Received Reduced-intensity Conditioning Research Articles

Retrospective Study of Allogeneic Hematopoietic Stem Cell Transplantation for Relapse or Refractory Peripheral T-Cell Lymphoma at Toranomon Hospital and Toranomon Hospital Kajigaya

[Background] Relapsed or refractory peripheral T-cell lymphoma (R/R PTCL) is known to have a poor prognosis. Although new medications have been introduced in recent years, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for R/R PTCL. We review the results of allo-HSCT for PTCL at our institution. [Methods] We performed a retrospective analysis of R/R PTCL patients who underwent first allo-HSCT at our hospital from February 2011 and April 2023. The primary endpoint was OS, which was defined as the time from allo-HSCT to death from any cause or the last follow-up. The secondary endpoints included progression-free survival (PFS), relapse/progression incidence (RI) and non- relapse mortality (NRM). PFS was defined as the time from allo-HSCT to relapse/progression, death, or the last follow-up. OS and PFS were estimated by the Kaplan-Meier method and multivariate Cox proportional hazard models. The cumulative incidence of relapse and NRM were investigated with a competing risk analysis using Gray's test and multivariable Fine and Gray competing risk regression. [Results] During the study period, a total of 44 patients received first allo-HSCT for PTCL (ALK positive ALCL: 2, ALK negative ALCL: 2, AITL: 10, PTCL-NOS: 21, CTCL: 7, HSTL: 2). The median follow-up months of survivors was 51.6 (range, 2.6-141.6). The median age of patients at transplantation was 50 years (range, 17-70). Clinical stage I/II at diagnosis was 10 cases, and clinical stage III/IV was 34 cases. Prognostic Index for PTCL(PIT) was score 1 in 20 cases, score 2 in 20 cases and score 3 in 3 cases. Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) ≧ 2 was 21 cases. Performance Status (PS) 0-1 was 32 cases and PS 2-4 was 12 cases. Primary induction failure (PIF) was 28 cases and relapse after first remission (REL) was 16 cases, including 5 cases of relapse after autologous stem cell transplantation. Median number of chemotherapy regimens received before allo-HSCT was 3 (range, 1-8). Clinical stage at transplantation was CR/PR in 23 patients and SD/PD in 21 patients.The majority, thirty-two had received unrelated cord blood transplantation (CBT), six did unrelated bone marrow transplantation (uBMT), and 6 did related peripheral blood stem cell transplantation (rPBSCT). Thirty-two patients received myeloablative conditioning (MAC), eighteen of which included total body irradiation (TBI) and 15 of which included busulfan (BU). Twelve patients received reduced-intensity conditioning (RIC) . Regarding the primary endpoint, the 4-year OS after allo-HSCT was 53.3%. The 4-year PFS, RI and NRM were 50.4%, 20.7% and 28.8%, respectively. The 4-year OS of CBT, uBMT and rPBSCT patients was 55.2%, 66.7% and 33.3%, respectively. The 4-year OS of REL and PIF patients was 79.1% and 39.5%, respectively (p<0.01). The 4-year OS of MAC and RIC was 49.5% and 64.3%, respectively (p=0.58). The 4-year OS of patients with TBI was superior to patients without TBI (71.1% vs 40.3%, p=0.05). The 4-year OS of CR/PR patients at transplant was superior to SD/PD patients (67.1% vs. 42.9%, p=0.05). In the univariate analysis, PS 0-1, HCT-CI 0-1, REL, CR/PR patients at transplant, patients with TBI and patients without BU were favorable prognostic factors. In the multivariable analysis, REL was associated with better OS (p=0.01, HR 0.16; 95% CI: 0.04-0.65). Except for 3 patients who died from transplant complications before engraftment, 41 patients achieved neutrophil engraftment, with a median engraftment date of 19 days (range, 11-31 days) after transplantation. Twenty-seven patients had acute GVHD (Grade I: 3, Grade II: 13, Grade III: 8, Grade IV: 3), and 11 patients had chronic GVHD. Eleven patients relapsed after transplant, and the median time from transplant to relapse was 26.3 months (range, 0.6-87.1 months). Three patients survived at the last follow up, and the median follow-up time of survivors from relapse was 430 days (range, 12-1301). [Conclusion] Our data indicated good results of allo-HSCT for R/R PTCL, and significantly better in relapse after first remission patients.

A Novel and Cost-Efficient Measurable Residual Disease (MRD) Detection Assay Using a Single Molecule Molecular Inversion Probe-Based Next Generation Sequencing (NGS) Assay Predicts Overall Survival in Patients with Acute Myeloid Leukemia Undergoing Allogeneic Stem Cell Transplantation

Introduction Relapse remains the main reason for poor outcomes of patients (pts) with acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred post-remission treatment in pts at high risk of relapse. The presence of measurable residual disease (MRD) after intensive frontline treatment or before or after HSCT has emerged as an important predictor of relapse. Various methods are used for MRD detection, including flow cytometry and molecular assays detecting individual gene mutations (mut) such as NPM1mut. Next generation sequencing (NGS)-based assays covering multiple genes commonly mutated in AML may allow sensitive MRD detection in a broad range of pts with diverse genetic characteristics. Methods We established a targeted, error corrected NGS MRD assay utilizing single-molecule molecular inversion probes (smMIPs). The smMIP protocol uses a hybridization-capture approach to selectively enrich and amplify both DNA strands of 92 regions in 32 genes in a single reaction. Unique molecular identifiers (UMIs) facilitate computational correction of sequencing errors to enable reliable detection of variants ≥0.5% variant allele frequency (VAF), with the additional advantage of relatively low reagent and sequencing costs of < $100 per sample. The smMIP assay was used to evaluate MRD status on pre-HSCT bone marrow samples from 98 AML pts who received an HSCT in first (n=83) or second (n=15) complete remission with or without count recovery. Median age at HSCT was 59 (range 20-75) years, 42% were female; 70% had de novo AML, 19% had an antecedent myeloid neoplasm and 11% had AML post cytotoxic therapy. European LeukemiaNet (ELN)-2022 risk groups at diagnosis were favorable in 11%, intermediate in 33%, adverse in 20% and unknown in 22%. All pts had received intensive induction chemotherapy. Twenty-nine percent received a myeloablative conditioning regimen (MAC), while 23% received reduced intensity conditioning (RIC) and 48% a non-myeloablative (NMA) conditioning regimen. Donors were matched related (18%), haploidentical (6%), or matched (55%) or mismatched (21%) unrelated. The median follow-up for pts alive was 34.8 months. Results Overall, we detected 190 variants in 71 (72%) of 98 pre-HSCT remission samples. The most commonly affected genes were DNMT3A (in 37% of pts), TET2 (21%), PPM1D (12%), IDH2 (10%) and TP53 (5%). Twenty-nine percent of pts had only variants affecting the clonal hematopoiesis-related genes DNMT3A, TET2 or ASXL1 (‘DTA‘), while 44% of patients had ≥1 variant involving a non-DTA gene. MRD-positive pts, defined as those with ≥1 non-DTA variant, had similar baseline and HSCT-related characteristics (includingage, sex, ELN risk group, de novo vs. secondary AML) compared to pts without non-DTA variants. Overall survival (OS) was significantly inferior in NGS MRD-positive pts compared to those with no non-DTA variant (Figure A, 5-year OS, 49% vs. 85%, P=.011). MRD-positive pts also had a non-significant higher cumulative incidence of relapse at 5 years (46% vs. 24%, P=.14), while non-relapse mortality was similar in both groups (P=.72). We next performed multivariable analyses, considering variables associated with OS at an univariable P<.10 (MRD status, patient sex, therapy-related AML, conditioning intensity), and using stepwise backward variable selection to identify factors significantly associated with OS (Figure B). In the final multivariable model, pre-HSCT MRD detection remained associated with inferior OS (hazard ratio 2.51; 95% confidence interval, 1.07 - 5.91; P=.035). Female sex associated with favorable OS, while myeloablative conditioning (MAC) showed a borderline significant association with superior OS. Of note, we did not detect an interaction between conditioning intensity and detection of MRD with regard to OS, i.e. the prognostic association of MRD detection was not different between pts receiving myeloablative or less-intensive conditioning. However, this analysis was limited by the small patient number. Conclusion Detection of MRD by targeted NGS using the smMIPs approach provides prognostic information in pts undergoing allogeneic HSCT, including those without established molecular markers such as NPM1mut. This method is applicable to a large proportion of AML pts and is cost-efficient for broad clinical use. S.M.K. and T.H., and M.J. and K.H.M. contributed equally to this abstract.

