High Hematopoietic Cell Transplantation-specific Comorbidity Index Research Articles

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.

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.

Increased Intestinal Permeability and Stool Zonulin, Calprotectin and Beta-Defensin-2 Concentrations in Allogenic Hematopoietic Cell Transplantation Recipients.

Significant progress has been made in understanding the connection between intestinal barrier function and allogenic hematopoietic cell transplantation (allo-HCT) recipients' outcomes. The purpose of this study was to further evaluate gut barrier permeability and other potential intestinal barrier disruption markers in the allo-HCT setting. Fifty-one patients were enrolled in the study. Intestinal permeability was assessed with the sugar absorption test and faecal concentrations of the zonulin, calprotectin and beta-defensin-2 levels in the peri-transplantation period. Most patients undergoing allo-HCT in our department had a disrupted intestinal barrier at the baseline, which was associated with older age and higher Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI). Regardless of this, we observed a further increase in gut barrier permeability after allo-HCT in most patients. However, there was no association between permeability assay and other markers (zonulin, calprotectin and beta-defensin-2). Patients with acute GVHD had significantly higher median calprotectin concentrations after allo-HCT compared with the patients without this complication. Our findings indicate that gut barrier damage develops prior to allo-HCT with progression after the procedure and precedes further complications, but did not prove other markers to be useful surrogates of intestinal permeability.

Risk and Predictive Factors for Candidemia After Allogeneic Hematopoietic Cell Transplantation: JSTCT Transplant Complications Working Group

Although antifungal prophylaxis that covers Candida species is a standard of care in allogeneic hematopoietic cell transplantation (HCT), candidemia mainly caused by non-albicans Candida species still occurs and is associated with a high mortality rate. This study aimed to evaluate the risk factors for candidemia after allogeneic HCT. Particularly, we evaluated the impact of patient factors such as hematopoietic cell transplantation–specific comorbidity index (HCT-CI) and performance status (PS) in addition to well-recognized risk factors including donor type, delayed engraftment, and graft-versus-host disease (GVHD). By using data from a Japanese transplant registry database, we analyzed 26,236 pediatric and adult patients with hematological malignancies who underwent their first allogeneic HCT. The posttransplant period was divided into early (days 0-40), late (days 41-100) and very late (days 101-365) phases. The 1-year cumulative incidence of candidemia was 1.8%. When we analyzed pretransplantation factors, age ≥40 years (hazard ratio [HR] 1.85), male (HR 1.34), HCT-CI (HCT-CI 1-2, HR 1.56; HCT-CI ≥ 3, HR 2.21), PS ≥ 2 (HR 2.01), high-risk disease (HR 1.78) and donor type including HLA-mismatched related donor (MMRD) (HR 1.96), HLA-mismatched unrelated donor (HR 2.05), and cord blood (CB) (HR 2.85) were significantly associated with an increased incidence of candidemia. Focusing on the early phase (days 0-40), HCT-CI, PS, high-risk disease and CB transplantation together with engraftment and severe acute GVHD significantly affected the development of candidemia. In the late phase (days 41-100), higher HCT-CI, male, and donor type including MMRD, and CB were associated with the occurrence of candidemia together with acute GVHD and disease relapse. In the very late phase (days 101-365), HCT-CI ≥ 3 and high-risk disease significantly affected the occurrence of candidemia together with acute and chronic GVHD, and disease relapse. In addition to well-recognized risk factors including donor type, engraftment and GVHD, patient factors such as HCT-CI and PS were associated with the development of candidemia, which suggests that severely ill patients with transplantation-associated complications are more likely to develop candidemia.

A New Risk Assessment Tool for Allogeneic Hematopoietic Stem Cell Transplantation

