Hematopoietic Cell Transplantation Comorbidity Index Research Articles

Significance of absolute neutrophil count before allogeneic hematopoietic stem cell transplantation in adult patients with aplastic anemia.

The impact of absolute neutrophil count (ANC) before allogenic hematopoietic stem cell transplantation (HSCT) on the outcomes for patients with aplastic anemia (AA) remains unclear. We retrospectively evaluated the relationship between ANC before transplantation and patient outcomes, involving 883 adult Japanese patients with AA who underwent allogeneic HSCT as their first transplantation between 2008 and 2020. Patients were divided into three groups based on ANC: 0/µL (n = 116); 1-199 (n = 210); and ≥ 200 (n = 557). In the low ANC groups (ANC < 200), patient age was higher, previous anti-thymocyte globulin (ATG) treatments were infrequent, duration from diagnosis to transplantation was shorter, hematopoietic cell transplantation-comorbidity index (HCT-CI) was higher, ATG-based conditioning was used infrequently, and peripheral blood stem cell from related donor and cord blood were used frequently. In multivariate analysis, patient age, previous ATG treatment, HCT-CI, stem cell source, and ANC before transplantation were significantly associated with 5-year overall survival (OS) ("ANC ≥ 200": 80.3% vs. "ANC 1-199": 71.7% vs. "ANC 0": 64.4%). The cumulative incidence of bacterial infection, invasive fungal disease, and early death before engraftment were significantly higher in the low ANC groups. Among patients with ANC of zero before transplantation, younger patient age, shorter duration from diagnosis to transplantation, HCT-CI of 0, and bone marrow from related donor as stem cell source were significantly associated with better OS. Consequently, ANC before allogeneic HSCT was found to be a significant prognostic factor in adult patients with AA. Physicians should pay attention to ANC before transplantation.

Prognostic impact of the conditioning intensity on outcomes after allogeneic transplantation for MDS with low blasts: a nationwide retrospective study by the adult MDS working group of the Japan Society for Transplantation and Cellular Therapy.

Poor prognostic factors, such as transfusion dependency and chromosomal risk, need to be considered in the indication of allogeneic hematopoietic cell transplantation (allo-HCT) for patients harboring myelodysplastic syndromes with less than 5% marrow blasts (MDS-Lo). We analyzed the post-transplant outcomes of 1229 MDS-Lo patients who received myeloablative (MAC)(n = 651), reduced-intensity (RIC)(n = 397), and non-myeloablative conditioning (NMAC) regimens (n = 181). The multivariate analysis revealed that the RIC group had better chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS) (P = 0.021), and GVHD- and relapse-free survival (GRFS) than the MAC group (P = 0.001), while no significant differences were observed between the NMAC and MAC groups. In the subgroup analysis, the MAC group has better overall survival (P = 0.008) than the RIC group among patients with an HCT-comorbidity index (HCT-CI) score of 0, while the RIC group had better overall survival (P = 0.029) than the MAC group among those with an HCT-CI score ≥3. According to the type of conditioning regimen, total body irradiation 12 Gy-based MAC regimen showed better OS and CRFS than the other MAC regimen, and comparable outcomes to the RIC regimen. In conclusion, the RIC and NMAC regimens are promising options for MDS-Lo patients in addition to the MAC regimen.

The impact of pre-transplant respiratory virus detection on post-transplant outcomes in children undergoing hematopoietic cell transplantation.

Pre-transplant respiratory virus (RV) infections have been associated with negative transplant outcomes in adult hematopoietic cell transplantation (HCT) recipients. In the era of HCT delay due to high-risk RVs, we examined the impact of pre-transplant RV detection on transplant outcomes in a pediatric HCT recipients. This retrospective cohort study included myeloablative allogeneic HCT recipients from 2010 to 2019. All patients were screened for RV at least once within 90 days before HCT using RT-PCR, regardless of symptoms. Post-transplant outcomes included days alive and out of hospital (DAOH) and progression to lower respiratory tract infection (LRTI). Among 310 patients, 134 had a RV detected in the 90 days prior to HCT. In univariable analysis, transplant factors including younger age, total body irradiation, umbilical cord blood transplantation, lymphocyte count less than 100/mm3, and HCT comorbidity index score ≥3, and viral factors including symptomatic infection, human rhinovirus (HRV) as a virus type, and symptomatic pre-transplant upper respiratory tract infection (URTI) were associated with fewer DAOH. In multivariable analysis, transplant factors remained significant, but not viral factors. There was a higher incidence of progression to post-transplant LRTI with the same pre-transplant RV if the last positive PCR before HCT was ≤30 days compared to >30 days (p=0.007). In the setting of recommending HCT delay for high-risk RVs, symptomatic URTI, including HRV infections, may lead to increased duration of hospitalization and early progression to LRTI when transplantation is performed within 30 days of the last positive PCR test.

Treosulfan- Versus Busulfan-based Conditioning in Allogeneic Hematopoietic Cell Transplantation for Myelodysplastic Syndrome: A Single-center Retrospective Propensity Score-matched Cohort Study