Feasibility of Utilizing a Virtual Health Assistant during Inpatient Reduced-Intensity Allogeneic Transplantation

Background:Artificial intelligence (AI) promises to revolutionize hematology care.Patients undergoing inpatient allogeneic hematopoietic stem cell transplantation (HCT) often experience psychological consequences, some of which may be attributed to anxiety about how to optimally care for themselves when returning home.Care.coach Avatar TM is a tablet-based ‘human-in-the-loop’ virtual health assistant (VHA) that utilizes generative AI and deterministic software to provide psychosocial support and health coaching to inpatients. It has been shown to improve loneliness, depression, anxiety, hospital delirium, and falls in older adults in the hospital (Chi, Geriatr Nurs 2017; Bott, J Med Internet Res 2019). Methods: We adapted the care.coach Avatar TM VHA for inpatient HCT, designing an education program to prepare patients for safe return to the home setting. The VHA engages patients with reminders for hydration, medications, food, or activity; education modules adapted for HCT; playing games such as jeopardy, chess, blackjack, trivia, or bingo; playing the news or music; having free-form conversations; going through therapeutic activities and exercises; and practicing mindfulness and guided meditation. Avatar protocols were updated based on feedback from a structured focus group (n=10) of nurse navigators, inpatient HCT nurses, and HCT physicians at the Dana-Farber/Harvard Cancer Center that was convened to discuss perspectives on implementation of care.coach Avatar TM VHA for HCT. Seven HCT-specific educational modules were created. A feasibility pilot was then performed in 3 sequential cohorts of 6 patients receiving reduced intensity conditioning (RIC) HCT. In the first cohort, patients were given the VHAs without any recommendations for how long to use them. The second cohort was given a recommendation for 30 minutes per day, and the third cohort was offered a $20 gift card for completion of at least 4 modules. Responses were measured through patient surveys and engagement data analysis. The predefined retention rate for feasibility was 67%, a standard for introduction of a novel AI technology (Teresi, Med Care 2022). Dissatisfaction rate for the overall VHA experience was defined as responding “disagree” or “strongly disagree” with recommending the VHA to others. Results: The study included 18 patients, with a majority female (61%) and white (72%; Table). The median age of the patients was 63 (interquartile range [IQR] 56-66). The retention rate from enrollment to discharge or three weeks (whichever came first) was 78% (95% exact confidence interval: 52-94%). The median length of use was 9 days (IQR 6-11). A post-pilot survey was completed by 16 patients (90%), revealing a dissatisfaction rate of 28%. The dissatisfaction rates decreased from 50% to 20% to 0% across the 3 cohorts. Frequency of completion of the post-pilot survey for the full study was 72% within 1 week of disenrollment, and 90% overall. Average completion rate was 52% for all seven HCT modules in the whole study population. Across cohorts, module completion rates changed from 5% to 88% to 62%, reflecting evolving guidance to patients at study initiation. The median average daily interaction time with the avatar for all 18 patients was 28 minutes with an interquartile range from 20 to 38 minutes. The most frequently used VHA functions by time of usage were music (35%), exercise (20%), and education (15%; Figure). The least frequently used VHA functions were the rounds optimizer (a tool to remind patients of their questions during rounds; 1%) and humor (1%). Overall, 52% of time using the VHA was spent on social engagement activities. Conclusions: The pilot study demonstrated the feasibility of implementing the care.coach Avatar TM VHA for inpatient HCT patients. Despite modest dissatisfaction and variability in completion rates, the VHA showed promise in providing HCT education, social, and emotional support for inpatient RIC HCT. Further research is needed to assess the impact of this novel technologic intervention on HCT outcomes and quality of life, as well as application to the outpatient HCT setting.

Relapse Incidence Post Unrelated Allogeneic Stem Cell Transplantation with Post-Transplant Cyclophosphamide (PTCy) Versus Conventional Anti-Graft Versus Host Disease Prophylaxis in Patients with Acute Myeloid Leukemia: A Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation

Background: Recently, the BMT CTN 1703 phase III study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as graft- versus-host disease (GVHD) prophylaxis post allogeneic transplantation (HSCT), demonstrating a lower incidence of severe acute (a) GVHD and chronic (c) GVHD and better GVHD-free, relapse-free survival (GRFS). The control arm did not include anti-thymocyte globulin (ATG), used in many centers for GVHD prophylaxis. Methods: The study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) to ATG combined with TAC and MTX (ATG/TAC/MTX) in acute myeloid leukemia (AML) patients (pts) undergoing HSCT from matched siblings (MSD) or 9-10/10 unrelated donor (UD) in first complete remission (CR1). Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. Results: 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC/MTX as GVHD prophylaxis. Median follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p<0.0001). The median year of the transplant was 2018 (2010-2020) and 2016 (2007-2020) (p<0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) versus 51.5 (8-77.8) years (p=0.024). The diagnosis was de novo AML in 84.1% vs 85.3% and secondary (s) AML in 15.9% vs. 14.7% (p=0.49). The cytogenetic risk was categorized as intermediate (70.9% vs. 67.1%), adverse (22.2% vs. 25.7 %), and favorable (6.9% vs. 7.2%) for pts in the PTCy/TAC or CSA & MMF and ATG/TAC/MTX groups, respectively (p=0.35) (data missing for 2214 pts). Karnofsky performance status (KPS) did not differ between the groups. There was a higher frequency of pt cytomegalovirus (CMV) seropositivity and female (F) donor to male (M) pt combination in the PTCy/TAC or CSA & MMF versus the ATG/TAC/MTX groups, 77.8% vs. 71.8% (p=0.009) and 18.4% vs. 14.4% (p=0.029), respectively. More pts in the PTCy/TAC or CSA & MMF group received reduced intensity conditioning (RIC) 51.5% versus 41.1% in the ATG/TAC/MMT group, respectively (p<0001). Day 60 neutrophil engraftment (ANC >0.5 x 10 9/L) was 98.7% vs. 98.6% (p=0.84). Day 180 incidence of a GVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p=0.92) and 8.1% vs. 6% (p=0.1), in pts receiving PTCy/TAC or CSA & MMF versus the ATG/Tac/MTX GVHD prophylaxis, respectively. The 2-year (y) total and extensive chronic (c) GVHD were 33.7% vs. 30% (p=0.09) and 10.7 % vs. 11.2% (p=0.81), respectively. GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD (grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios (HRs) =1.15 (95% CI 0.86-1.53, p=0.35), HR=0.87 (95% CI 0.56-1.34, p=0.52), HR=0.91 (95% CI 0.7-1.18, p=0. 47 and HR=1.51 (95% CI 0.96-2.36, p=0.074). Two-y NRM was significantly lower in pts that received PTCy/TAC or CSA & MMF versus ATG/TAC/MTX for GVHD prophylaxis, HR=1.57 (95% CI 1.07-2.3, p=0.022). Other HSCT outcome parameters did not differ between the groups. The HR for 2-y RI was 0.99 (95% CI 0.77-127, p=0. 93). The HRs for 2-y leukemia-free survival (LFS), overall survival (OS), and GRFS were HR=1.15 (95% CI 0.94-1.42, p<0.18), HR=1.18 (95% CI 0.94-1.49, p=0.16) and HR=1.12 (95% CI 0.93-1.36, p=0.22), respectively. Donor type and conditioning regimen were poor prognostic factors for grade II-IV, III-IV aGVHD, and total and extensive cGVHD. For cGVHD, additional poor prognostic factors were F donor to M pt combination and pt CMV seropositivity. Poor prognostic factors for LFS, OS, and GRFS were 9/10 UD, age (by 10 y), sAML, adverse-risk cytogenetics, lower KPS, and pt CMV seropositivity. For NRM, factors were the same apart from cytogenetics risk which was not a prognostic factor. In addition, time from diagnosis to HSCT was a prognostic factor for NRM and RI. Other poor prognostic factors for RI were lower KPS and pt CMV seropositivity. Conclusions: In this registry-based retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. NRM was significantly lower with the PTCy-based GVHD prophylaxis, while all other transplant outcome parameters were similar.