Introduction:Allogeneic hematopoietic stem cell transplantation (HSCT), can be curative for many hematologic disorders. However, HSCT is still associated with significant risks. HSCT outcomes are dependent on patient, disease and transplant related factors. There are a number of assessment tools being used to predict outcomes. Some use patient related variables such as the hematopoietic cell transplantation specific comorbidity index (HCT-CI), some use disease-related variables such as the disease-risk index (DRI) and some others incorporate combined variables. We aimed to incorporate disease, patient comorbidities, donor, and transplant characteristics into one comprehensive prognostic model to predict 2 year disease-free survival (DFS).Methods:273 consecutive patients (162 males, 111 females) receiving an initial HSCT from 2010 and 2016 were identified and retrospectively analyzed. Median age was 56 years (range 18-76 years) and a broad representation of hematologic disorders (119 AML, 46 ALL, 60 MDS, 18 NHL, 30 other) were included. All pts received peripheral blood as graft source. The majority received an unrelated donor transplant (166) and were conditioned with a myeloablative regimen (199).The dataset was randomly split in a 2:1 ratio to create training and testing dataset prior to data analysis. Variables under consideration as predictors of 2 year disease-free survival included: patient (age, sex, blood type, CMV status, Karnofsky Performance Status, HCT-CI), donor (age, sex, blood type, CMV status), disease (type, time since diagnosis, Disease Risk Index), and transplant (prep regimen, year of transplant, related/unrelated, match/mismatch) characteristics. Using the training dataset, a lasso penalized Cox regression was applied with the penalty parameter being derived as the mean of 1,000 iterations of 10-fold cross-validation. Patient risk scores was computed from the model and used to stratify patients based on a median split of risk scores; survival differences were evaluated using the log-rank test. Model performance was evaluated in the training and testing datasets by deriving time-dependent AUC curves, evaluating survival differences by risk strata, and comparing predicted to observed survival probabilities at 2 years.Results:Karnofsky Performance Status (<90, 90+), Disease Risk Index (Low, Intermediate/High), HCT-CI (Low, Intermediate/High), prep regimen (RIC/Non-myeloablative, myeloablative), and donor age (<30, 30+) were selected by the model. More specifically, lower performance status (HR 1.3), higher Disease Risk Index (HR 1.4), higher HCT-CI (HR 1.3), RIC/non-myeloablative prep regimen (HR 1.1), older donor age (HR 1.1) were associated with poorer disease-free survival. The prognostic model derived from the training dataset demonstrated good discrimination for the prediction of 2 year DFS with a median AUC value of 0.72 (IQR 0.69-0.73). When applied to the testing dataset, an AUC value of 0.73 was obtained. Across time, results were relatively consistent between 1 and 2 years post-transplant. A significant difference between the two risk strata was evidenced in the training and testing dataset (Figure 1, p<0.01). Comparison of predicted and observed survival probabilities at 2 years demonstrated agreement in both datasets.Conclusion:This comprehensive prognostic model is able to stratify patients into high risk and low risk groups with significantly different outcome. The inclusion of additional variables in the model increased accuracy (higher AUC) relative to existing models, which highlights the importance of taking into consideration additional constructs when trying to predict DFS. Further independent validation of our findings is necessary. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Comparison of Dinakara and Cotes Method on Correction of Diffusion Limit of Carbon Monoxide and the Impact on Outcomes of Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI)

AIMHaematopoietic stem cell transplantation poses significant physiological stresses on the recipient. Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) described by Sorror in 2005 aims to provide risk stratification to these patients.Respiratory comorbidity, which takes into account diffusion limit of carbon monoxide (DLCO) and forced expiratory volume in 1 second (FEV1), is the most common comorbidity scored on the HCT-CI. The original publication utilised Dinakara method for correction of DLCO to haemoglobin concentration (Hb). Recommendation of the American Thoracic Society (ATS) and European Respiratory Society (ERS) and therefore, our institution utilises the Cotes method for correction.We compared the effect of Dinakara and Cotes method on correction of DLCO, HCT-CI scoring and non-relapse mortality (NRM). MethodWe retrospectively collected HCT-CI scores, relapse, deaths from 195 consecutive allogeneic stem cell transplants at the Royal Brisbane and Women's Hospital between May 2014 and May 2016 with median follow up of 394 Days. Non-relapse mortality defined as any death in the absence of relapsed disease. ResultsDuring our follow up period, 44 patients relapsed and 50 deaths occurred with median survival not reached. When utilising Dinakara method for scoring respiratory co-morbidity, number of patients who scored 2(moderate) or 3(severe) was 22.1% and 8.7% respective. However, by utilising the Cotes method, this increased the moderate and severe respiratory co-morbidity to 43.1% and 23.1% respectively, thereby pushing the total HCT-CI score higher Figure 1 . By utilising the Cotes instead of Dinakara method, number of patients classified as high risk HCT-CI increased from 32.3% to 49.7%.There were no significant difference in non-relapse mortality between the two methods at Day 100 or 2 years. The high risk patients had NRM using Dinakara vs Cotes of 9.2 % vs 10.1% at day 100 and 16.9% vs 22.8% at 2 years Figure 2 and Figure 3 . ConclusionUtilising Cotes method rather than Dinakara method for the correction of DLCO significantly increased the number of high risk patient on HCT-CI, however, there was no significant impact on non-relapse mortality. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Low Pre-Treatment Hemoglobin and Creatinine Clearance Correlate with Worse Overall Survival, Treatment-Related Mortality, and Regimen-Related Toxicities in Patients Undergoing a Reduced-Intensity Allogeneic Stem Cell Transplantation with Fludarabine and Melphalan

