Hematopoietic Cell Transplantation-specific Comorbidity Index Research Articles

Venetoclax Plus Azacitidine as a Bridge Treatment to Allogeneic Stem Cell Transplantation in Unfit Patients with Acute Myeloid Leukemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) is rarely recommended for unfit patients with newly diagnosed acute myeloid leukemia (AML). Patient survival can improve with venetoclax plus azacitidine (VEN plus AZA). However, the long-term outcome of this treatment strategy is still unsatisfactory. The high response and low treatment toxicity rates of patients receiving VEN plus AZA can provide an opportunity for HSCT among unfit patients. Nevertheless, the outcomes and complications of VEN plus AZA, followed by HSCT, remain unclear. This single-center retrospective study aimed to compare patients with newly diagnosed AML receiving VEN plus AZA as induction therapy (n = 27) to those receiving the conventional I3A7 regimen as induction therapy (n = 34). The 1-year overall survival, relapse, and non-relapse mortality rates in the two groups were similar. The cytogenetic risks and the hematopoietic cell transplantation-specific comorbidity index are the most significant predictive factors of overall survival. In older patients unfit for intensive chemotherapy, a low-intensity regimen with VEN plus AZA is a suitable bridge therapy. Furthermore, allo-HSCT is feasible and can be a curative option.

Development of an umbilical cord blood transplantation–specific nonrelapse mortality risk assessment score

AbstractHigher rate of nonrelapse mortality (NRM) remains yet to be resolved in umbilical cord blood transplantation (UCBT). Considering that UCBT has some unique features compared with allogeneic hematopoietic cell transplantation from other graft sources, a UCBT-specific NRM risk assessment system is required. Thus, in this study, we sought to develop a UCBT-specific NRM Risk Assessment (CoBRA) score. Using a nationwide registry database, we retrospectively analyzed 4437 recipients who had received their first single-unit UCBT. Using the backward elimination method, we constructed the CoBRA score in a training cohort (n = 2687), which consisted of recipients age ≥55 years (score 2), hematopoietic cell transplantation–specific comorbidity index ≥3 (score 2), male recipient, graft-versus-host disease prophylaxis other than tacrolimus in combination with methotrexate, performance status (PS) 2 to 4, HLA allele mismatch ≥ 2, refined Disease Risk Index high risk, myeloablative conditioning, and CD34+ cell doses < 0.82 × 105/kg (score 1 in each). The recipients were categorized into 3 groups: low (0-4 points), intermediate (5-7 points), and high (8-11 points) groups according to the CoBRA score. In the validation cohort (n = 1750), the cumulative incidence of NRM at 2 years was 14.9%, 25.5%, and 47.1% (P < .001), and 2-year overall survival (OS) was 74.2%, 52.7%, and 26.3% (P < .001) in the low, intermediate, and high groups, respectively. In summary, the CoBRA score could predict the NRM risk as well as OS after UCBT. Further external validation will be needed to confirm the significance of the CoBRA score.

Pretransplantation Inflammatory and Nutritional Status in Elderly Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Value of C-Reactive Protein-to-Albumin Ratio

There are no clear criteria for selecting elderly patients with hematologic malignancies eligible for allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate inflammatory and nutritional status biomarkers as prognostic indicators of allogeneic HSCT in elderly patients. We compared the prognostic effects of 4 representative pretransplantation biomarkers: C-reactive protein-to-albumin ratio (CAR), Glasgow Prognostic Score (GPS), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR). A total of 143 patients age ≥60 years who underwent their first allogeneic HSCT for a hematologic malignancy were enrolled between 2010 and 2020 in our single-center cohort. The median patient age was 65 years (range, 60 to 72 years). Pretransplantation high CAR, high GPS, and low PNI scores were associated with poor overall survival (OS), but the AGR was not associated with OS. Among the 4 biomarkers, CAR stratified OS most significantly (P < .001). Multivariate analyses identified only high CAR as an independent prognostic factor associated with OS (hazard ratio [HR], 1.98; P = .031) and showed that a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥3 also was associated with OS (HR, 2.04; P = .012). High CAR was correlated with poor performance status, male sex, and high Disease Risk Index, but not with high HCT-CI score. When the patients were stratified into 3 groups according to a composite risk assessment using CAR and HCT-CI, the 3-year OS decreased significantly with increasing scores (82.8%, 50.3%, and 27.0%, respectively; P < .0001). In conclusion, CAR is the most useful prognostic indicator among the inflammatory and nutritional status biomarkers for allogeneic HSCT in elderly patients. Inflammatory and nutritional status in the elderly may be important prognostic factors for allogeneic HSCT independent of HCT-CI score.

Preconditioning Frailty Phenotype Influences Survival and Relapse for Older Allogeneic Transplantation Recipients

Hematologic malignancies disproportionately affect older adults. Hematopoietic cell transplantation (HCT) is potentially curative, but poor overall survival (OS) has limited its use in older adults. Fried's frailty phenotype (FFP) is a geriatric assessment tool that combines objective and subjective performance measures: gait speed, grip strength, activity level, exhaustion, and weight loss. People meeting ≥3 criteria are classified as frail; 1 or 2 criteria, as pre-frail; and 0 criteria, as fit. To evaluate the association of pre-HCT FFP with post-HCT outcomes, we assessed FFP prior to conditioning for 280 HCT recipients age ≥60 years with acute leukemia or a myeloid neoplasm at 3 institutions. When analyzing survival by age group, patients age ≥70 years had inferior OS compared to patients age 60 to 69 years (P = .002), with corresponding OS estimates of 38.9% (95% confidence interval [CI], 27.8% to 49.9%) and 59.3% (95% CI, 51.9% to 65.9%). Nonrelapse mortality (NRM) also was significantly higher in the older patients (P = .0005); the 2-year cumulative incidences of NRM were 38.5% (95% CI, 27.5% to 49.2%) and 17.2% (95% CI, 12.3% to 22.8%), for older and younger recipients, respectively. The cumulative incidences of relapse did not differ by age group (P = .3435). Roughly one-third (35.5%) of the patients were fit, 57.5% were pre-frail, and 7.5% were frail, with corresponding 2-year OS estimates of 68.4% (95% CI, 57.9% to 76.8%), 45.5% (95% CI, 37.4% to 53.2%), and 45.8% (95% CI, 23.4% to 65.8%) (P = .013). FFP was not significantly associated with NRM, but being frail or pre-frail was associated with a higher rate of disease-related deaths (33.3% and 27.3%, respectively, compared with 17.4% for fit patients; P = .043). In univariate modeling of restricted mean survival time with a 3-year horizon (RMST_3y), the factors that were significantly associated were FFP, age, Karnofsky Performance Status (KPS), Disease Risk Index (DRI), and HCT-specific Comorbidity Index (HCT-CI). Of those factors, only FFP (P = .006), age (P = .006), KPS (P = .004), and DRI (P = .005) were significantly associated in multivariate modeling of RMST_3y. Estimates of RMST_3y were computed and 5 risk-groups were created with survival ranging from 31.4 months for those who were age 60 to 69 years, fit, had KPS 90 to 100, and low/intermediate-risk DRI compared to 10.5 months for those who had high-risk features for all the evaluated factors. In univariate and multivariate analyses for restricted mean time to relapse with a 3-year horizon (RMRT_3y), FFP (pre-frail versus fit, P = .007; frail versus fit, P = .061) and DRI (P = .001) were the only significant factors. Predicted RMRT_3y was longest (30.6 months) for those who were fit and had low/intermediate-risk DRI scores and shortest (19.1 months) for those who were frail and had high-risk or very high-risk DRI scores. Both age and FFP impact survival after HCT. Incorporation of FFP into pre-HCT evaluations may improve decision-making and counseling regarding HCT risk for older adults. Our findings support future trials designed to reverse frailty, such as pre-HCT supervised exercise programs, and correlative analyses to unravel the connection of frailty and relapse to generate future targets for intervention. Finally, exploration of novel HCT platforms to reduce relapse in pre-frail and frail patients, as well as reduce NRM in adults age >70 years, are warranted.

