Higher Incidence Of Non-relapse Mortality Research Articles

Allogeneic hematopoietic cell transplantation for older patients with AML with active disease. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Older adults with acute myeloid leukemia (AML) refractory to initial or reinduction chemotherapy have a dismal prognosis if they do not undergo hematopoietic stem-cell transplantation (HCT). However, data assessing HCT outcomes from different donors are scarce. We evaluated results from a retrospective analysis on patients aged ≥70 years, with AML not in remission who received an allogeneic HCT from HLA-matched sibling donor (MSD), HLA-10/10 matched unrelated donor (MUD), or T-cell replete haploidentical (Haplo) donor, from 2010 to 2021, reported to the ALWP-EBMT database. A total of 360 patients (median age 72 years, range 70-79) were included in the analysis. Median follow-up for the entire population was 35.5 months. Donors were MSD (n = 58), 10/10 HLA-MUD (n = 228), and Haplo (n = 74). A total of 213 (59.2%) patients were primary induction failures, while 147 (40.8%) were in first or subsequent relapse. Graft source was peripheral blood in 92% of the patients. Patients transplanted from Haplo donors more frequently received marrow grafts (p < 0.01) and presented the combination female donor to male recipient (p < 0.01). The overall 2-year rates of overall survival (OS) and leukemia-free survival (LFS) were: 62.4% (95% CI 47.2-74.3) and 47.6% (95% CI 33.1-60.8) for MSD, 43% (95% CI 35.8-49.9), and 37.5% (95% CI 30.7-44.4) for MUD, and 25.9% (95% CI 15.8-37.2), and 26.5% (95% CI 16.3-37.8) for recipients of Haplo transplants. The 2-year cumulative incidence of relapse (RI) was slightly lower for Haplo recipients at 29.6% (95% CI 19-40.9), for MUD it was 30.2% (95% CI 23.9-36.7), and for MSD 34.9% (95% CI 22-48.2); counterbalanced by a higher incidence of non-relapse mortality (NRM) of 43.9% (95% CI 31.6-55.6) for Haplo recipients, 32.2% (95% CI 26-33.1) for MUD and 17.5% (95% CI 8.4-29.3) for MSD. Graft-versus-host disease (GVHD-free, relapse-free survival (GRFS) was 35.3% (95% CI 22.3-48.5) for MSD, 29.6% (95% CI 23.2-36.2) for MUD, and 19.2% (95% CI 10.7-29.6) for Haplo patients. In the multivariate model, compared to the referent group of MSD recipients, the risk of NRM was higher among patients transplanted from Haplo donors ([hazard ratio] HR 5.1, 95% CI 2.23-11.61, p < 0.001) and MUD (HR 3.21, 95% CI 1.48-0.6.94, p = 0.003). Furthermore, both Haplo and MUD were associated with inferior OS, (HR 3.6, 95% CI 1.98-0.6.56, p < 0.001, and HR 2.3, 95% CI 1.37-0.3.88, p = 0.002, respectively), and LFS (HR 2.24, 95% CI 1.31-0.3.84, p = 0.003, and HR 1.64, 95% CI 1.04-0.2.60, p = 0.034, respectively). Patients transplanted from Haplo donors were also associated with worse GFRS (HR 1.72, 95% CI 1.07-2.77, p:0.025) compared with MSD patients. Older adult AML patients with active disease transplanted from MSD experienced prolonged OS and LFS compared to 10/10 MUD and Haplo due to lower NRM. Prospective clinical trials are warranted.

Lower Cumulative Incidence of Relapse but Higher Incidence of NRM in Patients with Poor Graft Function Following Allogeneic Stem Cell Transplantation

Introduction Poor Graft Function(PGF), defined as multilineage cytopenias in the setting of complete donor chimerism is a significant complication of allogeneic stem cell transplantation (alloSCT). Recently our group, in a published retrospective analysis of 929 patients, demonstrated that the following factors were associated with the development of PGF: Non matched sibling donor, ICU admission/ positive blood cultures within 1 st 30 days of alloSCT, severe graft versus host disease (GVHD), CMV viremia (Prabahran et al 2021). We extended our prior cohort study to validate risk factors previously associated with PGF and describe outcomes such as recovery from PGF, relapse and non-relapse mortality following a diagnosis of PGF. Methods This was a retrospective analysis of alloSCT recipients at our institution from 2017-2020. Patients 17 years and older were included. Patients who died prior to D60 of alloSCT were excluded as chimerism data was often not available prior to this timepoint. PGF was defined as follows: 1) ≥95% donor chimerism at last reading OR ≥95% CD3 negative chimerism; 2) ≥2 Lineage cytopenias defined as: Thrombocytopenia :≤30x10 9 /L from D40-D60 OR ≤50 x10 9/L from D60 onwards; neutropenia requiring filgrastim support at any time post D40; Hb &amp;lt;80g/L. Factors associated with PGF were evaluated using a logistic regression, with development of PGF being the dependent variable. The predictive power of the subsequent logistic regression model was validated utilizing bootstrapping re-sampling procedure and testing of the concordance index (C-index). Variables associated with PGF were also evaluated in a cox-proportional model and coded as time-dependent covariates. Relapse and non-relapse mortality (NRM) were evaluated in a competing risk model from a landmark of 200 days post alloSCT, performed as per the method of Fine and Gray. Results 308 patients were included in the analysis of which 259 patients did not have PGF (nPGF) and 49 had PGF. Baseline variables of nPGF and PGF patients were matched for median age (53 versus 56 p=0.28), recipient sex (68% versus 65% male, p=0.74)), median CD34 dose (5.00 versus 5.2 x10 9/L p=0.49), donor source (p=0.12) and CMV serostatus (p=0.23). In multivariate analysis, ICU admission within 30 days (p=0.002), non-CMV viral infections (p=0.032) and GVHD (p&amp;lt;0.001) were associated with the development of PGF. The c-index of the model at baseline was 0.77 and 0.75 after bootstrapping validation indicating reasonable predictive performance of this model. ICU admission, non-CMV viral infections and GVHD were still significantly associated with the development of PGF when utilised as time dependent variables in a cox-regression model. Patients with PGF had worse 2-year survival compared to nPGF (60 versus 75% p=0.02). PGF patients without marrow recovery at last follow up had a 6-month OS of 20%. Twenty three out of 49 patients recovered marrow function at last follow up with a median duration of cytopenias of 142 days (51-789). The cumulative incidence (CI) of recovery was 44% and 53% at 1- and 2-years following onset of cytopenias respectively. From a landmark of 200 days (33 patients excluded due to death prior to this timepoint) PGF patients had a higher CI of NRM (Figure 1A =0.001) but lower CI of relapse (Figure 1B p=0.027) compared to nPGF patients. Conclusions PGF is strongly associated with early ICU admission, severe GVHD and non-CMV viral infections. Survival is inferior in patients with PGF particularly those with poor marrow recovery and this is mainly driven by non-relapse mortality. The lower CI of relapse in PGF is a novel finding of this study and may suggest a protective effect of PGF against the development of relapse but this finding requires further validation in external cohorts.