The reduced-intensity conditioning (RIC) regimen consisting of fludarabine and melphalan 140 mg/m2 (Flu/Mel140) prior to allogeneic hematopoietic stem cell transplant (HSCT) has been widely adopted in clinical practice. However, pharmacokinetic (PK) studies report up to a 10-fold interpatient variability in melphalan exposure (AUC). Specifically, melphalan binds to proteins in the red blood cell membrane, leading to higher plasma concentrations in patients with lower hemoglobin. Likewise, since renal elimination contributes significantly to melphalan clearance (~ 40%), the presence of renal impairment also leads to higher concentrations. We previously identified lower hemoglobin and/or creatinine clearance as strong predictors of survival and toxicities after high dose melphalan and autologous transplant. Given this, we hypothesized that clinical variables, in particular, pre-treatment hemoglobin, could predict for outcomes after Flu/Mel140 and HSCT. We analyzed 67 consecutive patients who received Flu/Mel140. In addition to standard clinical parameters, hemoglobin (Hgb) and creatinine clearance (CrCl) on day -6 were obtained. Hemoglobin was grouped as low or high relative to the median (&lt;9.5 or ≥ 9.5 g/dL), and CrCl was divided into two groups (&lt; 60 or ≥ 60 ml/min). In the entire cohort, the median age was 57 (21-73) years, with most patients being female (n=37; 55.2%) and white (n=27; 40.3%) or African-American (n=16; 23.9%). Most patients were diagnosed with AML/MDS (n=27; 40.3%) or idiopathic myelofibrosis (n=14; 20.9%), and the median lines of prior therapy was 2 (0-7). Prior to HSCT, 36 (53.7%) patients presented with intermediate disease risk index (DRI) and 19 (28.4%) with high DRI, while 31 (62%) patients had a high hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score. Thirty (45.5%) patients received a matched related donor transplant, while 31 (47%) received a matched unrelated donor transplant. The median time to neutrophil and platelet engraftment was 15 (9-26) and 16 (8-104) days, respectively. The median overall survival (OS) was significantly shorter in patients with a lower Hgb (113 vs. 2536 days; p=0.004). This difference was attributed to an increased rate of transplant-related mortality (TRM) in patients with a lower Hgb (n=26; 81.3%) versus a higher Hgb (n=11; 36.7%) (p=0.0005). Time to relapse between patients with a lower and higher Hgb was not different (p=0.89). The median OS in patients with a lower CrCl was significantly worse (75 vs. 317 days; p=0.003). The rate of TRM was also found to be significantly worse in patients with a lower CrCl (n=10; 90.1%) compared to patients with a higher CrCl (n=27; 52.9%) (p=0.0023). Time to relapse was not different between patients with a lower and higher Cr Cl (p=0.29). Patients with both a low Hgb and CrCl experienced a shorter median OS (75 days vs. not reached; p&lt;0.0001; Figure 1). Multivariate Cox proportional hazards model with adjustment for clinical and prognostic factors found that a higher Hgb strongly predicted for better OS (HR 0.12, 95% CI 0.03-0.52; p=0.004) and less TRM (HR 0.13, 95% CI 0.03-0.53; p=0.004). The combination of a higher Hgb and CrCl ≥ 60 ml/min predicted for better OS (HR 0.08, 95% CI 0.01-0.63; p=0.017) and trended towards a decreased rate of TRM (HR 0.16, 95% CI 0.02-1.43; p=0.102). We then analyzed regimen-related toxicities among patients with a lower and higher Hgb and lower and higher CrCl. In patients with a lower hemoglobin, the median duration of hospitalization (35 vs. 29 days; p=0.02) and the mean duration of diarrhea (14.6 vs. 7.2 days; p=0.008) were significantly longer. In patients with a lower CrCl, the median duration of hospitalization (40 vs. 29 days; p=0.06) and the mean duration of diarrhea (20.9 vs. 8.6 days; p=0.0009) were longer, and the rate of infection was higher (90.9% vs. 49.1%; p=0.02). We show for the first time that pre-treatment Hgb and CrCl represent important determinants of clinical outcomes after Flu/Mel140 and HSCT. A lower hemoglobin in particular was strongly associated with a shorter OS and TRM. This is consistent with PK studies showing increased melphalan exposure in patients with low Hgb and CrCl. We conclude that consideration of clinical factors that affect melphalan exposure and implementation of PK-directed dosing may be beneficial in achieving optimal outcomes in patients receiving FluMel140 and HSCT. Figure Disclosures Galvin: Incyte: Consultancy. Patel:Celgene: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Janssen: Speakers Bureau.

