade 3). In the subgroup receiving first vaccine at 9–12 months after HCT, cumulative incidence of cGVHD was similar to historical controls at predefined time points between 9–15 months (unadjusted incidence rate ratio [IRR] 1.1 [95% CI 0.84–1.44], adjusted IRR 1.05 [95% CI 0.8–1.38]); there was also no difference in severity of cGVHD, or incidence of death or disease relapse. There were 4 (2.5%) HZ cases during the study period with IR 28.34/1000 person-years over median follow up 281 days (IQR 190, 354) in the mTVC. All cases occurred after antiviral prophylaxis discontinuation and one case resulted in death.ConclusionTwo doses of RZV after allogeneic HCT was safe and acceptable despite high rates of reactogenicity. There was no evidence of an increase in cGVHD, relapse, or death compared to historical controls and overall low rates of breakthrough HZ similar to those reported after autologous HCT. Immunogenicity studies and placebo-controlled trials are needed to determine vaccine response and efficacy so that timing of RZV and its potential impact on discontinuation of antiviral prophylaxis can be determined.Disclosures Nicolas C. Issa, MD, AiCuris (Scientific Research Study Investigator)Astellas (Scientific Research Study Investigator)GSK (Scientific Research Study Investigator)Merck (Scientific Research Study Investigator)

STUDY OF CYTOKINE BIOMARKERS FOR EARLY DETECTION OF CHRONIC GRAFT VERSUS HOST DISEASE IN ALLOGENEIC STEM CELL TRANSPLANT PATIENTS

Allogeneic transplantation represents the most efficient consolidation treatment for most cases of malignant diseases. Some progression was made in the practice of transplantation but still, GvHD, relapse, and infection are the main obstacles. The cumulative incidence of cGvHD by 1 year after transplant ranged from 30-70 %. GvHD is the most common non-relapse mortality (NRM), and accounts of about 10–25 % of all transplanted patients.CGvHD is defined by the National Institutes of Health (NIH) Consensus depending on clinical manifestations, changing the classical and rather arbitrary chronological “beyond Day 100” definition. There are two types of cGvHD: Classic and overlap. The severity of cGvHD also assessed by the NIH global severity of cGvHD.Types of Hematopoietic stem-cell transplantation (HSCT) types: Allogeneic or autologous HSC.Chronic GvHD types: Classic chronic GvHD: occurs at any time after transplantation. Overlap syndrome: May occur at any time after transplantation, with a mixture of features of both cGvHD and aGvHD.Biomarker Panel for Chronic Graft-Versus-Host Disease:NIH Biomarker Working Group in 2006 meeting, declared cGvHD biomarkers utilization for clinical trials and disease management in the following conditions to (1) predict the risk of developing cGvHD; (2) diagnose cGvHD ; (3) measure disease activity or predict prognosis; (4) predict therapy response; and (5) serve as the surrogate endpoint for therapeutic response.