Treosulfan has shown promise in allogeneic hematopoietic cell transplantation (HCT) for its myeloablative properties and low toxicity. In this single-center retrospective propensity score-matched cohort study we compared treosulfan- and busulfan-based conditioning in allogeneic HCT for patients with myelodysplastic syndrome (MDS). This study included 138 adults who underwent allogeneic HCT for MDS or chronic myelomonocytic leukemia (CMML) at Princess Margaret Hospital, Toronto 2015-2022. Using propensity score matching, we compared transplant outcomes between two well-matched cohorts who received conditioning with either fludarabine-treosulfan (FT) (n=46) or fludarabine-busulfan with total body irradiation (FBT200) (n=92). A scoring system based on patient age, Karnofsky performance score and hematopoietic cell transplant comorbidity index was used to assign patients based on fitness to low-dose (30 g/m2) or high-dose (42 g/m2) treosulfan: 32 (69.6%) received high-dose treosulfan. The racial composition of the two groups was similar, with 27.2% and 21.7% of FBT200 and FT recipients, respectively, identifying as non-Caucasian (P=0.61). Primary outcomes were analyzed at a median follow-up of 747 days. Of all participants, 116 (84.0%) received graft-vs-host disease (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCY) and anti-thymocyte globulin (ATG) . Patients who received FT had a superior 2-y overall survival (OS) compared to those who received FBT200: 66.9% (95% confidence interval (CI): 46.1-81.2) vs. 44.5% (95% CI: 34-54.4), hazards ratio (HR): 0.43, 95% CI: 0.22-0.84 (P=0.013). In multivariate analysis (MVA), only the use of fresh grafts (P=0.02) and FT (P=0.01) were associated with improved OS. FT was associated with superior 2-y relapse-free survival (RFS) compared to FBT200: 63.1% (95% CI: 42.6-77.9) vs. 39.1% (95% CI: 29.1-49.1), HR: 0.44 (95% CI: 0.24-0.81), P=0.008. In MVA, the use of fresh grafts (P=0.03) and FT (P=0.009) were associated with improved RFS. Recipients of FT demonstrated superior 2-y graft versus host disease relapse-free survival (GRFS) compared to those who received FBT200: 57.4% (95% CI: 37.8-72.8) vs. 35.1% (95% CI: 25.5-45). In MVA, only FT was associated with superior GRFS (P=0.02). FT recipients exhibited markedly superior 1-y event-free survival (EFS) compared to recipients of FBT200 in univariate analysis (40.3% (95% CI: 25.9-54.2) vs. 9.2% (95% CI: 4.4-16.3), HR: 0.47 (95%CI: 0.30-0.72), P<0.001) and MVA (P=0.004). FT was associated with lower 1-y non-relapse mortality (NRM) compared to FBT200 in univariate analysis (9.9% (95% CI: 3.0-21.8) vs. 29.7% (95% CI: 20.6-39.3), HR: 0.41 (95% CI: 0.17-0.96), P=0.04) and MVA (P=0.04). Our study utilized propensity score matching to demonstrate superiority of treosulfan- over busulfan-based conditioning in stem cell transplantation of patients with MDS and is the first to evaluate the performance of treosulfan-based conditioning in combination with ATG and PTCY. As such, it contributes to the increasing body of evidence supporting the safety of treosulfan, even at the dose of 42 g/m2.

Nephrons and non-relapse mortality: simplified comorbidity index and acute kidney injury are associated with NRM in adults undergoing allogeneic hematopoietic cell transplant

The Simplified Comorbidity Index (SCI) is a recently published 5-component, pre-transplant tool to predict non-relapse mortality (NRM) in allogeneic hematopoietic cell transplantation (alloHCT) patients. The SCI captures chronic kidney disease (CKD) using estimated glomerular filtration rate (eGFR) based on the CKD-EPI equation (KDIGO 2021 CKD-EPI), which may be more sensitive to predict risk of NRM than the creatinine cut-off in the 16-component, Hematopoietic Cell Transplant—Comorbidity Index (HCT-CI). We retrospectively assessed the ability of the SCI to risk-stratify patients and the impact of acute kidney injury (AKI) to NRM in adults who underwent alloHCT at the University of Minnesota. We included 373 patients who underwent their first alloHCT between 2015 and 2019. Through multivariate analysis, we found that patients with an SCI of greater than 4 had a higher risk of NRM. Additionally, we noted that AKIs stages 2–3 prior to day +100 was independently associated with a 3-fold greater NRM than patients who did not experience clinically significant AKI.

Treosulfan (Trecondyv)

&#x0D; CADTH recommends that Trecondyv in combination with fludarabine should be reimbursed by public drug plans as part of conditioning treatment before allogeneic hematopoietic stem cell transplantation (alloHSCT) in adult patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at increased risk for standard conditioning therapies if certain conditions are met.&#x0D; Trecondyv in combination with fludarabine should only be covered to treat adult patients with AML or MDS who are eligible for alloHSCT, are at least 50 years old at transplant, and/or have a Hematopoietic Cell Transplantation-Comorbidity Index score greater than 2. Patients should have good performance status.&#x0D; Trecondyv should only be reimbursed in combination with fludarabine if prescribed by clinicians with appropriate training and experience in transplant centres with alloHSCT programs and if the cost of Trecondyv is not more than the least costly alternative conditioning treatment.&#x0D;

Development and Validation of a Concise Objectifiable Risk Evaluation Score for Non-Relapse Mortality after Allogeneic Hematopoietic Stem Cell Transplantation

We aimed to develop a concise objectifiable risk evaluation (CORE) tool for predicting non-relapse mortality (NRM) and overall survival (OS) after allogeneic hematopoietic stem cell transplantation (allo-HCT). A total of 1120 adult patients who had undergone allo-HCT at our center between 2013 and 2020 were divided into training, first, and second validation cohorts. Objectifiable, patient-related factors impacting NRM in univariate and multivariate analyses were: serum albumin, serum creatinine, serum C-reactive protein (CRP), heart function (LVEF), lung function (VC, FEV1), and patient age. Hazard ratios were assigned points (0–3) based on their impact on NRM and summed to the individual CORE HCT score. The CORE HCT score stratified patients into three distinct low-, intermediate-, and high-risk groups with two-year NRM rates of 9%, 22%, and 46%, respectively, and OS rates of 73%, 55%, and 35%, respectively (p &lt; 0.001). These findings were confirmed in a first and a second recently treated validation cohort. Importantly, the CORE HCT score remained informative across various conditioning intensities, disease-specific subgroups, and donor types, but did not impact relapse incidence. A comparison of CORE HCT vs. HCT Comorbidity Index (HCT-CI) in the second validation cohort revealed better performance of the CORE HCT score with c-statistics for NRM and OS of 0.666 (SE 0.05, p = 0.001) and 0.675 (SE 0.039, p &lt; 0.001) vs. 0.431 (SE 0.057, p = 0.223) and 0.535 (SE 0.042, p = 0.411), respectively. The CORE HCT score is a concise and objectifiable risk evaluation tool for adult patients undergoing allo-HCT for malignant disease. External multicenter validation is underway.

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

Analysis of risk factors for fatal renal complications after allogeneic hematopoietic cell transplantation.

Various complications can influence hematopoietic cell transplantation (HCT) outcomes. Renal complications can occur during the early to late phases of HCT along with various factors. However, studies focusing on fatal renal complications (FRCs) are scarce. Herein, we analyzed 36,596 first allogeneic HCT recipients retrospectively. Overall, 782 patients died of FRCs at a median of 108 (range, 0-3,440) days after HCT. The cumulative incidence of FRCs was 1.7% and 2.2% at one and five years, respectively. FRCs were associated with older age, male sex, non-complete remission (non-CR), lower performance status (PS), and HCT comorbidity index (HCT-CI) associated with renal comorbidity in multivariate analysis. The risk factors within 100 days included older age, multiple myeloma, PS, and HCT-CI comorbidities (psychiatric disturbance, hepatic disease, obesity, and renal disease). Older age and male sex were risk factors between 100 days and one year. After one year, HCT-CI was associated with the presence of diabetes and prior solid tumor; total body irradiation was identified as a risk factor. Non-CR was a common risk factor in all three phases. Furthermore, acute and chronic graft-versus-host disease, reactivation of cytomegalovirus, and relapse of underlying disease also affected FRCs. Systematic follow-up may be necessary based on the patients' risk factors and post-HCT events.