The Haemato-Oncology Frailty (HOF) score to assess frailty in lymphoma.

Morbidity and mortality during chemotherapy in older adults with haematological malignancy can be unpredictable. The Haemato-Oncology Frailty (HOF) score was previously found to predict outcomes in a cohort of patients with plasma cell myeloma. In this study, we assess its utility in assessing frailty in patients with lymphoma, and compare its performance to that of two other frailty scores. The HOF score was able to predict progression-free survival in this population, and was also shown to have potential in assessing the dynamism of frailty during chemotherapy. It performed well when compared to the Charlson Comorbidity Index (CCI) score and the Haematopoietic Cell Transplantation-Specific Comorbidity Index (HCTCI), although the study was not powered to assess for non-inferiority. The HOF score is a new score with the potential for application in different haematological malignancies.

Acute kidney injury in multiple myeloma patients undergoing autologous hematopoietic stem cell transplant: a cohort study

BackgroundAutologous hematopoietic stem cell transplant plays an important role in multiple myeloma (MM) treatment. Increasing incidence of MM and growing awareness of acute kidney injury (AKI) as a complication of hematopoietic stem cell transplant results in the need to better understand AKI in these patients. We aimed to evaluate incidence, risk factors and 5-year prognostic impact of AKI in MM patients undergoing autologous hematopoietic stem cell transplant.MethodsRetrospective cohort study. AKI was defined by the KDIGO classification using creatinine and urinary output criteria. We used survival analysis methods considering competing events for risk factors and disease-free survival, Cox proportional regression for overall survival and stepwise regression methods for multivariable models.ResultsWe analyzed data regarding 143 patients. The cumulative incidence of AKI and moderate-to-severe AKI was 49.7% and 14.1%, respectively. Factors with independent impact on AKI were obesity (HR: 1.83, 95% CI 1.07–3.11; p = 0.026), Hematopoietic cell transplantation—specific comorbidity index (HCT-CI) ≥ 2 (HR: 1.85, 95% CI 1.08–3.17), chronic kidney disease (CKD) (HR: 2.06, 95% CI 1.05–4.04), amyloidosis (HR: 2.25, 95% CI 1.25–4.06), mucositis grade 3–4 (HR: 2.19, 95% CI 1.25–3.86) and exposure to nephrotoxic drugs (HR: 2.0856, 95% CI 1.04–4.19). Moderate-to-severe AKI had an impact (HR: 1.62, 95% CI 1.15–2.31) on 5-year overall survival.ConclusionAcute kidney injury affects almost half of MM patients undergoing autologous hematopoietic stem cell transplantation, and reduction in urinary output allows early diagnosis in almost a quarter of the patients. Obesity, HCT-CI ≥ 2, CKD, amyloidosis, mucositis grade 3–4 and exposure to nephrotoxic drugs are significant risk factors. Moderate-to-severe AKI is associated with lower 5-year overall survival.Graphical abstract

Standard Risk Assessment Tools Fall Short to Assess Risk in Transplant Patients

Introduction: The HCT-CI (Hematopoietic Cell Transplantation-specific Comorbidity Index) predicts survival after HCT in patients with hematologic malignancies. HCT-CI ≥3 is associated with higher Non-Relapse Mortality (NRM) and lower overall survival in both allogeneic (allo) and autologous (auto)-HCT patients. The Disease Risk Index (DRI) Assessment Tool is a validated tool to categorize patients undergoing allo- transplant into risk categories based on disease status. It was developed to predict overall survival per disease status. This study was done to understand reasons for increased mortality in transplant patients at our center in 2021 compared to 2020 by comparing HCT-CI and DRI of transplant patients between the two years. Methods: The study was approved by our institution's IRB. A retrospective chart analysis of adult patients who underwent auto- or allo-HCT at Henry Ford Hospital in the years 2020 and 2021 was conducted. Relevant patient demographics, comorbidities, disease characteristics, and transplant-related data were collected. HCT-CI scores were calculated on all patients using the online calculator (https://www.mdcalc.com/calc/3980/hematopoietic-cell-transplantation-specific-comorbidity-index-hct-ci). Patients were also risk stratified based on the DRI Assessment Tool (https://cibmtr.org/CIBMTR/Resources/Research-Tools-Calculators/Disease-Risk-Index-DRI-Assignment-Tool). Data was reviewed and collected by investigators and compiled in a confidential platform. Results: A total of 166 patient records between 2020 and 2021 were reviewed. In 2020, 46 patients underwent auto-HCT and 28 underwent allo-HCT. In 2021, 58 patients underwent auto-HCT and 34 patients underwent allo-HCT. The one-year post transplant survival rates for patients are elucidated in Table 1. The median HCT-CI scores amongst the patients who underwent transplant was 3 in 2020 and 4 in 2021(refer Table 2). When assessing the Disease Risk Index, overall, more patients with higher disease risk were transplanted in 2021 compared to 2020 (refer Table 3). 16 patients (12 in 2021 and 4 in 2020) underwent transplant for diseases that are not included in the DRI assessment tool. Of these, 8 patients in 2021 underwent allo-HCT. These included aplastic anemia (AA), inherited bone marrow failure syndromes (BMF), solid tumors, primary CNS lymphomas, mycosis fungoides and hemophagocytic lymphohistiocytosis (HLH). Conclusion: The HCT-CI and the DRI are both tools used in transplant centers to risk stratify patients pre-transplant. The use of both tools can give a good sense of post-transplant outcomes, combining both individual patient characteristics as well as diseases specific variations. These data are also important for monitoring outcomes at transplant centers. In this study, patients who had an HCT-CI &amp;gt;/3 were similar in both years. The DRI however could not be ascertained in 16 patients, as these diseases are not currently included in the DRI. This makes outcome prediction for these particular patients suboptimal especially if they do not have as many comorbidities but still higher risk diseases. Furthermore, this precludes effective outcome monitoring in and amongst transplant centers. The combination of both the HCT-CI and the DRI would perform better if the DRI tool is revised to become more comprehensive or by creating a DRI that is specific for non-malignant disorders like AA, HLA and BMF. We intend to propose this to CIBMTR for further consideration.

Impact of Conditioning Intensity and Regimen on Outcomes after Unrelated Cord Blood Transplantation for Patients with Myelodysplastic Syndrome