Allogeneic Hematopoietic Cell Transplantation in the Outpatient Setting.

Conditioning with fludarabine and low-dose total-body irradiation before allogeneic hematopoietic cell transplantation (HCT) enabled treating older or medically infirm patients with advanced hematologic malignancies in the outpatient setting. Between December 1997 and June 2017, 1037 patients with hematologic malignancies received peripheral blood stem cell (PBSC) grafts from HLA-matched or 1 HLA antigen/allele-mismatched related or unrelated donors. Median age was 58 (range, 18 to 80) years. Serious comorbidities with Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) scores ≥3 were present in 52% of patients. We found that 47% of patients were either never hospitalized or only had an overnight hospital stay for infusion of late-arriving PBSCs while 53% were admitted for a median of 6 days. Main reasons for admission were infection, fever, graft-versus-host disease, and regimen-related toxicity. Two thirds of admissions occurred within 3 weeks of HCT. The 5-year risk of nonrelapse mortality (NRM) was 26% among hospitalized patients and 13% among nonhospitalized patients. Significant risk factors for hospitalization included unrelated transplants, 1 HLA antigen-mismatched transplant, high HCT-CI scores, and diagnosis of nonmyeloma malignancies. Significant risk factors for NRM were hospitalization, older age, unrelated transplants, and high HCT-CI scores. Ambulatory allogeneic HCT is feasible and safe.

Assessment of Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) As a Predictor for Higher Level of Care after Discharge for Patients Undergoing Autologous Stem Cell Transplantation for Multiple Myeloma and Lymphoma

Introduction Hematopoietic cell transplantation-specific comorbidity index (HCT-CI) is a validated scoring system that assesses the risks of patients (pts) undergoing allogenic stem cell transplant. [Sorror et al. 2005] There has been emerging evidence of its value in risk discussion for pts undergoing autologous stem cell transplantation (ASCT). In a recent large (N=1730) retrospective study in pts with multiple myeloma (MM) or lymphoma, a high-risk HCT-CI was associated with higher rates of orotracheal intubation (OTI), 100-day non-relapsed mortality (NRM), and 1-year mortality. [Berro et al. 2017] Not well studied was disposition of a pt at the time of discharge post-transplant as it relates to HCT-CI risk. This could be an additional useful variable in pts/caregiver discussions pre-ASCT. Herein, we report a retrospective single institution review of our experience as it relates to HCT-CI to post-ASCT outcomes including level of care requirements at time of discharge. Methods We performed a retrospective review of pts with MM or lymphoma who received consolidative ASCT between May 2013 and March 2018. Pt demographic were collected. Pts HCT-CI were collected per defined variables by Sorror et al. Each pt was divided into three cohorts: low risk (HCT-CI score of 0), intermediate risk (HCT-CI score of 1-2), and high risk (HCT-CI ≥ 3). Discharge location was categorized into five dispositions: home with caregiver, home with supplemental care, skilled nursing facility, acute rehab facility, and died during transplant. Results Four hundred sixty-one charts were reviewed. Males were 62.0% of the population with a median age of 58.5. Disease populations were balanced with MM/lymphoma at 48.4%/51.6% respectively. MM pts received melphalan (140 or 200 mm/m2) and lymphomas received BEAM based conditioning. We found no statistical correlation of high-risk HCT-CI patients requiring higher rates of OTI during ASCT (p=0.1066) nor requiring a higher level of care post-ASCT transplant (p=0.2998). Furthermore we were unable to statistically correlate high-risk HCT-CI score with an increased rates of 100-day NRM (p=0.0681) or 1-year mortality (p=0.0656). We further investigated the breakdown of HCT-CI scoring of high-risk pts (n=177). The dominant comorbid conditions that appeared to be driving points towards a high-risk designation was cardiopulmonary (70.5%) and psychiatric (34.5%). Conclusion In our single center experience the categorization of high-risk HCT-CI prior to ASCT did not portend a higher risk with regards to OTI, 100-day NRM, or 1-year NRM when compared to pts categorized as low and intermediate risk in ASCT. A high risk HCT-CI score did not predict for a statistically significant increase in need for higher level of care post ASCT beyond caregiver support.