Outcomes of Patients with Accelerated/Blast-Phase MPNs That Received Allogeneic Stem-Cell Transplant in the Current Era of Myeloid Therapies

Background Patients (pts) with Philadelphia chromosome-negative (Ph-neg) myeloproliferative neoplasms (MPNs) that progress to an accelerated phase (AP) or blast phase (BP) have a median overall survival (mOS) of less than 1 year (Odenike, Blood 2018; Tam et al, JCO 2009). Allogeneic hematopoietic stem cell transplant (allo-HCT) is the only curative approach for MPN-AP/BP, but mOS remains about a year for pts with MPN-BP that undergo allo-HCT (2005-2019) (Orti et al, AJH 2023). We previously reported on outcomes of pts with MPN-AP/BP treated in the current era of myeloid therapies (2017 onward) and found a mOS of 0.73 years in a multi-center cohort of 80 pts (Patel et al, ASH 2022). We aim to characterize treatment patterns and outcomes of pts with MPN-AP/BP that underwent allo-HCT via a multi-center retrospective analysis. Methods Retrospective chart review was performed at 8 institutions to identify pts with pathology-confirmed Ph-neg MPN-AP/BP diagnosed in 2017 or later. All patients that met inclusion criteria were included. Response was assessed using 2017 European Leukemia Net AML (2017 ELN) criteria (Dohner et al, Blood 2017). OS from diagnosis of MPN-AP/BP and from time of allo-HCT was calculated utilizing Kaplan-Meier analysis. Results The full MPN-AP/BP cohort consists of 180 pts. This analysis includes 58 pts that underwent allo-HCT for MPN-AP/BP across 8 institutions. Median age at MPN-AP/BP diagnosiswas 64 years. The most common therapies for chronic-phase MPN included hydroxyurea (55%), JAK inhibitor (JAKi) (26%), interferon (9%), and hypomethylating agent (HMA, 4%). No patient previously received allo-HCT for chronic-phase MPN. Driver mutations included JAK2 (60%), CALR (22%), MPL (10%), but some pts had triple-negative disease (7%). Sixty-two percent of pts had high-risk disease by 2017 ELN criteria. Forty-four pts had next-generation sequencing performed at time of MPN-AP/BP diagnosis. The most frequently co-occurring mutations detected at time of MPN-AP/BP diagnosis were ASXL1 (30%), SRSF2 (23%), RUNX1 (23%), TP53 (18%), TET2 (16%), IDH2 (11%), U2AF1 (7%), EZH2 (7%), and IDH1 (9%). Additional characteristics are in Table 1. One pt proceeded directly to allo-HCT at time of MPN-AP/BP diagnosis. Frontline therapies (1L) for MPN-AP included intensive chemotherapy (IC) (n=26), hypomethylating agent (HMA) + venetoclax (VEN) (n=16), HMA monotherapy (n=14), and low-dose cytarabine (LDAC) + VEN + JAKi (n=1). Responses are summarized in Table 2A. Thirty-seven pts proceeded to allo-HCT after 1L therapy (17 after IC, 10 after HMA+VEN, 9 after HMA, 1 after LDAC+VEN+JAKi). Twenty pts proceeded to allo-HCT after 2 nd-line and beyond (2L+) therapies. Therapies utilized and responses are summarized in Table 2B. Transplant-specific characteristics include 15 pts receiving myeloablative conditioning while 43 received reduced-intensity conditioning. Donor source was matched unrelated donor for 33 pts, haploidentical donor for 10 pts, matched related donor for 9 patients, mismatched unrelated donor for 5 patients, and cord blood for 1 patient. Twenty-two pts developed acute GVHD while 15 developed chronic GVHD. Amongst the 58 pts that underwent allo-HCT, 19 had relapse of disease and 8 patients received treatment after relapse. Amongst the full cohort of 180 patients, mOS was 0.72 years from time of MPN-AP/BP diagnosis. The mOS for the 58 pts that underwent allo-HCT was 1.82 years from time of MPN-AP/BP diagnosis and 1.30 years from time of allo-HCT. Survival analysis by initial MPN-AP/BP therapy demonstrated a mOS from time of MPN-AP/BP diagnosis of 1.9 years for HMA-based therapy, 1.9 years for HMA + VEN, and 1.5 years for IC ( p=0.006). We also analyzed mOS by disease status prior to transplant. Thirty-four pts had a complete response (CR) or CR with incomplete count recovery (CRi) with mOS of 1.7 years from time of allo-HCT, 12 pts with a partial response (PR) or morphologic leukemia-free state (MLFS) had mOS of 1.8 years, and 11 pts with treatment failure (TF) had mOS of 0.47 years (p=0.82). Conclusions Our cohort of 180 pts with MPN-AP/BP treated in the current era of myeloid therapies had limited survival with a mOS of 0.72 years from MPN-AP/BP diagnosis. Amongst the 58 pts that underwent allo-HCT the mOS was 1.82 years with longer mOS seen in pts that received HMA or HMA + VEN as their 1L therapy when compared to IC. This underscores the need for novel management strategies even in pts eligible for allo-HCT.

Post-Transplant Cyclophosphamide, Tacrolimus or Cyclosporine a and Mycophenolate Mofetil Compared to Anti-Thymocyte Globulin tacrolimus or Cyclosporine a and Methotrexate Combinations As Graft- versus -Host Disease Prophylaxis Post Allogeneic Stem Cell Transplantation from Sibling and Unrelated Donors in Patients with Acute Myeloid Leukemia: a Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow

Background: Recently, the BMT CTN 1703 phase III study compared post-transplant cyclophosphamide with tacrolimus with mycophenolate mofetil (PTCy/TAC/MMF) to TAC /methotrexate (MTX) as graft- versus-host disease (GVHD) prophylaxis post allogeneic transplantation (HSCT), demonstrating a lower incidence of severe acute (a) GVHD and chronic (c) GVHD and better GVHD-free, relapse-free survival (GRFS). The control arm did not include anti-thymocyte globulin (ATG), used in many centers for GVHD prophylaxis. Methods: The study aim was to compare PTCy with TAC or cyclosporine A (CSA) and MMF (PTCy/TAC or CSA & MMF) to ATG combined with TAC or CSA and MTX (ATG/TAC or CSA & MTX) in acute myeloid leukemia (AML) patients (pts) undergoing HSCT from matched siblings (MSD) or 9-10/10 unrelated donor (UD) in first complete remission (CR1). Statistical tests included a multivariate analysis (MVA) adjusting for potential confounding factors using a Cox proportional-hazards regression model for main outcomes. . Results: 6050 pts met the inclusion criteria, 402 received PTCy/TAC or CSA & MMF and 5648 received ATG/TAC or CSA & MTX as GVHD prophylaxis. Median follow-up was 23.4 (IQR, 20.3-24.9) and 41.8 (IQR, 39.6-43.3) months (p<0.0001). The median year of the transplant was 2018 (2010-2020) and 2016 (2007-2020) (p<0.0001). Pts in the PTCy/TAC or CSA & MMF group were younger, with a median age of 48.7 (range 18-5.6) versus 51.5 (8-77.8) years (p=0.024). The diagnosis was de novo AML in 84.1% vs 85.3% and secondary (s) AML in 15.9% vs. 14.7% (p=0.49). The cytogenetic risk was categorized as intermediate (70.9% vs. 67.1%), adverse (22.2% vs. 25.7 %), and favorable (6.9% vs. 7.2%) for pts in the PTCy/TAC or CSA & MMF and ATG/TAC or CSA & MTX groups, respectively (p=0.35) (data missing for 2214 pts). Karnofsky performance status (KPS) did not differ between the groups. There was a higher frequency of pt cytomegalovirus (CMV) seropositivity and female (F) donor to male (M) pt combination in the PTCy/TAC or CSA & MMF group, 77.8% vs. 71.8% (p=0.009) and 18.4% vs. 14.4% (p=0.029). More pts in the PTCy/TAC or CSA & MMF group received reduced intensity conditioning (RIC) 51.5% versus 41.1% in the ATG/TAC or CSA & MTX group, respectively (p<0001). Day 60 neutrophil engraftment (ANC >0.5 x 10 9/L) was 98.7% vs. 98.6% (p=0.84). Day 180 incidence of a GVHD grade II-IV and III-IV was 21.2% vs. 20.4% (p=0.92) and 8.1% vs. 6% (p=0.1), in pts receiving PTCy/TAC or CSA & MMF versus the ATG/TAC or CSA & MTX GVHD prophylaxis, respectively. The 2-year (y) total and extensive chronic (c) GVHD were 33.7% vs. 30% (p=0.09) and 10.7 % vs. 11.2% (p=0.81), respectively. GVHD was the cause of death in 11.6% vs. 13.9% of pts who died. In the MVA, both aGVHD (grade II-IV or III-IV) and cGVHD (total or extensive) did not differ between the groups with hazard ratios (HRs) =1.15 (95% CI 0.86-1.53, p=0.35), HR=0.87 (95% CI 0.56-1.34, p=0.52), HR=0.91 (95% CI 0.7-1.18, p=0. 47 and HR=1.51 (95% CI 0.96-2.36, p=0.074). Two-y NRM was significantly lower in pts that received PTCy/TAC or CSA & MMF versus ATG/TAC or CSA & MTX for GVHD prophylaxis, HR=1.57 (95% CI 1.07-2.3, p=0.022). Other HSCT outcome parameters did not differ between the groups. The HR for 2-y RI was 0.99 (95% CI 0.77-127, p=0. 93). The HRs for 2-y leukemia-free survival (LFS), overall survival (OS), and GRFS were HR=1.15 (95% CI 0.94-1.42, p<0.18), HR=1.18 (95% CI 0.94-1.49, p=0.16) and HR=1.12 (95% CI 0.93-1.36, p=0.22), respectively. Donor type and conditioning regimen were poor prognostic factors for grade II-IV, III-IV aGVHD, and total and extensive cGVHD. For cGVHD, additional poor prognostic factors were F donor to M pt combination and pt CMV seropositivity. Poor prognostic factors for LFS, OS, and GRFS were 9/10 UD, age (by 10 y), sAML, adverse-risk cytogenetics, lower KPS, and pt CMV seropositivity. For NRM, factors were the same apart from cytogenetics risk which was not a prognostic factor. In addition, time from diagnosis to HSCT was a prognostic factor for NRM and RI. Other poor prognostic factors for RI were lower KPS and pt CMV seropositivity. Conclusions: In this registry-based retrospective analysis, comparing PTCy in combination with TAC or CSA and MMF to ATG in combination with TAC or CSA and MTX as GVHD prophylaxis, we observed a similar incidence and severity of both aGVHD and cGVHD. NRM was significantly lower with the PTCy-based GVHD prophylaxis, while all other transplant outcome parameters were similar.