Comparative Study for Haplo, MSD and MUD Allo-Hcts for AML Patients with KMT2A Rearrangement: A Study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background Acute myeloid leukemia (AML) patients with KMT2A rearrangement (KMT2Ar, except for t(9;11)(p21.3;q23.3)/MLLT3::KMT2A) are classified as adverse risk in the 2022 European LeukemiaNet (ELN) classification. There is uncertainty on their outcome following allogeneic cell transplantation (allo-HCT). We compared, in an European Society for Blood and Marrow Transplantation (EBMT) global multi-center registry-based analysis, outcomes following an allogeneic stem cell transplantation (allo-HCT) with either a matched sibling donor (MSD), matched unrelated donor (MUD) or haploidentical donor (HAPLO). Methods Data from 586 AML patients with KMT2Ar receiving a first allo-HCT in 183 EBMT centers from 2010-2022 were analyzed. All patients achieved first complete remission (CR1) before transplantation. Patients with t(9;11), without details on translocation, receiving mismatched UD (&amp;lt;10/10), umbilical cord blood, or grafts with ex-vivo manipulation were excluded. Univariant analysis and Cox regression models were used. Results KMT2A rearranged AML patients received allo-HCT from 201 MSD, 256 10/10 MUD, and 129 HAPLOs. For KMT2Ar type, t(6;11), t(11;19), t(10;11) or other translocations account for 27.8%, 37.5%, 23.9% and 10.8%, respectively. Peripheral blood was the major graft source (83.2%), and myeloablative conditioning accounted for the majority (60.2%) of all allo-HCTs. Engraftment rates were comparable in the three cohorts (MSD 99.5%, MUD 98.4% and HAPLO 96.9% p=0.17). AML relapse was the major cause of death in each donor cohort. On univariate analysis, HAPLO was associated with a lower 2-year relapse incidence (RI) (MSD 41.1%, MUD 37.2%, HAPLO 20%) but a higher 2-year non-relapse mortality (NRM) (MSD 6.1%, MUD 19.3%, HAPLO 21.3%) compared with MSD and MUD. The 180-day cumulative incidence of grade II-IV acute GVHD (aGVHD) was lower in MSD (18.8%) than in MUD (31.3%) or HAPLO groups (26.5%), respectively. The 2-year leukemia-free survival (LFS), overall survival (OS) and GVHD-free/relapse free survival (GRFS) were comparable among the three cohorts. Lower RI was observed in patients with t(11;19) compared with t(6;11) or t(10;11). Complex karyotype (CK) (at least 3 abnormalities) or monosomal karyotype (MK) were both associated with higher RI compared with those without. In addition, in-vivo T cell depletion was related to lower intensive chronic GVHD (cGVHD) incidence. On multivariate analysis, HAPLO HCT was associated with lower RI (hazard ratio [HR=0.46], 95% CI 0.28-0.77; p&amp;lt;0.01) but higher incidence of NRM (HR=2.36, 95% CI 1.17-4.78; p&amp;lt;0.01) compared with MSD, while HAPLO had no significant impact on LFS, OS and GRFS. MUD HCT was associated with higher incidence of grade II-IV aGVHD (HR=1.82, 95% CI 1.19-2,78; p&amp;lt;0.01), NRM (HR=2.73, 95% CI 1.51-4.94; p&amp;lt;0.01), and lower LFS (HR=1.37, 95% CI 1.03-1.83; p&amp;lt;0.05) compared with MSD (reference). Concerning translocation type, t(11;19) was associated with a lower RI (HR=0.64, 95% CI 0.43-0.94; p=0.022), a better LFS (HR=0.66, 95% CI 0.48-0.91; p=0.012), OS (HR=0.63, 95% CI 0.45-0.89; p=0.008) and GRFS (HR=0.75, 95% CI 0.57-1; p=0.049) compared with t(6;11)(reference). Translocations other than t(6;11), t(11;19) or t(10;11) were related to a lower RI (HR=0.45, 95% CI 0.24-0.87) and better OS (HR=0.57, 95% CI 0.34-0.95) compared to t(6;11). MK was associated with higher RI (HR=1.59, 95% CI 1.04-2.45; p&amp;lt;0.05) and lower LFS (HR=1.47, 95% CI 1.01-2.14; p&amp;lt;0.05). Conclusions For AML patients with KMT2Ar, HAPLO HCT was associated with a lower RI but higher NRM, leading to similar LFS, OS and GRFS compared with MUD and MSD HCTs. In the setting of allo-HCT, t(11;19) seems to be associated with favorable outcomes compared with other KMT2Ar.

Reduced-Intensity Compared to Nonmyeloablative Conditioning in Patients with Non-Hodgkin Lymphoma Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Reduced-intensity conditioning (RIC) and nonmyeloablative (NMA) conditioning are preferred for patients with non-Hodgkin lymphoma (NHL) undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT). Although prior studies have suggested that higher-intensity regimens in RIC-NMA conditioning are associated with inferior outcomes in patients with NHL, the optimal conditioning regimen remains unknown. We performed a retrospective single-center analysis to determine outcomes of adult patients with B cell and T cell NHL who underwent allo-HCT and received either RIC or NMA conditioning between March 2008 and December 2019. RIC regimens included fludarabine-cyclophosphamide-thiotepa-4 Gy-total body irradiation (Flu-Cy-TT-4Gy-TBI), fludarabine-melphalan (Flu-Mel), fludarabine-cyclophosphamide-4 Gy-total body irradiation (Flu-Cy-4Gy-TBI), and fludarabine-busulfan-4 (Flu-Bu-4). The NMA regimen comprised fludarabine-cyclophosphamide-2 Gy-total body irradiation (Flu-Cy-2Gy-TBI). The primary outcome was overall survival (OS); secondary outcomes included progression-free survival (PFS), nonrelapse mortality (NRM), and the incidence of acute and chronic graft-versus-host-disease (GVHD). Of 279 transplants recipients (median age, 58 years), 110 received RIC (55% Flu-Mel, 38% Flu-Cy-TT-4Gy-TBI, 6% Flu-Bu-4, 1% Flu-Cy-4Gy-TBI) and 169 received NMA conditioning with Flu-Cy-2Gy-TBI. With a median of 64 months of follow-up post-allo-HCT, there was no significant difference in OS between the NMA and RIC groups (median, not reached [NR] versus 103 months; P=.1), and this was maintained on multivariable analysis. Similarly, after adjustment for all independently significant covariates (age, Karnofsky Performance Status [KPS], Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI], and disease histology), the regression analysis showed no significant difference in PFS with RIC compared to NMA conditioning (hazard ratio [HR] 1.38; 95% confidence interval [CI], .92 to 2.09; P=.24). On univariable analysis, there was no significant difference in NRM between the RIC and NMA arms (100-day estimate, 10.0% versus 1.8%; P=.5). After adjustment for age, ethnicity, KPS, HCT-CI, GVHD prophylaxis, and donor source, RIC conditioning was associated with a significantly higher incidence of NRM compared to NMA conditioning (HR, 2.61; 95% CI, 1.04 to 6.52; P=.039). On multivariable analysis, compared with the NMA arm, the RIC arm had higher rates of grade II-IV (HR, 2.25; 95% CI, 1.31 to 3.86; P=.002) and grade III-IV acute GVHD (HR, 5.62; 95% CI, 2.03 to 15.6; P < .001). The findings of this study suggest that NMA conditioning with Flu-Cy-TBI-2Gy may be considered over more intensive RIC regimens for patients with NHL undergoing allo-HCT.

Weight-adjusted urinary creatinine excretion predicts transplant outcomes in adult patients with acute myeloid leukemia in complete remission

Sarcopenia is a prognostic factor for cancer. Because creatinine is formed from creatine phosphate in muscle tissue, urinary creatinine excretion (UCE) serves as an index of muscle volume. However, as of yet, there are no studies assessing the clinical impact of UCE or weight- adjusted urinary creatinine excretion (WA-UCE) on allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. We analyzed the association between pre-transplant WA-UCE and transplant outcomes among 164 adult patients with acute myeloid leukemia in complete remission who underwent their first allo-HSCT at our center. The patients were classified into a high (n = 106) and a low WA-UCE group (n = 58) for predicting overall survival (OS) based on the receiver operating characteristics curve. On multivariate analysis, low WA-UCE was associated with poor OS, progression-free survival and a high incidence of non-relapse mortality. WA-UCE has the potential to be an objective biomarker for predicting transplant outcomes, especially the incidence of infection-related death.