Promising Outcome of Umbilical Cord Blood Transplantation in Patients with Multiple Comorbidities

The hematopoietic cell transplantation–specific comorbidity index (HCT-CI) has been recently proposed to predict the probability of nonrelapse mortality (NRM) and overall survival (OS) in allogeneic hematopoietic stem cell transplantation (HSCT). However, the usefulness of the HCT-CI in single-unit umbilical cord blood transplantation (UCBT) remains unclear. We investigated the impact of the HCT-CI on the clinical outcomes of allogeneic HSCT in a single-center retrospective study including 53 recipients of UCBT (UCBT group) and 90 recipients of other HSCT (non-UCBT group). In the non-UCBT group 2-year OS rates for HCT-CI score < 3 and ≥3 were 67% (n = 74; 95% confidence interval [CI], 54% to 78%) and 26% (n = 16; 95% CI, 7% to 51%), respectively (P = .001). In the UCBT group these rates were 66% (n = 39; 95% CI, 48% to 79%) and 69% (n = 14; 95% CI, 36% to 87%), respectively (P = .73). In the non-UCBT group 1-year NRM rates for HCT-CI score < 3 and ≥3 were 14% (95% CI, 6.4% to 22%) and 37% (95% CI, 14% to 61%), respectively (P = .02). In the UCBT group these rates were 6.1% (95% CI, 3.4% to 24%) and 7.7% (95% CI, .4% to 29%), respectively (P = .78). Using multivariate analysis we showed that HCT-CI score ≥ 3 was significantly associated with lower OS (hazard ratio, 3.06; 95% CI, 1.47 to 6.38; P = .003) and higher NRM (hazard ratio, 2.87; 95% CI, 1.18 to 6.96; P = .02) for the non-UCBT group. UCBT showed good OS with low incidence of NRM, even in patients with high HCT-CI scores. Altogether, we propose single-unit UCB to be a promising stem cell source for improving survival in patients with multiple comorbidities.

The hematopoietic cell transplantation specific comorbidity index and survival after extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation conditioning prior to allogeneic stem cell transplantation

Hematopoietic-cell-transplantation-specific-comorbidity-index (HCT-CI) has been reported as a predictor of survival in allogeneic-transplant recipients; however its validity has recently been challenged. We evaluated the association of HCT-CI with survival of transplant recipients who underwent reduced-intensity-conditioning (RIC) with photopheresis, pentostatin, and total-body-irradiation. Median age of 103 patients selected was 55 years. Most patients (58.3%) had high (≥ 3) HCT-CI. Median OS was 298 days. Age, disease-type, disease-status, HCT-CI correlated with survival on bivariate analysis. On multivariate analysis, only HCT-CI was significantly associated with OS (low HCT-CI HR=0.29, CI 0.091-0.886; intermediate HCT-CI HR=0.41, CI 0.226-0.752). Our findings suggest HCT-CI as an independent predictor of survival in the setting of RIC transplants.

The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) and Survival After Extracorporeal Photopheresis, Pentostatin, and Reduced Dose Total Body Irradiation (TUFTs) Conditioning Prior to Allogeneic Stem Cell Transplantation (SCT)