Prospective Evaluation of Patient-Reported Outcome up to 10 Years after Allogeneic Stem Cell Transplantation Using FACT-G/BMT and EORTC-QLQ30 Questionnaires

Introduction Increasing outpatient care in all medical departments will pose a challenge for daily routines and force us to rethink established processes. In hemato-oncology there is good evidence for the continuous improvement of overall survival after allogeneic stem cell transplantation (allo-HCT) during the last decades. However, the chronic character of the underlying hematopoietic malignancy and the accompanying long-lasting consequences of an allo-HCT are often not properly addressed in follow-up care. The health care status of this population should be determined on physical and mental condition and serious longer-term sequelae need to be monitored more closely than on quarterly basis. Patient-reported outcome measurements (PROMs) are able to address this issue in clinical routine and capture the multidimensional construct of quality of life (QoL). PROMs focus mainly on how a patient survives after a treatment, and not only on whether she/he survives and how long. Patients and Methods We performed a cross-sectional survey including all adult allo-HCT recipients who attended follow-up care in the period from March to July 2023 at the University Hospital Tübingen, Germany. Eligible participants completed both, the EORTC Core Quality of Life questionnaire (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy General (FACT-G) with the subscale for Bone Marrow Transplantation (FACT-BMT). We built 8 cohorts (day 30, day 100, month 6, month 12, year 3, year 5, year 10 and >10 years) to evaluate QoL after allo-HCT and to identify predictors like age, performance status (PS), conditioning regime, graft-versus-host disease (GvHD) development and relapse. Results We included 200 recipients (93 women, average age 54.2 years) who received allo-HCT between 2004 and 2022. The majority was treated for acute leukemia (n=95), followed by chronic leukemia (n=16), myelofibrosis (n=25), myelodysplastic neoplasm (n=20), lymphoma/myeloma (n=14) and others (n=30). 82.5% (n=165) received reduced-intensity conditioning (RIC) and 17.5% (n=35) myeloablative conditioning (MAC). 75.5% (n=151) of allogeneic donors were HLA-matched, 14.5% (n=29) HLA-mismatched and 8.5% (n=17) haplo-identical. The median follow-up was 43.4 months with the following patient numbers in the 8 cohorts: n=25 (d30), n=21 (d100), n=24 (m6), n=34 (m12), n=32 (y3), n=30 (y5), n=23 (y10) and n=11 (>10y). 73% (n=146) showed complete remission at last follow up, 14% (n=28) relapsed. Acute GvHD was observed in 39% (n=78) with additional 6.5% (n=13) suspected to have one. Chronic GvHD was observed in 39.5% (n=79). Average GHS in the EORTC QLQ-30 was 59.2%, average total scores in the FACT-G and FACT-BMT were 77.68 (max. score 108) and 105.37 (max. score 148), respectively. Both PROMs (EORTC QLQ30, FACTs) demonstrated the same biphasic course with a significant QoL recovery over time (Figure 1), comparing for example the global health status (GHS) on d30 (50%) with y10 (68,8%, p=0.07). Interestingly, allo-HCT recipients again experience a drastic decrease achieving y3, mainly caused by worse emotional and physical well-being. The median ECOG PS before allo-HCT was 0 and degraded to 1 in all cohorts until y10, where a return to baseline was seen. Current PS and PRO results showed a significant correlation (p<0.001). No correlations between QoL and age, GvHD or conditioning regime were found. Conclusion Allo-HCT recipients manage to regain a good QoL in long-term follow-up over 10 years but experience a significant low around y3. PROMs are able to detect such developments and can help to improve patient management. As indicated by our data, a higher degree of support in y3 could improve QoL and well-being of allo-HCT patients. However, until today, we lack the implementation of efficient strategies to do so in clinical routine.

Analysis of the Impact of Whole Blood and T-Cell Donor Chimerism after Allogeneic Stem Cell Transplant

Background: Allogeneic stem cell transplant (alloSCT) is one of the few currently available therapies to cure acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Positive outcomes are dependent on engraftment of donor cells to provide hematopoiesis as well as a graft-versus-tumor effect. Measurement of whole blood (WB) and T-cell (TC) chimerism at routine intervals post alloSCT allows for monitoring of engraftment. Development of mixed donor chimerism (MC) may indicate impending graft failure or disease relapse. The ideal frequency for chimerism measurements as well as the role of WB versus TC chimerism remains unclear. In this study, we analyzed the impact of WB versus TC mixed chimerism on survival outcomes in patients with AML and MDS. Furthermore, we studied baseline factors associated with the development of MC. Methods: In this retrospective analysis, adults with AML or MDS who received an alloSCT between January 1, 2016 and February 1, 2022 that had at least 1 donor chimerism measured on Day 30 (D30), Day 60 (D60), Day 90 (D90) at Juravinski Hospital and Cancer Centre (Hamilton, ON, Canada). Baseline demographic and transplant-related characteristics were collected. AML and MDS diagnoses were based on WHO 2016 classification of myeloid neoplasm and acute leukemia. Conditioning intensities were classified according to CIBMTR definitions. A total of 271 transplants were completed during the study period for AML or MDS. 128 were excluded from the analysis (chimerism testing not performed (n=121), second transplants (n=7)). We analyzed a total of 143 patients with median age of 63 years (19 - 76) who were transplanted for AML (n=105) and MDS (n=38). Donors were HLA-matched siblings (MRD, n=26), unrelated donors (MUD (8/8 or 7/8), n=85) or haploidentical related donor (MMRD, n=32). All patients except one received peripheral blood stem cell grafts. For alloSCT, 20 % of patients received myeloablative conditioning (MAC) and 80% received reduced-intensity conditioning (RIC). Complete chimerism (CC) was defined as ≥95%, whereas MC was defined as ≤95%. All chimerism measurements were measured using a PowerPlex® 16 System (Promega) (Hamilton Regional Laboratory Medicine Program, Hamilton, ON). Results: In our cohort, OS at 2 years was 57% and RFS 49%. Of the baseline factors, only disease-risk based on ELN 2022 for RFS with a hazard ratio (HR) of 1.43, 95% CI [0.83, 2.49] for adverse risk and HR 0.53 95% CI [0.23, 1.03] (p=0.03) for favourable risk. WB MC was detected in 22%, 22%, 23% of patients on D30, D60, and D90, respectively. TC MC was detected in 48%, 46%, and 43% of patients on D30, D60, and D90, respectively. WB MC had a strong negative impact on RFS, with a HR of 2.81, 95% CI [1.69, 4.66; p<0.001] on D30, 3.07, 95% CI [1.67, 5.66; p<0.001] on D60 and 4.77, 95% CI [2.47, 9.22; p<0.001] on D90. The influence of TC MC on RFS was also significant at all time points. Of 101 patients who were alive and did not have a relapse prior to D90 and had D30 chimerism and D90 chimerism evaluated, the patients who had a mixed WB and TC chimerism on D90 had a HR of 6.13, 95% CI [2.23, 16.85] and HR 2.73, 95% CI [1.24, 5.98] for RFS, which was statistically significant even after adjusting for known information of D30 WB/TC chimerism status (Table 1). WB MC had a strong negative impact on OS with a HR of 2.67, 95% CI (1.54, 4.64; p=0.001) on D30, 2.81, 95% CI (1.47, 5.38; p=0.002) on D60 and 4.78, 95% CI (2.47, 9.24; p<0.001) on D90. Again, the later time points remained statistically significant, when adjusting for known D30 chimerism status. The influence of TC MC on OS was also significant at all time points, however only a non-significant trend remained at later time points when adjusting for D30 TC chimerism (Table 2). We analyzed baseline factors predictive for D30 chimerism. For WB chimerism, only donor source remained statistically significant (p=0.038) with MMRD having a lower HR for MC 0.39, 95% CI [0.11, 1.41] and MRD having a higher HR for MC 2.33, 95% CI [0.9 - 5.99]. Conclusions: Our data confirm that a mixed chimerism as early as D30 post-alloSCT can have a detrimental impact on outcomes (RFS and OS) in alloSCT. Patients receiving haploidentical alloSCT had a lower risk to develop mixed chimerism in our cohort. These dismal outcomes of patients with mixed chimerism in our cohort provides a strong rationale to study interventions such as novel maintenance strategies or donor-lymphocyte infusions in this patient group.