Impact of Human Leukocyte Antigen Epitope Matching on Outcomes after Unrelated Bone Marrow Transplantation

Impact of Human Leukocyte Antigen Epitope Matching on Outcomes after Unrelated Bone Marrow Transplantation

Acute GvHD after HLA-Haploidentical Hematopoietic Cell Transplantation with Regulatory and Conventional T Cell Immunotherapy Does Not Adversely Affect Transplantation Outcomes

IntroductionAdoptive immunotherapy with CD4+CD25+FOXP3+ regulatory T cells (Tregs) and conventional T cells (Tcons) has been employed after allogeneic hematopoietic stem cell transplantation (HSCT) to prevent Graft-versus-Host Disease (GvHD) while mantaining Graft-versus-Leukemia effect in the absence of any further immune suppressive GvHD prophylaxis (Di Ianni, Blood 2011; Martelli, Blood 2014). A recent study of age-adapted haploidentical HSCT with Treg/Tcon adoptive immunotherapy (Treg/Tcon haplo-HSCT) resulted in an unprecedented 75% chronic GvHD (cGvHD)/leukemia-free survival (CRFS) in acute myeloid leukemia patients. Acute GvHD (aGvHD) occured in 33% of patients and was the most frequent complication of the procedure (Pierini, Blood Advances 2021). Here, we analyzed clinical and histological characteristics of aGvHD and evaluated its impact on outcomes in patients who received Treg/Tcon haplo-HSCT.MethodsWe retrieved data of patients who underwent Treg/Tcon haplo-HSCT at Perugia University Hospital and who were evaluable for aGvHD from January 2015 until June 2021 (clinicaltrials.gov: NCT03977103). Histological features and lymphoid infiltration by immunohistochemistry were analyzed in gut samples of patients who received diagnostic colonscopy and biopsy for gastrointestinal symptoms.ResultsA total of 105 patients engrafted after Treg/Tcon haplo-HSCT. Mean age at transplant was 48 years (range 18-70). Acute leukemia was the most frequent diagnosis (78/105 myeloid, 23/105 lymphoblastic), 4 patients had myelodisplastic syndrome and 2 multiple myeloma. Twenty-seven (26%) patients had active disease at the time of HSCT. Fourteen (13%) patients received Treg/Tcon haplo-HSCT as a second HSCT procedure. Thirty-one (29%) patients developed grade II-IV aGvHD. Four patients had grade II aGvHD, 23 grade III, and 4 grade IV. Almost all patients (90%) presented gut involvement, while skin was involved in 64% of them and liver in 35%. To explain why gut symptoms such as diarrhea and abdominal pain were more frequently present than symptoms of skin or liver involvement, we evaluated 40 histological samples from 34 patients who received colonoscopy for suspected aGvHD. Twenty-two of them (65%) received a clinical diagnosis of aGvHD and pharmacological immune suppression was promptly started. Clinical diagnosis did not always match histological findings: biopsies were suggestive of aGvHD in 20/22 patients who required treatment, but also in 8/12 patients who did not. We found no difference in median CD3+ cell infiltration among patients who did not need immune suppressive treatments and patients with aGvHD (460 cells/mmq vs 446 cells/mmq). However, FOXP3+ Tregs preferentially infiltrated gut mucosa of patients who resolved clinical symptoms with no need of immune suppressive treatments (120 cells/mmq vs 59 cells/mmq, p = 0.008; FOXP3/CD3 ratio: 0.27 vs 0.18, p = 0.004). This observation suggested Treg defective homing to gut mucosa of aGvHD patients. Indeed, we found infused Tregs expressed lower levels of gut homing receptor α4β7 in comparison with Tcons (p< .001).Despite severe presentation at diagnosis, aGvHD resolved in the majority of patients (71%), and immune suppressive therapy could be completely withdrawn after a relatively short-course (median: 98 days, range 48-404). Sixteen/31 patients (52%) were steroid refractory and required further treatments after first-line (e.g. Ruxolitinib). Only two of them developed moderate/severe cGvHD and one is alive and off-therapy.Indeed, aGvHD diagnosis did not result in higher incidence of non-relapse mortality (cumulative incidence of 29% in aGvHD patients vs 27% in controls; p=non significant, ns, Fig.1A), relapse (13% vs 20%; p=ns, Fig.1B), or cGvHD (6.5% vs 3%; p=ns, Fig.1C). In fact, CRFS of aGvHD patients was similar to CRFS of patients that did not develop aGvHD (Fig. 1D, p=ns, median follow up of live patients: 1246 days).ConclusionsTreg/Tcon haplo-HSCT is followed by low rates of relapse and cGvHD and results in good CRFS in high risk leukemia patients. aGvHD after Treg/Tcon haplo-HSCT preferentially involves the gut where Treg homing is defective. Strategies that enhance Treg homing in the gut (e.g. low-dose IL-2) may help reduce aGvHD after Treg/Tcon haplo-HSCT. In conclusion, despite aGvHD occurred in 29% of patients, it was responsive to treatments and it did not result in disease relapse or cGvHD. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Remission Status at Transplantation and Treatment History Determine the Survival Chances of Patients after Allogeneic Hematopoietic Stem Cell Transplantation for Chronic Lymphocytic Leukemia Who Had Received Pre-Treatment with Idelalisib: A Report from the EBMT Chronic Malignancies Working Party

BACKGROUND: Numbers of patients with high-risk Chronic Lymphocytic Leukemia (CLL) who have failed Ibrutinib, Idelalisib or Venetoclax when they are referred for allogeneic hematopoietic stem cell transplantation (alloHCT) are increasing. No data is available on patients with CLL who were referred for alloHCT and were on Idelalisib prior to the start of the conditioning regimen. Therefore, we retrospectively analyzed registry data on patients with CLL who had been exposed to idelalisib prior to alloHCT.METHODS: Patients were eligible if they had been registered with the EBMT data office for alloHCT for CLL after exposure to idelalisib at any time before transplantation. Minimal essential transplant data were collected on standard forms.RESULTS: As of June 23, 2017, 45 patients with CLL (67% male) had received alloHCT after exposure to idelalisib and were registered with EBMT. Median age at alloHCT was 58 (36-68) years. Almost all patients (98%) had a Karnofsky Performance Status of 80% or higher. 42% of patients had CLL with deletion 17p and/or TP53-mutation. The median number of treatment lines prior to alloHCT was 4 (1-7), including treatment with ibrutinib in 11 patients (24%) and venetoclax in 2 patients (4%). Idelalisib plus Rituximab was the last regimen administered prior to alloHCT in 38 patients (84%). Complete or partial remissions were reported for 80% of patients at the time of alloHCT. Reduced intensity and myeloablative conditioning was administered in 71% and 29% of patients. Anti-Thymocyte globulin was given to 64% of patients and alemtuzumab to 27% of patients. Donors were HLA-identical siblings for 36% of patients, mismatched related donors for 13% of patients and unrelated donors for the remaining patients. One patient received cord blood and three patients received bone marrow, while the predominant graft sources were peripheral blood stem cells. No primary graft failure and one secondary graft failure were reported. Acute GVHD grade 2-4 was observed in 44% of evaluable patients, and chronic GVHD in 25% of patients at risk.Thirty-three patients were alive at last follow-up with a median observation time of 8 (0-24) months after alloHCT and 12 patients had died. Three patients died following relapse or progression whereas 9 patients died from complications after alloHCT with infections being the cause of death which was reported most often. For the whole cohort of patients, the probability of 12-month progression-free and overall survival (OS), relapse incidence and non-relapse mortality was 57% (95%-CI, 38% to 75%) and 60% (95%-CI, 41% to 79%), 14% (95%-CI, 2% to 26%), and 29% (95%-CI, 12% to 47%) respectively. Overall survival of patients who had received Idelalisib as last treatment prior to alloHCT was not statistically different to patients who had received Idelalisib in their pre-treatment history but had received other bridging therapy immediately prior to alloHCT. Patients who were not in remission at the time of alloHCT had a trend towards worse OS (OS at 6-months 63% versus 85%, log-rank test p=0.07). Notably, patients who had received greater or equal versus less than 4 lines of pre-treatment had a lower survival probability (74% versus 84%, log-rank test, p=0.009). Also, patients who had been treated with both pathway inhibitors, ibrutinib and idelalisib, had worse survival chances compared to patients pre-treated with idelalisib only (OS at 6-months 51% versus 89%, log-rank test, p=0.03).CONCLUSIONS: The relatively high incidence of non-relapse mortality in the first year after alloHCT in this contemporary cohort of patients is a warning signal. However, the pattern of results (better survival in patients who achieved a remission prior to alloHCT and with less extensive pre-treatment) indicates that idelalisib itself is a valuable bridging option for patients with high-risk CLL scheduled for alloHCT in time. Patients with far advanced disease stages especially after failure on BTK-inhibition are at high risk of early mortality after alloHCT. DisclosuresSchetelig:Sanofi Aventis: Consultancy, Research Funding; Roche: Honoraria; Abbvie: Honoraria; Janssen: Consultancy, Honoraria. Delgado:Abbvie, Jansen, Gilead, Roche: Consultancy, Speakers Bureau. Mayer:Novartis: Research Funding; Eisai: Research Funding. Thieblemont:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