Introduction Allogeneic hematopoietic stem cell transplantation (allo-HSCT) provides curative outcomes in patients with myelodysplastic syndromes (MDS). Unrelated cord blood transplantation (CBT) is an alternative donor option in MDS patients who lack an HLA-matched donor, and the increased availability of CBT expand indications for allo-HSCT in MDS patients. Because concerns have been expressed regarding decreased hematopoietic recovery and increased relapse after CBT, many studies have been conducted to develop the conditioning regimen in CBT. The optimal intensity of conditioning regimen needs to be addressed based on patient- and disease-related factors. However, the optimal intensity of conditioning regimen in CBT for MDS remains unclear. We here conducted a nationwide retrospective study to clarify the optimal conditioning intensity for MDS in CBT. Methods This study included patients diagnosed with de novo MDS according to the WHO classification. The clinical data of 856 de novo MDS patients (i) who were 16-69 years old and (ii) who underwent their initial single-unit CBT between 2001 and 2020 were collected from the Japanese Data Center for Hematopoietic Cell Transplantation. Cox proportional hazards regression models were used to evaluate variables potentially affecting overall survival (OS), chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS), and GVHD- and relapse-free survival (GRFS). Fine and Gray proportional hazards models were used to evaluate variables potentially affecting cumulative incidences of relapse (CIR) and non-relapse mortality (NRM), using cumulative incidence curves to accommodate competing events. Results In this study, 501 and 355 patients received myeloablative conditioning (MAC) and reduced-intensity conditioning (RIC), respectively. The median age at CBT was 53 (range,17-69) and 62 years (range,18-69) in MAC and RIC groups, respectively. The most frequently used MAC regimen consisted of total body irradiation &amp;gt;8 Gy-based regimen (n=209, 41.7%), followed by fludarabine (Flu) with myeloablative doses of busulfan (Bu 9.6 to 12.8 mg/kg)-based regimen (n=93, 18.6%). The most frequently used RIC regimen consisted of Flu with reduced doses (80 to 120 mg/m 2) of melphalan-based regimen (n=245, 96.1%), followed by Flu with reduced doses of Bu (6.4 mg/kg)-based regimen (n=63, 17.7%). The 3-year OS were 44.3 % and 48.8 % in MAC and RIC groups, respectively; the 3-year CRFS were 33.8 and 37.2%; the 3-year GRFS were 19.2 % and 26.9%; the 3-year CIR were 27.1% and 30.0%; and the 3-year NRM were 18.6% and 18.2 %. The univariate analysis revealed that RIC group tended to correlate with higher GRFS than MAC group (Hazard ratio (HR) 0.86 [95% confidential interval 0.74-1.00]; P=0.057), but there was no significant difference of OS (HR 0.95 [0.79-1.13]; P=0.552), CRFS (HR 0.95 [0.80-1.12]; P=0.522), CIR (HR 1.11 [0.87-1.41]; P=0.401) and NRM (HR 0.96 [0.77-1.20]; P=0.735) between MAC and RIC groups. The multivariate analyses confirmed the better GRFS in RIC group than MAC group (HR, 0.73 [0.61-0.89]; P=0.001). Apart from the conditioning intensity, the following six factors were associated with worse overall mortality: patient's age (40-60 years; P=0.039 and &amp;gt;60 years; P&amp;lt;0.001), patient's sex (male; P=0.038), performance status (PS) at CBT (PS 2-4; P=0.033), hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (HCT-CI ≥3; P=0.035), high number of platelet transfusion before HSCT (≥20 times; P&amp;lt;0.001) , and cytogenetic risk group (poor risk; P=0.001). We next performed the subgroup analysis stratified by the patient's characteristic affecting OS, such as age, sex, PS, HCT-CI, the number of platelet transfusion, and cytogenetic risks. The subgroup analysis showed the better OS (HR, 0.74 [0.59-0.92]; P&amp;lt;0.007), CRFS (HR 0.74, [0.60-0.94]; P=0.012), and GRFS (HR 0.62, [0.50-0.78]; P&amp;lt;0.001) of RIC group than MAC group among patients with patients aged &amp;gt;60 years, but no significant impact on CIR and NRM. Conclusion This study showed no significant difference of OS, CRFS, CIR and NRM between MAC and RIC groups, but RIC group correlated with better GRFS in the entire population. Furthermore, the subgroup analysis showed that RIC regimen may be preferable for patient aged &amp;gt;60 years. These findings would improve the management for CBT candidates with MDS.

Trends in Outcomes over Three Decades after Upfront Autologous Stem Cell Transplant for Multiple Myeloma at MD Anderson Cancer Center

Introduction Remarkable advances have been made in the treatment of multiple myeloma (MM) with the advent of novel therapies and the use of post-transplant maintenance. We report trends in outcomes of MM patients who received upfront autologous hematopoietic stem cell transplantation (autoHCT) at our institution over more than three decades. Methods We conducted a single-center retrospective study of patients with newly diagnosed MM undergoing upfront autoHCT between 1988 to 2021. Patients were grouped by the year of autoHCT: 1988-2000 (n=249), 2001-2005 (n=373), 2006-2010 (n=568), 2011-2015 (n=815) and 2016-2021 (n=1036). High-risk cytogenetic abnormalities were defined as del17p, t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. Progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and group differences were assessed using the log-rank test. Associations between demographic and clinical factors and survival outcomes were evaluated using Cox proportional hazards regression analysis. Results A total of 3041 patients were included in our analysis. Median age at autoHCT increased from 52 years (1988-2000) to 62 years (2016-2021), with only 1% of transplanted patients being ≥ 65 years of age in 1988-2000, compared to 38% in 2016-2021 (p&amp;lt;0.001). The proportion of African-American patients increased from 9% in 1988-2000 to 19% in 2016-2021 (p=0.004). The incidence of high-risk cytogenetics increased from 15% in 1988-2000 to 40% in 2016-2021 (p&amp;lt;0.001). The comorbidity burden, as measured by the hematopoietic cell transplantation-specific comorbidity index (HCT-CI), increased over time, with 17% of patients having HCT-CI&amp;gt;3 in 1988-2000 compared to 28% in 2016-2021 (p&amp;lt;0.001). Induction regimens evolved over time from predominately conventional chemotherapy (39%) in 1988-2000 to immunomodulatory drug (IMiD) and proteasome inhibitor (PI)-based regimens, with 74% receiving an IMiD-PI containing triplet [39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone (KRD)] between 2016-2021 (p&amp;lt;0.001). Maintenance therapy was used in &amp;gt;80% from 2011 onwards (Table 1). Response rates prior to autoHCT steadily improved with 4% and 10% patients achieving ≥CR and ≥VGPR between 1988-2000, compared to 19% and 65% between 2016-2021, respectively. At day 100 post-transplant, 24% and 49% patients achieved ≥CR and ≥VGPR between 1988-2000 compared to 41% and 81% between 2016-2021, respectively. At best post-transplant response, 33% and 53% patients achieved ≥CR and ≥VGPR between 1988-2000 compared to 63% and 91% between 2016-2021, respectively. The median PFS in the entire study population was 38.3 months (95% CI 36.4-40.3), improving from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (hazard ratio [95% CI]: 0.42 [0.36-0.50], p&amp;lt;0.001; Figure 1A). Notably, patients with high-risk cytogenetics also had an improvement in PFS in recent years, with a median PFS of 28.0 months (0.38 [0.26-0.55], p&amp;lt;0.001) and 36.8 months (0.32 [0.22-0.46], p&amp;lt;0.001) in 2011-2015 and 2016-2021, respectively, compared to only 13.7 months in 2001-2005. Patients aged ≥65 years also had an improvement in median PFS from 33.6 months (95% CI 23.1-44.2) between 2001-2005 to 52.8 months (95% CI 40.0-68.5, p&amp;lt;0.001) between 2016-2021. Median OS was 99.4 months (95% CI 94.2-104.0) in the entire study population, steadily improving from 55.1 months to not reached (0.41 [0.33-0.52], p&amp;lt;0.001) in 1988-2000 and 2016-2021, respectively (Figure 1B). Similarly, in those with high-risk cytogenetics, OS improved with a median OS of 32.9 months in 2001-2005 compared to 66.5 months (0.39 [0.26-0.61], p&amp;lt;0.001) in 2016-2021. Between 1988-2000, day 100 non-relapse mortality (NRM) was 6%, whereas from 2001 onwards NRM remained ≤ 1% (p&amp;lt;0.001). Conclusions This single-center analysis of over 3,000 newly diagnosed MM patients undergoing upfront autoHCT demonstrates significant improvements in the depth of response and survival outcomes over the past three decades, even in patients with high-risk disease. NRM remained &amp;lt;1% despite increasing age and comorbidity burden.