AbstractAbstract 1337 Background:Reduced-intensity conditioning and allogeneic stem cell transplant (RIST), offers an alternative for patients with hematologic malignancies who are not candidates for myeloablative conditioning (MAC) due to the high risk of treatment related toxicity. Despite the reduced “intensity” of RIST preparative regimens, a high incidence of early treatment-related morbidity and mortality persists. The TUFTS regimen represents one such RIST regimen and consists of extracorporeal photopheresis, pentostatin, and reduced dose total body irradiation. The hematopoietic cell transplantation-specific Comorbidity index (HCT-CI) has been reported as an informative predictor of post-transplant survival recipients of fludaribine-based conditioning and SCT, however, its usefulness in patients undergoing allogeneic transplant using alternative conditioning regimens has not been determined. The specific aim of this study was to evaluate the relationship between HCT-CI scores and survival after TUFTS conditioning. Study Design and Methods:The study employed a retrospective, description design. The sample consisted of adults who underwent allogeneic SCT after a TUFTS preparative regimen at the University of Rochester Medical Center from 2001–2006. Indications for transplant included both myeloid and lymphoid malignancies; recipients of stem cells from either related or unrelated donors, and recipients of prior autologous transplant were also included. The TUFTS conditioning was administered as follows: photopheresis on days -6 and -5, pentostatin 4 mg/m2 on days -4 and -3, reduced dose fractionated total body irradiation to a total of 400–600cGy on days -2 and -1, and SCT on day 0. Sixty-three subjects met the study criteria and we collected study defined and de-identified clinical data from the medical records. Subjects received either tacrolimus and mycophenolate mofetil (MMF) or low-dose methotrexate, or sirolimus and MMF as prophylaxis for graft-versus-host disease. For this study, overall survival (OS) was defined as the time elapsed from date of SCT to the date of death. The HCT-CI score was inclusive of 17 comorbid factors and was calculated for each subject. Total HCT-CI scores were trichotomized three categories; low, intermediate, and high. Results:All statistical analyses were performed utilizing SPSS version 15 with an alpha significance set at 0.05. Mean OS was 534.4 days (+/− 515.5). The median survival was 303 days (range 10 to 1673). Subjects were grouped into low (n=7), intermediate (n=20), and high (n=36) HCT-CI score groups. Median survival for each group was 1127, 645, and 181 days, respectively. The Kruskal-Wallis Test was used to evaluate the relationship between trichotomized HCT-CI groups and OS which was re-coded into 6 time-based categories. Mean rank scores for survival were significantly related to HCT-CI categories (p=0.01). A median test on these same variables was also significant where 85.7% (low), 60% (intermediate), and 27.8% (high) of subjects survived to the median survival time point (p=0.004). A Kaplan-Meier survival analysis showed an OS of 46%; HCT-CI group stratification of the survival curve demonstrated that the high CI score group had the lowest survival with a median survival of 202 days (95% CI 64.7, 339.3). Conclusion:Our findings contribute to the validity of HCT-CI as a valuable instrument for assessing risks that impact survival due to comorbidities in patients conditioned with TUFTS prior to SCT. In this sample, OS was inversely proportional to HCT-CI score and median survival was less than 7 months in the high risk group. To our knowledge, this is the first study that has found a statistically significant correlation between survival and HCT-CI groups in subjects conditioned with TUFTS to treat multiple types of malignancies. We conclude that the HCT-CI assessment should be routinely performed to facilitate decision making with patients who are ineligible for MAC and SCT. This assessment will further add to discussions regarding the risks/benefits of RIST, and decision making with patients in the high risk category who are likely to have low actuarial survival. Further prospective studies are needed to confirm these findings and to evaluate the HCT-CI as a predictor of survival in patients with specific malignancies, different histologic/molecular disease-related factors, varying duration of relapse, and remission status at SCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Pre-Transplant Predictors and Post-Transplant Sequels of Acute Kidney Injury After Allogeneic Stem Cell Transplantation.