Allogeneic Blood or Marrow Transplantation (BMT) with Post-Transplantation Cyclophosphamide (PTCy) Based Graft Versus Host Disease (GVHD) Prophylaxis for Myelodysplastic Syndrome/ Myeloproliferative Neoplasm-Overlap Syndromes (MDS/MPN)

INTRODUCTION: MDS/MPN are a group of clonal hematopoietic disorders with overlapping features of MDS and MPN, and include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN-unclassifiable along with juvenile myelomonocytic leukemia and MDS/MPN with ring sideroblast and thrombocytosis. Therapeutic options for MDS/MPN remain limited and BMT remains the only modality with curative potential. However, the overall survival of these patients following BMT remains poor marked by a high incidence of non-relapse mortality (NRM) and relapse. Moreover, most of the published cohorts consisted of patients receiving matched related donor grafts, with limited data on the outcomes of patients receiving grafts from alternative donors. In the current study, we aim to describe outcomes of BMT for MDS/MPN using PTCy as the GVHD prophylaxis platform and primarily haploidentical related (haplo) donors. PATIENTS AND METHODS: We performed a retrospective analysis of patients with MDS/MPN who underwent BMT with PTCy at Johns Hopkins between 1/2011-1/2019. Kaplan-Meier analysis was used to evaluate overall survival (OS), relapse-free survival (RFS), and GVHD/relapse-free survival (GRFS). Cumulative incidence of relapse and non-relapse mortality (NRM) were estimated non-parametrically in presence of competing events where NRM was a competing event of relapse, and vice versa. Univariate analysis was used to evaluate the impact of donor type, HCT-CI, and karyotype on these clinical outcomes via Cox proportional hazard models for OS/RFS/GRFS, and Fine-Gray's sub-distribution (s) hazard models for relapse/NRM/GVHD. RESULTS: Thirty-four consecutive patients (11 women and 23 men) with a median age of 63 years (range 51-74) at the time of BMT were identified. Of these, 21 (61.8%) had haplo donors and 31 (91%) received non-myeloablative conditioning with fludarabine, cyclophosphamide and total body irradiation. Median follow up was 3.9 years (range: 24 days - 8.4 years) based on reverse Kaplan-Meier approach. Other patient, disease and BMT related details are shown in Table 1. Time to neutrophil and platelet recovery was 22 days (range 19 - 28 days) and 31 days (range 22 - 67 days), respectively. Two (6%) patients had primary graft failure, both had received a marrow graft. At 3-years, probability of OS was 46% (95% CI: 31% - 68%), 3 RFS was 30% (17% - 51%), GRFS was 26% (14%-48%), cumulative incidence of relapse was 59% (95% CI: 41% - 77%) and incidence of NRM was 12% (95% CI: 1% - 23%). The incidence of grade 2-4 acute GVHD at 1 year following HCT was 24% but no patients had grade 3-4 acute GVHD. The cumulative incidence of any chronic GVHD at 3 years was 20% with 3 (9%) patients requiring systemic therapy. Univariate analysis showed that HCT-CI score at the time of HSCT was associated with higher incidence of relapse (sHR 5.22, 95% CI 2.26-12.08) and inferior RFS (HR 3.09, 95% CI 1.16-8.2). Other patient-, disease- and HCT-related factors were not statistically significantly associated with these clinical outcomes. The outcomes of patients with haplo donors (n=21) were also estimated at 3 years and estimates of OS were 56% (95% CI 38% - 82%), RFS 42% (95% CI 26% - 70%), GRFS 37% (21% - 66%), cumulative incidence of relapse 43% (95% CI 21% - 66%), NRM 14% (95% CI 1% - 30%), chronic GVHD 21% (95% CI 2% - 40%). No patients developed grade 3-4 acute GVHD. While the sample size is limited, comparison of K-M estimates for RFS and relapse with haplo donor (n=21) and matched related/unrelated donor (n=12), is shown in Figure 1. CONCLUSIONS: We report, for the first time, clinical outcomes of BMT for MDS/MPN with the PTCy based GVHD platform, and outcomes appear comparable with those previously described in other retrospective studies using conventional approach. Although limited by sample size for a statistical analysis, the outcomes with haplo donor BMT appear promising. The relatively high incidence of relapse in these patients appears to be the major factor contributing adversely to outcomes, while NRM and GVHD incidence with our non-myeloablative conditioning PTCy platform are low. We are currently exploring strategies to decrease relapse rates to further improve BMT outcomes in these patients. Disclosures Levis: Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Menarini: Honoraria; Astellas: Honoraria, Research Funding. DeZern:MEI: Consultancy; Astex: Research Funding; Abbvie: Consultancy; Celgene: Consultancy, Honoraria. Gojo:BMS: Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Amgen: Research Funding; Merck: Research Funding; Amphivena: Research Funding. Jain:Takeda: Consultancy, Honoraria; CareDx: Other: Advisory Board; Bristol Myer Squibb: Other: for advisory board participation.