Evolving Racial/Ethnic Disparities in AML Survival in the Novel Therapy Era: Real-World Evidence of Improved Survival in Older Patients with the Largest Improvement in Non-Hispanic Black Patients

Introduction: The approval of venetoclax (VEN)-based frontline therapy for acute myeloid leukemia (AML) in November 2018 marks a new era of AML care. Racial/ethnic disparities have been increasingly recognized in AML with historically inferior outcomes reported in non-Hispanic Black (NHB) patients relative to non-Hispanic White (NHW) patients. The advances of novel therapeutics offer an unprecedented opportunity to narrow the care gaps between patient groups; but they also create new challenges related to testing, clinical decision-making, and care coordination. Currently, little is known about the impact of race/ethnicity on the recent advances in AML management. We performed a retrospective analysis leveraging real-world data to examine the magnitude and mechanisms of racial/ethnic disparities in modern AML care. Methods: Adult patients from Flatiron Health, a nationwide, electronic health record derived, de-identified database, with AML diagnosed between January 2014 to December 2018 (Pre era) and January 2019 to October 2022 (Post era) who identified as NHW, NHB or Hispanic and received at least one line of anti-leukemic therapy were included. Overall survival (OS) was defined from the time of therapy initiation to the time of death. Multivariable Cox regression models were used to compare the hazards of death for NHB and Hispanics relative to NHW. Predicted survival curves were then computed. Pre-planned sensitivity analyses including patients with 1) no ethnicity information, 2) no anti-leukemic therapy, and 3) care gap &amp;gt;100 days from diagnosis to induction were performed. Results: 2998 patients in Pre era (2566 NHW, 221 NHB, 211 Hispanics) and 2098 patients in Post era (1809 NHW, 162 NHB, 127 Hispanics) were included. Older patients with more comorbidities and worse disease biology (Table 1) were treated in Post era. After adjusting for race/ethnicity, age and Hematopoietic Cell Transplant Specific Comorbidity Index (HCT-CI), patients in Post era had a 10% decrease in the hazard of death compared to Pre era (HR 0.90, 95% CI 0.83-0.96). The difference was driven by OS benefits observed in patients aged &amp;gt;70 years (HR 0.82, 95% CI 0.75-0.91). NHB and Hispanics were younger at diagnosis than NHW in both eras. Lower socioeconomic status was observed in NHB and Hispanics. No difference in ELN2017 risk stratification was observed (Table 1). After adjusting for age and HCT-CI, NHB had a 22% increased hazard of death compared to NHW in Pre era (HR 1.22, 95% CI 1.04-1.43); whereas Hispanics had comparable outcomes (HR 1.01, 95% CI 0.84-1.21). Strikingly, the survival disparity between NHB and NHW in Pre era was not observed in Post era with predicted 2-yr OS rate being 45.3% and 39.9%, respectively (HR 0.86, 95% CI 0.69-1.08) (Figure 1). Predicted 2-yr OS rates improved for NHB patients in both ≤70 years (42.3% vs. 53.2%) and &amp;gt;70 years group (13.6% vs. 37.0%). No significant change in OS was observed in Hispanics between Pre and Post era (Figure 1). Results of all sensitivity analyses were consistent with primary analyses. Molecular testing at diagnosis significantly differed by eras across race/ethnicity groups (overall 66.4% vs. 82.9%, p&amp;lt;0.001). In contrast, molecular testing occurred more frequently in NHB at relapse in Post era (45.6% vs. 65.4%, p=0.020). Despite being older, more NHW received allogeneic transplant than NHB in Pre era (25.8% vs. 18.6%, p=0.046). In Post era, NHW were more likely to receive VEN-based induction therapy (46.9%, 37.0%, 35.4% in NHW, NHB and Hispanic, respectively, p= 0.003). Among patients who were tested and qualified, no difference was observed in the use of gemtuzumab ozogamicin, CPX-351, FLT3 inhibitors or IDH1/2 inhibitors across race/ethnicity. Conclusions: In this large, real-world dataset, we demonstrate OS improvements in the era of modern AML care, particularly among patients &amp;gt;70 years though their outcomes remain inferior to younger patients. Intriguingly, the largest OS improvement was observed in NHB, where the OS disparity between NHB and NHW in Pre era appears to have been mitigated. Hispanics have not experienced similar OS improvement in modern AML care. Ongoing analyses are focused on examining the mechanisms of survival trends observed with focus on assessing the contribution(s) of patient-, disease biology- and treatment-related factors in order to identify potential targets for intervention. • Dr. Kelly Getz and Dr. Catherine Lai contributed equally

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&amp;lt;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 Comprehensive Model for Predicting 1-Year Survival after Allogeneic Hematopoietic Cell Transplantation in Older Patients

Background: As the number of elderly patients referred to and undergoing allogeneic hematopoietic cell transplantation (alloHCT) continues to rise, there is a growing need for a comprehensive risk assessment model to accurately predict transplantation outcomes in this specific patient population. The widely used Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) does not fully capture factors influencing transplant outcomes in elderly patients. This study aims to enhance risk stratification for elderly patients undergoing alloHCT by integrating additional functional, nutritional, and clinical indicators. Methods: This is a retrospective study utilizing the data registry of HCT patients who received their treatment at UF Health Cancer Center. The inclusion criteria included all patients age &amp;gt; 65 years, who underwent their first alloHSCT between January 2012 and December 2022, regardless of graft type, conditioning regimen, donor type, or graft source. Patient data were extracted through chart review. The primary endpoint was 1-year Overall Survival (OS). Prognostic significance of each variable was assessed using Cox proportional hazard models. We subsequently used all variables to build a comprehensive prediction model to assess 1-year survival outcomes in elderly patients undergoing alloHCT. The predictive model's performance was measured by the Concordance-statistic (c-statistic). Results: A total of 69 patients satisfied the inclusion criteria and were included in the analysis. Median age was 69 years (range 66-81) and 65.2% were male. Unrelated donors were used in 66.6% of patients, while the remainder received grafts from related donors. Most patients received peripheral blood stem cell grafts (91%). Myeloid malignancies comprised the most common indication for alloHCT in this group of patients (89.8%). 59.4% had abnormal cytogenetics. 35 variables were considered in the analysis. In the univariate analysis, variables with impact on 1-year OS post-transplant included creatinine (HR 3.35, CI 1.62-6.91, p=0.001), blood urea nitrogen (HR 1.03, CI 1.01-1.06, p=0.007), estimated glomerular filtration rate (HR 0.93, CI 0.89-0.93, p=0.001), hemoglobin (HR 0.8, CI 0.66-0.97, p=0.02), abnormal cytogenetics (HR 2.27, CI 1.20-4.31, p=0.012) and high and very high disease risk index (HR 0.51, CI 0.27-0.98, p=0.04). Notably, both hemoglobin and cytogenetics demonstrated a c-statistic greater than 0.6 in the univariate analysis. In the multivariate analysis, variables impacting 1-year OS included hemoglobin (HR 0.69, CI 0.48-0.99, p=0.04), remission status at the time of transplant i.e., not reached (NR) vs complete remission 1 (CR1) (HR 0.05, CI 0.00-0.71, p=0.027), and abnormal cytogenetics (HR 7.55, CI 2.32-24.58, p=0.001). Interestingly, the HCT-CI did not significantly impact 1-year OS in the univariate analysis (c-statistic 0.51, HR 0.99, CI 0.85-1.15, p=0.896). Our prediction model showed good performance with a mean area under the receiver operating characteristic curve of 0.82. Conclusion: We developed a comprehensive prediction model to assess 1-year OS in elderly patients undergoing alloHCT to overcome some of the limitations of the HCT-CI in this unique age group. This model holds potential to enhance decision-making regarding candidacy for elderly patients undergoing alloHCT.