Impact of stem cell selection between bone marrow and peripheral blood stem cells for unrelated hematopoietic stem cell transplantation for hematologic malignancies: on behalf of the Donor/Source Working Group of the Japanese Society for Transplantation and Cellular Therapy

Background aimsThis study aimed to comprehensively assess the impact of stem cell selection between bone marrow (BM) and peripheral blood (PB) in unrelated hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Our objective was to identify specific factors associated with better transplant outcomes. MethodsA retrospective analysis was conducted using data from the Japanese HSCT registry. Inclusion criteria were patients aged 0–70 years who underwent their first unrelated HSCT with BM or PB, with an 8/8 or 7/8 allele HLA match for hematological malignancies between 2010 and 2020. ResultsAmong 10 295 patients, no significant difference was observed in overall survival, relapse, graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) or non-relapse mortality between the groups. Patients who received PB showed no clear difference in acute GVHD but had a greater rate of chronic GVHD, resulting in poor chronic GVHD-free, relapse-free survival (CRFS). Subgroup analyses highlighted the importance of patient-specific factors in source selection. Patients with non-Hodgkin lymphoma and a greater hematopoietic cell transplantation-comorbidity index showed better CRFS and GRFS when BM was the preferred source. Similar trends were observed among patients with standard-risk disease for CRFS. However, no such trends were evident among patients aged 0–24 years, indicating that both sources are viable choices for young patients. ConclusionsThis real-world retrospective analysis showed similar basic outcomes for BM and PB in an unrelated setting. The results support that BM may still be preferred over PB, especially when the long-term quality of life is a major concern. A consideration of individual factors can further optimize transplant success. Further research is warranted to explore the long-term implications of stem cell source selection.

What makes a pediatric or young adult patient an appropriate transplant candidate?

A 3-year-old child with chronic granulomatous disease was brought to the transplant clinic by his parents. The patient has a history of Aspergillus fumigatus pneumonia, which required mechanical ventilation, and sepsis, resulting in several intensive care stays. He has failure to thrive and developmental delay. His parents are seeking guidance whether allogeneic hematopoietic cell transplantation (HCT) is a reasonable treatment option given concerns about his upfront major health limitations. Based on the original HCT-Comorbidity Index (CI), this child's risk for nonrelapse mortality (NRM) would be negligible with a score of 0. With use of the validated youth-nonmalignant HCT-CI, the score increases to 5, due to prior mechanical ventilation (+3), history of fungal infection (+1), and being underweight (+1), with at least 2-fold increase in risk of NRM. The role of developmental delay is unclear and not currently validated to prognosticate survival. While HCT was ultimately recommended in this case, the family was counseled to have a more realistic sense of NRM risk.

Stratification Using ECOG, ADL and HCT-CI Scales, but Not CGA Enables Identifying Elderly AML Patients Fit for Intensive Chemotherapy - a Multicenter Study from Polish Adult Leukemia Group

Introduction: A key part of decision-making in older AML patients is an insightful clinical assessment before qualification for treatment with intensive chemotherapy (IC). It was demonstrated that among the patients initially deemed “fit” for IC, there are vulnerable patients who experience greater treatment toxicity and have poorer outcomes. Comprehensive geriatric assessment (CGA) is a well-recognized tool for identifying such patients. However, due to its time-consuming nature, it is not commonly used. A number of other prognostic models exist, but none of them enable fast and optimal identification of patients eligible for IC. Aim: In this prospective observational study our group aimed to I) assess clinical outcomes of elderly AML patients who were stratified by Eastern Cooperative Oncology Group Performance Status (ECOG PS), Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), Activity of Daily Living (ADL) scales and received IC and II) evaluate the predictive and prognostic value of CGA components. Material and methods: AML patients aged between 60 and 75 were considered fit for IC if they met all 3 stratification criteria: ECOG PS&amp;lt;2 and HCT-CI&amp;lt;3 and ADL=6. IC regimens included daunorubicin and cytarabine (DA) or daunorubicin, cytarabine and cladribine (DAC) followed by 2 consolidation cycles according to local references. CGA was performed by a qualified medical professional before treatment initiation. CGA included Instrumental Activities of Daily Living Score (iADL), timed up and go test (TUG), geriatric depression scale (GDS), Mini-mental scale Examination (MMSE) and Mini Nutritional Assessment (MNA). The correlations between CGA and complete response (CR) rate were determined by Chi-square test or Fisher's exact test. The Kaplan-Meier analysis and log-rank test were used to compare relapse-free survival (RFS) and overall survival (OS) Results: In total, 85 patients with a median age of 65 years [IQR:63.5-69.0] and slight male predominance (53%) were included in the study. Most patients had HCT-CI score &amp;lt;2 (71.8%). Secondary AML was diagnosed in 23.5% of patients, and most patients had intermediate (32.9%) or adverse (37.6%) ELN cytogenetic risk. Fifty-five (58.8%) patients achieved CR after induction. Median OS reached 16.0 months [95% CI: 11.0-21.00] with median RFS 15.3 months [95% CI: 12.1-18.4]. No significant difference in CR rate (p=0.451), OS (p=0.484) or RFS (p=0.529) was demonstrated between DA or DAC groups. Regardless of induction regimen, patients with CR presented significantly improved OS (p=0.015 for DA, p=0.029 for DAC) compared with non-CR patients. None of the CGA components was shown to influence the CR rate, OS or RFS. Conclusions: In patients aged 60-70 years with AML, stratification by ECOG, ADL, and HCT-CI is an effective tool for qualifying patients for intensive chemotherapy. Comprehensive geriatric assessment does not improve identification of vulnerable patients in this group.