Early Immunosuppressive Therapy for Idiopathic Pneumonia Syndrome Prior to Bronchoscopy Is Associated with Favourable Outcomes

Introduction: Idiopathic pneumonia syndrome (IPS) is a dangerous complication following haematopoietic stem cell transplantation (HSCT). Immunosuppressive therapy (IST) using high-dose methylprednisone and etanercept produces complete response (CR) in the majority of IPS cases. However, exclusion of respiratory pathogens by bronchoscopy prior to IST commencement carries procedural risks that may worsen respiratory failure and IPS severity, with potential negative impact upon IST response and survival. Given this, we perform bronchoscopy post-IST commencement only in those patients with only mild (nasal oxygen) or severe (already intubated) respiratory failure. We commence IST within 24 hours of clinical and radiological suspicion of IPS, and cease IST if alternative aetiologies are subsequently proven. Aim: We aimed to evaluate the safety and efficacy of our local early-intervention IST strategy in patients with new-onset suspected IPS following HSCT. Methods: We performed a retrospective, single-centre descriptive cohort study of patients who received IST for IPS between 2014-2019. Details collected included: patient demographics, IPS diagnostic details/severity, IST response, and survival. The primary study objectives were the incidence of complete response (CR), defined by cessation of supplemental oxygen for at least 48 hours, and overall survival (OS) following IST. IST comprised high-dose corticosteroids (methylprednisolone 2mg/kg/day or equivalent) and etanercept (25mg twice weekly for 4 weeks, then weekly to complete 12 total doses). Results: Of the 480 HSCT performed during the study period, 17 patients developed suspected IPS and received IST. At IPS diagnosis, 10 (59%) required intensive care admission. Non-invasive (NIV) and invasive (IV) ventilation was required in 4 (24%) and 5 (29%) patients, respectively. All patients met clinical and radiological American Thoracic Society (ATS) criteria for IPS. Bronchoscopy was only performed in 9 (53%), comprising all 5 receiving IV and 4 who were only requiring supplemental nasal oxygen. All 4 patients receiving NIV were considered too high-risk for post-bronchoscopy intubation, so did not proceed. Of those who underwent bronchoscopy, none experienced worsening respiratory failure, however 1 received a revised diagnosis of bacterial pneumonia and ceased IST within 3 days of commencement, and survived. In the remaining 16 patients, CR to IST was achieved in 14 (88%) patients, with 1-year OS of 44%. However, at a mean 17 months follow-up, OS for the whole cohort was 31% (Figure 1), reflecting a high incidence of non-relapse mortality (NRM) at 63% (Table 1). There was no significant difference in response or survival between patients who did or did not undergo bronchoscopy. Conclusion: Our early-intervention IST strategy for IPS appears to produce similar response rates and survival as those reported in other prospective and retrospective series, without any obvious safety concerns. Although adherence to ATS diagnostic criteria and exclusion of occult infectious aetiologies is preferred, bronchoscopy may be safely delayed or omitted in a subset of patients. Early intervention may arrest the respiratory failure and ultimately avoid mechanical ventilation. Disclosures No relevant conflicts of interest to declare.

Glucagon-like peptide 2 for intestinal stem cell and Paneth cell repair during graft-versus-host disease in mice and humans

AbstractAcute graft-versus-host disease (GVHD) is a life-threatening complication after allogeneic hematopoietic cell transplantation (allo-HCT). Although currently used GVHD treatment regimens target the donor immune system, we explored here an approach that aims at protecting and regenerating Paneth cells (PCs) and intestinal stem cells (ISCs). Glucagon-like-peptide-2 (GLP-2) is an enteroendocrine tissue hormone produced by intestinal L cells. We observed that acute GVHD reduced intestinal GLP-2 levels in mice and patients developing GVHD. Treatment with the GLP-2 agonist, teduglutide, reduced de novo acute GVHD and steroid-refractory GVHD, without compromising graft-versus-leukemia (GVL) effects in multiple mouse models. Mechanistically GLP-2 substitution promoted regeneration of PCs and ISCs, which enhanced production of antimicrobial peptides and caused microbiome changes. GLP-2 expanded intestinal organoids and reduced expression of apoptosis-related genes. Low numbers of L cells in intestinal biopsies and high serum levels of GLP-2 were associated with a higher incidence of nonrelapse mortality in patients undergoing allo-HCT. Our findings indicate that L cells are a target of GVHD and that GLP-2–based treatment of acute GVHD restores intestinal homeostasis via an increase of ISCs and PCs without impairing GVL effects. Teduglutide could become a novel combination partner for immunosuppressive GVHD therapy to be tested in clinical trials.

ST2 and REG3α as Predictive Biomarkers After Haploidentical Stem Cell Transplantation Using Post-transplantation High-Dose Cyclophosphamide.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a curative procedure for several hematological malignancies. Haploidentical HSCT (haplo-HSCT) using high-dose post-transplantation cyclophosphamide (PTCy) makes transplantation possible for patients with no HLA-matched sibling donor. However, this treatment can cause complications, mainly infection, graft-vs.-host disease (GVHD), and conditioning-related toxicity. In recent years, different biomarkers in the form of tissue-specific proteins have been investigated; these may help us to predict complications of allo-HSCT. In this study we explored two such biomarkers, suppression of tumorigenicity 2 (ST2) and regenerating islet-derived 3α (REG3α), in the largest series reported of T cell–replete haplo-HSCT with PTCy. Plasma samples drawn from 87 patients at days +15 and +30 were analyzed. ST2 and REG3α levels at day +15 were not associated with post-transplant complications. ST2 levels at day +30 were higher in patients with grade II-IV acute GVHD, mainly those who received reduced intensity conditioning (RIC; median 2,503 vs. 1,830 ng/ml; p = 0.04). Of note, patients with higher plasma ST2 levels at day +30 also presented a higher incidence of non-relapse mortality (HR, 7.9; p = 0.004) and lower 2-year overall survival (25 vs. 44 months; p = 0.02) than patients with lower levels. Patients with REG3α levels higher than 1,989 pg/ml at day +30 presented a higher incidence of acute gastrointestinal GVHD in the whole cohort (HR, 8.37; p = 0.003) and in the RIC cohort (HR 6.59; p = 0.01). These data suggest that measurement of ST2 and REG3α might be useful for the prognosis and prediction of complications in patients undergoing haplo-HSCT with PTCy.

HLA-10/10 matched unrelated donor versus sibling donor hematopoietic stem cell transplantation for adult acute myeloid leukemia

目的观察人类白细胞抗原（HLA）匹配的无关供者造血干细胞移植（MUD-HSCT）治疗成人急性髓系白血病（AML）的疗效。方法回顾性分析2008年1月至2017年4月接受MUD-HSCT的成人AML病例资料，并以同期同胞全相合供者移植（MSD-HSCT）病例为对照，分析两组患者总生存（OS）率、无病生存（DFS）率、复发率、非复发死亡率（NRM）、植活率及急慢性移植物抗宿主病（aGVHD、cGVHD）发生率的差异。结果共247例连续性病例入组，MUD组46例，MSD组201例。除1例MSD组患者早期死亡外，两组患者均获粒细胞植活，但MUD组中位植活时间长于MSD组（15 d对14 d，P=0.017），血小板累积植活率差异无统计学意义（93.5%对98.0%，P=0.128）。两组患者aGVHD、cGVHD累积发生率差异无统计学意义（50.0%对46.3%，P=0.421；37.8%对43.0%，P=0.581）。与MSD组相比，MUD组患者3年累积NRM显著升高（22.0%对10.4%，P=0.049），但累积复发率差异无统计学意义（20.5%对28.3%，P=0.189）。两组患者3年OS率和DFS率差异均无统计学意义（61.6%对63.3%，P=0.867；57.5%对61.6%，P=0.760）。经多因素分析发现，患者年龄≥45岁、移植前第2次完全缓解（CR2）及以上或未缓解状态、有髓外浸润病史及Ⅲ~Ⅳ度aGVHD是影响生存的独立危险因素。结论与MSD-HSCT相比，MUD-HSCT治疗成人AML的NRM较高，粒细胞植活中位时间较长，但GVHD发生率、复发率、OS率及DFS率并无显著差异，是缺乏MSD的成人AML患者的理想替代移植方案。

Reduced Intensity Vs Myeloablative Conditioning Regimen for Pediatric Therapy-Related Myelodysplastic Syndrome/Acute Myeloid Leukemia