Outcome of Allogeneic Stem Cell Transplantation in FLT3-TKD-Mutated AML - a Study on Behalf of the Acute Leukemia Working Party of the EBMT

Introduction The overall prognostic impact of point mutations in the tyrosine-kinase domain 1 of FLT3 (FLT3-TKD mut) in patients (pts) with acute myelogenous leukemia (AML) remains controversial. Furthermore, co-occurrence of FLT3-TKD mut and mutated nucleophosmin-1 (NPM1 mut) was shown to have a favorable prognostic impact on AML pts receiving conventional chemotherapy. However, little is known about the outcome of AML pts with FLT3-TKD mut with or without co-occurring NPM1 mut treated with allogeneic stem cell transplantation (alloSCT). Patients and Methods This is a retrospective study of the acute leukemia working party (ALWP) of the European Society for Blood and Marrow transplantation (EBMT) investigating the outcome of adult AML pts with FLT3-TKD mut with or without NPM1 mut after first alloSCT using matched sibling (MSD), unrelated (UD) or haploidentical (haplo) donors between 2005 and 2022. All patients were in first or second complete remission (CR1 of CR2). Information on cytogenetic risk was necessary for inclusion. No ex-vivo T-cell depletion (TCD) was allowed. The primary endpoint was leukemia-free survival (LFS) at two years after alloSCT. Secondary endpoints were overall survival (OS), cumulative incidence of relapse (RI), non-relapse mortality (NRM), acute and chronic graft-versus-host disease (GVHD) and GVHD-free, relapse free survival (GRFS). One hundred and eighty-two adult AML pts with FLT3-TKD mut were identified, of which 74 (40.7%) had a co-occurring mutation in NPM1. Median age was 55.1 years (range 18.6-79.1) and 46.7% were male. Median follow-up was 21.4 months [IQR 13.6-28.1]. 78% of the pts were in CR1. Cytogentic risk was favorable, intermediate and adverse in 12.6%, 75.3% and 12.1% of pts, respectively. Additional FLT3 internal tandem duplication (FLT3-ITD) was present in 25.8% of pts. Information on measurable residual disease (MRD) was available for 68.7% of pts, being positive in 48% of these. Karnofsky performance score was &amp;lt; 90% in 21.1%, and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was &amp;gt;=3 in 28.1% of pts. 69.6% of pts were cytomegalovirus (CMV) positive. Conditioning was myeloablative in 52.8% and reduced intensity in 47.2% of pts. Stem cell donors were MSD, UD and haplo in 25.8%, 55.5% and 18.7% of cases. Stem cell source was bone marrow in 10.4%, peripheral blood in 87.4% and both in 2.2%. In-vivo TCD was performed in 59.2% of pts. GVHD prophylaxis was calcineurin inhibitor-based in 92.2% of pts. Results Engraftment was achieved in 99.4% of pts with a day-60 absolute neutrophil count (ANC) &amp;gt;0.5 x 10 9/L of 97.7% [95% CI: 93.7-99.2]. Day-180 rates of acute GVHD (aGVHD) grade II-IV and grade III-IV were 26.2% (95% CI:19.9-32.9) and 8.1% (95% CI:4.6-12.8), respectively. At two years, rates of total chronic GVHD (cGVHD) and extensive cGVHD were 30% (95% CI: 22.5-38) and 16.6% (95% CI:10.6-23.7), respectively. Two-year LFS and OS were 66.1% (95% CI: 57.6-73.2) and 74% (95% CI: 65.4-80.8), respectively. Two-year RI, NRM and GRFS were 22.5% (95% CI:16-29.8), 11.4% (95% CI: 7-17), and 51.1% (95% CI: 42.4-59.1), respectively. Cause of death was original disease in 47.5%, infection in 27.5%, GVHD in 22.5% and non-SCT related in 2.5% of cases. In univariate analysis the only factor with significant impact on LFS was donor type (haplo [n=34] vs. others, p=0.006). For GRFS, patient CMV negativity (p=0.014) and in-vivo TCD (p=0.01) were significant. Interestingly, co-occurring mutations in FLT3 (FLT3-ITD) or NPM1 were not identified as having a significant impact on LFS or GRFS. Moreover, MRD status before alloSCT was also not shown to have a significant impact on these outcomes. In multivariate analysis of LFS and GRFS, only donor type (haplo [n=34] vs. others) was shown to be significant for both endpoints, hazard ratio (HR) 2.54; 95% CI: 1.4-4.6; p=0.002, and HR 2.01; 95% CI: 1.18-3.41; p=0.01, respectively. Conclusion Acknowledging the limitations of our retrospective study in this rare entity results are encouraging given the high-risk population (median age 55.1 years, CR2 in 22%, co-occurring FLT3-ITD in 25.8%, positive MRD in 48%, HCT CI &amp;gt;=3 in 28.1%). LFS, OS and GRFS rates were 66.1%, 74% and 51.1%, respectively, and both RI and NRM were comparably low with rates of 22.5% and 11.4%, respectively. No positive prognostic impact of co-occurring mutations in FLT3-TKD and NPM1 was detected, unlike what was found for conventional chemotherapy.

Assessment of Inpatient Mortality in the Peri-Transplant Period in Elderly Allogeneic Stem Cell Transplant Recipients with Co-Existing Mental Health Illnesses

Background Allogeneic hematopoietic stem cell transplant (alloHCT) is a potentially curative treatment for patients with hematological malignancies and nonmalignant conditions. AlloHCT involves invasive procedures, conditioning chemotherapy regimens, and prolonged isolation during hospitalization, which is physically and emotionally challenging. Transplant related mortality is higher in older individuals. Careful assessment of mortality risk before transplant is essential for optimal patient selection and informed decision-making, especially in elderly patients. Hematopoietic cell transplantation-specific comorbidity index (HCT-CI), an important prognostic scoring tool used in patients before alloHCT, includes psychiatric comorbidity as one of the scoring criteria. Patients with depression or anxiety disorders receive one point on the scoring scale, with the assumption that the two groups of patients are at an equivalent risk. However, there is literature showing decreased overall survival and worse inpatient outcomes in patients receiving alloHCT with co-morbid depression. Our primary objective was to evaluate the inpatient outcomes of elderly patients undergoing allogeneic stem cell transplant with a concurrent diagnosis of depression and patients with anxiety and adjustment disorders. Methods: Patients of ages ≥ 60 years, admitted with a principal procedure code of allogeneic stem cell transplant, were recruited from the 2016-2020 National Inpatient Sample. Three cohorts were created based on ICD-10 diagnostic codes for Depression and Anxiety and adjustment disorders: patients without depression and anxiety disorders, patients with depression only, and patients with anxiety and adjustment disorders only. Patients with diagnoses of other mental illnesses were excluded. The patient characteristics between the three cohorts were evaluated. Multiple Logistic Regression models were used to determine the impact of depression and anxiety disorders on inpatient mortality. Results: We evaluated 11655 hospital admissions with the primary procedure code for Allogeneic Stem Cell Transplant in patients aged 60 years and above. 8375 patients did not have any mental illness. 800 patients (9.5%) had a diagnosis of Depression, and 1640 patients (19.5%) had a diagnosis of Anxiety and adjustment disorders. Comparing the primary outcomes in patients with and without Depression, the length of stay was 31.3 days vs 28.2 days (p&amp;lt;0.01), the mean hospital charge was 558398.01 USD vs 498971.9 USD (p &amp;lt;0.01), and in-patient mortality was 8.1% vs 5.9% (aOR = 1.359, 95% CI 1.010-1.829, p=0.04). Utilization of mechanical ventilation was more prevalent in patients with depression (8.8 %vs 5.8 %, p &amp;lt;0.01). Out of different infectious complications, pneumonia was more common in patients with depression (14.4 % vs 9.8 %, p &amp;lt;0.01) (Table 1a). Baseline socio-demographic characteristics that were associated with having depression included: Female gender, White race, and Medicare insurance. Patients with depression had an increased prevalence of congestive heart failure, prior stroke, Obesity with BMI &amp;gt;= 35, chronic kidney disease, and COPD compared to patients without depression (p&amp;lt;0.01). For the primary outcomes in patients with and without anxiety and adjustment disorders, the length of stay was 29.15 days vs 28.2 days (p &amp;lt;0.01), the mean hospital charge was 474274.71 USD vs 498971.94 USD (p 0.612), and the in-patient mortality was 4% vs 5.9 % (aOR=0.61, 95% CI 0.45-0.83, p&amp;lt;0.01). Baseline socio-demographic characteristics that were prevalent in patients with anxiety and adjustment disorders were: female gender, white race, and Medicare as the most common insurance (P&amp;lt;0.01) (Table 1b). Conclusion We found that in elderly patients admitted for alloHCT, depression was independently associated with worse inpatient outcomes, while anxiety was not. Patients with depression were noted to have an increased incidence of infectious complications as compared to those without depression, possibly accounting for their increased mortality. Prognostic scoring systems like HCT-CI may need to be modified to assign more weight to depression as a psychiatric co-morbidity. Elderly transplant recipients with depressive disorders are a vulnerable group and multidisciplinary teams such as psychiatry and palliative care should be involved in their care.