Low-Dose Decitabine Plus Venetoclax As Post-Transplant Maintenance for High-Risk Myeloid Malignancies

Background: Allogeneic stem cell transplantation (allo-SCT) is potentially curative for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). However, post-SCT relapse remains a major cause of treatment failure for these patients and strategies to prevent post-transplant relapse are urgently needed. The combination of venetoclax (VEN) with either azacitidine (AZA) or decitabine (DEC) has shown promising results in older or unfit patients with AML and is now being investigated in younger patients as well. Herein, we report our experience of administering low-dose DEC and VEN as post-transplant maintenance in patients with high-risk myeloid malignancies. Methods: A retrospective chart review was performed to evaluate outcomes of patients with AML and MDS that received post-SCT maintenance with DEC and VEN at the University of Alabama at Birmingham. DEC was administered at 10mg/m 2 on days 1-3 per cycle and VEN was given at a target dose of 200mg on days 1-28 for AML and days 1-14 for MDS. The dose of VEN was reduced to 20mg when administered with voriconazole or posaconazole or 100mg when administered with fluconazole or isavuconazium. The cycle length was 4 weeks. Results: We identified 19 patients between March 2021 and May 2023 that received post-SCT DEC/VEN for AML and MDS (Table 1). The median follow-up was 10m (range 3-26m). The median age was 60y (range 34-69y). There were 10 (53%) females and 13 (68%) non-Hispanic whites (NHWs). Fourteen patients had AML and 5 had MDS. For patients with AML, 10 had poor-risk and 4 had intermediate-risk disease per ELN 2017. At the time of transplant, 11 patients with AML were in CR1 (CR1=6, CRi1=5), 2 were in CR2 (CR2=1, CRi2=1) and 1 was in CR3. Three patients with AML had MRD+ at the time of transplant (CRi1=2, CR3=1). For patients with MDS, 2 had very-high and 2 had high-risk disease per R-IPSS. One patient had therapy-related MDS. Two patients with MDS had CR, 2 had stable disease and 1 had hematological-improvement at the time of transplant. Overall, 6 patients (32%) had a TP53 mutation. Donor type was matched-related in 5 patients, matched-unrelated in 12 patients and haploidentical in 2 patients. Seventeen patients received reduced-intensity conditioning (RIC). GVHD prevention consisted of tacrolimus and methotrexate in 14 patients and post-transplant cyclophosphamide-based in 5 patients. The median time to initiating maintenance therapy was 69d (range 54-200d) post-SCT. The median number of cycles administered was 6 (range 2-24). Grade III-IV neutropenia, anemia and thrombocytopenia occurred in 5, 1 and 2 patients, respectively. Two patients had febrile neutropenia and one patient had candida esophagitis. Five patients required a reduction or interruption in the dose due to adverse events. In all cases, the VEN duration was shortened by 1 week. The cumulative incidence (CI) of day 100 grade II-IV and III-IV aGVHD was 13% and 5%, respectively. There were no grade IV cases. The 1y CI of moderate-severe cGVHD was 26%. To date, one patient who received a RIC haplo-SCT for poor-risk AML in CR2 relapsed 14m after SCT. The 1y non-relapse mortality was 11%. The 1y OS for the entire cohort was 84% (Figure 1). Conclusion: Our preliminary data suggests that the combination of low-dose DEC plus VEN is a safe and potentially effective strategy to reduce the risk of post-SCT relapse. Adverse effects mainly included manageable cytopenias with no increase in risk of GVHD. The efficacy of the combination appears to be promising but needs longer follow-up as well as confirmation in large, randomized studies.

DURABLE LONG‐TERM REMISSION IN HIGH‐RISK RELAPSE REFRACTORY LYMPHOMA—20 YEARS’ EXPERIENCE OF ALLOGENEIC HAEMOPOIETIC STEM CELL TRANSPLANT IN SINGAPORE

Background: Allogeneic hematopoietic stem cell transplantation (AlloHSCT) is a curative option for those who have high risk relapsed/refractory lymphoma in the era of novel and cellular therapies including CAR-T cell. There is a paucity of data evaluating the long term outcomes of AlloHSCT in Asian lymphoma patients. We performed a retrospective analysis of 20 years to evaluate the prognostic factors and outcomes of AlloHSCT for lymphoma patients in Singapore. Methods: We evaluated 121 lymphoma patients (both non-Hodgkin (NHL) and Hodgkin lymphoma (HL)) from two major transplant centres in Singapore who had AlloHSCT over a 20-year period (2003–2022). Results: The 121 patients have a median age of 41 (range 16–71). Diagnoses include B-NHL (N = 41, diffuse large B cell lymphoma n = 21, follicular lymphoma n = 2, mantle cell lymphoma n = 6, primary mediastinal B cell lymphoma n = 5, chronic lymphocytic leukemia n = 7), T-NHL (N = 38, peripheral T cell lymphoma n = 32, other T-NHL n = 6), NK T cell (N = 24) and HL (N = 18). 84% received reduced intensity conditioning (RIC), and 27.3% had a previous transplant. Donor types include matched sibling donor (N = 54), matched unrelated donor (N = 35), Haplo-identical donors (N = 23) and Cord blood (N = 9). With a median duration of follow up of 56 months (range 0–232 months), the 4-year progression free survival (PFS) and overall survival (OS) were 38% and 45% respectively. The non-relapse mortality was 11.6% at day 100 and 24% at 1 year. The cumulative incidence of acute graft-versus-host disease (GvHD) was 36.4% with 5 patients having grade IV acute GvHD. On univariate analysis, patients who were in complete remission (CR) at the time of AlloHSCT and those who have been given RIC had improved OS. Subset analyses showed that the outcomes of AlloHSCT for relapsed/refractory Hodgkin lymphoma were the most favourable (4-year PFS and OS at 61.2% and 62% respectively), whereas patients with T-NHL, B-NHL and NK T cell lymphoma had lower survival rates (4-year PFS 35%, 44%, 19%; 4-year OS 52%, 43%, 30% respectively). Keyword: Stem Cell Transplant No conflicts of interests pertinent to the abstract.