Introduction Therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML) are rare but well-recognized complications of cancer therapy. Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning (MAC) remains the mainstay of treatment but is associated with a high incidence of non-relapse mortality (NRM). Reduced intensity conditioning (RIC) may reduce NRM in these heavily pre-treated patients. The primary objective of this study was to compare outcomes following RIC and MAC regimens in patients receiving an allogeneic HCT. Methods Retrospective chart review of patients Results One hundred and forty-seven patients were included with 29 (19.7%) receiving RIC and 115 (78.2%) MAC (Table 1). The median follow-up of entire cohort was 13.4 (0-246) months. OS and EFS of the entire cohort was 44.7% (95% CI: 37.1-53.9) and 40.2% (95% CI: 32.8-49.3) at 3 years, respectively, and there was no significant difference between MAC and RIC cohorts (Fig A & B). Karnofsky performance status of the patients (>=90) was the only factor that was found to be statistically associated with improved EFS (HR 0.49, p=0.01). NRM was noted in 61% of patients after MAC compared to 28% after RIC, however disease relapse was a major cause of death after RIC (Fig C & D). The majority of transplants were performed after 2005 (81.6%) and outcomes seem to be slightly better in contemporary era due to improved supportive care and decreased NRM. Conclusion This is one of the largest reported cohorts of pediatric patients receiving allogeneic transplantation for t-MDS/AML. Outcomes are poor relative to de novo MDS/AML due to high rate of NRM with MAC and high rate of disease related death after RIC. Novel strategies that lead to a reduction in transplant-related mortality in these heavily pre-treated patients while providing sufficient disease control are needed to improve survival in t-MDS/AML patients receiving HCT.

CD34+Selected Hematopoietic Stem Cell Transplants Conditioned with a Myeloablative Regimen Is Well Tolerated and Results in Good Outcomes in Patients with Myelofibrosis

Background: Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) remains the only curative treatment for myelofibrosis (MF). Due to high incidence of non-relapse mortality (NRM) in patients with MF who underwent allo-HCT with myeloablative conditioning (MAC), transplants in these patients are mostly done by utilizing a reduced intensity conditioning regimen with calcineurin inhibitors for graft versus host disease (GVHD) prophylaxis. We previously published very good outcomes in patients with acute leukemia (AML and ALL) and myelodysplastic syndrome (MDS) who underwent Ex- vivo CD34+-selected T-cell depleted (TCD) allo-HSCT following MAC regimens (Barba P et al. BBMT 2017; Tamari R et al. BBMT 2018).Aim: To study retrospectively the outcomes of patients with primary or secondary myelofibrosis (PMF or SMF) who underwent a CD34+ cell-selected Allo-HSCT.Methods: Twenty-one MF patients who underwent a CD34+-selected Allo-HSCT at a single center between October 2010 and November 2017 were included in this retrospective analysis. All patients received MAC regimen including busulfan, melphalan and fludarabine and antithymocyte globulin to prevent graft rejection. None of the patients received post-transplant GVHD prophylaxis. G-CSF mobilized peripheral blood stem cell grafts were depleted of T-cells using immunomagnetic CD34+ selection by CliniMACS device. Overall survival (OS), relapse free survival (RFS), relapse, NRM and the composite endpoint of GVHD-free/relapse-free survival (GFRS: defined as grade 3-4 acute GVHD, chronic GVHD requiring systemic treatment, relapse, or death) were estimated using the Kaplan-Meier and cumulative incidence method, with death considered a competing risk for relapse. Log-rank and Gray's tests were used to assess differences in patient and treatment characteristics.Results: Patient's and donor's characteristics are summarized in table 1. Neutrophils engraftment occurred in all patients at a median of 11 days (range: 8 - 14) and 90% (N = 19) achieved platelet engraftment at a median of 24 days (range, 14 - 77). Another patient achieved platelet engraftment only after splenectomy which was performed on post-transplant day 54. With a median follow-up of 54.06 months, the estimated 3-year OS and RFS were 84.4 % (95% CI, 69.6% to >99.9%) and 74.7% (95% CI, 57.6 to 96.9%), respectively (figure 1). The cumulative incidence of grade II-IV acute GVHD at day 100 was 33.3% (95% CI 11.2-54.1%); majority (N=5) had grade II and 2 patients had grade III (N=1) and grade IV (N=1) acute GVHD. Chronic GVHD developed in 2 patients including only 1 case requiring systemic treatment. The 3-year cumulative incidence rate of relapse was 9.5% (95% CI, <0.1 to 22.4%); three relapse cases include 2 patients with molecular/cytogenetic relapse and 1 patient with clinical relapse. Patients who relapsed were treated with donor lymphocyte infusion (DLI) (N=1), with azacytidine plus DLI (N=1) and both are alive with minimal molecular disease. The 3rd patient is alive without evidence of disease recurrence 43 months after second unmodified Allo-HSCT from the original donor. NRM at 3 years was 15.6% (95% CI, <0.1% to 32.4%) and the cause of all deaths (n=3) was primarily attributed to acute GVHD. The estimated 3-year GRFS was 66.7% (95% CI, 49.3 to 90.2%) (figure 2). TCD boost and unmodified boost were conducted successfully for patients with poor graft function (N=1) and late graft failure (N=1). Six patients received 8 DLIs for the following indications: mixed chimerism (N=3), relapse (N=3) and poor immune reconstitution (N=2).Conclusions: In this analysis we demonstrate that CD34+ selected Allo-HSCT following a chemotherapy only based MAC regimen is well-tolerated and an effective treatment for patients with myelofibrosis. We noted higher incidence of acute GVHD when compared to our reported outcomes in patients with acute leukemia and MDS undergoing a CD34+ selected allo-HSCT and all cases of mortality in this analysis were secondary to GVHD. This may suggest differences in the biology of the diseases and a more inflammatory milieu in pts with MF. Relapse incidence was notably low and all patients who relapsed were salvaged with further cellular therapy suggesting a strong graft-versus-leukemia effect in this disease. DisclosuresSauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Perales:Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Novartis: Other: Personal fees; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees.

Graft-Versus-Leukemia Effect after Haplo-Identical Stem Cell Transplantation with Post-Transplant Cyclophosphamide in Patients with AML- No Association with Graft-Versus-Host Disease: A Study on Behalf of the Acute Leukemia Working Party of EBMT