Frail and Pre-Frail Older Adults with Acute Myeloid Leukemia Have Inferior Survival Due to Higher Rates of Disease-Related Deaths

Introduction: The intensity of initial remission-inducing therapy for patients with newly diagnosed acute myeloid leukemia (AML) may be high (anthracycline and cytarabine-based), intermediate (venetoclax combinations), or low (single hypomethylating agent or targeted therapy). In older adults, it is important to consider “fitness” when selecting initial therapy. Current methods to determine “fitness” in AML include subjective measures such as physician assessment (“clinician gestalt, CG”) semi-subjective measures such Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance status (KPS), and those based on clinical comorbidity data like the hematopoietic cell transplantation-comorbidity index (HCT-CI). Geriatric assessments in older adults with cancer may improve therapy selection and decision-making, but whether unfit patients have better outcomes with lower intensity compared to higher intensity therapies is unknown. Freid's Frailty Phenotype (FP) combines subjective (self-reported exhaustion, weight loss &amp;gt;5%, activity level) and objective (4-meter walk speed and grip strength) measures to categorize patients into fit, pre-frail, and frail. We hypothesized that being frail by FP is associated with higher overall mortality (OM) and inferior overall survival (OS) and may inform decision-making for older adults. Methods: Eighty-fivepatients 60 years or older admitted to the Hospital of the University of Pennsylvania at the time of AML diagnosis or electively admitted for AML chemotherapy initiation were prospectively enrolled from September, 2018 to May, 2023 on an IRB approved study. FP, HCT-CI, KPS, ECOG, gait speed, and recorded CG (fit or unfit) were performed prior to initiation of disease-directed therapy. Results: Themedian age of the cohort was 71 (range60-91). Patients in our cohort had high-risk disease features: 64% were adverse risk by European LeukemiaNet (ELN) 2017 with 73% of patients harboring mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) (Table 1). 39% of patients received IC, 52% received HMA/ven, 6% received HMA alone or targeted therapy, and 2% received best supportive care. By FP, 18% of patients were fit, 38% were pre-frail, and 45% were frail. Higher ECOG, KPS, CG, and HCT-CI were associated with frail phenotypes (Table 1). For the entire population, 60-day and 100-day OM rates were 18% and 33%, respectively. For fit, pre-frail, and frail patients 60-day OM was 7%, 13%, and 24% and 100-day OM was 13%, 22%, and 42%, respectively. Two-year OS was 65% for patients aged 60-69 years old and 15% for patients ≥70 years old (p=0.002). FP was significantly associated with OS (Figure 1; p=0.0474): 2-year OS was 57%, 42%, and 21% in fit, pre-frail, and frail patients, respectively. Of the individual components of FP, self-reported exhaustion and slower gait speed were both associated with inferior OS (p=0.0015 and p=0.0005). Neither activity level, (p=.0864), weight loss (p=0.1988), or grip strength (p= 0.7136) were associated with OS. Of the total population 19% went on to hematopoietic cell transplant (HCT) with 8% of frail patients receiving HCT compared to 27% of fit and 28% of pre-frail patients. ECOG, HCT-CI, CG, and gait speed ≤8 meters/sec were all significantly associated with OS, but KPS was not. The 6-month OS for frail patients receiving IC was 75% compared with 49.7% for those receiving HMA/Ven, although not significant due to small sample size. Cause of death was leukemia-related for 40% of fit patients, 76% of pre-frail patients, 77% of frail patients. Conclusions: FP was associated with a doubling of early mortality and inferior 2-year OS. Pre-frail and frail patients had increased disease-related deaths. This work supports that most geriatric assessments, including FP and clinician intuition, can be utilized to risk-stratify newly diagnosed older adults with AML. Future work is needed to evaluate whether we can integrate geriatric assessments, such as individual components of FP or gait speed, with molecular features to improve risk stratification of older adults with AML. Given frailty's association with disease-related deaths, further study is warranted to determine whether this is due to adverse disease biology or whether frail patients are undertreated.

A Simple Prediction Model of Outcomes after Allogeneic Hematopoietic Stem Cell Transplant (HCT) in Myelodysplastic Syndromes Using HCT-Comorbidity Index, Cytogenetic Risk, and Platelet Count

Introduction: Allogeneic hematopoietic stem cell transplant (HCT) is currently the only potentially curative option for patients (pts) with myelodysplastic syndromes (MDS). However, many pts relapse after HCT. While the International Prognostic Scoring System-Molecular (IPSS-M) is useful, next generation sequencing is not always available particularly in resource limited settings. Hence, we aimed to develop a prediction model utilizing readily available pt and HCT characteristics of post-HCT outcomes in pts with MDS treated with hypomethylating agent (HMA) therapy pre-HCT. Methods: Pts with MDS treated with HMA (azacitidine or decitabine) who received an HCT at Dana-Farber Cancer Institute from 01/2014-12/2020 were included. The primary outcome was progression free survival (PFS) post-HCT, defined as time from transplant to disease relapse or progression. Univariable analysis (UVA) and multivariable analysis (MVA) were used to identify predictors of PFS and build a model. Variables were pt age, sex, donor type (matched related donor (MRD) vs. matched unrelated donor (MUD) vs. 7/8 MUD vs. haploidentical), HCT-comorbidity index (HCT-CI), CMV status of donor/recipient, MDS subtype, graft versus host disease prophylaxis (GVHD ppx), HMA type, number of HMA cycles, conditioning intensity (myeloablative vs. reduced intensity), cell source (bone marrow vs. peripheral blood), response to HMA assessed by IWG 2023 criteria ( Zeidan Blood 2023), IPSS-Revised (IPSS-R) pre-HCT, and cytogenetic risk (very good, good, intermediate, poor, very poor) at diagnosis and pre-HCT. Results: A total of 148 pts with MDS received HMA and underwent subsequent HCT. Median age was 64 years (range 26-79) and 61.5% were men. Pts were treated with 7 days azacitidine (54.1%), 5 days decitabine (39.2%) and other schedules (6.7%) and received a median of 4 HMA cycles (range 1-20). Prior to HCT, IWG 2023 responses were: CR (15.5%), CRbi (14.9%), CRuni (19.6%), CRh (0.7%), PR (1.4%), HI (9.5%), and no response (38.5%). Most donors were MUD (60.8%) or MRD (18.2%), and most pts received reduced intensity conditioning (74.3%). GVHD ppx was tacrolimus (tac)/methotrexate (MTX) (54.7%), tac/MTX/sirolimus (19.6%), cyclophosphamide/mycophenolate mofetil/tac (15.5%), and other (10.1%). Median HCT-CI was 2 (range 0-13); 48.6% had HCT-CI ≥3. Median follow-up time among ongoing survivors was 48.3 months (range 5.5-101.3). The only statistically significant variables associated with post-HCT PFS in both UVA and MVA (with Cox MVA results shared here) were HCT-CI (≥4 vs. 0-3: HR 1.94, 95% CI 1.18-3.19, p=0.009), platelet count pre-HCT (platelets &amp;lt;40 vs. &amp;gt;70: HR 2.46, 95% CI 1.33-4.54, p=0.004; platelets 40-70 vs. &amp;gt;70: HR 1.84, 95% CI 1.02-3.32, p=0.044) and cytogenetic risk pre-HCT (very poor vs. other: HR 2.52, 95% CI 1.43-4.44, p=0.001). HCT-CI impacted non-relapse mortality (NRM) and not relapse whereas very poor cytogenetics impacted relapse and not NRM. A model predicting post-HCT outcomes was built with the following risk scores: HCT-CI: 0-3 (0), ≥4 (1.5); platelet count pre-HCT: &amp;gt;70 (0), 40-70 (1), &amp;lt;40 (2); cytogenetic risk pre-HCT: not very poor (0), very poor (2). Based on the sum risk score, patients were defined as low (0-1), intermediate (int) (1.5-2) or high (≥2.5) risk. The risk classification was significantly associated with post-HCT outcomes. Four-year post-HCT PFS was 68% (95% CI 56-78%), 36% (95% CI 22-51%) and 15% (95% CI 5-31%) for low, int and high risk, respectively (p&amp;lt;0.00001) ( Figure A). Accordingly, 4-year cumulative incidence of relapse was 23% (95% CI 14-33%) for low, 54% for int (95% CI 38-68%) and 62% for high (95%CI 39-78%) risk scores (p=0.00005). Four-year overall survival was 70% (95% CI 58-80%), 45% (95% CI 29-59%), and 19% (95% CI 7-36%) (p&amp;lt;0.00001), for the same respective risk groups ( Figure B). In contrast, NRM did not differ between risk categories (low: 9%, int: 10%, high: 23%; p=0.1). The predictability of this simple risk model (C-index: 0.72) was found to be superior to IPSS-R pre-HCT (C-index: 0.61) and IWG 2023 response pre-HCT (C-index: 0.617). Conclusion: We developed a simplified prognostic model of post-HCT outcomes for pts with MDS treated with HMA based on HCT-CI, platelet count, and cytogenetic risk post-HMA therapy and pre-HCT. We expect that this model will be particularly useful in resource-limited settings without easy access to next generation sequencing.

