Moderate-severe Chronic GVHD Research Articles

Reassessing blood product irradiation in haploidentical transplantation: a single-center perspective

ABSTRACT Objectives: The main objective was to investigate the incidence of transfusion-associated graft-versus-host disease (TA-GVHD) in patients who underwent haploidentical hematopoietic cell transplants (HCT) and received non-irradiated leukoreduced blood components. The secondary objective was to describe our leukodepletion results in blood products obtained by the filters employed at our center. Study Design and Methods: Clinical records from 2018 to 2023 were retrospectively analyzed, along with a prospective evaluation of residual leukocytes in blood components from June to November 2023 in order to confirm effectivity of our leukodepletion method. Results: 150 patients were included, no cases of TA-GVHD were reported after using non-irradiated blood products. The incidence of grade 3–4 acute and moderate-severe chronic GVHD was 12.7% (n = 19) and 2.7% (n = 4), respectively. The cumulative incidence of death was 39.3% (n = 52) with a 3.7-year overall survival (CI 95%, 3.3- 4.1 years). Leukodepletion analysis showed a reduction of 99.93% in platelet concentrates and 99.98% in packed red blood cells. Discussion: TA-GVHD in HCT remains a concern traditionally mitigated using blood product irradiation. Recent evidence obtained in favor of leukoreduction techniques question this need, especially in resource-limited settings. Conclusion: These findings support leukoreduction as a primary TA-GVHD preventive measure,along with the advantage in cost reduction.

Reduced Dose of Post-Transplant Cyclophosphamide with Tacrolimus for the Prevention of Graft-versus-Host Disease in HLA-Matched Donor Peripheral Blood Stem Cell Transplants: A Prospective Pilot Study.

PTCY 50 mg/kg/day on days +3/+4 is an excellent strategy to prevent GVHD. However, its use is associated with adverse outcomes such as delayed engraftment, increased risk of infection, and cardiac complications. This pilot study evaluates the efficacy and toxicity of a reduced dose of PTCY (40 mg/kg/day) combined with tacrolimus in 22 peripheral blood HLA-matched alloHSCT patients. At day +100, the cumulative incidences of grade II-IV and III-IV acute GVHD were 18.2% and 4.5%, respectively. No grade IV acute GVHD or steroid-refractory disease was observed. The cumulative incidences of all-grade and moderate-severe chronic GVHD at 1-year were 11.4% and 6.4%, respectively. No patient died from transplant-related complications. Two-year OS and RFS were 77.1% and 58.3%, respectively. All patients engrafted, with neutrophil and platelet recovery occurring at a median of 15 (IQR 14-16) and 16 days (IQR 12-23), respectively. The cumulative incidences of bloodstream bacterial infections, polyomavirus BK hemorrhagic cystitis, HHV6 reactivation, CMV reactivation, and fungal infections were 13.6%, 9.1%, 9.1%, 4.6%, and 6%, respectively. Only one early cardiac event was observed. These results suggest that PTCY 40 mg/kg/day on a +3/+4 schedule provides adequate immunosuppression to allow for engraftment and prevent clinically significant GVHD with a low toxicity profile.

Dual T-cell depletion with individually tailored anti-thymocyte globulin and attenuated dose of post-transplant cyclophosphamide in haploidentical peripheral stem cell transplantation

This study aimed to assess the efficacy of dual T-cell suppression using individually tailored doses of antithymocyte globulin (ATG) and attenuated dose of post-transplant cyclophosphamide (PTCy) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). We conducted a retrospective analysis of 78 adults with acute leukemia or myelodysplastic syndrome who underwent haplo-HSCT using intravenous busulfan and fludarabine conditioning. Thirty-two patients received attenuated ATG/PTCy, while 46 patients received ATG (7.5 mg/kg) as GVHD prophylaxis. The 100-day cumulative incidence of grade III-IV (9.7% vs. 32.4%, P = 0.018) acute GVHD, as well as 2-year moderate-severe chronic GVHD (13.9% vs. 43.9%, P = 0.018) in the ATG/PTCy group were significantly lower than those in the ATG group. The 2-year overall survival was comparable between the two groups. However, 2-year GVHD-free, relapse-free survival in the ATG/PTCy group was significantly higher compared to that in the ATG group (38.9% vs. 21.7%, P = 0.021). Moreover, during post-engraftment period, the ATG/PTCy group exhibited lower incidences of life-threatening bacterial (12.5% vs. 37%, P = 0.033) and viral infection (0% vs. 17.4%, P = 0.035) than the ATG group. In conclusion, the combination of individually tailored ATG and low-dose PTCy appears to be a promising strategy in haplo-HSCT.

Differences in Patterns of Infections Among Allogeneic Hematopoietic Cell Transplant Patients Receiving Letermovir Prophylaxis for Cytomegalovirus

Cytomegalovirus (CMV) infection remains a common complication after allogeneic hematopoietic- cell transplantation (HCT) with a significant increase in morbidity and mortality among patients who acquire such infection. Pre-emptive prophylaxis in which antiviral agents are started based on detection of CMV in the blood to prevent clinical disease has been the standard practice for many years. This approach was limited by the toxicity of available anti-CMV medications and increased complications among patients who activate CMV(1, 2). Letermovir, an antiviral agent that inhibits replication by binding to components of the terminase complex (UL51, UL56, or both) was approved in 2017 for prevention of CMV infection and disease among HCT recipients(3). Letermovir has been shown to delay polyfunctional CMV-specific cellular immune reconstitution as well as cause a decrease in absolute polyfunctional CD8+ T cell responses(4). The impact of such delayed immune reconstitution on infections other than CMV has not been widely described especially in the setting of post-transplant cyclophosphamide as GVHD prophylaxis. To study the impact of Letermovir on non-CMV infections during the first 6 months post HCT and to assess its effect on other transplant endpoints including OS, DFS, NRM, relapse, acute and chronic GVHD, we analyzed 409 consecutive patients who received their HCT at our center between 2016 and June of 2021. Letermovir prophylaxis was started at our center in January 2018 and is given to patients receiving MUD or haploidentical transplant and are either CMV+ or donor is CMV+. The final dataset included 321 subjects with the following characteristics: Median age 54 years (19-80); disease AML/ALL/MDS 81%, NHL/HD/Other 19%; donor type haplo (69%), MUD 31%; Cell Source PBSC 88%; Myeloablative conditioning 38% ; Donor/Recipient +/+ 50%, +/- 12%, -/+ 38% . The median follow up for survivors was 31.2 (11.5-52.6) months for letermovir group versus 66.2 (53.1-76.9) months for no letermovir group. Patients in the letermovir group were less likely to have received a reduced intensity regimen (22% vs 33%, p=0.05) and to have received a marrow graft (8% vs 16%, p=0.02). The survival endpoints at 3 years were OS (72.7% vs 68.8% p=0.5), DFS (64.4% vs 58.0% p=0.27), relapse (21.2% vs 28.6% p=0.08) and non-relapse mortality NRM (14.5% vs 13.5% p=0.5) for letermovir compared to no letermovir . The cumulative incidences for grade II-IV acute and moderate-severe chronic GVHD were 50.7% vs 40.2%, p=0.08 and 24.3% vs 24.1%, p=0.85 for Letermovir and no letermovir respectively The cumulative incidence of CMV reactivation was significantly lower for letermovir 24.4% compared to 57.1% for letermovir (p<0.001) figure 1, whereas non-CMV infections were similar between both groups with a trend towards lower infections for letermovir recipients 75.2% vs 83% p=0.07, figure 1. When assessing the difference in non-CMV infections per infection, there was no difference in the mean number of infections at 6 months post-HCT where patients in both groups had a mean of 2.5 infections. When looking at different types of infections between Letermovir and no letermovir groups, there was no difference in mean number of bacterial infections (1.58 vs 1.43), viral infections (0.90 vs 0.95) and fungal infections (0.16 vs 0.22), P =NS for all. Our data shows that in a large cohort of allogeneic HCT recipients, mostly haploidentical with Post-transplant cyclophosphamide, letermovir significantly decreases CMV reactivation without changing the pattern or incidence of non-CMV infections. 1. Teira P, Battiwalla M, Ramanathan M, Barrett AJ, Ahn KW, Chen M, et al. Early cytomegalovirus reactivation remains associated with increased transplant-related mortality in the current era: a CIBMTR analysis. Blood. 2016;127(20):2427-38. 2. Boeckh M, Ljungman P. How we treat cytomegalovirus in hematopoietic cell transplant recipients. Blood. 2009;113(23):5711-9. 3. Marty FM, Ljungman P, Chemaly RF, Maertens J, Dadwal SS, Duarte RF, et al. Letermovir Prophylaxis for Cytomegalovirus in Hematopoietic-Cell Transplantation. The New England journal of medicine. 2017;377(25):2433-44. 4. Zamora D, Duke ER, Xie H, Edmison BC, Akoto B, Kiener R, et al. Cytomegalovirus-specific T-cell reconstitution following letermovir prophylaxis after hematopoietic cell transplantation. Blood. 2021;138(1):34-43. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abatacept for the Prevention of Gvhd in Pediatric and Adult Patients Receiving 7/8 HLA-Mismatched Unrelated Transplant for Hematologic Malignancies: A Real-World Analysis