Frailty Impact on Outcomes of Patients Undergoing Chimeric Antigen Receptor T-Cell (CAR T) Therapy at Princess Margaret Cancer Centre: A Prospective Pilot Study

Introduction Princess Margaret Cancer Centre is 1 of 3 adult centres in Ontario, Canada providing Chimeric Antigen Receptor T-Cell (CAR T) therapy as a standard of care treatment for adult patients with relapsed and refractory B-cell lymphomas. There is no upper age limit for treatment consideration, and frailty may be an important factor in assessing fitness for treatment. This study aims to determine if frailty assessments pre-CAR T can predict those at higher risk for acute toxicities, PFS, and OS, as well as evaluate changes in frailty over time. Methods We performed a cohort study of consecutive patients with lymphoma undergoing CAR T cell therapy at our institution, from April 2021 to date. Frailty was evaluated using the Clinical Frailty Scale (CFS), Grip Strength, Gait Speed, Mini-Cog, Edmonton Symptom Assessment System (ESAS) and Patient Health Questionnaire (PHQ-2 and PHQ-9) at 5 time points: baseline (clearance visit), and 1, 3, 6 and 12 months post-CAR T. At baseline, additional assessments were completed to further characterize frailty including the Vulnerable Elders Survey (VES-13), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and Cumulative Illness Rating Scale (CIRS). We present data on patients enrolled to date. Results Fifty-two patients have had their data analyzed thus far. Mean age is 57.9 ± 12.7 years and 54% are male. 50% have de novo diffuse large B-cell lymphoma, 24% transformation from follicular lymphoma,14% HGBCL, 6% PMBCL and 6% FL. Most patients (83%) received axi-cel. Median follow-up is 3.80 months (IQR 0.56-24.7 mo). All 52 patients completed assessments at baseline, 44 completed 1 month, 25 completed 3 month, 12 completed 6 month and 11 completed 12 month assessments. Median scores (and IQR) for the HCT-CI, CIRS, VES-13 and CFS at baseline were 1.5 (0-5), 3.0 (0-13), 1.0 (0-7), and 3.0 (1-7) respectively. There were clinically significant changes observed in CFS over time ( p=&amp;lt;0.001), with mean scores of 3.3 at baseline, 3.7 at 1 month, 2.8 at 3 months and 2.1 at 12 months. There were no significant changes ( p=0.051; p=0.078) between timepoints for either of the physical assessments of grip strength or gait speed. Sixteen patients (31%) experienced immune effector cell neurotoxicity syndrome (ICANS) (4% Grade 4, 4% Grade 3, 8% Grade 2, 15% Grade 1) and forty-nine patients (94%) experienced cytokine release syndrome (CRS) (2% Grade 3, 65% Grade 2, 27% Grade 1), during the 30 days following cell re-infusion. Seven patients (13%) were admitted to the ICU, with a median in-hospital length of stay for all 52 patients of 12.5 days (IQR 7.0, 99.0). None of the variables tested (age, sex, bridging therapy, LDH, CRP and frailty assessments) were significantly associated with the development or grade of CRS or ICANS. There have been 21 progression events and 18 deaths (6 without progression); 9 pts remain alive post-progression (Figure 1). On univariable analysis of baseline data, ECOG performance status, LDH level, and the VES-13 score were predictive of PFS, while ECOG, LDH, CRP, VES-13 score, CFS and the time to walk 4m were predictive of OS. The HCT-CI and CIRS score were not significantly associated with outcomes. On multivariable analysis of PFS, baseline VES-13 score (HR 1.17, p=0.04) and LDH (HR 1.002, p=0.05) remained significant. Multivariable analysis for OS was not performed due to insufficient number of events. Analyses incorporating repeated measures were performed, and on univariable analysis, the CFS, 4m walk test (s), LDH, VES-13 were significantly associated with PFS and the same variables and CRP were associated with OS (Table 1). On multivariable repeated measurements analyses, only the CFS was still associated with PFS, and CFS and LDH with OS (Table 1). Conclusions Conducting serial frailty assessments in patients undergoing CAR T therapy is feasible. The only longitudinal measurement of frailty found to have clinically significant changes between timepoints was the CFS, suggesting an element of reversible functional impairment related to patients' lymphoma. Within the limits of our sample size, baseline measures of frailty were not predictive of CRS or ICANS; the relationship of CFS change over time with PFS and OS may be indicative of lymphoma response. Enrollment is ongoing and data on larger number of patients with longer term follow-up are needed.

Increased Exceptional Response and Overall Survival Advantage for Patients with Multiple Myeloma Receiving Melphalan 200mg/m 2 Vs 140 Mg/m 2 Conditioning for Autologous Hematopoietic Stem Cell Transplantation

The standard conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplant (HSCT) is intravenous melphalan dosed at 200mg/m 2 (mel200). Prior retrospective studies indicated that dose reduction to melphalan 140 mg/m 2 (mel140) confers similar progression-free (PFS) and overall survival (OS), leading to increased use of mel140 in patients with comorbidities or advanced age. A recent single-center retrospective study (Sharma et al, Leukemia Lymphoma 2023) identified an OS advantage yet similar PFS for mel200 vs mel140, suggesting that certain patient cohorts may benefit from mel200. These findings require confirmation and better understanding of the risks and benefits to different dosing strategies. We performed a single-center retrospective study of mel dosing and transplant outcomes at the University of Nebraska Medical Center between 2008-2018. Three hundred and sixty-two patients underwent a first autologous HSCT with mel conditioning; 95 received mel140 while 267 received mel200. Nearly all patients received maintenance therapy (n= 357, 99%). Patient demographic and disease factors were largely comparable between mel140 and mel200 cohorts including sex, response prior to HSCT (both 73% for very good partial response or better), and presence of high-risk cytogenetics (t(4;14), t(14;16), t(14;20), del17p; 15% vs 14%). The mel140 group was older (65.1 years vs 59.7 years), had higher hematopoietic cell transplantation-specific comorbidity index (HCT-CI) scores (64% vs 40% at ³3), and International Staging System (ISS) stages (40% vs 22% at stage III) than the mel200 group. Average creatinine clearance at transplant was 71 vs 91 mL/min/m 2 in the mel140 vs mel200 cohorts, respectively. OS favored mel200 with a median survival time of 94.4 vs 69.1 months (mel200 vs mel140, Figure 1, p = 0.002). There was no statistical difference in PFS between mel200 vs mel140 (median PFS 73.0 vs 60.5 months, p = 0.43, respectively). With Cox proportional hazards regression, we performed a multivariate analysis of risk factors on PFS and OS. For OS, age ( p = 0.02) retained statistical significance within the model. Mel dosing and high-risk cytogenetics (both p = 0.09) did not retain significance. HCT-CI may have an effect ( p = 0.04), but due to missing data on n= 125/362 subjects this could not be well evaluated. Response prior to HSCT, creatine clearance at transplant, and ISS stage were not statistically significant. Given the multiple variables assessed and missing data for HCT-CI we separately analyzed mel dosing together with the most significant variable in the model, age. In this subset OS model, mel200 was associated with an improved OS (hazard ratio (HR) 0.64, p = 0.03) while age was associated with an adverse effect (HR 1.11 per 5-year increase, p = 0.06). For the multivariate PFS model, only high-risk cytogenetics (HR 1.82 yes vs no, p = 0.004) retained statistical significance. Median engraftment was faster in mel200 cohort (67% vs 92% engraftment starting at ³D+12, p &amp;lt;0.001). We next examined the impact of mel dosing on the rate of exceptional response (Paquin et al, Blood Cancer Journal 2020), defined as alive and progression-free for 8 or more years. Twenty-nine of 362 patients (8%) met the requirements for exceptional response. Two (7%) received mel140 while 27 (93%) received mel200. Exceptional responders were younger and split evenly between male and female. The majority had at least a very good partial response prior to HSCT (79%). Only 2 exhibited high-risk cytogenetics; one received bortezomib and lenalidomide maintenance, the other only bortezomib. On multivariate analysis, only two factors contributed to exceptional response: mel dose (mel200 odds ratio (OR) 5.22, Table 1, p = 0.01) and HCT-CI (OR 0.66 for increasing score, Table 1, p = 0.02. High-risk cytogenetics was not associated with exceptional responders (OR 0.43 yes vs no, p = 0.38) which may be due to low sample size. We conclude that mel dosing impacts OS but not PFS in our cohort, though this effect is confounded by increasing age and potentially comorbidity. We report for the first time that mel200 dosing increases the rate of exceptional response compared to mel140. Overall, these data support recent conclusions by Sharma et al and challenge the previous reports of similar OS outcomes between mel200 and mel140 dosing.