AbstractAbstract 4515 Introduction:Acute kidney injury (AKI) is one of the most common complications after allogeneic stem cell transplantation (SCT). Although various post-transplant risk factors for AKI have been reported, there have been few studies which comprehensively assessed pre-transplant comorbidities and investigated their impact on the occurrence of AKI. Methods:We performed a retrospective analysis of 207 consecutive adult patients undergoing myeloablative or non-myeloablative SCT between 2001 and 2009. Cumulative incidence of AKI during the first 100 days was analyzed. AKI was defined and classified according to Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria. Renal dysfunction considered to be associated with multiple organ dysfunction syndromes before death was excluded. The time to the development of severe AKI (defined as RIFLE class I or class F) was calculated and the multivariate analysis of pre- and post-transplant variables was performed by a Cox proportional hazards model. Post-transplant factors were assessed as time-dependent variables. As a representative of pre-transplant comorbidities, we used the hematopoietic cell transplantation-specific comorbidity index (HCT-CI). To analyze the outcomes of patients who developed AKI, the multivariate analysis of OS and NRM was carried out by a landmark approach, in which the follow-up was started at the onset of AKI class R or severe AKI in patients who developed AKI class R or severe AKI, and at the median time of the incidence of AKI in patients who did not develop AKI. Results:Among 207 patients, myeloablative SCT was performed in 149 patients and non-myeloablative SCT in 58 patients. Overall, 158 patients (76.3%) developed AKI, and 92 patients (44.4%) developed severe AKI. The median interval to the occurrence of severe AKI was 30 days after SCT. The cumulative incidence of severe AKI within 100 days in patients with a HCT-CI score 0, 1–2, and ≥3 was 21.3 %, 48.8%, and 73.9%, respectively. In a multivariate analysis, the HCT-CI was independently and most strongly associated with severe AKI (HCT-CI 1–2: adjusted hazard ratio [HR] 2.42, P<0.01; HCT-CI ≥3: adjusted HR 4.69, P<0.01), although no patients had renal dysfunction defined by the HCT-CI scoring system (pre-transplant creatinine > 2.0 mg/dl) before SCT in our cohort. Among post-transplant factors, sepsis (HR 2.66, P<0.01) and use of vancomycin (HR 1.79, P=0.04) were significantly associated with the development of severe AKI. In total, 101 of 207 patients (48.8%) died, of which 52 patients (51.5%) died of non-relapse causes. In a landmark analysis, the 3-year OS was 61.4% in patients without AKI, 53.9% in patients with AKI class R, and 39.3% in patients with severe AKI (P<0.01). The 3-year NRM was 5.6% in patients without AKI, 16.6% in patients with AKI class R, and 40.8% in patients with severe AKI (P<0.01). Multivariate analysis showed that severe AKI was a significant risk factor for worse OS (HR: 2.10, P=0.01) and NRM (HR: 6.15, P<0.01), while the occurrence of AKI class R did not have a strong impact on OS (HR: 1.14, P=0.69) or NRM (HR: 2.31, P=0.20). According to the cause of death, 24 patients died of severe AKI within 100 days after SCT, consisting of 2 on-disease patients (8.3% of the 24 patients who relapsed within 100 days after SCT) and 22 patients in remission (12.0% of the 183 patients who did not relapse within 100 days after SCT). There was no significant difference in the proportions of severe AKI as a mortality cause between patients with or without relapse (P=1.0). Conclusions:We found that high HCT-CI scores, particularly ≥3, were the most important pre-transplant predictor of severe AKI. The development of severe AKI within the first 100 days after SCT was independently associated with worse prognosis, irrespective of the status of the primary disease. Therefore, the strategy to prevent the occurrence of life-threatening severe AKI in patients with a high HCT-CI score would be imperative to improve their survival after allogeneic SCT. Disclosures:No relevant conflicts of interest to declare.

Pretransplant Predictors and Posttransplant Sequels of Acute Kidney Injury after Allogeneic Stem Cell Transplantation

Acute kidney injury (AKI) is a common complication after allogeneic stem cell transplantation (SCT). Although various risk factors for AKI have been reported, the influence of pretransplant comorbidity on the incidence of AKI has not been well investigated. We performed a retrospective analysis of 207 consecutive patients undergoing myeloablative or nonmyeloablative SCT between 2001 and 2009, using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) as a representative of pretransplant comorbidities. According to Risk, Injury, Failure, Loss, and End-stage kidney disease (RIFLE) criteria, 158 patients (76.3%) developed AKI, and 92 patients (44.4%) developed severe AKI (RIFLE class I or class F) within 100 days after SCT. The cumulative incidence of severe AKI within 100 days in patients with an HCT-CI score 0, 1-2, and ≥3 was 21.3%, 48.8%, and 73.9%, respectively. In multivariate analysis, the HCT-CI was independently associated with severe AKI (HCT-CI 1-2: adjusted hazard ratio [HR] 2.42, P < .01; HCT-CI ≥3: adjusted HR 4.69, P < .01). In a landmark analysis, patients with severe AKI had a lower 3-year overall survival (OS) (39.3% versus 61.4%, P < .01), and a higher 3-year nonrelapse mortality (NRM) (40.8% versus 5.6%, P < .01) than those without AKI. Multivariate analysis showed that severe AKI was a significant risk factor for worse OS (HR: 2.10, P = .01) and NRM (HR: 6.15, P < .01). Thus, it is important to assess the HCT-CI to predict the incidence of AKI, which is a strong indicator of worse prognosis after SCT.