Allogeneic Hematopoietic Stem Cell Transplantation with Treosulfan -Fludarabine and Busulfan-Fludarabine Conditioning Have Similar Efficacy in Patients ≥65 Years Old or Those with Comorbidities

Background: Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative treatment for hematological malignancies. Myeloablative conditioning (MAC) results in a better disease-free survival (DFS) compared to reduced-intensity conditioning (RIC). However, the use of MAC in older adults or in those with comorbidities is limited due to a high rate of non-relapse mortality (NRM). Treosulfan-based conditioning regimens were found to result in superior DFS compared to RIC, without increased NRM. However, patients over the age of 65 were less represented in trials assessing the safety and efficacy of treosulfan-based conditioning relative to MAC. In recent years, fludarabine-treosulfan (FT) conditioning was used at Rambam for patients ≥65 years old, or for those with an HCT - comorbidity index (HCT-CI) score &amp;gt;2. This study aimed to evaluate the efficacy of the FT conditioning protocol and fludarabine-busulfan for 4 days (FB4) in older adults or in those with comorbidities. Methods: This single-center retrospective study included the following 3 groups: 1) patients who received the FT protocol; 2) patients aged &amp;lt;65 years with HCT-CI ≤2, who received the FB4 protocol; 3) patients aged ≥65 and/or with HCT-CI &amp;gt;2, who received the FB4 protocol. The results of patients included in group 2 were used as a reference. Data were retrieved from the electronic medical records. Baseline characteristics, transplant outcomes and complications were compared. Categorical variables and non-parametric variables were evaluated with the Fisher's exact test and Mann-Whitney U test, respectively. Results: One hundred and ninety patients were analyzed. All underwent HSCT between January 2015 and December 2021 (table 1). The FT group, younger and older FB4 groups included 57, 61 and 72 patients, respectively. Patient median age was 65 years in both the FT and older FB4 groups, compared to 58 in the younger FB4 group (p&amp;lt;0.05). Patients in the FT group had significantly more comorbidities compared to younger FB4 (p&amp;lt;0.001) and older FB4 groups (p=0.005), with a median HCT-CI of 4, 0 and 3, respectively. During a median follow-up of 48.8 months, there were no significant differences between the groups in terms of the incidence of acute graft-versus-host disease (GVHD), disease relapse, NRM or overall survival (table 2). However, the chronic GVHD rate was 34.4% in the younger FB4 group and only 15.8% in the FT group (p=0.035). This rate was 25% in the older FB4 group (p=NS). Mucositis rate was significantly lower in the FT group, with 31.6% of patients being mucositis-free, compared to 6.6% and 13.9% in the younger and older FB4 groups, respectively. However, the rate of bacteremia events was significantly increased in the FT group (49.1%) relative to the younger FB4 (13.1%) and the older FB4 (23.6%) groups. Conclusions: In older patients or in those with comorbidities, FT appears to be as efficient as FB4 conditioning. Furthermore, these outcomes are comparable to those observed in younger patients conditioned with FB4. Hence, both of the evaluated regimens could be considered in these patient populations. Prospective randomized studies are warranted to further evaluate these findings.

Evaluation of Atrial Fibrillation Risk and Outcome after Allogeneic Transplantation Using an Artificial Intelligence ECG Algorithm and Echocardiographic Parameters in an MDS Cohort