Introduction. Allogeneic stem-cell transplantation (SCT) is a curative approach in acute myeloid leukemia (AML) by providing dose-intensive chemo-radiotherapy and enhancing a graft-versus-leukemia (GVL) effect. The GVL effect is provided by alloimmune T- cells and is usually closely associated with graft-versus-host disease (GVHD). Patients with GVHD have a lower incidence of relapse, but at high grades a higher incidence of non-relapse mortality (NRM). However, GVL can also occur independently of GVHD. The use of haplo-identical SCT is rapidly increasing over the last decade due to the introduction of non-T depleted methods, in particular with post-transplant cyclophosphamide (PTCy), with expected outcomes that are similar to other donor sources. The GVL effect after T- depleted haplo-identical SCT is mostly related to natural-killer cell alloreactivity and is not necessarily associated with GVHD. However, there is no definite data whether GVL after SCT in the non-T depleted setting is similarly associated with GVHD as in the matched donor setting.Methods. We assessed the impact of acute and chronic GVHD on SCT outcomes in patients with AML following non-T depleted haplo-identical SCT with PTCy, by using a series of landmark analyses.Results. The study included 605 patients with AML in CR1 (73%) or CR2 (27%) after non-T depleted haplo-identical SCT with PTCy, given during the years 2009-2016. The median age was 53 years (range, 18-76). 71% had myeloablative conditioning and 29% had reduced-intensity conditioning . The overall rate of acute GVHD grade II-IV and III-IV was 28.4% and 8.0%, respectively. The rates of chronic GVHD all grades and extensive were 32.7% and 12.3%, respectively. The rate of relapse and NRM were 21.8% and 18.2% and the rates of leukemia-free survival (LFS) and overall survival, 2 years after SCT were 59.9% and 64.1%, respectively. 509 patients were alive and leukemia-free 100 days after transplant. 366 had no prior acute GVHD at this landmark, 107 had acute GVHD grade II and 36 had grade III-IV. The overall rate of subsequent relapse was 20.3%, 18.3% and 11.9%, respectively (P=0.60). The overall rates of subsequent NRM were 10.3%, 19.0% and 35.7%, respectively (P<0.001). The rates of LFS were 69.4%, 62.6% and 52.4%, respectively (P=0.01). Multivariate analysis showed that acute GVHD grade II before day 100 was not associated with subsequent relapse (Hazard ratio (HR) 1.02, P=0.93), had borderline association with NRM (HR 1.79, P=0.09) and no association with LFS (HR 1.28, P=0.27). Acute GVHD grade III-IV before day 100 was not associated with subsequent relapse (HR 0.92, P=0.87), while it was associated with higher NRM (HR 5.23, P<0.001) and inferior LFS (HR 2.35, P=0.003). Both acute GVHD grade II and grade III-IV were associated with subsequent extensive chronic GVHD, HR 2.02 (P=0.04) and 6.93 (P<0.001), respectively. 393 patients were alive and leukemia-free 6 months after transplant. Out of them 316 had no prior chronic GVHD at this landmark, 55 had limited and 22 extensive chronic GVHD. The overall rate of subsequent relapse was 14.3%, 9.2% and 23.9%, respectively (P=0.60). The overall rates of subsequent NRM were 7.3%, 10.4% and 31.7%, respectively (P=0.003). The rates of LFS were 78.4%, 80.4% and 44.4%, respectively (P=0.01). Multivariate analysis showed that limited grade chronic GVHD occurring before 6 months was not associated with subsequent relapse (HR 0.69, P=0.44), NRM (HR 1.43, P=0.55) or LFS (HR 0.88, P=0.74). Extensive chronic GVHD was not associated with subsequent relapse (HR 1.44, P=0.56) but was associated with higher NRM (HR 5.77, P=0.004) and inferior LFS (HR 2.75, P=0.01). Similar results were seen for prior chronic GVHD at the 1 year landmark.Conclusions. By a series of landmark analyses at 100 days, 6 months and 1 year after SCT, we did not find any association of acute GVHD grade II or III-IV or chronic GVHD (limited or extensive) with subsequent relapse. Acute GVHD grade III-IV was associated with a higher NRM and lower LFS rates after day100. All grades of acute GVHD were associated with a higher incidence of chronic GVHD. Previous extensive chronic GVHD was also associated with a higher NRM and a lower LFS. GVL is thus not associated with GVHD after non T-deleted haplo-identical SCT with PTCy. Future novel strategies for prevention of significant GVHD are warranted. DisclosuresAngelucci:Vertex Pharmaceuticals Incorporated (MA) and CRISPR CAS9 Therapeutics AG (CH): Other: Chair DMC; Roche Italy: Other: Local (national) advisory board; Novartis: Honoraria, Other: Chair Steering Comiittee TELESTO Protocol; Celgene: Honoraria, Other: Chair DMC; Jazz Pharmaceuticals Italy: Other: Local ( national) advisory board. Mohty:MaaT Pharma: Consultancy, Honoraria.

Effect of pre-transplantation serum ferritin on outcomes in patients undergoing allogeneic hematopoietic stem cell transplantation: A meta-analysis.

Background:Pre-transplantation serum ferritin (SF) has been considered to be a potential prognostic biomarker in patients undergoing allogeneic hematopoietic stem cell transplantation (allogeneic HSCT), but this conclusion remains controversial. Thus, we performed a meta-analysis to investigate the prognostic significance of pre-transplantation SF in patients undergoing allogeneic HSCT.Methods:We systematically searched PubMed, Embase, and Web of Science up to September 2017, and finally identified a total of 25 eligible studies with 4545 patients.Results:The pooled results of our meta-analysis showed that high pre-transplantation SF was markedly related to worse overall survival (OS) [hazard ratio (HR) = 1.82; 95% confidence interval (95% CI): 1.47–2.26; P < .001], nonrelapse mortality (NRM) (HR = 2.28; 95% CI: 1.79–2.89; P < .001), and progression-free survival (PFS) (HR = 1.72; 95% CI: 1.27–2.33; P < .001). In addition, high pre-transplantation SF was closely associated with a lower incidence of chronic graft versus host disease (cGVHD) (OR = 0.74, 95% CI: 0.58–0.96; P < .05), and a higher incidence of blood stream infections (BSIs) (OR = 1.67, 95% CI: 0.93–3.01; P = .09). However, no significance relationship was found between elevated pre-transplantation SF and acute graft versus host disease (aGVHD) (OR = 1.08, 95% CI:.72–1.62; P = .70).Conclusion:In patients undergoing allogeneic HSCT for hematological malignancies, elevated pre-transplantation SF was significantly associated with worse OS and PFS, higher incidence of NRM and BSI, and lower incidence of cGVHD, but it had no effect on aGVHD. Considering the limitations in our meta-analysis, more prospective and homogeneous clinical studies are needed to further confirm our findings.

Late Gastrointestinal Complications of Allogeneic Hematopoietic Stem Cell Transplantation in Adults

Gastrointestinal (GI) complications including graft-versus-host disease (GVHD) are a major cause of morbidity and mortality in allogenic stem transplant recipients. Although several studies have previously looked into the acute GI complications, fewer smaller studies have reported late complications. In this large study we focus on the late (100 days post-transplant) GI complications in allogenic stem transplant recipients. In this single-center, retrospective study of all adult allogenic stem cell transplant recipients who had their transplant at Duke University over a 6-year period, 479 patients underwent allogenic stem cell transplant, of whom 392 recipients survived for at least 100 days post-transplant. Late GI symptoms were noted in 71 patients, prompting endoscopic evaluation. The primary endpoint of our study was the diagnosis of GI-GVHD based on endoscopic findings, whereas overall survival and nonrelapse mortality were the secondary endpoints. Of the 71 patients who underwent endoscopy, 45 (63%) had GI-GVHD. Of these 45 patients, 39 (87%) had late acute GVHD, 1 (2%) had chronic GVHD, and 5 patients (11%) had overlap disease. Of the patients who did not have GVHD, the symptoms were mostly related to infectious and inflammatory causes. Less common causes included drug toxicity, food intolerance, disease relapse, and motility issues. In a multivariate analysis the factors most indicative of GI-GVHD were histologic findings of apoptosis on the tissue specimen (odds ratio, 2.35; 95% confidence interval, 1.18 to 4.70; P = .015) and clinical findings of diarrhea (odds ratio, 5.43; 95% confidence interval, 1.25 to 23.54; P = .024). The median survival time from the first endoscopy was 8.5 months. The incidence of nonrelapse mortality at 6 months was 31% in patients with GI-GVHD and 19% in patients without GI-GVHD (P = .42). All patients with GI-GVHD were on steroid therapy, and 31% of them received total parenteral nutrition. In our population close to one-fifth of allogenic transplant recipients experienced late GI complications, warranting endoscopic evaluation. Most of these patients were found to have GI-GVHD that had a high incidence of nonrelapse mortality at 6 months and close to one-third of these patients needed total parenteral nutrition.