Background: Recipients of HLA mismatched unrelated donor (MMURD) hematopoietic cell transplant (HCT) are at increased risk for severe acute graft versus host disease (aGVHD) and treatment related mortality (TRM). Abatacept, CTLA4-Ig was granted FDA approval for the prevention of aGVHD in patients receiving unrelated donor HCT in part based on results of ABA2, a phase II trial evaluating abatacept in addition to standard immunoprophylaxis (calcineurin inhibitor (CNI)/ methotrexate (MTX) for GVHD prevention in either 8/8 MUD or 7/8 MMURD HCT (Watkins et al., 2021). The 7/8 MMURD cohort from ABA2 showed a significant reduction in grade III-IV aGVHD compared with a matched cohort from the CIBMTR receiving CNI/MTX alone (2.3% vs 30.2%, P<0.001). The lower rates of severe aGVHD translated into significant improvements in TRM and overall survival (OS) at 2 years for patients receiving abatacept. While ABA2 included pediatric and adult patients in the analysis, outcomes were not reported separately. Furthermore, there may be selection bias associated with study eligibility and participation that could result in benefits that may not translate into everyday clinical practice. Objectives: To determine the real-world impact of abatacept combined with CNI/MTX on the development of acute and chronic GVHD, survival, and relapse in pediatric and adult patients with hematologic malignancies receiving of 7/8 MMURD HCT as standard of care (off-study). Methods: We conducted a multi-center retrospective analysis of outcomes for pediatric and adult patients receiving a 7/8 MMUD HCT (bone marrow (BM) or peripheral blood stem cells (PBSC)) for hematologic malignancies and received GVHD prophylaxis with abatacept (4 doses on days -1, +5, +14, and +28) combined with CNI/MTX between January 2015 and December 2021. Patients were excluded if they were on ABA2, not in remission at time of HCT, received a prior HCT, or required additional GVHD prophylaxis. The analysis included consecutive adult patients transplanted at Emory University and pediatric patients transplanted at Children's Healthcare of Atlanta and Boston Children's Hospital. Data were analyzed for all patients and for pediatric and adult patients as separate cohorts. Results: A total of 50 consecutive patients (27 pediatric patients and 23 adult patients) met inclusion criteria. Median follow up was 759 days. Twenty-five of 27 pediatric patients received BM grafts while 20 out of 23 adult patients received PBSC. Grade II-IV aGVHD at day 180 was 40%, 48% and 28% for all patients, pediatric patients and adult patients, respectively. Grade III-IV aGVHD at day 180 was 10%, 5% and 15% for all, pediatric and adult patients respectively. Moderate-severe chronic GVHD (cGVHD) at 1 year was 49%, 56% and 42% for all, pediatric and adult patients respectively. TRM at day 180 was 8%, 7% and 9% for all, pediatric and adult patients respectively. OS at 1 year was 82%, 85% and 78% for all, pediatric and adult patients respectively. Relapse at 1 year was 16%, 15% and 17% for all, pediatric and adult patients respectively Disease-free survival (DFS) at 1 year was 73%, 77% and 70% for all, pediatric and adult patients respectively. Grade III-IV aGVHD free, severe cGVHD free, relapse free survival at day 180 was 74%, 70% and 78% for all, pediatric and adult patients respectively. Conclusion: Our real-world results using abatacept prophylaxis for 7/8 MMUD HCT compared favorably with ABA2 results with low incidence of grade III-IV aGVHD and TRM and encouraging DFS. These results are promising given that our off-study patients had more advanced disease compared to the patients on ABA2 (27% vs 13%). This was especially true in our adult patients where 50% had advanced disease and almost all received PBSC grafts. This study was the first to analyze and report outcomes separately for pediatric and adult patients receiving abatacept for GVHD prophylaxis. Our results indicate that both pediatric and adult patients had favorable outcomes with abatacept. Similar to results from ABA2, cGVHD rates were not reduced with the 4 dose abatacept regimen and further studies are needed to evaluate the efficacy of extended dosing abatacept to mitigate this risk. Our real-world results mirrored the results from ABA2 and suggest that the addition of abatacept to standard immunoprophylaxis for our highest risk patients can be effective at substantially improving aGVHD related transplant outcomes in MMUD recipients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequential Therapy Vs. Salvage Chemotherapy for Patients with AML Refractory to First Induction Regimen- a Bi-Institutional Retrospective Cohort Analysis

Background: Induction-refractory acute myeloid leukemia (AML) occurs in approximately 30% of AML patients and is mostly associated with inferior outcome. A sequential approach offers shorter time to allogeneic hematopoietic cell transplantation (HCT), reduces salvage-associated toxicities while providing significant anti-leukemic activity. We hypothesized that early intervention with a sequential approach based on the original FLAMSA regimen salvage these patients more effectively as compared with a standard salvage therapy. Methods: We retrospectively compared results between 2 tertiary centers in Israel that apply different therapeutic modalities for first-induction failure: The first (TASMC -"cases" group), employs a transplant-based sequential approach for patients with first-induction-refractory AML, while the second center (RMC - "controls" group), applies mostly conventional salvage regimens. All consecutive patients ≥18 years who were treated in both centers between 2013 and 2021 and given either high-intensity induction chemotherapy or low-intensity venetoclax (VEN)-based regimens were included. Refractory to first induction was defined as either blasts >10% on day 30 marrow after 7+3 regimen, or after 2-3 cycles of a VEN-based regimen. We compared baseline characteristics between the 2 groups and used time-to-event analyses to calculate non-relapse mortality (NRM) and overall survival (OS) with day of allocation (either sequential therapy or non-sequential approach) defined as day 0. Controls who underwent HCT were not censored at transplant. Cox regression analysis was used to identify predictors for survival. This trial was approved by both Institutional Ethic Committees. Results: Between 01/2013 and 12/2021 we identified 91 patients that fulfilled the eligibility criteria (cases, n=55; controls, n=36). Characteristics of cases and controls were similar, except for higher % of patients with metabolic syndrome in the control group, Table. Mean days from diagnosis to HCT in the cases group was 69±25 with longer mean time in patients who were given VEN-based compared to high-intensity induction chemotherapy (94±23 vs. 62±21 days, respectively, p<.001). All patients advanced to transplantation. Median days to neutrophils and platelets engraftment were 10 (range, 7-16) and 16 (range, 9-35), respectively. Incidences of grade 2-4 and 3-4 acute GVHD were 55% (95%CI 47%-63%) and 15% (95%CI 47%-63%), respectively, and incidences of overall and moderate-severe chronic GVHD at 3 years were 64% (95%CI 44%-84%) and 37% (95%CI 25%-49%), respectively. In the controls group, patients were given high-dose cytarabine-based salvage regimens (n=21, 58%), novel targeted therapies (n=5, 14%), HCT (n=4, 11%), VEN-based regimen (n=3, 8%), and palliation (n=2, 6%). Of those patients who were given chemotherapy/other targeted therapies (n=30), 11 (37%) responded and of them, 9 (82%) proceeded to HCT. Five additional patients underwent HCT in active disease. Thus, overall, 18 patients (50%) in the controls group underwent HCT. Percentage of complete remission was higher in the cases group (measured at 1 month after HCT) vs. controls group (measured at any time after allocation) (87% vs. 39%, p<.001). 1-year NRM was higher in the cases group compared to controls group, however this did not reach statistical significance (37% (95%CI 32%-42%) vs. 20% (95%CI 14%-26%), p=0.126). Median OS was similar in patients given intensive induction chemotherapy between the cases and controls groups (8.3 (95%CI 2.74-14.4) months vs. 7.1 (95%CI 2.15-11.4) months, p=0.66), although in patients with adverse ELN risk, OS within the intensive group was better (8.2 (95%5.1-11/7) months vs. 2.4 (95%CI 0-4.8) months, p=0.027). Importantly, OS was better in cases refractory to VEN-based induction regimens compared to controls (22 (95%CI n/a) months vs. 7.8 (95%CI 0-15.9) months, p<.001). Cox regression analysis identified adverse ELN risk group and lower performance status as predictors for mortality (HR=2.5, p=0.02 and p=0.008, respectively). Conclusions: sequential therapy in refractory to induction therapy AML may benefit patients with poor salvage options such as those with adverse risk AML and those with refractory disease to VEN-based induction regimens. Better salvage regimens and improved transplantation techniques may improve both strategies to enhance patients’ outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Sequential Therapy with Fitcy Preparative Regimen for Patients with Primary Refractory AML - a Single Center Retrospective Analysis