Introduction Atrial fibrillation/flutter (Afib) contributes independently to the hematopoietic cell transplant comorbidity index (HCTCI) and is a known complication of allogeneic hematopoietic transplantation (AlloHCT) which has been linked to inferior outcomes, particularly in older patients. An electrocardiogram (ECG)-based artificial intelligence (AI) algorithm to predict Afib and cardiac contractile dysfunction risk has been validated (Lancet 394:861, 2019). We hypothesized that assessment of pre-transplant Afib risk using the AI algorithm may predict future development of Afib and help identify patients at higher risk for this complication. Methods 191 consecutive MDS patients undergoing AlloHCT with curative intent using myeloablative (28.3%) or reduced intensity conditioning (62.3%) in the Mayo Clinic Comprehensive Cancer Center (Rochester, Jacksonville, Phoenix) between November 2015 and January 2022 were included in this retrospective analysis. Primary outcome was Afib within 100 days and 365 days of transplantation, and we also assessed the outcomes of Death and Relapse. Revised IPSS (IPSS-R) and HCTCI scores were included for all patients. Elevated Afib risk score using the AI algorithm was calculated from pre-transplant ECG, performed during vital organ testing at AlloHCT clearance. In addition to left ventricular (LV) ejection fraction (EF) we evaluated detailed echocardiographic (Echo) parameters including LV volume and mass indices, left atrial volume index (LAVI), maximum trans mitral flow velocities during LV filling (E velocity) and during the diastolic phase due to atrial contraction (A velocity), the velocity of the annulus away from the apex during the protodiastolic phase (e' velocity), E/A and E/e' ratios, the presence of valvular disease, and right ventricular systolic pressure (RVSP). We performed an analysis using a Cox proportional hazards regression models (adjusting for age and sex) to evaluate associations with Afib risk, Relapse, and Overall Survival. Results The median age was 64 years (18-75), 58.6% were male, 6.9% non-white race, and 3.7% Hispanic/Latino ethnicity. Most patients had an HCTCI score of 0-3 (76.3%). GVHD prophylaxis was predominantly with calcineurin inhibitor-based regimes plus/minus methotrexate or mycophenolate mofetil (83.8%). 5.2% of patients had a history of Afib before transplant. Non-relapse mortality was 7.9% at 100 days, and 18.3% at 365 days. N=25 patients (13.1%) developed Afib within 100 days, and n=28 (14.7%) within 1-year after AlloHCT. On multivariable analysis, Age [Hazard Ratio (HR) 2.83, 95% Confidence Interval (CI) 1.36-5.89, p=0.0055] and Echo parameters [including LAVI (HR 2.10, CI 1.23-3.58, p=0.0067), E velocity (HR 3.28, CI 1.29-8.80, p=0.013), E/A ratio (HR 3.74, CI 1.75-7.97, p=0.0006), E/e ' ratio (HR 1.81, CI 1.07-3.07, p=0.026) and RVSP (HR 1.68, CI 1.04-2.70, p=0.032)] were significantly associated with Afib risk; elevated AI risk score was significant in the univariate model (HR 2.74, CI 1.15-6.53, p=0.023) but was borderline in the multivariate model (HR 2.34, CI 0.98-5.60, p=0.056) ( Table 1). Based on previous observations we evaluated the association of AI and Echo parameters with Relapse and Death after AlloHCT ( Table 1). Age (HR 1.32, CI 1.01-1.71, p=0.041) and IPSS-R (HR 1.20, CI 1.08-1.33, p=0.0009) were significantly associated with Death after AlloHCT, while HCTCI (HR 1.10, CI 1.00-1.22, p=0.052) and higher LV EF (HR 0.63, CI 0.38-1.06, p=0.084) were borderline. For Relapse, only IPSS-R (HR 1.52, CI 1.31-1.75, p=1.22E-08) was significant, while increase Echo E velocity was of borderline significance (HR 0.45, CI 0.20-1.02, p=0.057). Conclusions Afib is a common post-AlloHCT complication and is more frequent with increasing Age. Echo parameters (specifically E/A ratio) predict significantly higher Afib risk, while the baseline ECG AI algorithm was of borderline significance. The selection of patients with lower HCTCI scores, and the low background prevalence of Afib in this cohort (i.e., selection of patients with lower baseline cardiac morbidity) are possible explanations for non-significance of the AI algorithm. As anticipated Age and IPSS-R are the greatest predictors of Death after AlloHCT, although the suggestion of an association with baseline Echo parameters highlights the importance of identifying those who may benefit from preemptive Cardiology intervention.

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Patients with Active Primary Malignancy at HCT - a Bi-Institutional Retrospective Cohort Analysis

Background: Patients diagnosed with hematologic malignancies may be candidates to proceed to allogeneic hematopoietic cell transplantation (HCT). In those with active solid malignancy, given the cumulative toxicity associated with additional chemotherapy and the intensive immunosuppression required after HCT, there has been a concern that outcomes of HCT would be suboptimal. Specifically, prior malignancy may relapse early after HCT or transform to a more aggressive phenotype. We aimed to evaluate the bi-directional relationship between HCT and active solid malignancy. Methods: We retrospectively reviewed charts of patients in 2 large transplant centers who received first allogeneic HCT between 2012 and 2022 with concurrent active solid malignancy (defined as receiving any treatment for solid malignancy within 5 years prior to HCT). Hematologic relapse was treated as a competing event in time-to-event analyses of graft vs. host disease (GVHD) and non-relapse mortality (NRM). Analysis of chronic GVHD was performed only among patients who survived more than 3 months post HCT. Mortality was treated as a competing event in the analysis of relapse of solid malignancy. Modified GVHD-relapse free survival (mGRFS) was defined as survival with no prior GVHD and/or relapse of either solid or hematology malignancies. This trial was approved by the hospital ethic committee. Results: Between 01/2012 and 12/2022 we identified 45 patients (females, 62%) who fulfilled the eligibility criteria. Median age was 63 (range, 21-74) years and median post HCT follow-up was 41 (range, 7.1-122.5) months. Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) (n=35 and n=6, respectively) were the most common hematologic malignancies. Status of hematologic malignancy at HCT was complete remission (n=27, 60%), partial remission (n=1, 2%) and stable/progressive disease (n=17, 38%). Most common diagnoses of active solid malignancies were breast cancer (n=22, 49%) and colon cancer (n=6, 13%) with 24% patients receiving active treatment at HCT and 7% with progressive disease at HCT. HCT comorbidity index (HCT-CI) was 3-5 in 82% (&amp;gt;5, 18%). Majority received reduced intensity conditioning (n=29, 64%) with an allograft mainly derived from unrelated donors (n=31, 69%). Early HCT complications included severe mucositis (16%), bacteremia (20%), and invasive fungal infections (4%). There were no cases of sinusoidal obstruction syndrome. 27% resumed maintenance treatment for solid malignancies post HCT with no significant toxicity. Incidences of grade 2-4 and 3-4 acute GVHD at day 200 were 48% and 3%, respectively. Incidences of overall and moderate-severe chronic GVHD at 3 years were 53% and 24%, respectively. Hematologic relapse incidence at 6 months, 1 and 3 years were 31%, 37%, and 48%, respectively with no impact of conditioning intensity (p=.95). Incidences of NRM at 3 months, 1 and 3 years were 7%, 15%, and 25%, respectively. Cumulative progression of solid malignancies at 3 years was 12%, Figure 1A. Incidence of mRGFS at 1 year was 16%. Overall survival at 3 years was 53% in all cohort, 54% in patients with AML/MDS and 61% in patients with concomitant breast cancer, Figure 1B. Cox regression model identified both progressive solid and hematologic malignancy to be associated with increased risk of mortality (HR=4.3, p=.049 and HR=1.8, p=.028, respectively), while sex, age, conditioning intensity and HCT-CI did not impact survival. Conclusions: HCT is safe and efficacious in patients with active solid malignancy. However relapse incidence of hematologic malignancy is high and mGRFS is low. Progression of the solid malignancy after HCT is in fact uncommon. Therefore in this specific patient cohort, improved transplantation techniques to better control the hematologic disease post-transplant are warranted to make HCT more effective and long lasting.

