Hematopoietic Cell Transplantation-specific Comorbidity Index Research Articles

The impact of matched and mismatched donor-recipient genotypes for MDR1 polymorphisms (G2677TA, C1236T and C3435T) on the outcomes of patients after allogeneic haematopoietic stem cell transplantation.

In this study, we investigated whether matched and mismatched multidrug resistance gene (MDR1) genotypes (G2677TA, C1236T and C3435T) were associated with prognosis in patients after allogeneic haematopoietic stem cell transplantation (allo-HSCT). One hundred patients after transplantation and their donors were enrolled. Matched MDR1 G2677TA donor-recipient was associated with an increased risk of non-relapse mortality (NRM) (29.5% vs. 6.2%, p = 0.002), poor overall survival (OS) (51.7% vs. 63.8%, p = 0.024) and disease-free survival (DFS) (38.6% vs. 67%, p = 0.005). There were no differences in OS, DFS or NRM between MDR1 C1236T- and C3435T-matched and -mismatched groups. Subgroup analysis suggested that within the matched MDR1 G2677TA group, male gender, haematopoietic cell transplantation-specific comorbidity index ≥1, serum creatinine >137.2 μmol/L and post-transplantation thrombocytopenia were associated with poor survival. Our results demonstrated that patients receiving matched MDR1 G2677TA allo-HSCT experienced a poorer prognosis compared with the mismatched group. The potential mechanism may involve increased expression of P-glycoprotein, leading to decreased accumulation of antimicrobial agents and ultimately contributing to the progression of inflammation. This identification of MDR1 G2677TA genotype compatibility holds promise as a valuable molecular tool for selecting donors for allo-HSCT.

Superiority of BM over PBSC for recipients with pre-transplant lung dysfunction in HLA-matched allogeneic HCT

Background aimsPre-transplant lung dysfunction is known to be a risk factor for non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (allo-HCT). It is unclear which cell source gives better outcomes for patients with pulmonary dysfunction. MethodsWe analyzed 3289 adult patients with standard-risk disease who had received HLA-matched allo-HCT, and compared outcomes between those who received peripheral blood stem cell (PBSC) vs. bone marrow (BM) in two cohorts based on the presence of a lung score by the Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI): the Lung-scored (LS) and non-LS cohorts. ResultsIn the LS cohort, the 2-year overall survival (OS) in the BM group tended to be higher than that in the PBSC group (72.4% vs. 61.4%; P = 0.044). In the non-LS cohort, there was no significant difference between the two groups (71.7% vs. 73.2%; P = 0.13). Multivariate analyses confirmed that PBSC was significantly associated with inferior OS in the LS cohort (hazard ratio [HR], 1.66; 95% CI, 1.09-2.54; P = 0.019). On the other hand, the cell source did not affect OS in the non-LS cohort (HR, 0.92; 95% CI, 0.76-1.12; P = 0.41). We found that PBSC was associated with an increased risk of NRM in the LS cohort (HR, 2.17; 95% CI, 1.16-4.05; P = 0.016), while the cell source did not significantly affect NRM in the non-LS cohort. PBSC was not identified as a risk factor for relapse in either cohort. ConclusionsOur results suggest that BM might be beneficial for recipients with lung dysfunction in HLA-matched allo-HCT.

High-dose chemotherapy and autologous hematopoietic stem cell transplantation for progressive systemic sclerosis: a retrospective study of outcome and prognostic factors

PurposeSystemic sclerosis (SSc) is a rare autoimmune disease associated with high morbidity and mortality. SSc treatment is still challenging, and evidence is scarce. In the last decades high-dose chemotherapy and autologous stem cell transplantation (HD-ASCT) has proven to be effective. However, treatment related morbidity and mortality (TRM) are high. We conducted a retrospective, single-center analysis of SSc patients following HD-ASCT focusing on TRM and risk factors.Methods32 patients who underwent HD-ASCT at our hospital between June 2000 and September 2020 were included. Clinical characteristics were evaluated based on chart review before and after HD-ASCT. Analyses focused on overall survival (OS), TRM, and response to HD-ASCT.ResultsMedian OS was 81 months (range 0–243). Within one year, 20 of 32 (76.9%) patients responded to HD-ASCT. Overall, 6 patients (18.8%) died in the context of HD-ASCT. Patients with subjective response to HD-ASCT (p = 0.024) and those with shorter time to platelet engraftment (p = 0.047) had significantly longer OS. Impaired renal function, age at HD-ASCT ≥ 55, disease duration < 12 months, high Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and Charlton Comorbidity Index (CCI) scores were associated with higher TRM. Patients receiving conditioning chemotherapy with thiotepa needed longer time for neutrophil (p = 0.035) and platelet engraftment (p = 0.021).ConclusionThis study confirms the efficacy of HD-ASCT for patients with SSc in a single center real-world setting. High TRM is still a challenge. However, TRM could be reduced by exclusion of high-risk patients and attention to prognostic parameters and scores as suggested in this study.