Introduction - primary refractory AML is associated with a dismal prognosis. Only 30% of patients will respond to salvage chemotherapy and continue to allogeneic hematopoietic cell transplantation (HCT) with a 10-20% long- term overall survival. Following from the FLAMSA protocol, we implemented a modified RIC regimen - FITCy (fludarabine, cytarabine +/- idarubicin and 4 Gy TBI) in all primary refractory patients with a donor available for transplant.Methods - all patients who were admitted with AML, were identified by the transplantation coordinator nurse and underwent donor evaluation within 2 days from diagnosis. Patients who received induction chemotherapy had a day 14 marrow examination and where leukaemia blasts were identified, donor search was prioritized. These patients went on to have a day 28 bone marrow examination to confirm refractory disease. Patients who were treated with azacitidine ±venetoclax had a 2-month BM evaluation and donor search was prioritized in case of refractory disease. All consecutive patients, diagnosed with primary refractory AML, underwent HCT with the FITCy regimen in the Tel Aviv Sourasky Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) or a second HCT were excluded from this analysis. The protocol was amended on January 2018 to include ATG for all patients after interim analysis showed a high rate of GVHD.Results - Between January 2014 and June 2021, 48 patients were identified with primary refractory disease and were eligible for the protocol. Median age was 63 (range, 22-75) years (Table). Median follow-up for surviving patients was 33 (range, 1-81) months. Prior to HCT, 12 (25%) patients had ongoing documented infections (either microbiology or clinically). Median days to engraftment of neutrophils (>500/dL) and to complete engraftment of platelets (>20000/dL) were 10 (range, 7-20) days, and 16 (9-35) days, respectively. 7 patients with early progression/non relapse mortality were not evaluated for this outcome. No patient had primary/secondary graft rejection. Severe mucositis was observed in only 7 patients (15%) and was mostly observed in the upper gut. 18 patients (38%) developed microbiology documented infections during the neutropenic period and in 7 (40%) this directly contributed to mortality. Only 2 patients (4%) developed sinusoidal obstruction syndrome. Complete remission was documented on day 30, in all but 1 patient with a median whole marrow donor chimerism of 98% (range, 73-100%).Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 55% and 15%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 64% and 24%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 24% and 30%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 13%, 20%, and 32%, respectively. Cumulative incidences of 1, 2, and 3 years overall survival were 50%, 42%, and 42%, Figure. Cox regression analysis for overall survival identified increased time from diagnosis (HR-1.03, p=.046), mismatched donor (HR-1.4, p=.05) and the use of ATG (HR=.33, p=.006) to impact survival, while age, sex and comorbidity index were not predictive.Conclusions - Sequential therapy in patients with primary refractory AML provides a remarkable anti- leukemic effect. A timely donor search program is essential for the succession of this approach. Nevertheless, infection control and GVHD prophylaxis is still suboptimal and future protocols should focus on these domains while preserving graft vs. leukemia function. [Display omitted] DisclosuresMoshe: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Ram: Novartis: Honoraria; Gilead: Honoraria. OffLabel Disclosure:Off label Cellcepet for prophylaxis of GVHD

Impact of Age on Hospitalization and Readmission on Post Allogeneic Stem Cell Transplantation Outcome, Single Center Experience

Background: Recent advances and improvement of supportive care allowed allogeneic stem cell transplantation (HCT) to be offered to selected older patients. However, data regarding outcome and factors affecting the outcomes are limited.Method: We retrospective analyzed the outcome in 332 patients, median age 65 years (60-76), who underwent HLA-matched related (n=85), matched unrelated (n=205) and haploidentical donor (n=42) HCT, between January 2014 to December 2019. Of these 60% were male. Diagnosis was leukemia: 193, MDS: 76, MF: 46 and others: 17. Graft source was PBSC in 98%. Reduce-intensity conditioning regimen was used in 95%, and in vivo T-cell depleted in 89% of patients. We categorized them to 3 age-groups (G): G1 60-65y, (n=175), G2 >65-70y (n=127), and G3 >70y (n=30).Cox models were used to compare the rates of overall survival (OS), non-relapse mortality( NRM), event free-survival (EFS), length of hospitalization for HCT, GVHD and reasons of re-hospitalization during the first year post HCT.Results: The median follow up was 14 months (range: 1-123 months). Median days of hospitalization during HCT period were 30-days (range: 20-132 days), with trend towards significance when stratified by age group (p=0.049). HCT-CI scores were 0-1 (n=143), 2-3 (n=107) and >3 (n=70). The cumulative incidences of grade II-IV acute-GVHD was 38.3% and 16.3% for grades III-IV. Moderate-severe chronic-GVHD was 23.7%. Increasing age was not associated with increases in acute GVHD (p=0.86) or chronic-GVHD (p= 0.6). Overall, 188 (56%) patients were re-hospitalized within the first 6-month of HCT, and 61 (18%) in the second 6-month period. The 2-year OS rate (Fig 1) were 56% in G1, 53% in G2 and 34% in G3 (p=0.05). The 2-year EFS rate (Fig 2) were 54% for G1, 49% for G2, and 31% for G3 (P=0.04). Cumulative incidence of NRM at 2-year (Fig 3) were 25% in G1, 36% in G2 and 52% in G3 (p=0.008). Further results are illustrated in Table 1. Risk factors such as age, KPS, HCT-CI, donor-type, readmission and GVHD were analyzed for their associations with outcomes using univariate analyses, those with significant results entered in multivariate-analysis Table 2. Patients aged 60-≤65 had significantly better EFS (p=0.04) and associated with a border line significant trend for lower NRM (p=0.05) than those aged >70. Re-admission in the first 6-month post HCT had a significant impact on the OS, EFS and NRM. HCT-CI >3 had significant impact on NRM.Conclusion: Age had a significant impact on hospitalization period during HCT. Age >70 had significant impact on EFS and trend toward higher NRM. HCT-CI, acute and chronic-GVHD and readmission in first 6-month post-HCT were significant risk factors. Readmission in the first 6 months correlated with lower OS, EFS and higher NRM. Acute GVHD III-IV or moderate-severe chronic GVHD associated with poor outcomes. Selecting patients based on HCT-CI, and good management of GVHD and post-HCT complication may improve the clinical outcome. [Display omitted] DisclosuresLaw: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding.