Predictors of survival outcomes in patients with MECOM EVI1 rearrangement aberrations in AML or MDS.

e19078 Background: MECOM (EVI1) rearrangements in MDS/AML are rare and carry an unfavorable prognosis. Although allogeneic stem cell transplantation (allo-HSCT) may prolong survival, factors impacting outcomes are not known. We conducted a retrospective analysis of patients with MECOM (EVI1) to associate clinicopathologic variables with prognosis. Methods: This study was approved by the Mayo Clinic IRB. Patients >18 years of age with MDS or AML and MECOM EVI1 at Mayo Clinic between 01/2012 and 12/2022 were included. Response was defined by ELN criteria. Intensive chemotherapy was defined as 7+3 or high dose cytarabine. Non-intensive chemotherapy included hypomethylating agents with or without venetoclax. Median overall survival (OS) and median leukemia free survival (LFS) were estimated using the Kaplan-Meier method. Outcome differences between sub-groups and univariate analyses were assessed with Cox regression. Results: Sixty patients met criteria for inclusion. Sixty-three percent (n = 38) were male and the median age at diagnosis was 67.8 yrs (range, 56 – 75). Eighty percent had AML (n = 48) and 18% had MDS (n = 11). Sixty-seven percent of patients had secondary AML/MDS (n = 40). Inv(3)/t(3;3) was present in 65% (n = 39) and t(3;21) was present in 12% (n = 7). Thirty-eight percent (n = 23) of patients had cooccurring monosomy 7 or 7q deletion and 5% had complex karyotype (n = 3). SF3B1 was the most common cooccurring mutation in 31% (n = 10), followed by KRAS in 19% (n = 6). Thirty-eight percent of patients (n = 23) received intensive chemotherapy. Complete response (CR) rates were 36% with intensive treatment (n = 8) and 4% with non-intensive treatment (n = 1; p = 0.007). Thirty percent (n = 18) underwent SCT (78% in CR1 and 22% in CR2) and of those, myeloablative conditioning (MAC) was used in 38% while 61% received reduced intensity conditioning (RIC). The mOS in the entire cohort was 11 months (95% CI 6.2, 17). Patients who received a SCT had longer mOS compared to patients who did not (19 vs 6.2 months, HR = 0.31, 95% CI 0.16,0.64; p = 0.001). AML-MRC was a poor prognostic factor in the HCST group for OS (HR = 4.23, 95% CI 1.02, 17.5, p = 0.047). Intensive vs. non-intensive chemotherapy, response prior to transplant (CR vs. no CR), or having 2 or more mutations on NGS did not significantly impact OS or LFS. Conclusions: In line with previous reports, allo-HSCT was associated with improved survival outcomes. Our results showed a high frequency of secondary AML/MDS, but only AML-MRC was associated with decreased survival outcomes. Regardless of therapy type, outcomes were poor. Novel therapies are urgently needed for these patients.

Allogeneic hematopoietic stem cell transplantation remains a feasible approach for elderly with acute myeloid leukemia: a 10-year experience

The incidence of AML increases with age. The implementation of reduced intensity conditioning and progress in supportive care enabled to perform allo-HSCT in elderly patients. The main objective of the study was to assess the safety and efficacy of allotransplantation in elderly AML.Forty nine patients (33 males) at median age of 68 years were identified. Data on patients’ and transplant’s related variables were retrieved from our local transplant registry. Most patients (65%) were transplanted from 10/10-HLA or 9/10-HLA matched unrelated donor, seven patients (14%) received stem cells from matched related donor and ten patients (20%) from haploidentical donor. All patients received reduced-intensity conditioning (RIC). Peripheral blood was a source of stem cells in all patients except one (98%). Acute GVHD developed in 22 patients (44%) with 5 individuals presenting grade III-IV. CMV reactivation was demonstrated in 19 patients (39%) till day + 100. In total, 22 patients (45%) have died. The main causes of death included infectious complications (n = 9), relapse with subsequent chemotherapy resistance (n = 7), steroid-resistant GvHD (n = 4) and other causes (n = 2). Twenty-seven patients (55%) were alive at the last contact, presented full donor chimerism and remained in the complete remission. The probability of OS and relapse-free survival (RFS) were 57% and 81% at 2 years, respectively. Older donor age showed negative impact on relapse. CMV reactivation, the severity of acute graft versus host disease and older donor age negatively influenced survival. Allo-HSCT remains a safe, feasible and effective procedure for elderly AML patients.

Impact of Donor Age in Haploidentical-Post-Transplantation Cyclophosphamide versus Matched Unrelated Donor Post-Transplantation Cyclophosphamide Hematopoietic Stem Cell Transplantation in Patients with Acute Myeloid Leukemia

Haploidentical hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy) graft-versus-host-disease (GVHD) prophylaxis is associated with inferior overall survival (OS) compared to HLA-matched unrelated donor (MUD) HCT with PTCy prophylaxis in patients receiving reduced-intensity conditioning (RIC). Given prognostic implications of donor age, we investigated the differences in outcomes of patients with acute myeloid leukemia (AML; n=775) undergoing RIC-HCT with a younger MUD (age <35 years; n=84) versus a younger haploidentical donor (age <35 years; n=302) versus an older haploidentical donor (age ≥35 years; n=389). The older MUD group was excluded from the analysis because of small numbers. The younger haploidentical donor group (median age, 59.5 years) was somewhat younger than the younger MUD group (median age, 66.8 years) and the older haploidentical donor group (median age, 64.7 years). More patients in the MUD group received peripheral blood grafts (82%) compared to the haploidentical donor groups (55% to 56%). In multivariate analysis, compared to the younger MUD group, the younger haploidentical donor group (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.22 to 3.12; P=.005) and the older haploidentical donor group (HR, 2.36; 95% CI, 1.50 to 3.71; P < .001) had a significantly inferior OS, and the younger haploidentical donor group (HR, 3.72; 95% CI, 1.39 to 9.93; P=.009) and older haploidentical donor group (HR, 6.91; 95% CI, 2.75 to 17.39; P < .001) had a significantly higher risk of nonrelapse mortality. The older haploidentical group had a significantly higher risk of grade II-IV acute GVHD (HR, 2.29; 95% CI, 1.38 to 3.80; P=.001) and grade III-IV acute GVHD (HR, 2.70; 95% CI, 1.09 to 6.71; P=.03). There were no significant differences across the groups in the incidence of chronic GVHD or relapse. Among adult AML patients in CR undergoing RIC-HCT with PTCy prophylaxis, a young MUD may be preferred over a young haploidentical donor.

Infection-related mortality after HLA-identical and haploidentical hematopoietic cell transplantation using reduced-intensity conditioning in an outpatient setting.

Despite the improvements in supportive care for allogeneic-hematopoietic cell transplantation (allo-HCT) recipients, infectious complications and infection-related mortality (IRM) continue to be a major issue for transplantation centers. We herein report the infectious complications and IRM of 107 and 89 patients that underwent haploidentical (haplo-HCT) or HLA-identical HCT at a tertiary referral center during 2013-2020. Patients in the haplo-HCT group received post-transplant cyclophosphamide (PT-Cy), and all received reduced-intensity conditioning regimens. More haplo-HCT recipients presented severe infections in the pre-engraftment period (22.4% vs. 6.7%, p=0.003). Viral (14.9% vs. 4.5%, p=0.016) and fungal (12.1% vs. 1.1%, p=0.003) etiologies were more common in this period in this group. The 100-day and 2-year cumulative incidence of IRM was 15% and 21% for the haplo-HCT and 5.6% and 17% for the HLA-identical group; no significant differences were observed between the groups. Fungal pathogens mainly contributed to IRM (33.3%). Infections were the most common cause of mortality (40/81, 49.4%). There were significant differences in donor/recipient CMV serostatus between transplant groups (0.002). No differences in IRM were observed based on allo-HCT type, with more haplo-HCT patients suffering from severe infections in the pre-engraftment period. Studies to assess future prevention, diagnostic, and treatment strategies to reduce IRM are warranted.

The impacts of total body irradiation on umbilical cord blood hematopoietic stem cell transplantation.