Trends in Outcomes After Upfront Autologous Transplant for Multiple Myeloma Over Three Decades

Upfront autologous stem cell transplantation (auto-SCT) remains standard of care for eligible patients with newly diagnosed multiple myeloma (NDMM), although recently its role has been questioned. The aim of the study was to evaluate trends in patient characteristics, treatment, and outcomes of NDMM who underwent upfront auto-SCT over three decades. We conducted a single-center retrospective analysis of patients with NDMM who underwent upfront auto-SCT at MD Anderson Cancer Center between 1988 to 2021. Primary end points were progression-free survival (PFS) and overall survival (OS). Patients were grouped by the year of auto-SCT: 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 del (17p), t (4;14), t (14;16), and 1q21 gain or amplification by fluorescence in situ hybridization. We included 3041 MM patients in the analysis. Median age at auto-SCT increased from 52 years (1988-2000) to 62 years (2016-2021), as did the incidence of high-risk cytogenetics from 15% to 40% (P < .001). Comorbidity burden, as measured by a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) of >3, increased from 17% (1988-2000) to 28% (2016-2021) (P < .001). Induction regimens evolved from predominantly chemotherapy to immunomodulatory drug (IMiD) and proteasome inhibitor (PI) based regimens, with 74% of patients receiving IMiD-PI triplets in 2016-2021 (39% bortezomib, lenalidomide and dexamethasone (VRD) and 35% carfilzomib, lenalidomide and dexamethasone [KRD]). Response rates prior to auto-SCT steadily increased, with 4% and 10% achieving a ≥CR and ≥VGPR compared to 19% and 65% between 1988-2000 and 2016-2021, respectively. Day 100 response rates post auto-SCT improved from 24% and 49% achieving ≥CR and ≥VGPR between 1988-2000 to 41% and 81% between 2016-2021, respectively. Median PFS improved from 22.3 months between 1988-2000 to 58.6 months between 2016-2021 (HR 0.42, P < .001). Among patients with high-risk cytogenetics, median PFS increased from 13.7 months to 36.8 months (HR 0.32, P < .001). Patients aged ≥65 years also had an improvement in median PFS from 33.6 months between 2001 and 2005 to 52.8 months between 2016-2021 (HR 0.56, P = .001). Median OS improved from 55.1 months between 1988-2000 to not reached (HR 0.41, P < .001). Patients with high-risk cytogenetics had an improvement in median OS from 32.9 months to 66.5 months between 2016-2021 (HR 0.39, P < .001). Day 100 non-relapse mortality from 2001 onwards was ≤1%. Age-adjust rates of second primary malignancies were similar in patients transplanted in different time periods. Despite increasing patient age and comorbidity burden, this large real-world study demonstrated significant improvements in the depth of response and survival outcomes in patients with NDMM undergoing upfront auto-SCT over the past three decades, including those with high-risk disease.

Symptom burden in adult survivors of allogeneic hematopoietic stem cell transplantation.

6557 Background: Progress in allogeneic hematopoietic cell transplantation (HCT) and supportive care has significantly improved transplant outcomes and expanded the number of HCT survivors. A growing responsibility exists to address long-term morbidity and symptom burden. We sought to investigate symptom burden in adult survivors of HCT using a set of validated tools. Methods: We analyzed adults aged 19 years or older with hematologic malignancies who were treated with allogenic HCT at our institution from June 2018 to November 2022. Patients required at least one visit to our survivorship clinic for inclusion. We assessed symptom burden using the National Comprehensive Cancer Network (NCCN) Survivorship Assessment Questionnaire, which is a 25-question survey designed to assesses symptoms related to the following domains: cardiac, mood, cognition, fatigue, lymphedema, hormonal, pain, sexual dysfunction, and sleep. The short physical performance battery (SPPB) and short blessed test were used to assess physical function and conduct cognitive screen, respectively. Finally, we compared scores between patients &lt;60 and ≥60 years old to examine an association between age and post-transplant symptoms. Results: A total of 152 patients have a median age of 61 years (range 21-76); 59.2% were males, and 28.5% had a BMI ≥30. Median Hematopoietic Cell Transplantation-specific Comorbidity Index was 3. The most common indication for transplant was acute myeloid leukemia (48.0%), and the most common donor type was matched unrelated (57.2%). The median time from transplant to the first survivorship clinic visit was 99 days. The most common symptom domains affected, according to the NCCN questionnaire results, were fatigue (50.7%), sleep (45.3%), and cognition (42.0%) whereas the least affected domains were pain (29.5%), cardiac (26.2%), and sexual (19.4%). When we stratified patients by &lt;60 years old and ≥60 years old, we saw similar rates of reported symptoms, particularly regarding sleep disorder (44.3% vs. 45.7%, respectively), mood disturbance (31.4% vs. 34.1%, respectively), and sexual dysfunction (17.9% vs. 20.5%, respectively). Older patients, however, had higher rates of physical impairment according to SPPB scores (50.0% vs. 15.7%, OR = 5.4 [95% CI = 2.2-14.3]). Blessed test showed impaired cognitive screen in 7.2% without a significant difference based on age. Conclusions: Adult survivors of allogeneic HCT at 3-month post-transplant commonly suffer from symptoms across a variety of domains, especially pertaining to fatigue, sleep, and cognition. These symptoms affect both younger and older patients, although older patients are more likely to have physical impairment. The NCCN Survivorship Assessment Questionnaire captures a number of symptoms related to quality of life and can be more widely utilized as a tool to evaluate survivorship symptoms in patients who undergo HCT.