Comparison of Two Reduced Intensity Conditioning Regimens (Baltimore with Clofarabine vs Thiotepa-Busulfan-Fludarabine) in Adults Receiving Peripheral Blood Stem Cell Haploidentical Transplantation for Myeloid Malignancies: A Retrospective Study of the SFGM-TC

Background: Haploidentical transplantation (haploT) has become a routine practice in many centers but the optimal conditioning regimen has yet to be determined. Indeed, the historic Baltimore reduced intensity conditioning (RIC) regimen has been associated with poor outcomes in myeloid malignancies. Two alternative RIC regimens have recently demonstrated promising results in this setting. One of them replaces fludarabine with second-generation nucleoside analogue clofarabine (Clo-Baltimore regimen [CloB], Chevallier et al., Oncotarget 2018) and the other combines thiotepa-busulfan-fludarabine (TBF, Duléry et al., BBMT 2019). Here we compared outcomes in order to determine if one of these two regimens was superior for the treatment of myeloid malignancies. Methods: This was a multicenter retrospective study conducted by the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). All consecutive adults having received a haploT after a CloB or a TBF RIC regimen for a myeloid malignancy between September 2013 and May 2023 were eligible. Patients data were extracted from the PROMISE database. CloB consisted of clofarabine 30 mg/m²/day (d) 5 d, cyclophosphamide (Cy) 14.5mg/kg/d 2 d, and 2-Gy TBI on d-2. TBF consisted of thiotepa 5mg/kg 1 d, busulfan 3.2 mg/kg 2 d, a fludarabine total dose of 120 to 150 mg/m². Graft-versus-host disease (GVHD) prophylaxis consisted of post-transplant Cy (2 doses of 50mg/kg), followed by cyclosporine A and mycophenolate mofetil starting on d+5. Some patients received antithymocyte globulin (ATG) 2.5mg/kg/d on d-2. Graft source was exclusively peripheral blood stem cells (PBSC). To minimize bias between the CloB and the TBF groups, a propensity score matching (PSM) was constructed using a logistic regression model that included age, donor and recipient sex, hematopoietic cell transplantation-specific comorbidity index (HCT-CI), disease, cytogenetic risk (European LeukemiaNet [ELN] 2022), previous transplant, use of ATG, and cytomegalovirus (CMV) status, with the nearest-neighbor algorithm, and strict matching of key factors. Matched groups were then compared for time to engraftment (absolute neutrophil count &amp;gt; 0.5 x 10 9/L) and platelet (PLT) recuperation (&amp;gt;50 x 10 9/L), overall survival (OS), progression-free survival (PFS), GVHD-free, progression-free survival (GRFS), non-relapse mortality (NRM), and incidences of relapse as well as acute and chronic GVHD. Results: A total of 329 patients from 25 centers were included, 267 (81%) receiving TBF and 62 (19%) CloB. After PSM, 51 patients remained in each group, with comparable baseline characteristics except for the proportion of previous allotransplants ( Table). Median age was 60 years, and median HCT-CI score was 2. Main diagnoses comprised acute myeloblastic leukemia (AML, n=72 [71%]), including 42% with adverse genetic risk, and myelodysplastic syndrome (MDS, n=22 [22%]), including 25% with high or very high Revised International Prognostic Scoring System (R-IPSS). Thirty-eight (37%) patients received ATG. Time to engraftment was equivalent after both TBF and CloB (19 d vs 19.5 d, respectively, p=0.70), but TBF patients achieved PLT recuperation faster (27 d vs 31 d, p=0.03). Median follow-up was 24 months. Two-year OS, PFS and GRFS were 55% vs 60% (p=0.19), 52% vs 60% (p=0.25), and 37% vs 50% (p=0.15) for TBF and CloB patients, respectively. No differences were observed in terms of grade 3-4 acute GVHD at 3 months (18 vs 20%, p=0.86) nor two-year extensive chronic GVHD (16% vs 8.3%, p=0.25). However, two-year NRM was significantly higher after TBF (41% vs 16%, p=0.003), while relapse incidence was lower (7.1% vs 24%, p=0.02, Figure). In multivariate analysis, CloB was associated with a lower risk of NRM (hazard ratio [HR] 0.31, 95%CI: 0.1-0.7, p=0.008) and a higher risk of relapse (HR 4.03, 95%CI: 1.2-13.9, p=0.03). Finally, in patients aged &amp;gt;60y, two-year OS was significantly lower for those receiving TBF conditioning (39% vs 61%, p=0.02, Figure) due to higher NRM (56% vs 23%, p=0.005). Conclusions: In this retrospective study, a TBF RIC regimen used for PBSC haploT in adults with myeloid malignancies appeared substantially more toxic than a CloB RIC regimen. However, its enhanced anti-leukemic effect suggests that it should be offered to younger patients with no comorbidities or to those with high-risk disease. Conversely, CloB should be proposed for older or frail patients.

R-GemOx Plus Nivolumab Vs R-GemOx As Second-Line Therapy for Large B-Cell Lymphoma in Transplant-Ineligible Patients: Interim Analysis of the Niveau Trial, an International, Randomized Phase 3 Study of the AGMT, GLA, HOVON, Lysa and PLRG