The Impact of Age in Allogeneic Stem Cell Transplantation with Thiotepa Busulfan and Fludarabine (TBF) for Myelofibrosis : A Retrospective Analysis

Allogeneic hematopoietic stem-cell transplantation (HSCT) currently remains the only curative therapy for intermediate or high risk disease.myelofibrosis (MF). We are reporting 56 patients (pts) who underwent an allogeneic HSCT in our Centre between 2016 and 2020, and assessed factors predictive of outcome.The median age was 59 years (36-72). Most patients (72%) were JAK2+ and had int2-high DIPSS (92%). The conditioning regimen consisted of thiotepa, busulfan , fludarabine (TBF). All pts received thiotepa 10 mg/kg and fludarabine 150 mg/m^2. The dose of busulfan was adjusted considering the age and the comorbidity score. One pt received 3 days of busulfan (total dose 9.6 mg/kg); 47 received 2 days (total dose 6.4 mg/kg) and 8 received one day of busulfan iv (3.2 mg/kg). Donor was an identical sibling in 13 pt, haploidentical in 18, matched unrelated donor (UD) in 18 and a mismatchedUD in 7. Thus we had 31 HLA matched and 25 HLA mismatched grafts. Fortytwo patients received post-transplant cyclophosphamide (PTCy)-based GVHD (Graft versus host disease ) prophylaxis with cyclosporine and mycophenolate mofetil , and 14 patients received a standard GvHD prophylaxis (CSA+MTX+ATG).The 2 year survival (OS) was 73 % and disease free survival (DFS) was 66 % and the cumulative incidence (CI) of TRM was 23% and of relapse 11%.The incidence of acute GvHD grade II-IV was 22% in HLA matched and 50% in HLA mismatched pts (p=0.022), grade III-IV was 6% and 25% respectively (p=0.042) . The incidence of moderate-severe chronic GvHD was 25% in HLA matched and 36% in HLA mismatched grafts (p=0.36). HLA had a major impact on survival : 85% vs 49% survival for matched vs mismatched patients (p=0.01). Patients age >60 years had a major impact on outcome, with a 2 year survival of 51% vs 88% in patients over (n=24) or under 60 years of age (n=32) (p=0.007; the DFS was 46 % and 80% respectively and the CI of TRM was 42% vs 9% (p=0.003).As to the total dose of busulfan, we found 26% TRM in patients receiving busulfan for 2 days (total doe 6.4 mg/kg) (n=47) and 0% in older patients receiving 1 day only (total dose 3.2 mg/kg) (n=8) ; relapse rate was 10% and 20% respectively.In multivariate cox analysis including age, spleen size ,DIPSS score, number of transfusion received and donor type, only HLA matching influenced the incidence of acute GvHD; transfusion burden and age plays a role in NRM and OS; DIPSS predicts relapse .In conclusion: older patients with MF have a high NRM and need to be prepared with a milder conditioning regimen. DisclosuresLaurenti: Janssen: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Honoraria; BeiGene: Honoraria. Sica: Pfizer: Honoraria.

Longitudinal Changes in Body Composition Following Hematopoietic Cell Transplantation

Sarcopenia, the loss of skeletal muscle tissue, has been identified as a potential risk factor for adverse outcomes in hematopoietic cell transplantation (HCT) recipients. However, much remains unknown about longitudinal changes in body composition following HCT. We retrospectively evaluated computed tomography (CT) imaging from 315 lymphoma patients undergoing HCT at our institution between 2000 and 2014. Two HCT cohorts were established: auto-HCT (did not receive allo-HCT, n=218) and allo-HCT (may have received previous auto-HCT, n=97). Cross-sectional area of lean muscle, subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT) were measured at the level of the third lumbar vertebral body (L3) on an axial CT image prior to HCT, 1 year post-HCT, and 2.5 years post-HCT. Lean muscle was normalized for height and reported as L3 skeletal muscle index (L3SMI). Sarcopenia was defined as L3SMI ≤39 cm2/m2 for women and ≤55 cm2/m2for men.Sarcopenia prior to HCT was observed in 50% of HCT recipients, 47% in the auto-HCT cohort and 57% in the allo-HCT cohort. The number of lines of therapy prior to HCT was predictive of sarcopenia prior to HCT (OR=1.29, p=.01). There was a significant decline in skeletal muscle mass over time for patients in the allo-HCT cohort when compared to the trend in the auto-HCT cohort (-6.52 cm2/imaging interval, p=<0.01) (Figure 1). In the allo-HCT cohort, the association between the change in muscle mass (per cm2) from prior to HCT to 2.5 years post-HCT and moderate-severe chronic GVHD did meet statistical significance (OR 1.04, p=0.03). The incidence of sarcopenia increased over time in all patients receiving HCT (OR=1.55; p=0.02), particularly driven by patients undergoing allo-HCT who experienced an increased rate of sarcopenia over time compared to auto-HCT (OR=1.66, p=0.02). The incidence of sarcopenia reached 66% at 2.5 years post-HCT in the allo-HCT cohort (Figure 2). In the allo-HCT cohort, the association between sarcopenia at 2.5 years post-HCT and moderate-severe chronic GVHD did not meet statistical significance (OR 3.32, p=0.07). Adipose tissue analysis showed allo-HCT recipients had lower measurements of SAT at all time point when compared to patients in the auto-HCT cohort. There was a significant increase in both VAT and SAT experienced by recipients of auto-HCT and allo-HCT when comparing CT images from 1 year post-HCT and 2.5 years post-HCT (p<0.05). However, there was no significant difference in change in SAT or VAT over time when comparing auto-HCT and allo-HCT cohorts.In conclusion, retrospective analysis of CT imaging revealed significant loss of muscle mass and an increased incidence of sarcopenia following HCT, especially in patients undergoing allo-HCT. Future studies are needed to further characterize changes in body composition in HCT recipients and investigate its impact on HCT outcomes. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Influence of VDR Polymorphisms on the Outcome of Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) within the Alovita Trial.