The Composite Health Risk Assessment Model (CHARM) to Predict 1-Year Non-Relapse Mortality (NRM) Among Older Recipients of Allogeneic Transplantation: A Prospective BMT-CTN Study 1704

Introduction: Allogeneic hematopoietic cell transplantation (HCT) remains the only therapy for long-term disease control for many high-risk hematologic malignancies (HM). HCT use in older HM patients (pts) continues to increase. However, concerns of excessive transplant-related morbidity and non-relapse mortality (NRM) limit referrals and broader application of curative intent HCT. The HCT-comorbidity index (HCT-CI) was initially developed to improve risk-stratification of NRM. More recently, geriatric assessment (GA) and biomarkers have emerged as promising additional tools that may refine estimates of these risks. We hypothesized that a combination of health assessments by GA and biomarkers would constitute a robust and valid model, CHARM, for accurate personalized estimation of one-year (1-yr) NRM. Here, we report the results of the largest, first of its kind, prospective study of older recipients of HCT through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1704 study (NCT03992352). Patients and Methods: Adults aged ≥60 years (yrs) with HM institutionally eligible for HCT were enrolled (n=1226) from 49 centers in the US between 2019 - 2021. Within 21 days of conditioning, 13 prospectively identified older pt.-specific health variables, informed from prior studies, were collected: age, HCT-CI, % of weight loss over the past yr, pt reported Karnofsky performance status, PROMIS physical function scale, instrumental activities of daily living (IADL), number of falls, PROMIS depression scale, number of prescribed medications, 4-meter walk speed, cognition by the Montreal Cognitive Assessment (MoCA), C-reactive protein (CRP) and albumin. The CHARM score to predict NRM within 1 yr was built using a multivariable (MVA) Fine-Gray model, with multiple imputation to handle modest missingness in covariates and grouped penalized variable selection using SCAD to identify variables to retain in the model. Final variables were used as continuous. The model further considered adjustment for conditioning intensity, CMV serostatus, and donor type. Area under the ROC curve (AUC) was calculated to validate the CHARM and compare to HCT-CI alone, with bootstrap sampling to correct for optimism in the within-sample AUC. MVA of overall survival (OS) within 1 yr used the CHARM score and adjusted for other significant variables derived from stepwise regression. Results: The primary analysis included 1105 pts who were confirmed eligible and proceeded to transplant. Median age was 67 (range 60-82) and 32% were ≥ 70 yrs. AML (45%) and MDS (30%) were the most common indications and matched donors the most frequent donor type at 72%. Reduced intensity conditioning with fludarabine (flu)-melphalan (38%) and flu-busulfan (20%) were the most common regimens. Baseline geriatric vulnerabilities among evaluable pts were frequent including slow walk speed (&amp;lt;0.8 meter/second) in 22%, any IADL limitation in 37%, and cognitive impairment (MoCA &amp;lt; 23) in 12%. 1-yr NRM was lower than expected at 14.4% with 1-yr OS of 72%. In the MVA model, albumin, CRP, HCT-CI, and weight loss were independently associated with NRM (Table) and comprised the CHARM. Of note, increasing age did not significantly affect NRM. The CHARM had within sample and bootstrap corrected AUC of 0.641 and 0.607 whereas the HCT-CI alone achieved corresponding AUC values of 0.601 and 0.598. NRM by tertiles is shown in Figure. Each point increase in the CHARM (median -2.2504, range -3.6327 to 0.1381), was associated with a hazard ratio (HR) of 2.83 (95% CI 2.12 - 3.78, p &amp;lt; 0.0001) for NRM. The CHARM also predicted overall mortality within 1-yr with a HR of 2.04 (1.65- 2.53, p &amp;lt;0.0001) per one point increase, independent of the disease risk index, which had a HR of 1.5 (95% CI 1.12 - 1.99, p =0.0059) for high/very high vs low/intermediate categories. Conclusions: We report on the first prospectively established tool, CHARM, to risk-stratify older adult HCT comprised of simple and readily available parameters in transplant and oncology clinics. Adopting CHARM in practice may promote HCT referrals and access for older pts, given low risks of NRM among CHARM lower 2/3 rd tertiles. Identifying high-risk CHARM pts pre-HCT will promote developing novel strategies to reduce NRM. Further analysis of the impacts of the 13 health assessment variables on geriatric morbidity such as disability trajectories is in-process.

Pre-Treatment Pulmonary Assessment Have Limited Utility in B-Cell Lymphoma Patients Treated with Autologous Anti-CD19 CAR T-Cell Therapy

Introduction Pulmonary function tests (PFT) play a pivotal role in hematopoietic cell transplantation (HCT), with routine evaluation in HCT candidates. However, their predictive value in chimeric antigen receptor T-cell (CAR-T) therapy outcomes remains uncertain. To address this gap, we conducted a retrospective analysis of PFT metrics and pulmonary comorbidity definitions, following the Hematopoietic Cell Transplantation-Comorbidity Index (HCT-CI), in B-cell lymphoma patients treated with autologous CD19-CAR-T cell therapy. Patients and Methods In this retrospective analysis, we included adult patients (age ≥ 18 years) with B-cell lymphoma who received treatment at a tertiary medical center with commercially available or point-of-care (POC) anti-CD19 CAR T-cell therapy (Kedmi et al., Transplant Cell Ther. 2022) as their 3rd line of treatment or above, between 2017 and 2022. Patients underwent routine PFT assessment before CAR-T cell therapy, as part of institutional practice, including spirometry, body plethysmography, and single-breath diffusing capacity for carbon monoxide (DLCO). Patients were categorized into three pre-treatment pulmonary comorbidity groups (normal, moderate, severe) based on HCT-CI definitions for forced expiratory volume in 1 second (FEV1) and DLCO expressed as precent of predicted value (&amp;gt;80%, 66-80%, &amp;lt;66%, respectively). Results A total of 192 patients (median age, 60 [range 46-69]) were included. Aggressive B-cell lymphoma was the predominant diagnosis (n=166, 86%) followed by indolent B-cell lymphoma (n=18, 9.4%), and Mantle cell lymphoma (n=8, 4.2%). Most patients had a good performance status (KPS ≥ 90, 78%), although with high-risk disease features (pre-lymphodepletion LDH was elevated in 108 [56%]). Seventy-eight (41%) patients received bridging therapy. POC CAR-T were used in 56%, while 44% received commercial CAR-T (26% axi-cel, 18% tisa-cel). Pre-CAR-T smoking history was documented in 25% of patients. The median pre-treatment measured-to-predicted DLCO and FEV1 were 96% and 92%, respectively. Seventy-four percent of patients had normal DLCO, and 77% had a normal FEV1. The calculated normal, moderate, and severe pulmonary comorbidity levels, per the HCT-CI, were 64%, 23%, and 13%, respectively. With a median follow-up of 17.6 months (IQR 8.5-29.7), the median overall survival (OS) was not reached, and the median progression-free survival (PFS) was 7.6 months. There was no correlation between pulmonary comorbidity level and the best overall response rate. Categorical PFT results (FEV1 and DLCO) and pulmonary comorbidity (per-HCT-CI) were not associated with reduced OS (p=0.3, p=0.4, p=0.6, respectively) or reduced PFS (p=0.058, p&amp;gt;0.9, p=0.2, respectively) in a univariable Cox regression analysis. However, FEV1 as continuous measure and FEV1 categorized into 2 levels (normal vs. moderate-severe) were associated with reduced PFS ( Figure 1). FEV1 (as a continuous metric) association with PFS remained consistent (HR 0.99 [95% CI 0.98-1], p=0.007) in a multivariable Cox regression adjusted for pre CAR T KPS score, elevated LDH level, and co-stimulatory CAR-T domain. Nevertheless, this association is minor, with unclear clinical significance. No association was observed between pulmonary function measures and immune-toxicities, including cytokine release syndrome grade &amp;gt;2 or immune effector cell-associated neurotoxicity grade &amp;gt; 2. Conclusions To the best of our knowledge, this is the first study evaluating the relationship between PFTs and the outcomes of CAR T-cell treatment. Our results indicate that among standard measures of pulmonary assessment, only FEV1 was predictive of poor PFS, though with minor association, with unclear clinical significance. We did not observe any association with overall survival. These findings suggest that pre-CAR-T pulmonary assessment may have limited utility in evaluating CAR-T candidates. Nevertheless, further validation in a multicenter setting is required.