The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) Predicts Survival and Non-Relapse Mortality in Lymphoma and Myeloma Patients Undergoing Reduced-Intensity or Non-Myeloablative Allogeneic Stem Cell Transplantations .

The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) has been developed to identify patients at high risk of toxic mortality after an allogeneic stem cell transplant (alloSCT). Reduced intensity (RIC) and non-myeloablative regimens have decreased the non-relapse mortality (NRM) in heavily pre-treated and elderly patients. We performed a retrospective multicenter study to assess whether comorbidities, according to the HCT-CI, might influence the outcome of lymphoma and multiple myeloma patients undergoing RIC or non-myeloablative alloSCT. Two-hundred and three patients affected by non Hodgkin's lymphoma (n=108), multiple myeloma (n=69) and Hodgkin's lymphoma (n= 26) received an alloSCT from HLA matched sibling (n= 121) or unrelated (n=82) donors. Median age at transplant was 53 years (range, 17–69). The median number of previous chemotherapy was 3 (range, 0–7) and 68% of the patients received at least one autologous stem cell transplant (autoSCT). Twenty-five percent of the patients were transplanted in complete remission (CR), 50% in partial response (PR) and 25% in progressive disease (PD). RIC fludarabine-based regimens were used in 154 patients, whereas 49 patients received a non-myeloblative conditioning based on 2 Gy total-body irradiation+/− fludarabine. Variables included in multivariate analysis were age (<55 vs ≥55), HCT-CI (0 vs 1–2 vs ≥3), the Karnofsky Performance Status (PS) (>80% vs ≤80%), disease type (lymphoma vs myeloma), disease status before transplant (CR vs no-CR), the number of previous lines of therapy (≤2 vs >2), a previous autoSCT (0 vs ≥1), the donor type (sibling vs matched unrelated) and the conditioning regimen (non-myeloablative vs RIC). Patients with a HCT-CI of 0, 1–2 and ≥3 were 32%, 31% and 37%, respectively. The cumulative incidence of NRM was 5%, 16%, 20% at 1 year and 6%, 24% and 27% at 2 years, for patients with HCT-CI of 0, 1–2 and ≥3, respectively (p=0.04). The multivariate analysis for NRM showed that a high HCI-CI score (HR=1.60, p=0.03), as well as a low Karnofsky PS (HR=2.12, p=0.04) were correlated with a significantly worst outcome. Similarly, HCT-CI and the Karnofsky PS were able to predict overall survival (OS, HR=1.62, p<0.001 and HR=3.10, p<0.001, respectively) and unexpectedly, only HCT-CI retained significance in multivariate analysis for progression-free survival (PFS, HR=1.43, p=0.002). Univariate lymphoma subgroup analysis revealed that OS was better for patients with HCT-CI of 0 (p<0.001), with Karnofsky PS >80% (p<0.001), in CR at transplant (p=0.01) and receiving a RIC regimen (p=0.03). In myeloma patients, a previous autoSCT influenced OS (p<0.02) and there was a trend towards a significant correlation with HCT-CI of 0 and Karnofsky PS >80% (p=0.09 and p=0.07, respectively). When patients were analysed separately based on the conditioning regimen, OS was different for HCT-CI of 0, 1–2 and ≥3 either with RIC (p=0.001) or non-myeloablative regimens (p=0.02). Patients with HCT-CI 0, 1–2, and ≥3 had a similar NRM (p=0.19 for HCT-CI 0, p=0.87 for HCT-CI 1–2, p=0.33 for HCT-CI ≥3) and OS (p=0.94 for HCT-CI 0, p=0.76 for HCT-CI 1–2, p=0.18 for HCT-CI ≥3) when transplanted with non-myeloablative or reduced intensity conditioning. HCT-CI was inversely associated with Karnofsky PS (p<0.001, rho=−0.34) and the number of previous lines of therapy (p=0.002, rho=0.21), but not with age (p=0.38), time from diagnosis to transplantation (p=0.68) and pre-transplant disease status (p=0.73). Patients with a higher HCT-CI were not at higher risk of grade 2–4 acute GVHD (p=0.72) or chronic GVHD (p=0.77). These results demonstrated that HCT-CI may be a useful tool to predict NRM, OS and also PFS in lymphoma and myeloma patients undergoing RIC or non-myeloablative alloSCT.