BackgroundVitamin D (VD), due to its interaction to vitamin D receptor (VDR), has a potent immunomodulator effect. Some retrospective studies have shown that VDR polymorphisms (which determine the affinity of VDR towards VD) can influence on the outcome and the incidence of GVHD after allo-HSCT. We have recently described in a phase I/II prospective trial (ALOVITA) that the use of VD in the post-transplant setting decreases the risk of overall and moderate-severe chronic GVHD (Caballero-Velazquez, Clin Cancer Res 2016).ObjectiveTo analyze the effect of VDR polymorphisms on post-transplant outcomes and on the effect of VD on cGVHD incidence in patients included in the ALOVITA clinical trial.MethodsPatients and donors with genomic DNA, extracted from peripheral or bone marrow blood prior to transplant, available were analyzed. A group of patients who received 1000 UI/day or 5000 UI/day of VD (n=71), and a control group (n=36) were included. Overall, 107 patients and 93 donors were selected. The polymorphisms FokI C>T, BsmI A>G, ApaI T>G, TaqI T>C were detected by TaqMan SNP genotyping assay.ResultsBaseline characteristics of patients are shown in table 1.The median follow-up was 453 days (13-1256d). The frequencies of genotypes coincided with that of the European population as described in international databases.There were no statistically significant differences in terms of NRM depending on polymorphisms for FokI, BsmI ApaI or TaqI neither in patients nor in donors, although a trend towards a decreased NRM was observed in patients whose donors were ApaI GG (10%) as compared to TG+TT (27.8%), (p=0.07).A higher relapse incidence (RI) was observed in patients with TaqI CC genotype (42.9%) vs those with TC+TT genotype (20.6%), p=0.02 as well as in patients with BsmI GG (37.5%) vs AA+GA (21%), p=0.04. Also, patients whose donors had an ApaI GT+TT genotype had a higher RI (26,8) as compared to GG (7,1), p=0.05.A trend towards a better EFS was observed for BsmI AA in donors (75.6%) vs GA+GG (48.7%), p=0.06. Regarding OS, significant differences were observed depending on the genotype of the patients for FokI: CT (84%) vs CC+TT (62,1%), p=0.03. .We analyzed BsmI, ApaI and TaqI haplotypes in 95 patients. The most frequent combination within our series were AAGGTT (group 1: n=23) and GATGTC (group 2: n=23). We named ‘group 3‘ to include the rest of the combinations (n=49). We observed significant differences in terms of OS: 73% vs 51.1% vs 81.6% for groups 1, 2 and 3, respectively (p=0.02).As far as cGVHD is concerned, data are shown in Table 2/3. The following patient genotypes influenced on the efficacy of VD as cGVHD prophylaxis, the incidence of overall cGVHD being: FokI, CT (22.5% vs 80%, p=0.0004); ApaI, GG (23% vs 60%, p=0.009); TaqI, TT (20% vs 64.7%, p=0.001), BsmI, AA (18.2% vs 73.3%, p=0.0004) for those patients receiving or not VD. These differences were also observed for moderate-severe cGVHD. The same analysis was performed for donors' genotypes, and differences in overall and moderate-severe cGVHD were observed for the following genotypes: FokI, CC; ApaI, TT; TaqI, TC; BsmI, AA, (table 2).We also evaluated the benefit of GVHD prophylaxis with VD regarding patients' haplotype. Group 1 haplotype had the greatest benefit from receiving VD in terms of cGVHD: overall cGVHD: 75% vs 15.4% for patients who did and did not receive VD, p=0.008, and moderate-severe cGVHD: 75% vs 14.3%, respectively; p=0.01.Conclusion:Patient VDR polymorphisms influence on outcome after transplantation. The VDR genotypes from either the donor or the patient modulate the effect of VD used post-transplant on the risk of cGVHD, thus suggesting that genomic changes in VDR can modify its interaction to VD. [Display omitted] DisclosuresSanchez-Guijo:Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria.

Sequential Therapy for Patients with Primary Refractory AML — a Retrospective Analysis of the German and Israeli Experience

Introduction -primary refractory AML is associated with a dismal prognosis with only 30% of the patients responding to salvage chemotherapy and continuing to allogeneic hematopoietic cell transplantation (HCT). HCT with a standard myeloablative conditioning regimen ,given to patients with a primary refractory leukemia,is associated with 10-20% long- term overall survival. The fludarabine, amsacrine, and cytarabine (FLAMSA)-reduced-intensity conditioning (TBI-based or treosulfan-based) protocol, established by the German group, has been described to be effective approach in patients with relapse/refractory AML undergoing HCT. Modified protocol (without amsacrine and with TBI-based RIC, FITCy) has been also used in the last several years.Methods - We retrospectively analyzed the HCT characteristics and outcomes of all consecutive patients ,diagnosed with primary refractory AML who underwent HCT with either the FLAMSA or FITCy regimens in the University of Cologne and the Tel Aviv Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) were excluded from this analysis.Results - Between the years 2003 and 2017, we identified 43 patients that were eligible for this analysis. Median age was 54 (range, 23-73) years (Table). Median follow-up for surviving patients was 32 (range, 1-148) months. Twelve patients (28%) received only one line of chemotherapy (mostly 7+3) before proceeding at a refractory state to HCT. Preparative regimens were FLAMSA-TBI based, FLAMSA-Treo based and FITCy in 12 (28%), 12 (28%), and 19 (46%) patients, respectively. Prior to HCT, 5 (12%) patients had ongoing documented infections (either microbiology or clinically) - aspergilus pneumonia (n=3), atypical pneumonia (n=1), and scrotal abscess (n=1). Median days to engraftment of neutrophils (>500/dL) and to incomplete engraftment of platelets (>20000/dL) were 13 (range, 9-19) days, and 13 (7-30) days, respectively. Only 1 patient (2%) had primary graft rejection. Severe mucositis was observed in only 10% of the patients, and was mostly observed in the upper gut. 3 patients (7%) developed fungal pneumonia and 2 patients (5%) had blood stream infection during the neutropenic period. Only 2 patients (5%) developed sinusoidal obstruction syndrome.Complete remission was documented on day 30, in all but 1 patient. Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 40% and 20%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 76% and 52%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 22% and 25%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 7%, 10%, and 22%, respectively. Cumulative incidences of 1, 2,and 3 years overall survival were 66%, 60%, and 57% , Figure. Both older age and a mismatched donor were associated with decreased overall survival (HR=0.83, 95% CI=.335-.969, p=.02) and (HR=.25, 95% CI=.064-.954, p=.046), while time from 1st line regimen to HCT, uncontrolled infections at HCT, percentage of BM blasts prior to HCT, and type of the preparative conditioning were not predictive for survival.Conclusions - Sequential therapy in patients with primary refractory AML is safe and provides a remarakablre anti- leukemic effect. In patients with available donors, this strategy may be superior to repeating rounds of salvage chemotherapy and should be further studied in other settings (i.e. haploidentical donors and other diseases). Future protocols should focus on decreasing GVHD rate , maintaining the graft vs. leukemia effect. [Display omitted] DisclosuresScheid:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

Intermediate Post-HCT Exposure to Thymoglobulin Minimizes Mortality and High Exposure Minimizes the Composite of Death, Relapse or Chronic Graft-Versus-Host Disease

IntroductionGraft-versus-host disease (GVHD) remains a major problem after allogeneic-HCT as it is associated with high mortality, morbidity and poor quality of life. Rabbit anti-T cell globulin (ATG, Thymoglobulin) reduces GVHD without increasing relapse or mortality (Walker I: Lancet Oncol 2016). At multiple centers, including ours, ATG has become a standard component of conditioning. However, the efficacy of ATG is limited- at our center 40% patients still develop grade 2-4 aGVHD or moderate-severe cGVHD; 10% die of it and 25% survive with poor quality of life. We hypothesize that one of the reasons for the limited efficacy of ATG is suboptimal dosing (leading to low ATG levels in a fraction of recipients). Here we set out to determine the effect of pre- and post-HCT ATG exposure (area under the curve, AUC) on clinical outcomes and the factors influencing the AUCs in adult HCT recipients.MethodsA total of 141 patients receiving first allo-HCT in Calgary with a peripheral blood stem cell graft after conditioning with fludarabine (250 mg/m2), busulfan (~12.8 mg/kg) +/- TBI (4 Gy) and GVHD prophylaxis with rabbit ATG (0.5 mg/kg on day -2, 2 mg/kg on day -1 and 2 mg/kg on day 0 before graft infusion), methotrexate and cyclosporine were included. Serum was collected at the end of the last ATG infusion, immediately pre-graft infusion, 30 minutes after the end of graft infusion and days 7, 14 and 28.Serum levels of ATG capable of binding to lymphocytes were determined using a flow cytometric assay as previously described (Podgorny PJ: Biol Blood Marrow Transplant 2010). Pre-HCT ATG AUC was estimated from ATG levels at the end of the last ATG infusion and pre-graft infusion. Post-HCT ATG AUC was estimated from the ATG levels pre-graft infusion, 30 minutes post graft infusion and on days 7, 14 and 28. AUCs were split into terciles, quintiles and deciles for analysis.Multivariate Cox regression was used to determine if ATG AUC was associated with mortality due to any cause or a composite outcome of death, relapse or moderate-severe chronic GVHD (the inverse of chronic GVHD relapse free survival, cGRFS). Multivariate competing risks regression was used to determine whether ATG AUC was associated with the cumulative incidence of cause-specific outcomes.ResultsPre-/post-HCTAUC and Clinical OutcomesIntermediate post-HCT AUC appeared to be associated with lower mortality than low or high post-HCT AUC (Figure 1). This was significant when comparing the second tercile with the first tercile (HR=0.37, p=0.027) and the second with the third tercile (HR 0.38, p=0.032). However, high post-HCT AUC appeared associated with the lowest composite incidence of death, relapse or cGVHD (Figure 2). This was significant when comparing deciles 7-10 with deciles 1-6 (HR 0.60, p=0.047). The incidence of relapse was similar in all post-HCT AUC terciles/quintiles/deciles. As compared to deciles 1-6, deciles 7-10 were associated with a lower incidence of grade 2-4 aGVHD (HR 0.42, p=0.017) and moderate-severe cGVHD (HR 0.45, p=0.045), while GVHD-associated non-relapse mortality (NRM) (NRM preceded at any time by diagnosis of grade 2-4 aGVHD or moderate-severe cGVHD) trended towards a lower incidence (HR 0.28, p=0.097). Non-GVHD-associated NRM (NRM not preceded by diagnosis of grade 2-4 aGVHD or moderate-severe cGVHD) appeared to increase from the lowest to highest AUCs; however, there were too events for a meaningful statistical analysis.Pre-transplant AUC did not appear to influence any of the above outcomes.Factors influencing post-HCT AUCGiven that there appears to be an ideal (intermediate or high) post-HCT AUC and that low post-HCT AUC is deleterious, we next determined factors influencing the post-HCT AUC. The factors associated with (presumably influencing) the post-HCT AUC were body mass index (BMI) (Spearman correlation coefficient r = 0.24, p=0.005), day -2 (pre-ATG) blood lymphocyte count (r = -0.30, p<0.001) and possibly graft lymphocyte content (r = -0.14, p=0.081).ConclusionLow post-HCT ATG AUC is associated with the highest mortality and the highest composite of death, relapse or cGVHD. From the perspective of mortality, intermediate AUC may be ideal. In contrast, from the perspective of cGRFS, high AUC may be ideal. The post-HCT AUC appears influenced by BMI (when ATG is dosed per kg), pre-ATG blood lymphocyte count and graft lymphocyte content. We aim to develop a formula for ATG dosing that will avoid low post-HCT AUC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Who Is a Better Donor for Recipients of Allogeneic Hematopoietic Cell Transplantation: A Young HLA- Haploidenitcal Relative or an Older Fully HLA-Matched Sibling or Unrelated Volunteer?