Introduction: Patients (pts) with relapsed or refractory ( R/ R) large B-cell lymphoma (LBCL) after first-line treatment who are unable to undergo consolidative high-dose chemotherapy (HDCT) and hematopoietic stem cell transplantation (HSCT) have poor outcomes and limited treatment options. Rituximab, gemcitabine and oxaliplatin (R-GemOx) is a common immuno-chemotherapy regimen used in this setting. The objective of the open-label, phase 3, NIVEAU study (NCT03366272) was to evaluate the efficacy and safety of Nivolumab added to R-GemOx in pts with R/ R LBCL after 1 prior line of therapy not eligible for HDCT/HSCT owing to age and/or comorbidities. Patients and Methods: Eligible pts were adults with R/R LBCL that were refractory to or had relapsed after first-line immuno-chemotherapy and who were not deemed candidates for HDCT/HSCT based on physician's assessment and at least one of the following criteria: age ≥65 years; age ≥18 years and Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score ≥3; or age ≥18 years and prior ASCT (as 1st line consolidation). Therapy consisted of 8 cycles R-GemOx (arm A) or 8 cycles of nivolumab plus R-GemOx followed by nivolumab as maintenance for up to 1 year in total or until progression or unacceptable toxicity (arm B). The primary endpoint was progression-free survival (PFS) after 1 year. Major secondary endpoints were response rates, event-free- (EFS) (time to progression, relapse, death or unplanned anti-lymphoma treatment), overall survival (OS) and toxicity. The protocol specified a pre-planned interim analysis after the first 180 pts completed up to at least 1 follow-up investigation. Results: Between Jan 2018 and May 2021, 180 pts were randomized. Two pts did not receive any treatment (one withdrawn informed consent, one death) resulting in a full analysis set of n=90 (arm A) and n=88 (arm B). Median age was 76 years (range 44-87), 52% of pts were &amp;gt;75 years of age, 37% were primary progressive after first-line therapy, 62% had IPI 3-5. Overall response (OR) and complete response (CR) rates were similar with 34% and 20% (arm A) vs. 34% and 22% (arm B), respectively. Rates of progressive disease (PD) were 53% (arm A) vs. 50% (arm B). After a median follow-up of 21 months, 1-year PFS was 28% (95%-CI: 18%-37%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.827) in arm B (Figure A). 1-year EFS was 22% (95%-CI: 13%-31%) in arm A vs. 20% (95%-CI: 11%-28%), (p=0.654) in arm B. One-year OS was 48% (95%-CI: 38%-59%) in arm A vs. 58% (95%-CI: 47%-68%), (p=0.126) in arm B. At 2 years, PFS, EFS and OS were 15% (95%-CI: 6%-24%), 13% (95%.CI: 5%-21%) and 34% (95%-CI: 22%-46%) in arm A vs. 15% (95%-CI: 7%-23%), 15% (95%-CI: 7%-23%) an 43% (95%-CI: 32%-55%) in arm B. Because of an identical PFS but a trend toward better OS for arm B, we performed an event-driven OS analysis of pts after second progression or relapse (n=70 in arm A, n= 73 in arm B). OS survival was superior in arm B vs. arm A after second progression or relapse (Log Rank p= 0.010) (Figure B). There was a small increase in number of pts with grade 3-5 AEs in arm B (arm A/arm B: thrombocytopenia 37%/39%; anemia 19%/26%; leukopenia 19%/24%; infection 15%/22%). No increase in number of pts with immune-related grade 3-5 AEs was observed except asymptomatic increase of lipase (arm A/arm B: 23%/27%), (p=0.625) and amylase (arm A/arm B: 5%/11%), (p=0.192). Most common grade 3-5 AEs during nivolumab consolidation in arm B were leukopenia 13%, peripheral neuropathy 10%, increase of lipase 8%, anemia 5% and infection 5% of pts). In total, 7 treatment-related deaths occurred (arm A/arm B: 3 (3%)/4 (5%). After this interim analysis revealed futility to demonstrate superiority for the primary endpoint, recruitment was stopped in March 2023. At that point, 270 of 310 initially intended pts had been recruited. Conclusions: In pts with R/R LBCL, the addition of nivolumab to R-GemOx followed by nivolumab maintenance is feasible without relevant additive toxicity. The addition of Nivolumab did not improve PFS of the R-GemOx regimen alone. These results demonstrate the poor prognosis of R/R transplant-ineligible pts treated with immuno-chemotherapy. However, a trend towards a better OS was observed, which allows for the hypothesis that nivolumab might enhance the efficacy of subsequent therapies. The final analysis of the study is scheduled after completion of follow-up of the last patient included as defined by the study protocol.

Characteristics and Clinical Outcomes of Patients with Acute Myeloid Leukemia with TP53 Mutations - a Single Center Experience

Introduction TP53-mutated acute myeloid leukemia (AML) carries a dismal prognosis. Optimal induction therapy is uncertain, and it remains unclear whether allogeneic stem cell transplant (allo-SCT) improves survival. Methods We investigated 89 cases of TP53-mutated AML diagnosed at or referred to Thomas Jefferson Hospital between April 2016 and May 2023 and reviewed clinical characteristics and outcomes. Remission status was determined by bone marrow biopsy and aspiration after at least 1 cycle of anti-leukemic therapy (ALT). ALT was classified into high- or low-intensity treatment. High-intensity treatment was defined as regimens containing high-dose cytarabine (≥ 200 mg/m 2/day) for at least five consecutive days in combination with an anthracycline. Low-intensity treatment was defined as hypomethylating agent (HMA)-based therapy containing either azacitidine or decitabine with or without venetoclax. Results Median age at diagnosis was 66 (range, 23-91). Forty-nine percent had de novo AML, and the rest had secondary AML. Ninety-one percent had newly diagnosed AML and 9% were found to have a TP53 mutation at relapse. Median somatic mutation count as detected by next-generation sequencing (NGS) was 2 (range, 1-9). Thirty percent were treated with high-intensity treatment, 46% with low-intensity treatment, and 22% received supportive care only. Detailed patient characteristics are in Table 1. Median overall survival (OS) for the entire group was 3.17 months [95% confidence interval (CI) 1.90-5.13 months], and 5.13 months (95% CI 3.83-8.00 months) for patients who received any ALT. Of 69 patients who received ALT, composite complete remission (CRc) rates were 26% with high-intensity treatment and 34% with low-intensity treatment ( p = 0.56). Fifty-six percent did not achieve a remission, and 12% were not able to be assessed due to early mortality. The 30-day mortality was 15% and 7% with high- and low-intensity treatments, respectively. OS was not different between patients who received high- and low-intensity treatments (5.13 months vs 5.27 months, p = 0.65). Twenty-four percent underwent allo-SCT with a median follow-up of 15.2 months. The median time to transplant was 180 days from time of diagnosis (range, 119-341). Median hematopoietic cell transplantation-specific comorbidity index was 3 (range, 1-7). The majority of patients (69%) received a reduced intensity or non-myeloablative regimen, and 63% received a haploidentical transplant. Eighty-one percent of transplant recipients were in CR or CR with incomplete count recovery at the time of transplant; the remaining had either primary induction failure or relapsed disease. Median OS was significantly longer for patients who received allo-SCT compared to those who received chemotherapy only (18.0 months vs 3.7 months, p &amp;lt;0.0001) (Figure 1). Cumulative incidence of relapse post-transplant was 36% at 1 year and 79% at 2 years. Conclusions TP53-mutated AML is associated with a dismal outcome. In our single-center analysis, approximately one-third of patients achieved remission after initial ALT. Consolidation with allo-SCT is associated with improved survival, however relapse risk remains high. Treatment strategies aimed at reducing disease relapse post-transplant are warranted.

Hospital Associated Disability Among Older Adults with Plasma Cell Disorders Receiving Autologous Stem Cell Transplant

Background: An increasing number of older adults with Plasma Cell Disorders (PCDs) are receiving autologous stem cell transplant (ASCT) in the US. Hospital associated disability (HAD) is a loss in independence in one or more activities of daily living associated with acute care hospitalization and is a common complication among older adults. The prevalence and prognostic significance of HAD among older adults with PCDs undergoing ASCT is unknown. Methods: This retrospective cohort study used consecutive adults receiving ASCT at a large U.S. comprehensive medical center between 1/2013 and 5/2023. Trained nursing staff assessed Katz Activities of Daily Living (ADL) at admission and every 3 days thereafter under our Virtual Acute Care for Elders program. The primary outcome was development of HAD defined as ≥1 point decline on the Katz ADL scale from hospital admission to discharge. We also examined the association between development of HAD and various predictors including age, Karnofsky Performance Status (KPS), and Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) using modified Poisson regression models with robust variance estimators. Using similar models, we studied the impact of HAD on unplanned 30-day readmission rates. Results: Of 870 patients undergoing ASCT during the study period, 778 had at least two Katz ADL assessments and were included. The study population was comprised of 56% Caucasian/white ethnicity and 56% male with a median age of 62y (IQR 55-68y). In the overall population, 112 (14.4%) developed HAD. The incidence of HAD was much higher among adults ≥65y compared to their younger counterparts (22% vs. 9%; p=&amp;lt;0.01). In multivariate analysis, age ≥65y (RR 2.22; 95% CI 1.56-3.15; p=&amp;lt;0.001) and baseline KPS &amp;lt;=70 (RR 1.83; 95% CI 1.15-2.92; p=0.011) was associated with increased risk of developing HAD; HCT-CI scores did not have a significant association with HAD. Those with HAD had a two-fold higher risk of 30-day readmission as compared to those without HAD (RR 2.18; 95% CI 1.20-3.66; p=0.003). Conclusions: Nearly 1 in 4 adults ≥65y developed HAD while undergoing ASCT, which was associated with a two-fold increased risk of 30-day readmission. Interventions to prevent HAD and its downstream consequences are critically needed.