Artificial Intelligence Enabled ECG Interpretation Informs Outcomes after Autologous Transplantation for Multiple Myeloma

High dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is a standard therapy for patients with plasma cell disorders (PCD). A barrier to improving candidate selection for auto HCT is appraisal of risk for transplant related complications. Electrocardiography (ECG) is a standard pre-HCT test to evaluate the potential for arrhythmia and structural heart disease. We hypothesized that an artificial intelligence (AI) based interpretation of ECG waveform data (AI-ECG) could enhance risk prediction for cardiac-specific and other outcomes following auto HCT for patients with PCD. To test this hypothesis, we used several AI-ECG tools developed using a deep-learning based approach that were trained to predict comorbidity (Attia et al, Lancet 2019 &amp; Grogan et al, Mayo Clin Proc 2021). Model outputs include a scaled prediction value indicating increasing risk for atrial fibrillation/flutter (AF), reduced ejection fraction (EF), or cardiac amyloidosis. We evaluated this tool in 9,225 ECGs obtained from 849 patients (median 6 ECGs/patient, inter-quartile range: 3-12) who underwent first or subsequent auto HCT at Memorial Sloan Kettering Cancer Center between 2016-2022 and who had a diagnosis of multiple myeloma (N = 810), amyloidosis (N = 37), or other PCD (N = 2). The endpoints were to determine whether baseline AI-ECG prediction of AF risk correlated with peri-transplant AF events, and to explore whether model outputs correlated with survival and other cardiac clinical outcomes. The mean age of patients was 61.0 years (range 23.7 - 81.2) and median follow up was 2.7 years post auto HCT. Contributing cardiovascular risk factors included a prior history of AF (N = 101, 11.9%), coronary or cerebrovascular disease (N = 95, 11.2%), and diabetes mellitus (N = 98, 11.5%). Reduced dose melphalan (&amp;lt; 200 mg/m 2) was administered in 26%. The HCT-comorbidity index (HCT-CI) was high risk (≥3) in 52.7%. The one-year overall survival and progression-free survival in the whole cohort was 94% (95% confidence interval (95% CI): 92 - 95%) and 86% (84 - 89%), respectively. Among patients not in AF at pre HCT evaluation, the 90-day cumulative incidence of AF was 5.6% (4.2 - 7.3%). In univariable competing risk regression, baseline pre HCT AI-ECG appraisal of AF risk was strongly correlated with incidence AF in patients who were in sinus rhythm before HCT (hazard ratio (HR): 25.1, 95% CI: 11.7 - 53.7, p &amp;lt; 0.001). In a multivariable model adjusting for patient age and HCT-CI, AI-ECG AF predicted risk remained associated with incidence of post HCT AF (HR: 13.4, 95% CI: 5.9 - 30.4, p &amp;lt; 0.001). Considering a decision threshold identified during original model training, AI-ECG predicted AF events with an accuracy of 75% (Mcnemar's p &amp;lt; 2 x 10 -16). The precision, recall, and F1-score were 0.94, 0.77, and 0.85, respectively. AI-ECG predicted age correlated highly with actual patient age (Spearman rho = 0.59, p &amp;lt; 2 x 10 -16). Amyloid risk scores were highly correlated with a known clinical history of amyloidosis (median 0.45 versus 0.05, Wilcoxon rank-sum p &amp;lt; 0.001). Patients with EF &amp;lt; 50% had greater prediction scores for cardiomyopathy compared to patients with normal EF (median 0.23 versus 0.01, Wilcoxon rank-sum p &amp;lt;0.001). In univariable analysis, increasing AI-ECG predicted age (HR 1.02, CI: 1.003 - 1.04, p = 0.02) and predicted AF risk score (HR: 3.2, CI: 1.4 - 7.2, p = 0.006) were associated with risk for death, whereas predicted amyloid score and predicted low EF were not associated with decreased survival. In multivariable analysis of all patients that considered patient age, hematopoietic comorbidity index, and remission status at HCT, increasing predicted AF score trended towards association with increased risk for death (HR: 2.3, 95%CI: 1.0 - 5.5, p = 0.059). Predicted AF score correlated highly with the HCT-CI and patient age. Finally, we examined whether risk prediction for low EF correlated with peri-HCT fluid overload (FO) defined by absolute weight gain. The incidence of ≥ 10% weight gain (grade 2 FO) and ≥ 20% weight gain (grade 3 FO) at 180 days post HCT was 7.4% (95% CI: 5.8%, 9.3%) and 1.0% (95% CI: 0.5%, 1.8%), respectively. Predicted low EF was not associated with development of either grade 2 or grade 3 FO in this population. In summary, AI-ECG predicts episodes of AF in patients undergoing auto HCT for PCD and may augment transplant risk appraisal when considered in conjunction with other measures of comorbidity.