T-cell Replete HLA-haploidenitcal donor transplantation (HIDT) with post-transplant cyclophosphamide is increasingly considered an acceptable alternative for patients lacking timely access to an optimally matched related (MRDT) or unrelated donor (MUDT). Multiple recent registry and single center studies have shown comparable overall survival and disease free survival rates among the three donor sources with a significantly lower risks of acute and chronic GVHD among HIDT recipients(1). Donor age may also affect outcomes. Many candidates for allogeneic HCT will have access to multiple available donor sources. In this situation, it is unclear whether outcomes can be improved using a younger HID rather than an older MRD or MUD.We analyzed 406 consecutive allogenic HCT recipients, median age of 54 years (range 19, 77) comparing outcomes after a MRDT (n-222) or MUDT (n-91) using a donor ≥ 35 years old to HIDT performed using donors aged ≤ 35 years (n=93). Survival was calculated using the Kaplan-Meier estimator. Univariate analysis with Gray test and log-rank test were used for cumulative incidence and survival respectively. Pointwise comparison at 3 years post HCT was performed using the Wald test. Median follow up for survivors was 51.5 months. Compared to MRDT and MUDT, HIDT recipients had similar median age at time of HCT, hematopoietic cell transplant comorbidity index (HCT-CI), disease risk index (DRI) distribution and donor recipient sex matching. Recipients of HIDT were more likely to have received TBI based Myeloablative conditioning (39% vs 18% and 11% for MUDT and MRDT, p <0.001), bone marrow graft source (33% vs 11% and 2% for MUDT and MRDT, p<0.001) and more likely to be transplanted after 2011 (79% vs 56% and 56% for MUDT and MRDT, p<0.001). The median donor age for HIDT of 27 years (range 15, 34) was significantly younger than MRDT 53 years (range 35, 77) and MUDT 41 (35, 64), p=0.001. The survival estimates and relapse incidence at 1 and 3 years respectively post HCT were: OS (80% and 64% for MRDT, 79 and 54% for MUDT, 79% and 62% for HIDT), DFS (69% and 55% for MRDT, 61% and 44% for MUDT, 66% and 58% for HIDT), TRM (11% and 19% for MRDT, 8% and 16% for MUDT, 12% and 18% for HIDT), and relapse (20% and 26 % for MRDT, 31% and 37% for MUDT, 22% and 24% for HIDT). HIDT recipients had better 3-year relapse rates (p=0.048) and DFS (p=0.042) compared to MUDT with similar overall survival. Recipients of HIDT also had significantly lower incidence of moderate-severe chronic GVHD compared to MRDT and MUDT (23% HIDT vs 45% for MUDT and 38% for MRDT, p=0.01). When limiting the analysis to recipients age ≥ 50 years (n=258), there was no difference in OS, DFS or relapse between the 3 donor sources.Recipients of HIDT from a young donor ≤35 years, have similar overall survival and lower rates of chronic GVHD compared to transplants using MRD or MUD donor ≥ 35 years. Moreover, HIDT recipients have lower relapse and better DFS compared to MUDT. This study suggests that given a situation where a choice between a young Haploidenitcal relative and an older matched unrelated donor is to be made, one can achieve better disease free survival with haploidentical donor and significantly lower rates of chronic GVHD.1. Ciurea SO, Zhang MJ, Bacigalupo AA, Bashey A, Appelbaum FR, Aljitawi OS, et al. Haploidentical transplant with posttransplant cyclophosphamide vs matched unrelated donor transplant for acute myeloid leukemia. Blood. 2015;126(8):1033-40.Figure 1: Kaplan-Meier and Cumulative Incidence Curves for OS, DFS, Relapse, cGVHD, Grade II-IV and III-IV acute GVHD [Display omitted] DisclosuresSolh:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Amgen: Speakers Bureau.

Pretransplant bone marrow cellularity and blood count recovery are not associated with relapse or survival risk following allogeneic stem cell transplant for AML in CR.

Allogeneic hematopoietic cell transplantation (HCT) can be curative for acute myeloid leukemia (AML). Novel therapies may render patients' bone marrow hypocellularity and lead to prolonged post-therapy pancytopenia. Patients' bone marrow cellularity (BMC) at pretransplant assessment and post-treatment pancytopenia (classification CR-incomplete [CRi]) may manifest AML persistence. We retrospectively examined the impact of BMC and ELN response (ELNr) on a single-center cohort of 337 patients who underwent allogeneic HCT for AML in CR1. Median follow-up was 33months. Overall survival (OS) for the whole cohort was 55.8% at 2years, while cumulative incidence of relapse (CIR) was 20.8%, and non-relapse mortality was 27.5%. OS and CIR were not significantly different between BMC groups; and neither was ELNr. ELNr CRi was associated with BMC aplastic and hypocellular marrow states (P<2.6e-8). Multivariate analysis confirmed neither BMC nor attainment of ELNr CR vs CRi affected OS or relapse. Significant factors for survival included age at transplant, cytogenetic risk, development of acute Gr II-IV GvHD, and moderate-severe chronic GvHD, while cytogenetic risk and chronic GvHD affected relapse. Neither ELNr status nor pretransplant BMC influenced relapse post-HCT or OS. Hypocellularity and CRi are not negative prognostic factors for post-HCT outcomes of AML.

Moderate-severe grade of chronic graft versus host disease and younger age (less than 45 years old) are risk factors for avascular necrosis in adult patients undergoing allogeneic hematopoietic cell transplantation.