Clinical Impact of Pre-Transplant Microbial Diversity on Transplant Outcomes

IntroductionIn allogeneic stem cell transplantation (allo-SCT), recent reports have shown that post-transplant microbial diversity of the gastrointestinal tract is closely associated with clinical outcomes. Furthermore, pre-transplant microbial status has also been associated with the development of acute graft-versus-host disease (GVHD). These results indicate that pre-transplant microbial ecosystem may influence the immune system after allo-SCT, induce alloimmune response such as GVHD, and may finally affect the transplant outcome. Thus, we evaluate the association between pre-transplant microbial diversity and transplant outcomes.Patients and MethodsBetween April 2013 and March 2015, fecal samples were obtained from 107 patients in Komagome hospital. Fecal samples were collected within 2 weeks before conditioning. Microbial analysis was performed using 16S rRNA gene (hypervariable V1-2 region) sequencing. Operational taxonomic units (OTU)-based microbial diversity was estimated by calculating the Shannon index. Patients were classified into 3 groups based on the diversity index: low (<2), intermediate (2-3), and high (>3) diversity group, and we evaluated transplant outcomes such as survival, non-relapse mortality, and the cumulative incidence of GVHD, in these 3 groups.ResultsAmong the 107 patients, there were 18 (16.8%) patients in the low diversity group, 48 (44.9%) in the intermediate diversity group, and 41 (38.3%) in the high diversity group. The median age of all patients was 49 (range: 16-72) years. The median follow-up period for survivors was 597 days (range, 23-1,046 days). We found no significant differences among 3 groups in terms of age, gender, underlying disease, disease status, performance status, hematopoietic cell transplantation comorbidity index, GVHD prophylaxis, conditioning regimen, stem cell sources, and human leukocyte antigen disparity. However, the patients in the low diversity group received intravenous antibiotics just before the conditioning more frequently compared to the patients in the intermediate /high diversity groups.The patients in the low diversity group showed poor survival (p=0.37, Figure 1a), higher non-relapse mortality (p=0.25, Figure 1b) and higher incidence of grade II-VI gastrointestinal GVHD (p=0.77, Fgiure 1c) compared with the patients in the intermediate /high diversity group although these results were not statistically significant. The cumulative incidence of relapse was similar between 3 groups. When compared between patients with and without acute GVHD, the composition of microbiota did not differ significantly between these patients.Discussion and conclusionOur results indicate that pre-transplant microbial diversity did not affect transplant outcomes. Furthermore, in contrast to previous report, the microbial composition was also irrelevant to the development of GVHD. Bacterial translocation after allo-SCT is a key trigger for the development of acute GVHD. Thus, microbial status in this period would be more important than that before allo-SCT. However, the patients in the low diversity group tended to show poor survival, higher incidence of non-relapse mortality and GVHD. Thus, further evaluation with larger sample size might be necessary to confirm the association between pre-transplant microbial ecosystem and transplant outcomes. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Outcomes of Unrelated Cord Blood Transplantation in Patients with Multiple Myeloma a Eurocord, CBC-Cellular Therapy & Immunobiology Working Party and Chronic Malignancies Working Party-EBMT Study

Although outcomes for multiple myeloma (MM) have improved with the use of drugs such as bortezomib, thalidomide, lenalidomide and autologous stem cell transplantation (ASCT), it remains an incurable disease. Allogeneic stem cell transplantation (AlloSCT) is not a standard therapy for MM, but it potentially provides a graft versus myeloma effect. The use of reduced-intensity conditioning (RIC) and the autologous-allogeneic tandem transplantation have broadened the use of AlloSCT in patients (pts) with MM. Nevertheless, relapse incidence (RI) after AlloSCT remains high and investigation of this procedure in MM population is warranted.To date, few published reports describe outcomes of unrelated cord blood transplantation (UCBT) in MM pts. We retrospectively analyzed 95 pts, 85 with MM and 10 with Plasma cell leukemia, who underwent UCBT in EBMT centers from 2001 to 2013. Median follow-up was 41 (range 3.6-96) months. The Immunoglobulin (Ig) subtype was IgG in 41% of pts. Out of the 45 pts with available cytogenetic data, 32 had abnormal karyotypes including 11 with high risk alterations (e. g. t(4,14) and del17p). Eighty-two pts received proteasome inhibitors or immunomodulatory drugs before UCBT. The median age at UCBT was 53 years (yrs) and 36% of pts was at stage III ISS. Fifty-one pts were male (54%) and 53% of pts were CMV positive. Thirty-six pts (38%) received a single UCBT and 59 (62%) a double UCBT (dUCBT); 89 pts (96%) received at least one previous ASCT, 26 (30%) had a tandem auto-auto transplant while 18 (21%) had an auto-allotransplant. For those 18 pts, the median time between auto and UCBT was 3.4 (2-8) months. Disease status at UCBT was 1st complete remission (CR) in 10 pts, 2nd CR in 10 pts, very good partial response (VGPR) in 20 pts, partial response (PR) in 37 pts, stable or progressive disease in 14 pts and missing data in 4 pts. The majority of pts (85%, n=77) received a RIC and 17 a myeloablative conditioning. Among RIC, 78% of pts received cyclophosphamide+fludarabine+Total Body Irradiation (TBI) (2-6 Gy) and 23% received anti thymocyte globulin (ATG). Median number of infused total nucleated cells (TNC) was 3.3 x107/kg (0.8-7.82). Cumulative incidence (CI) of neutrophil (PMN) and platelet (PLT) engraftment was 97±3% at 60 days and 72±5% at 180 days after UCBT with a median time for achievement of 20 and 33 days, respectively. Among 7 pts who failed neutrophil engraftment, 4 died in a median time of 21 months after UCBT and 2 underwent ASCT. CI of 100-day acute GvHD grade II-IV and grade III-IV was 41±5% and 16±4% respectively; aGVHD was lower in pts who received ATG (18% vs 48%, p=0.02) and in those who did not receive TBI (15% vs 49% p=0.0008). CI of chronic GVHD (cGVHD) at 2 years was 22±4%, (median time 188 days, 5/23 pts had extensive cGvHD). CI of cGVHD was higher after dUCBT (30% vs 9%, p=0.015). CI of relapse at 3 years was 47±5% and it was higher in chemoresistant MM (75% vs 45%, p=0.05). Non relapse mortality (NRM) at 3 years was 29±5%. ATG use, myeloablative conditioning and TBI were associated with higher incidence of NRM, in the univariate analysis. Sixty-three pts died: 30 of relapse and 33 of transplant related causes (infections, n=16, GvHD, n=5 and others causes, n=12). The 3-yr progression free survival (PFS) and overall survival (OS) were 24±5% and 40±5%, respectively. In multivariate analysis, the use of ATG was associated with decreased incidence of aGVHD (HR=0.16, 95%, CI=0.03-0.78, p=0.023), higher incidence of NRM (HR=6.9, 95% CI 2.06-23.38, p=0.002), decreased OS (HR=5.53, 95% CI=2.35-12.98, p<0.001) and decreased PFS (HR=3.39, 95% CI=1.50-7.67, p=0.003). Pts with good cytogenetic risk had lower RI (HR=0.28, 95% CI=0.09-0.88, p=0.03) and better OS (HR=0.35, 95% CI=0.145-0.82, p=0.016) and PFS (HR=0.38, 95% CI=0.16-0.89, p=0.027). cGVHD as time dependent variable was associated with higher PFS and OS (HR=2.64, 95% CI=1.33-5.25, p=0.006, and HR=2.43, CI=1.15-5.1, p=0.02, respectively). Three pts received maintenance with lenalidomide after UCBT.These results show that UCBT may be beneficial in approximately 25% of MM pts. The main reason of transplant failure is probably the relatively high risk of relapse in pts heavily pretreated and with high disease burden. UCBT progress might be obtained with better patient selection. The role of immunomodulatory drugs as maintenance therapy after UCBT needs to be further investigated in well-designed protocol for improving UCBT outcomes. DisclosuresSanz:JANSSEN CILAG: Honoraria, Research Funding, Speakers Bureau.