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

Background: 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 common complication associated with acute care hospitalization among older adults. Objectives: To estimate the prevalence and prognostic significance of HAD among older adults with MM undergoing ASCT Study Design: This retrospective cohort study used consecutive adults ≥18y with PCD receiving ASCT at a single institution 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 Activities of Daily Living (ADL) scale from hospital admission to discharge. We examined the association between putative risk factors such as age, Karnofsky performance status (KPS), baseline ADL score, Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) and HAD using modified Poisson regression models with robust variance estimators. Subsequently, we studied the impact of HAD on downstream adverse events including 30-day readmission rates and long term survival. Results: We included 778 adults with a median age of 62y (QR 56-68y), with 56% males and 55% non-Hispanic Whites. In the overall population, 112 (14.4%) developed HAD, with much higher incidence among older adults ≥65y compared to those <65y at ASCT (22% vs. 9%, p value<0.01). In multivariable analysis, increasing age (RR 1.56; 95% CI 1.25-1.94, per 10y increase), female sex (RR 1.79; 95% CI 1.27-2.53) and KPS ≤70 (RR 2.55; 95% CI 1.32-4.94) were associated with an increased risk of developing HAD. As compared to those without, patients with HAD had a two-fold higher risk of 30-day readmission (95% CI 1.16-3.39) and a 3.7 fold increased risk of all-cause mortality (95% CI 2.15-6.22). Conclusions: Nearly one in 4 older 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.

Second Allogeneic Hematopoietic Cell Transplantation for Relapsed Adult Acute Myeloid Leukemia: Outcomes and Prognostic Factors

Second allogeneic hematopoietic cell transplantation (HCT2) is potentially curative for adults with acute myeloid leukemia (AML) or myelodysplastic neoplasm (MDS)/AML experiencing relapse after a first allograft (HCT1), but prognostic factors for outcomes are poorly characterized. To provide a detailed analysis of HCT2 outcomes and associated prognostic factors in a large single-center cohort, with a focus on identifying predictors of relapse and nonrelapse mortality (NRM), we studied adults ≥18 years who underwent HCT2 at a single institution between April 2006 and June 2022 for relapsed AML (n = 73) or MDS/AML (n = 8). With a median follow-up among survivors of 74.0 (range: 10.4 to 187.3) months, there were 30 relapses and 57 deaths, of which 29 were NRM events, contributing to the estimates for relapse, overall survival (OS), relapse-free survival (RFS), and NRM. Three-year estimates for relapse, RFS, and OS were 37% (95% confidence interval: 27% to 48%), 32% (23% to 44%), and 35% (26% to 47%). The rate of NRM at 100 days and 18 months was 20% (12% to 29%) and 28% (19% to 39%). Outcomes differed markedly across patient subsets and were substantially worse for patients who underwent HCT2 with active disease (ie, morphologic evidence of bone marrow and/or extramedullary disease), for patients who relapsed ≤6 months after HCT1, and for patients with higher HCT-specific Comorbidity Index (HCT-CI) or treatment-related mortality (TRM) scores. After multivariable adjustment, active disease was associated with a higher risk of relapse (hazard ratio [HR] = 3.19, P = .006) and shorter RFS (HR = 2.41, P = .008) as well as OS (HR = 2.17, P = .027) compared to transplant in morphologic remission without multiparameter flow cytometric evidence of measurable residual disease. Similarly, a relapse-free interval ≤6 months after the first allograft was associated with higher risk of relapse (HR = 5.86, P < .001) and shorter RFS (HR = 2.86; P = .001) and OS (HR = 2.45, P = .003). Additionally, a high HCT-CI score was associated with increased NRM (HR = 4.30, P = .035), and shorter RFS (HR = 3.87, P = .003) and OS (HR = 3.74, P = .006). Likewise, higher TRM scores were associated with increased risk of relapse (HR = 2.27; P = .024) and NRM (HR = 2.01, P = .001), and inferior RFS (HR = 1.90 P = .001) and OS (HR = 1.88, P = .001). A significant subset of patients with AML or MDS/AML relapse after HCT1 are alive and leukemia-free 3 years after undergoing HCT2. Our study identifies active leukemia at the time of HCT2 and early relapse after HCT1 as major adverse prognostic factors, highlighting patient subsets in particular need of novel therapeutic approaches, and supports the use of the HCT-CI and TRM scores for outcome prognostication.

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.

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.

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.

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

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.

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.

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.

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.

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.