Avascular necrosis (AVN) is a debilitating complication of allogeneic hematopoietic cell transplantation (HCT). A retrospective review of 845 patients who underwent HCT was conducted. Cumulative incidence of AVN was 6.3% at 4 years. The following risk factors were significantly associated with AVN risk on univariate analysis: age < 45 (p=0.004), moderate to severe chronic GvHD (p<0.001), reduced intensity conditioning (p=0.02), and a diagnosis of acute leukemia (p=0.045). Multivariate analysis confirmed two risk factors: younger age (<45 years), 9.0% vs 4.4% (p=0.011, hazard ratio (HR) 2.134), and moderate-severe chronic GvHD, 15.4% vs 2.1% (p<0.001, HR 4.950). A risk score model was generated assigning a score to each risk factor. A score of 1 was assigned to moderate-severe GvHD or those with age <45. Total score was calculated, thus dividing patient into three groups: low (score 0, n=349, 41.3%), intermediate (score 1, n=379, 44.9%), and high risk (score 2; n=116, 13.7%). This risk score could stratify the patients according to AVN risk (p<0.001). The risk of AVN was 1.5% in the low risk, 6.2% in the intermediate risk, and 20.8% in the high risk groups. Moderate-severe chronic GvHD and younger age (<45 years) are key risk factors for AVN following allogeneic HCT.

Impact of Minimal Residual Disease and Chimerism Monitoring at Different Timepoints after Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia

¶ Martin-Rojas RM and Oarbeascoa G contributed equally to this work. INTRODUCTION Relapse is the main cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for acute myeloid leukemia (AML). The evaluation of minimal residual disease (MRD) could provide a more accurate assessment of the depth of response, and therefore identify patients with higher risk of relapse. AIMS The aim of our study was to analyze the impact of pre-HSCT flow cytometry (FCM) and molecular MRD together with chimerism and MRD in the early post-HSCT period in patients with AML. METHODS We conducted a retrospective study in patients with complete remission AML who underwent a HSCT between 2008 and 2019 in our center. MRD was analyzed by flow cytometry in bone marrow aspirates and by quantitative RT-PCR (NMP1, RUNX1-RUNX1T1, CBFB-MYH11, KMT2A-MLLT3, WT1) in bone marrow aspirates and/or peripheral blood. MRD was determined within the 30 days preceding the HSCT and at day +30 and +90 post-HSCT. Bone marrow and selected CD34+ lineage chimerism was analyzed by STR (AmpFISTR SGM Plus, Thermo Fisher) at days +30 and +90 post-HSCT. This study was approved by our Institutional Ethics Committee. Data were analyzed using IBM SPSS Statistics version 24 and R version 3.5.1. RESULTS A total of 115 patients were analyzed. Pre-HSCT MRD was negative in 58 patients (50.4%) and positive in 57 patients (49.6%). We found no statistically significant differences in the characteristics between the two groups (Table 1). Median follow up was 39 months (IQR 10.4-55.8). 3-year overall survival (OS) for patients with pre-HSCT negative MRD was 72.5% versus 70.3% in patients with positive MRD (p=0.41), with an event free survival (EFS) of 66.9% versus 66.1 (p=0.48) respectively (Figure 1). Median time to the beginning of immunosuppression withdrawal was 82.5 days (IQR 59-93) for patients with negative MRD and 68 days (IQR 55.3-85.3) for patients with positive MRD (p&amp;lt;0.001). The cumulative incidence of grade II-IV acute graft versus host disease (aGVHD) and moderate-severe chronic GVHD did not show statistically significant differences based on the MRD status. Similarly, the cumulative incidence of relapse and the 2-year mortality was not significantly different between the two groups. Patients with negative MRD at day +30 showed a 2-year OS of 83.5% versus 58.1% in patients with positive MRD (p=0.03) and a EFS of 79.9% versus 48.6% (Figure 2). The cumulative incidence of relapse was more elevated in patients with positive MRD (29.8% versus 13.6%) at day +30. Patients with mixed chimerism (MC) at day +30 showed a significantly lower 3-year OS and EFS than patients with complete chimerism (CC). Likewise, the cumulative incidence of relapse was significantly higher in patients with MC, both if detected in bone marrow aspirate and in CD34+ cells. The multivariate analysis revealed that MRD status at day +30 post-HSCT was an independent prognostic factor for EFS (HR 3.74; 95% CI 1.38-10.1; p=0.009). CONCLUSIONS Patients with AML presenting a positive MRD in the early post-HSCT period and those who show a MC at day +30 post-HSCT have lower EFS, with positive MRD at day +30 being an independent prognostic factor for EFS. The evaluation of MRD and chimerism in the early post-HSCT period is useful to identify patients with higher risk of relapse, who may take advantage of preemptive measures. Disclosures Kwon: Gilead, Novartis, Pfizer, Jazz: Consultancy, Honoraria.

Increased Incidence of New-Onset Diabetes Mellitus Type II Following Haploidentical Bone Marrow Transplant with Post-Transplant Cyclophosphamide for Sickle Cell Disease

Introduction: Haploidentical bone marrow transplant (haplo-BMT) with post-transplant cyclophosphamide (PTCy) provides near universal donor availability and curative potential for individuals with severe sickle cell disease (SCD). However, a recently recognized late-effect following allogeneic hematopoietic cell transplant is new-onset post-transplant diabetes mellitus type II (PTDM), which occurs in up to 50% of patients and is associated with a three-fold increase in mortality (Griffith et al BBMT 2011, Engelhardt et al BBMT 2019). Known risk factors for PTDM include older age, total body irradiation, and non-Caucasian ethnicity. Studies have shown that pre-transplant insulin resistance and enhanced immune cell alloreactivity are other important contributing factors (Engelhardt et al Blood 2011). To our knowledge, the incidence of PTDM following haplo-BMT with PTCy for SCD has not been characterized, in a population which is predominantly African-American, with a crude prevalence of diabetes mellitus type II of 16.4 (14.7-18.2), and thus represents an unmet need. We hypothesized that the ethnicity and chronic inflammatory state that exists in individuals with SCD contributes to an increased risk of PTDM and may be associated with worse transplant-related outcomes. Methods: We analyzed a multi-center cohort of 33 patients with SCD who underwent haplo-BMT with PTCy. All patients received the reduced-intensity conditioning as shown in Figure 1. Ten patients (31%) had preconditioning with hydroxyurea, azathioprine and hyper-transfusion. Patients with existing diabetes mellitus or follow-up time less than one year were excluded. PTDM was defined as any random single blood glucose level of &amp;gt; 200 mg/dL between D0 and D+100 of transplant. Baseline patient and transplant-related variables were analyzed. Immune subsets were analyzed by flow cytometry at one, two, three, six, and twelve months post-haplo-BMT. Results: The median age at transplant was 11.5 years. Median at age last follow up was 16 years. Baseline and transplant-related data are summarized in Table 1. No patients experienced primary graft failure, while three patients had secondary graft failure at a median of 87 days (range 60-604 days) following haplo-BMT (Table 1). Donor chimerism at 6 months and 1 year was &amp;gt;95% for myeloid and lymphoid lineages for all patients. Fourteen patients (44%) developed PTDM at a median time of 18 days (range 3-40 days), though only three (21%) were treated with corticosteroids prior to the development of PTDM (Table 1). In the PTDM cohort, the median time to corticosteroid use was 22 days. Sixteen patients required corticosteroids for any indication (13 PTDM, 3 non-PTDM), with a median time of administration of 32 days. The starting dose in prednisone equivalents in both groups was 1 mg/kg. All four deaths occurred in the PTDM cohort. The cumulative incidence of grade II-IV acute GVHD was 6/33 (18%). One patient (3%) developed grade IV acute GvHD of the skin and gut, while moderate-severe chronic GvHD developed in six patients (18%). The median time to acute GvHD was 36 days for the entire cohort (36 days for PTDM group, 37.5 days for non-PTDM group). Quantitative reconstitution of CD8 T-cells was significantly lower at one and two months post-haplo-BMT for PTDM compared to non-PTDM patients. CD4 subsets tended to be lower in the PTDM cohort. No significant difference was seen for CD56 cellular subsets at any time period. Conclusion: PTDM is a frequent occurrence following haplo-BMT for SCD and developed prior to corticosteroid exposure. Early T-cell reconstitution may impact glucose homeostasis. Prospective studies with longer follow up are needed to determine the clinical implications in transplant survivors following allogeneic hematopoietic cell transplant for SCD. Disclosures Dholaria: bms: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&amp;J: Research Funding.