Umbilical cord blood hematopoietic stem cells are commonly used for hematopoietic system reconstitution in recipients after umbilical cord blood transplantation (UCBT). However, the optimal conditioning regimen for UCBT remains a topic of debate. The exact impact of total body irradiation (TBI) as a part of conditioning regimens remains unknown. The aim of this study was to evaluate the impacts of TBI on UCBT outcomes. This was a multi-institution retrospective study. A retrospective analysis was conducted on the outcomes of 136 patients receiving UCBT. Sixty-nine patients received myeloablative conditioning (MAC), in which 33 underwent TBI and 36 did not, and 67 patients received reduced-intensity conditioning (RIC), in which 43 underwent TBI and 24 did not. Univariate and multivariate analyses were conducted to compare the outcomes and the post-transplant complications between patients who did and did not undergo TBI in the MAC subgroup and RIC subgroup, respectively. In the RIC subgroup, patients who underwent TBI had superior overall survival (adjusted hazard ratio [aHR] = 0.25, 95% confidence interval [CI]: 0.09-0.66, p = 0.005) and progression-free survival (aHR = 0.26, 95% CI: 0.10-0.66, p = 0.005). However, in the MAC subgroup, there were no statistically significant differences between those receiving and not receiving TBI. In the setting of RIC in UCBT, TBI utilization can improve overall survival and progression-free survival. However, TBI does not show superiority in the MAC setting.

Allogeneic Blood or Marrow Transplantation with High-Dose Post-Transplantation Cyclophosphamide for Acute Lymphoblastic Leukemia in Patients Age ≥55 Years

Patients age ≥55 years with acute lymphoblastic leukemia (ALL) fare poorly with conventional chemotherapy, with a 5-year overall survival (OS) of ∼20%. Tyrosine kinase inhibitors and novel B cell-targeted therapies can improve outcomes, but rates of relapse and death in remission remain high. Allogeneic blood or marrow transplantation (alloBMT) provides an alternative consolidation strategy, and post-transplantation cyclophosphamide (PTCy) facilitates HLA-mismatched transplantations with low rates of nonrelapse mortality (NRM) and graft-versus-host disease (GVHD). The transplantation database at Johns Hopkins was queried for patients age ≥55 years who underwent alloBMT for ALL using PTCy. The database included 77 such patients. Most received reduced-intensity conditioning (RIC) (88.3%), were in first complete remission (CR1) (85.7%), and had B-lineage disease (90.9%). For the entire cohort, 5-year relapse-free survival (RFS) and overall survival (OS) were 46% (95% confidence interval [CI], 34% to 57%) and 49% (95% CI, 37% to 60%), respectively. Grade III-IV acute GVHD occurred in only 3% of patients, and chronic GVHD occurred in 13%. In multivariable analysis, myeloablative conditioning led to worse RFS (hazard ratio [HR], 4.65; P=.001), whereas transplantation in CR1 (HR, .30; P=.004) and transplantation for Philadelphia chromosome-positive (Ph+) ALL versus T-ALL (HR, .29; P=.03) were associated with improved RFS. Of the 54 patients who underwent RIC alloBMT in CR1 for B-ALL, the 5-year RFS and OS were 62% (95% CI, 47% to 74%) and 65% (95% CI, 51% to 77%), respectively, with a 5-year relapse incidence of 16% (95% CI, 7% to 27%) and an NRM of 24% (95% CI, 13% to 36%). RIC alloBMT with PTCy in CR1 represents a promising consolidation strategy for B-ALL patients age ≥55 years.

Effect of the COVID-19 pandemic on allogeneic stem cell transplantation in Japan.

The coronavirus disease 2019 (COVID-19) pandemic affected healthcare quality and access worldwide and may also have negatively affected the frequency and outcomes of allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the effect of the pandemic on allogeneic HSCT in Japan. Our subjects were patients who received allogeneic HSCT during January 2018-December 2020 in Japan. We assessed differences in yearly number of allogeneic HSCTs and 1-year outcomes in 2020 versus both 2019 and 2018. The total number of patients who received allogeneic HSCT increased from 3621 patients in 2018 and 3708 patients in 2019 to 3865 patients in 2020. Some following changes in allogeneic HSCT methods were observed: patients were older, fewer patients received bone marrow transplantation, fewer patients received transplants from unrelated donors, fewer patients received transplants from matched donors, more patients received reduced-intensity conditioning, and fewer patients received anti-thymocyte globulin in 2020 compared with previous years. HSCT outcomes were not affected, as 1-year overall survival was not significantly different (65.8% in 2020, vs. 66.5% in 2019 and 66.4% in 2018). Our results suggest that we can maintain transplant care during the pandemic by controlling the spread of COVID-19 and modifying HSCT methods.

Frequent Early Geriatric Complications after Allogeneic Hematopoietic Cell Transplantation (HCT) in Older Adults Impairs Disability-Free Survival (DiFS)

Introduction: Data continue to accumulate showing older adults with hematologic malignancies, such as AML and MDS, derive a survival benefit from HCT. However, as HCT expands into older and less fit patients (pts), the inability to describe and predict post-HCT toxicity presents a major barrier to appropriate and broader application. Standard endpoints of non-relapse mortality (NRM), organ toxicity, graft-versus host disease (GvHD), or overall survival (OS) miss important common geriatric complications (e.g., delirium, disability, falls). We aimed to estimate disability-free survival (DiFS), a composite endpoint of death, dementia or physical disability, used in older adult non-oncology trials (McNeil J, N Engl J Med 2018; 379; 1499-1508) by summarizing disability in the early post-HCT context. Methods: We reviewed electronic records for the development of disability through day 100 for pts ≥ 60 years undergoing first HCT from 2013 - 2019 at City of Hope National Medical Center. Disability events included delirium affecting instrumental ADLs (i.e., CTC ≥ 2), falls, ICU admission, or needing mobility assistance. Mobility assistance leveraged a standardized nursing flowsheet tool completed every shift for hospitalized pts, comprised of 5 categories of ambulation independence (independent, assistive equipment, assistive person, assistive equipment and person, complete dependent); mobility timepoints captured were pre-HCT, weekly starting on day 0 to d21 and at hospital discharge. Categorization of assistive person or more after HCT met the mobility assistance requirement. All pts required hospitalization post-HCT in this era. Failure events for DiFS included first disability event as above or death. Kaplan-Meier method was used to calculate DiFS at d30 and d100. A conditional landmark analysis examined the differences in unadjusted NRM among pts experiencing disability prior to d30 or d100 landmark dates and alive at the landmark date. Results: Among 699 pts, 19.7% were ≥ 70 years, 77.0% had AML/MDS/MPN, 95.6% received reduced intensity conditioning (RIC), 80.1% were conditioned with fludarabine/melphalan, and 86.7% received matched donors. Few pts needed mobility assistance pre-HCT (4.4%) although 28.3% developed mobility assistance by d21. The cumulative incidence of other disability events at d30 and d100 were: falls (4.9%, 14.3%), delirium (24.3%, 29.3%), and ICU admission (15.3%, 20.2%). NRM was 3.9% at d30 and 26.9% at 2 years. Figure 1 shows DiFS at d30 and d100 of 58.2% and 51.4%. The most common d30 disability events were delirium (41%) and mobility assistance (34.7%); all deaths by d30 (n=27) were preceded by a disability event. Baseline factors in univariate analysis associated with inferior d30 DiFS included KPS < 90% (p=.001), age ≥ 70 (.01), non-matched related donor (.003) but not HCT-CI ≥ 3, time period (<2018), conditioning regimen, GVHD prophylaxis, or baseline mobility assistance. D30 disability events were strongly linked to elevated 2 yr NRM by d30 landmark analysis (figure 2)(40% vs 15% without d30 disability events, HR=2.77; 95% CI 2.11-3.64). Similarly, disability by d100 negatively influenced d100 to 2 year NRM (HR =2.27, 95% CI: 1.65-3.11). Conclusions: HCT among older adults engenders frequent geriatric complications of delirium, loss of ambulation independence, falls and ICU admission in the early HCT period. Consequently, DiFS is approximately 60% at day 30. Further, early disability strongly predicts for higher risk of future NRM. DiFS should be further explored as a novel endpoint to summarize functional loss after older adult HCT. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Improved Gvhd and Relapse Free Survival Outcomes in Older Acute Leukemia Patients Receiving Young Haploidentical Donor Vs Older Matched Sibling Donor Reduced Intensity Conditioning Hematopoietic Cell Transplants