Full Donor Chimerism after Allografts for Myelofibrosis: The Role of Conditioning Regimen

Background : The conditioning regimen for patients with myelolfibrosis undergoing an allogeneic HSCT is usually composed of a combination of fludarabine (FLU) with one alkylating agent, busulkfan (BU), thiotepa (THIO) or melphalan. In a recent prospective randomized study comparing BU-FLU versus THIO-FLU, the proportion of patients with full donor chimerism at 6 months, was respectively 63% and 65% (Patriarca et al, BBMT 2019). Aim of the study. Assess the rate of full donor chimerism in patients with myelofibrosis, after conditioning with one or two alkylating agents. Methods. We analyzed 113 patients with myelofibrosis, for whom chimerism data were available on day +30 . There were two groups: 35 patients were conditioned with either thiotepa-cyclophosphamide , thiotepa-fludarabine or busulfan-fludarabine (ONE-ALK), whereas 78 patients were prepared with thiotepa, busulfan, fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years, p=0.008), were less frequently splenectomized pre-HSCT (30% vs 54%, p=0.03), had more frequently intermediate-2/high DIPSS scores (89% vs 74%, p=0.04) , and had comparable transfusion burden pre-HSCT (p=0.7). Chimerism was assessed via STR (PowerFlex-Promega) Results. The proportion of patients with full donor chimerism on day +30 in the TBF vs the ONE-ALK group was 87% vs 51% (p=0.00002); on day +60 these figures were 93% vs 13% (p&lt;0.0001) and on day +90 , the figures were 90% vs 21% (p&lt;0.00001). Full donor chimerism on day+30 was achieved in 81% of patients with DIPSS int1 (n=16), 74% of patients with int2 DIPSS, and 70% of patients with high risk DIPSS (p=0.6). Acute GvHD grade II-IV occurred in 27% vs 37% of patients in the two groups (p=0.7), and moderate severe chronic GvHD in 20% and 21% (p=0.8). The 5 year cumulative incidence of relapse was 8% in the TBF group, versus 50% for the ONE-ALK group (p&lt;0.0001), whereas the CI of TRM was 25% vs 11% (p=0.1). The 5 year actuarial disease free survival (DFS) was respectively 65% for TBF and 38% for the ONE-ALK group (p=0.004). Complete chimerism day+30. When looking at whether patients had (n=84) or not (n=29) full donor chimerism on day +30, the CI of relapse was respectively 44% vs 15% (p=0.002), the CI of TRM 18% vs 15% (p=0.5), and the 5 year DFS 65% vs 32% (p=0.001). Conclusions. Early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis undergoing an allogeneic HSCT. The combination of 2 alkylating agents in the conditioning regimen, provides a significantly higher chance of achieving full donor chimerism on day+30, and thus long term disease control. Figure Disclosures Angelucci: Vertex Pharmaceuticals Incorporated, and CRISPR Therapeutics: Other: Partecipation in DMC; Roche: Other: Local advisory board; Jazz Pharmaceuticals: Other: Local advisory board; BlueBirdBio: Other: Local advisory board; Novartis: Honoraria, Other: Chair Steering Committee TELESTO protocol; Celgene: Honoraria, Other: Partecipation in DMC.

Psychological and Social Factors Are a Strong Predictor of Survival after Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Independent of Disease Risk and Morbidity Score

Psychological and social factors are utilized as important part of the evaluation process for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). The integration of such factors into the selection of suitable candidates and predicting survival post HSCT is still not widely incorporated in HSCT as it is the case in solid organ transplantation. To evaluate the impact of psycho social risks on post HSCT outcomes such as overall survival (OS), transplant related mortality (TRM), disease free survival (DFS), relapse and length of hospital stay, we prospectively conducted psycho social assessment on 556 consecutive allogeneic HSCT recipients who received their first transplant at our center between 2005 and 2017. The Transplant evaluation rating scale (TERS) has been previously published and was found to be psychometrically sound within the HSCT population(Hoodin, F. and Kalbfleisch, KR., Journal of Psychosomatic Research, 2003.) . TERS score was prospectively assessed by a psychologist prior to transplantation and patients were labeled as low/intermediate risk versus high risk based on their TERS score. All patients were transplanted in the outpatient setting with admission to the inpatient unit if clinically warranted. Five hundred and seven low/intermediate TERS patients and 49 high TERS were included in the analysis. Patients in the low/intermediate risk TERS group were more likely to have a higher disease risk index (17% versus 10%, p&amp;lt;0.001) and more likely to be transplanted in recent years (35% in 2015-207 versus 20% for high risk; p 0.005). Patients in high TERS group had longer, yet not significant, hospital stay during the first 180 days post allogeneic HSCT ( 21 vs 14 days for low/intermediate TERS p=0.22). Both groups had similar median age, sex, disease distribution, donor type, graft source, regimen intensity, HCT-CI score and KPS score. Median follow up for survivors was 66.7 months (14.0-184.4) for low/intermediate risk versus 94.8 months (15.9-182) for high TERS p&amp;lt;0.001. The survival estimates for low/intermediate and high TERS at 1 year were as follows (figure 1): OS (82% vs 63%, p=0.015), DFS (72% vs 57%), TRM (10% vs 16%) and relapse (18% vs 27%). The cumulative incidence of grade 2-4 GVHD and moderate-severe chronic GVHD were 38% and 30% for low/intermediate versus 31% and 27% for high TERS (P=NS). A multivariate analysis using cox models for OS, DFS, TRM, relapse , acute and chronic GVHD was performed using the following variables that were selected based on significance (p&amp;lt;0.05): age (&amp;lt;55 vs ≥55 years), gender, diagnosis, donor type (MRD, MUD, Haplo), source (BM, PBSC), regimen intensity, disease risk (low, intermediate, high), HCT-CI (0-2, ≥3), KPS (60-80, &amp;gt;80) and year of transplant ( 2005-2009, 2010-2014, 2015-2017). High TERS score predicted for worse OS (HR 2.04; 95% CI 1.32-3.17; p=0.002), worse DFS (HR 1.71, 95% CI 1.12-2.63, p0.014), a trend towards higher TRM (HR 1.62, 95% CI 0.86-3.05, p0.136) and relapse (HR 1.56, 95% CI 0.87-2.78, p=0.132) (table 1). In a subset analysis of patients with low/intermediate disease risk, multivariate analysis showed that high TERS predicted for worse OS (HR 1.97, 95% CI1.24-3.14, p=0.004), DFS (HR 1.74, 95% CI 1.10-2.75, p=0.018), trend for higher TRM (HR 1.91, 95% CI 0.98-3.72, p=0.057) and similar relapse rates. 1-year OS and DFS were significantly better for low/intermediate TERS 83% and 75% compared to high TERS 63% and 55% (p&amp;lt;0.05 for both) for patients with low/intermediate disease risk. Among a subset of patients with low HCT-CI ≤2 (n=317), patients in the high TERS group had higher TRM (25% vs 7%, p0.009) but no significant difference in OS, DFS, relapse and GVHD rates. In a multivariate analysis for HCT-CI 0-2 patients, high TERS was significant for higher TRM (HR 2.17, 95% CI 1.45-6.97, p=0.004). Our findings show that psycho social factors as measured by TERS score are a strong predictor of morbidity and mortality after allogeneic HSCT. This effect is independent of disease risk and morbidity prior to transplant. Psycho social factors should be included in patient selection and survival prediction models for transplant recipients. Figure 1: Survival and Relapse Estimates Based on TERS score Disclosures No relevant conflicts of interest to declare.