Background: Allogeneic hematopoietic cell transplants (alloHCT) from HLA-matched sibling donors (MSD) or matched unrelated donors (MUD) may cure patients with acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), and myelodysplastic syndromes (MDS). Older patients with AML benefit from alloHCT, but donor selection may be complicated by the advanced age and comorbidities of HLA-matched siblings. Haploidentical (Haplo) HCT with post-transplant cyclophosphamide (PTCy) is an alternative approach to traditional HLA-matched alloHCT. HaploHCT is associated with reduced graft-versus-host disease (GVHD) risk but reduced overall survival (OS) in some series with older recipients. There are limited published data assessing outcomes using younger Haplo donors versus older MSD for older HCT recipients. The objective of this study is to characterize treatment outcomes and GVHD rates in older HCT recipients of younger HaploHCT compared to older MSD grafts. Methods: This retrospective cohort analysis included patients aged 50 years and older with AML, ALL, or MDS who received reduced intensity conditioning (RIC) and either a young Haplo donor or older MSD graft from 2014 to 2020. Young donors included those <50 years old, and older donors were ≥50 years old. The primary outcome was OS one-year post-HCT. Secondary analyses included aGVHD and cGVHD outcomes, relapse-free survival (RFS), GVHD-RFS (GRFS), non-relapse mortality (NRM), infection incidence, time to neutrophil recovery, and relapse incidence. Kaplan-Meier method with log-rank test was used to assess OS, RFS, and GRFS. All data presented are organized as Haplo versus MSD. Results: Twenty-nine patients received younger donor Haplo grafts and 47 patients received older MSD grafts. Median age for donors was 35.4 years vs 61.6 years in the Haplo and MSD cohort, respectively. The underlying hematologic disorder leading to alloHCT in the two cohorts were AML (83% vs 47%), ALL (3% vs 11%), and MDS (28% vs 43%) (p<0.001). Stratified cytogenetic risk categories for each diagnosis were not significantly different. RIC regimens included Fludarabine (Flu)/Melphalan or Flu/Busulfan for older MSD recipients, whereas the younger donor Haplo cohort received Flu/Cy/TBI (200cGy). PTCy/Tacrolimus (Tac) was the GVHD prophylaxis (ppx) regimen for all Haplo recipients, whereas 96% of MSD cohort got Tac/Methotrexate (MTX) and 4% of MSD cohort got Tac/MTX/MMF. Peripheral blood was the graft source in 62% of HaploHCT and 100% of MSD (p<0.001). Seventy-six percent of donors in the Haplo cohort were recipient offspring. One-year OS was 86% vs 72% (p=0.27), RFS was 69% vs 70% (p=0.76), NRM was 7% vs 9% (p=0.86), and GRFS 89% vs 62% (p=0.005) [Table 1] for Haplo vs MSD cohorts, respectively. Median OS (HR 0.88, p=0.785) and median RFS (HR 1.38, p=0.459) were not reached in either group. Median GRFS was longer in the Haplo cohort (190 vs 148 days, HR 0.52, p=0.021) [Figure 1]. One-year incidence of relapse was not different between cohorts (p=0.14). Incidence of aGVHD (38% vs 32%, p=0.51) was similar in both cohorts, although maximum aGVHD grade was lower in the Haplo group (p=0.04). cGVHD incidence numerically favored HaploHCT (45% vs 66%, p=0.08) [Table 1]. Individuals receiving HaploHCT had a longer median time to neutrophil engraftment (19 vs 14 days, p<0.001) and a shorter median time to full CD3 chimerism (32 vs 76.5 days, p<0.001). They also had a higher incidence of CMV viremia (p=0.014), BK viremia (p=0.05), and fungal infections (p=0.047) [Table 1]. Incidence of HHV6 (p=0.18) and EBV viremia (p=0.89) were not different between cohorts. Discussion: Our results demonstrate similar OS, RFS and incidence of aGVHD and cGVHD between younger donor HaploHCT and older MSD alloHCT for older patients. GRFS was significantly better in the Haplo cohort, which may have been primarily influenced by higher incidence of cGVHD and higher grades of aGVHD observed for recipients of older MSD grafts with Tac/MTX-based GVHD ppx. aGVHD and cGVHD rates may be reduced with the use of HaploHCT and incorporation of PTCy at the expense of more opportunistic infections. Our results suggest that young donor HaploHCT using PTCy may be a reasonable alternative for alloHCT and reduce risks for GVHD for older patients with leukemia even if a MSD is available. These data also suggest MSD alloHCT with PTCy should be explored. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Interventional Antibiotic Treatment Replacing Antibiotic Prophylaxis during Allogeneic Hematopoietic Stem Cell Transplantation Is Safe and Feasible: A Single-Center Analysis

Background: Patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) are at increased risk of infection-related mortality during the pre-engraftment period. Systemic antibiotic prophylaxis (SAP) is widely used during the period of neutropenia but is associated with disruption of the intestinal microbiome, an increased risk of Clostridium difficile infection (CDI) and colonization with multi-drug resistant (MDR) bacteria. Aims: We retrospectively assessed the safety and efficacy of a change in our center policy from SAP to an exclusively interventional antibiotic treatment (IAT) in adult patients undergoing allogeneic HSCT. Outcome measures were overall survival (OS) and non-relapse mortality (NRM) at 3 years, antibiotic administration, incidence of blood-stream infections (BSI) and incidence and severity of acute and chronic graft-versus-host disease (GVHD). Methods: Cefotaxime was used as standard of care prophylaxis during neutropenia after HSCT prior to January 2018. After a 12 months transition time during which both strategies were employed in parallel, SAP was replaced by an IAT strategy with meropenem being administered immediately by nursing staff in case of neutropenic fever or any other signs of infection, and subsequently deescalated to piperacillin/tazobactam (pip/taz) when appropriate. We compared 67 consecutive patients undergoing HSCT in 2017, all of whom received antibiotic prophylaxis (SAP cohort) with all patients in 2019 comprising the IAT cohort (n=68). Use of antibiotics is reported as number of daily doses per 100 care days (DDD/100CD) until discharge after HSCT. Results: Patient characteristics are summarized in table 1. Median age was 56 years, 82% of patients were grafted with peripheral blood stem cells (PBSC) for acute leukemia (74%) from a matched unrelated or related donor (MUD, 61%; MRD 17%). Patient characteristics were well balanced between the SAP and IAT cohorts, except those patients transplanted in 2019 were more likely to have an HCT-CI ≥ 3 (56% vs 36%, p=0.025) and receive reduced-intensity conditioning (62% vs 40%, p=0.025). In the SAP and IAT cohort, neutropenic fever was observed in 46% and 62% of patients (p=0.085). However, the cumulative incidence (CI) of BSI by day +100 post-HSCT was significantly higher in the IAT vs SAP cohort (40% vs 13%, p<0.001), which did not result in more patients admitted to the intensive care unit (13% vs 6%, p=ns) and did not translate into a higher CI of NRM at 3 years (10% vs 9%, p=ns). With a median follow-up of 1052 days, 3-year OS was 70% and 69% for the SAP and IAT cohort, resp. (p=ns, figure 1). CI of acute GVHD grade II-IV or chronic GVHD of any grade at 3 years was 34% (p=ns) and 45% (p=ns), resp., resulting in identical survival free of acute GVHD grade III-IV, chronic GVHD requiring systemic immunosuppressive therapy and relapse-free survival (GRFS) of 36% (p=ns) in both groups. We observed a tendency to a higher CI of severe chronic GVHD in the SAP cohort (27% vs 13%, p=0.08). There was no significant difference between the two cohorts in terms of newly detected colonization with MDR bacteria during conditioning and after HSCT (VRE 17%; ESBL 5%; 3/4 MRGN 5%; MRSA 0%) and the incidence of CDI was likewise equal in both cohorts (13%, p=ns). Compared to SAP, IAT resulted in significantly fewer days of antibiotic therapy (24 vs 18, p<0.001) and accordingly less administration of cefotaxime (12.8 vs 3.8 DDD/100CD), teicoplanin (26.2 vs 6.3 DDD/100CD), vancomycin (11.5 vs 8.3 DDD/100CD) and meropenem (23.1 vs 16.7 DDD/100CD). Solely use of pip/taz increased (14.3 vs 23.6 DDD/100CD), while the amount of imipenem remained unchanged (7.6 versus 7.8 DDD/100CD). Thus, we observed a significant 40% reduction of the median antibiotic consumption (p=0.0312) in 2019. In the multivariate analysis, only age > 60 years and a high or very high disease risk index were identified as negative prognostic factor for OS. Conclusion/Summary: Our single center experience in conducting HSCT without antibiotic prophylaxis but with strict guidelines for prompt antibiotic intervention demonstrated no disadvantage in OS and NRM, despite a higher CI of BSI. IAT resulted in considerably less consumption of cefotaxime, but also carbapenem and glycopeptide antibiotics. We conclude that the proposed procedure of IAT replacing SAP is safe and feasible. Larger patient numbers are needed to confirm a possible benefit of IAT on GVHD. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal