Pretransplantation Assessment Of Mortality Research Articles

Utility of theTreatment-Related Mortality (TRM)score to predict outcomes of adults with acute myeloid leukemia undergoing allogeneic hematopoietic cell transplantation.

There is long-standing interest in estimating non-relapse mortality (NRM) after allogeneic hematopoietic cell transplantation (HCT) for AML, but existing tools have limited discriminative capacity. Using single institution data from 861 adults with AML, we retrospectively examined the treatment-related mortality (TRM) score, originally developed to predict early mortality following induction chemotherapy, as a predictor of post-HCT outcome. NRM risks increased stepwise across the 4 TRM score quartiles (at 3 years: 9% [95% confidence interval: 5–13%] in Q1 vs. 28% [22–34%] in Q4). The 3-year risk of relapse was lower in patients with lower TRM score (26% [20–32%] in Q1 vs. 37% [30–43%] in Q4). Consequently, relapse-free survival (RFS) and overall survival (OS) estimates progressively decreased (RFS at 3 years: 66% [59–72%] in Q1 vs. 36% [29–42%] in Q4; OS at 3 years: 72% [66–78%] in Q1 vs. 39% [33–46%] in Q4). With a C-statistic of 0.661 (continuous variable) or 0.642 (categorized by quartile), the TRM score predicted NRM better than the Pretransplantation Assessment of Mortality (PAM) score (0.603) or the HCT-CI/age composite score (0.576). While post-HCT outcome prediction remains challenging, these findings suggest that the TRM score may be useful for risk stratification for adults with AML undergoing allogeneic HCT.

Validation of Scores Predicting Non-Relapse Mortality in Patients with Myelodysplastic Syndrome: A Study on 1276 Patients on Behalf the Chronic Malignancies Working Party of the EBMT

Allogeneic stem cell transplantation (HSCT) is the only potential curative treatment for myelodysplastic syndromes (MDS). Non-relapse mortality (NRM) remains a matter of concern despite the introduction of reduced-intensity conditioning in this disease, occurring mainly in an elderly population. Disease features and status at transplant are cornerstones for the risk of relapse. Different pre-transplant parameters have been analysed in various population without resulting in consensus.Here, we aim to evaluate the predictive role of different pre-transplant parameters including comorbidities on NRM, in 1276 patients who were transplanted for MDS between 2003 and 2014 in centers who participated to the EBMT Data Quality Initiative. The performance of the HCT-CI (Hematopoietic cell transplantation-specific comorbidity index) and PAM (Pretransplant Assessment of Mortality) scores1,2,3 in predicting NRM and overall survival (OS) was investigated according to principles and methods that have been described for external validation of prediction models4. Besides, model discrimination was assessed by the concordance (c) index and its adaptation for competing risks analyses5,6.Median age was 59 (18-79) and the median follow-up was 73 months. The different scores were categorized as initially published. According to the IPSS classification, two-thirds of the patients were classified within the low or intermediate groups of risk (score ≤1) and one-third within the higher-risk's categories (score ≥1.5). Donors were mostly matched related (34.3%) or unrelated (62.1%), use of peripheral blood stem cells was predominant (89.8%) and conditioning was non-myeloablative in 60% of the transplants. Overall, 731 patients died during the study period, including 445 non-relapse deaths. At 48 months, OS was 46.7% (95%CI 44.0 to 49.6) and NRM was 32.5% (95%CI 29.8 to 35.0).The c-index for HCT-CI score, HCT-CI/Age score and PAM were lower than for Karnofsky score meaning that the scores did not predict better the NRM and the OS than Karnofsky score. Furthermore, PAM score did not predict NRM but was able to predict OS (See Figure 1).In multivariate analysis including age, disease risk, conditioning, HCT-CI and KS, age ≥ 70 (HR 1.89, 95%CI 1.14-3.12, p=0.013; HR 1.63, 95%CI 1.09-2.45, p=0.018), HCT-CI ≥3 (HR 1.31, 95%CI 1.02-1.68, p=0.033; HR 1.31, 95%CI 1.08-1.59, p=0.006) and KS ≤ 80 (HR 2.08, 95%CI 1.57-2.76, p<0.0001; HR 1.75, 95%CI 1.41-2.17, p<0.0001) were statistically significantly associated with respectively increased risks for NRM and with a decreased OS. Disease risk and intensity of conditioning regimens had no significant influence on outcomes (Table 1).In conclusion, our study demonstrated on a large homogeneous population of MDS patients the ability of the different comorbidities scoring system to predict toxicity and survival outcomes after HSCT. Among them, Karnofsky score was the most powerful predictive tool. Patient's risk profile assessment is crucial to refine predictive models assessing disease features and transplant procedures.

Cardiopulmonary performance in allogeneic hematopoietic cell transplantation recipients\u2014evaluation of pre-transplant risk assessments

Cardiopulmonary performance reflects how well different organ systems interact. It is inter alia influenced by body composition, determines patients’ quality of life and can also predict mortality. However, it is not yet used for risk prediction prior to allogeneic hematopoietic cell transplantations (alloHCT). Thus, we aimed to examine the predictive power of peak oxygen consumption (VO2peak) as a representative of cardiopulmonary performance and that of body composition before alloHCT to determine overall survival (OS) and non-relapse mortality (NRM) 2 years after transplantation. We also compared it with the predictive power of four commonly-used risk scores: revised Pretransplant Assessment of Mortality (rPAM), Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI), revised Disease Risk Index (rDRI), European Society for Blood and Marrow Transplantation (EBMT). Fifty-nine patients performed a cardiopulmonary exercise test and body composition assessments before alloHCT and were observed for 2 years. Sixteen patients died. VO2peak and most risk scores assessed pre-transplant revealed no association with OS or NRM. Body composition parameters only within univariable analyses. But higher rDRI and the male sex, were associated with shorter OS and higher NRM. We thus propose that the current risk assessments be reconsidered. The predictive value of VO2peak and body composition need further clarification, however.

Performance of Prognostic Models in Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Comparison

Background Prediction of clinical outcomes following allogeneic hematopoietic stem cell transplantation (Allo-HSCT) may promote informed decisions and treatment personalization. We sought to evaluate the predictive performance of six commonly used models in the prediction of transplantation outcomes. Methods This was a single-center retrospective study including patients undergoing Allo-HSCT between 2011 and 2015. We calculated the following scores: Hematopoietic Cell Transplantation-Comorbidity Index (HCTCI), Comorbidity-Age index (AGE-HCTCI), Endothelial Activation and Stress Index (EASIx), Pretransplant Assessment of Mortality (PAM) and revised PAM (rPAM) scores, and European Group for Blood and Marrow Transplantation (EBMT) score. Predictive accuracy was measured by discrimination (AUC), a measure ranging from 0.5 to 1, corresponding with poor to excellent performance. Outcomes evaluation were overall survival (OS), non-relapse mortality (NRM), and relapse. Results Among 528 patients included, indications for transplantation varied, with acute myeloid leukemia (44%) being most common. Non-malignant causes accounted for 3% of cases. Most patients received myeloablative conditioning (74%, MAC) and grafts from HLA matched-sibling donors (46%). Median follow-up was 2.5 years (intra-quantile range 1.7-3.9). The rPAM, which includes patient, disease, donor, and transplantation characteristics, had the highest discrimination for OS, NRM, and relapse across all time-points (Figure 1). EASIx, a biomarker based-model integrating pre-transplantation creatinine, lactate dehydrogenase, and thrombocyte levels, had among the highest AUCs for day-100 OS. Across outcomes, AUCs were mostly 0.6 or below for the HCT-CI, AGE-HCTCI, and EBMT score. In a sub-analysis, the rPAM, EASIx, and AGE-HCTCI were more accurate in the prediction of 2-year OS in patients receiving MAC, while the EBMT score did better in patients receiving reduced-intensity conditioning (Figure 2). Conclusions Prognostic models in Allo-HSCT have limited predictive performance. Among models evaluated, the rPAM had the highest discrimination overall. Biomarker-based prediction with EASIx is promising for the prediction of short-term outcomes.

Validation of the Revised Pretransplant Assessment of Mortality Score in Patients with Acute Myelogenous Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Despite recent advances, allogeneic hematopoietic stem cell transplantation (allo-HSCT) continues to be accompanied by a high rate of morbidity and mortality. Several scores have been developed to predict outcome after allo-HSCT. The recently revised Pretransplant Assessment of Mortality (PAM) score is based on patient age, donor type, disease risk, cytomegalovirus (CMV) serostatus of patient and donor, and forced expiratory volume in 1 second (FEV1). The aim of this study was to analyze the predictive power of the PAM score in an independent large cohort of patients with acute myelogenous leukemia (AML). We selected adult patients with AML who underwent a first allo-HSCT at the University Hospital of Dresden, a tertiary care hospital with a large transplantation program. All adult patients treated between January 1, 2003, and July 1, 2015, were included. The PAM score was calculated as described previously. Overall survival (OS), cumulative incidence of relapse (CIR), and nonrelapse mortality (NRM) after allo-HSCT were analyzed. Age, AML type, sex match, CMV match, donor type, European Leukemia Net risk classification, type of conditioning, disease stage, and PAM score as a continuous variable were selected a priori for multivariate Cox regression analyses. A total of 544 patients met the inclusion criteria. The median patient age was 57 years. With a median follow-up of 47 months (range, 1 to 161 months), the estimated OS for the whole cohort at 4 years was 43%, with a CIR of 30% and an NRM of 31%. The probability of OS at 4 years was 65% for patients with a PAM score of 0, 52% in those with a PAM score of 1, 33% in those with a PAM score of 2, and 22% in those with a PAM score of 3 (P < .001, log-rank test). Both the CIR and NRM increased with higher PAM scores (P = .005 and P < .001, respectively, Gray test). In multivariate analysis, age (hazard ratio [HR], 1.02 per year; P = .004), disease stage (primary induction failure versus first complete remission (CR1); HR, 1.5; P = .03), and the PAM score (HR 1.04; P = .03) had a significant impact on OS. This is the first independent validation of the revised PAM score allowing for simple and valid estimation of transplantation outcomes. It can serve as an important tool in counseling patients with AML, as well as in designing future trials.

Age adjusted hematopoietic stem cell transplant comorbidity index predicts survival in a T-cell depleted cohort

ObjectivesAllogeneic hematopoietic stem cell transplant (HCT) continues to evolve with the treatment in higher risk patient population. This practice mandates stringent update and validation of risk stratification prior to undergoing such a complex and potentially fatal procedure. We examined the adoption of the new comorbidity index (HCT-CI/Age) proposed by the Seattle group after the addition of age variable and compared it to the pre-transplant assessment of mortality (PAM) that already incorporates age as part of its evaluation criteria. MethodsA retrospective analysis of adult patients who underwent HCT at our institution from January 2010 through August 2014 was performed. Kaplan-Meier’s curve, log-rank tests, Cox model and Pearson correlation was used in the analysis. ResultsOf the 114 patients that underwent allogeneic transplant in our institution, 75.4% were ≥40 years old. More than 58% had a DLCO ≤80%. Although scores were positively correlated (correlation coefficient 0.43, p < 0.001), HCT-CI/Age more accurately predicted 2-year overall survival (OS) and non-relapse mortality (NRM) in patients with lower (0–4) and higher (5–7) scores (52% and 36% versus 24% and 76%, p = 0.004, 0.003 respectively). PAM score did not reach statistical significance for difference in OS nor NRM between the low (<24) and high-risk (≥24) groups (p = 0.19 for both). ConclusionsDespite our small sample population, HCT-CI/Age was more discriminative to identify patients with poor outcome that might benefit from intensified management strategies or other therapeutic approaches rather than allogeneic HCT.

Clinical Characteristics, Biological Markers and Comorbidity Indexes As Predictors of Transplant-Related Mortality after Allogeneic Hematopoietic Stem Cell Transplantation: Which One Should We Choose?

Treatment-related mortality (TRM) after allogeneic hematopoietic stem cell transplantation (HSCT) is a major concern and remains difficult to predict adequately. Several pre-transplant characteristics of patients and disease are associated with TRM. Comorbidity indexes, including pre-transplant assessment of mortality (PAM) and the hematopoietic cell transplantation comorbidity index (HCT-CI), have been developed in an attempt to predict TRM. Biologic markers, such as ferritin, C-reactive protein (CRP) and, more recently, telomere length, also correlate with TRM. However, the cumulative impact of these factors on TRM has not been addressed. Here, we investigated the impact of pre-transplant clinical factors, comorbidity indexes and biologic markers on TRM in 670 consecutive patients from a single center who received a first allogeneic HSCT between January 2006 and June 2012. Clinical factors considered were: year of transplantation, donor and recipient ages, gender and CMV serological status, disease risk (based on the American Society for Blood and Marrow Transplantation Request for Information 2006 risk scoring schema), stem cell source, and HLA matching. Comorbidities were evaluated by PAM and HCT-CI, and coded prospectively for all patients by a single observer. HCT-CI and PAM scores were ranked into previously published categories (0, 1-2, ≥3 for HCT-CI and 9-16, 17-23, 24-30 and 31-44 for PAM; Sorror, Blood 2005; Parimon, Annals Intern. Med. 2006). Ferritin, CRP and biological data for comorbidity indexes were recorded within 2 weeks prior to HSCT. Recipient telomere lengths were determined in peripheral blood leukocytes by qPCR and adjusted for age by the telomere attrition rate observed in donors.Our analysis categorized the population into quartiles and divided patients into 2 groups: shorter telomeres (first quartile) versus longer telomeres (upper 3 quartiles). The entire patient cohort was subsequently divided into 3 groups by data availability: Group 1 (G1), the entire population (n=670) for whom all clinical data were available; G2, 488 patients with clinical and comorbidity index data (pulmonary function tests were not systematically performed during the early study period); and G3, for whom pre-transplant telomere length was available (n=178). Univariate and multivariate methods developed by Fine and Gray for competing risks studies were used to assess prognostic TRM factors, with relapse as a competing event. Table 1 shows patient characteristics. Significant differences between G1 and G2 were found for mean donor and recipient ages, sex mismatch, HLA matching, stem cell source, disease risk, and year of transplantation. Median follow-up was 36 months, overall survival at 5 years for the entire cohort was 60%, and TRM was 18%. In G1, factors significantly associated with higher TRM in multivariate analysis were: recipient age (HR, 1.02, 95%CI [1.0-1.03], p=0.005), CMV seropositive recipient/seronegative donor (R+/D-) (HR, 1.98, 95%CI [1.34-2.92], p=0.001) and mismatched unrelated donor (MMUD) (HR, 2.28, 95%CI [1.38-3.74], p=0.001). In G2, the same factors [recipient age (HR, 1.01, 95%CI [1.00-1.03], p=0.027), CMV R+/D- (HR, 1.91, 95%CI [1.22-2.99], p=0.005), MMUD (HR, 2.55, 95%CI [1.48-4.42], p=0.001)] were associated with higher rates of TRM, whereas PAM showed a trend for higher TRM (HR, 1.41, 95%CI [0.99-1.99], p=0.05). HCT-CI, ferritin, and CRP were not associated with TRM. In G3, only MMUD (HR, 2.82, 95%CI [1.06-7.46], p=0.037) was associated with higher TRM. However, in analysis restricted to patients transplanted from an HLA-matched related or unrelated donor, recipient age (HR, 1.03, 95%CI [1.00-1.06], p=0.027) and telomere length (HR, 2.45, 95%CI [1.07-5.59], p=0.033) were independently associated with higher TRM. This is the first study to investigate the impact of clinical and biological pre-transplant factors and comorbidity indexes on TRM after allogeneic HSCT in a large cohort of patients. Best results were obtained with young patients transplanted from an HLA-matched donor, with CMV other than R+/D-. High comorbidity scores (evaluated by PAM) were marginally associated with higher TRM. In G3 (pre-transplant telomere length available), only HLA-mismatch was significantly associated with higher TRM. [Display omitted] DisclosuresPeffault De Latour:Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Alexion: Consultancy, Honoraria, Research Funding.

External Validation of the Revised PAM Score for Patients with AML Scheduled for Allogeneic Hematopoietic Stem Cell Transplantation

PurposeCounselling of patients with AML about allogeneic hematopoietic stem cell transplantation (alloHSCT) is still an ambitious task in the light of the potential curative perspective after alloHSCT, poor outcomes after non-transplant approaches but a high risk of transplant-associated complications and still a significant risk of relapse even after HSCT. Several scores have been developed to predict outcome after HSCT, such as the HCT-CI and the Pre-transplant Assessment of Mortality (PAM) score. The PAM score has been revised recently, thereby acknowledging the shift to more frequently used reduced intensity conditioning. This score utilizes information on pts.age, donor type, disease risk, theserostatus for the CMV of pts.and donor, and the forcedexspiratory volume in the 1 second (FEV1). The aim of this study was to analyze the predictive power of the PAM score in an independent, large cohort of AML pts.who receivedalloHSCT within the last 12 years.Patients and MethodsWe selected all adult AMLpts.whoreceived the firstalloHSCTat the University Hospital of Dresden, a tertiary care hospital with a large transplant program, from January, 1, 2003 to July, 1, 2015.Pts.withhaplo-identical donors or after cord-blood transplantation were excluded. All patients gave their informed consent on analysing data. The PAM score was calculated as published (Au et al., BBMT 2015) and stratified into 4 groups: scores <17,scores17 to <24, scores 24 through 30, and scores >30.Overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR) and non-relapse-mortality (NRM) after alloHSCTwereanalyzed according to several factors known to impact outcome using the log-rank test for univariate comparison. Age, AML type (de novo vs. sAMLvs. t-MN), sex match (female donor/male recipient vs. all other), CMV match (negative/negative vs. all other), donor type (sibling vs. matched unrelated vs. mismatched unrelated), ELN risk classification, type of conditioning (RIC vs. MAC), disease stage (CR1 vs. primary induction failure vs. >= first relapse) and the PAM score as a continuous variable were selected a priori for multivariate Cox regression analyses.ResultsOverall, 544 pts.metthe inclusion criteria and were analyzed,the median age was 57 years (range, 18 to 76). Two-hundred-three pts.(37%) were treated with standard myeloablative conditioning (MAC) regimens while the remaining pts. received reduced intensity conditioning (RIC). Donors were siblings in 120 (22%), matched unrelated in 295 (54%) and mismatched unrelated donors in 129 (24%) pts. With a median follow up of 47 months (range, 1 to 161), the estimated OS for the whole cohort at five years was 43%, with a CIR of 30% and a NRM of 31% up to that time-point. The probability for OS at five years for pts.in PAM score group 0, 1, 2, and 3 was 65%, 50%, 33%, 22%, respectively (log-rank test, p= <.001). Both the CIR and NRM increased with increasing PAM scores (gray-tests, p= .005 and p= <.001, respectively). Notably, the PAM score contributed significantly to the prediction of OS even when added to a multivariate regression model which contained the single components of the score. In the final multivariate model, age (HR 1.02 per year, p= .004), disease stage (primary induction failure versus CR1, HR 1.5, p= .03), and the PAM score (HR 1.04, p= .03) had a significant impact on OS.ConclusionWe validated the revised PAM for the prediction of OS after HLA-compatiblealloHSCTin a large, well characterised cohort of AMLpts.treatedat a large German transplantcenter. To the best of our knowledge, this is the first external validation of the revised PAM score. OS prediction based on this tool will be useful for counselling of futurepts.withAML. [Display omitted] DisclosuresMiddeke:Sanofi: Honoraria. Thiede:AgenDix: Employment, Other: Ownership. Schetelig:Sanofi: Honoraria.

The Use of Biomarker Ferritin and Albumin As Well As HCT-CI, but Not PAM, Was Predictive of Suvival, Gvhd and, Relapse in Myeloid Malignancies

Developing the optimal models for pretransplant assessment as more reduced intensity conditioning regimens are implemented and the higher median age of transplant. The pre-transplant assessment of mortality (PAM) assesses all cause mortality at 2 years and the Hematopoietic Stem cell Transplantation specific comorbidity index (HCT-CI) which previously used Charlson comorbidity index (CCI) to assessed NRM based on history and organ function. Previous studies have shown that certain biomarkers such as ferritin and albumin may help optimize risk assessment before transplant. We tested the validity of PAM, HCT-CI, serum ferritin and albumin to predict GVHD, relapse and overall survival (OS) in our older patient population. IRB approval was obtained to retrospectively review clinical outcomes in patients undergoing allogeneic stem cell transplantation at our institution between, 2010 - 2013. We examined a total of 94 patients with myeloid malignancies (see Table 1 for patient characteristics). Risk variables assessed included calculated PAM, HCT-CI and KPS scores and pre HCT serum ferritin and albumin levels. We examined the predictive value of these biomarkers with respect to GVHD, relapse, and overall survival. Of the 94 patients 46% are alive and in remission, 20% have relapse and GVHD developed in 56% of patients. To determine the optimal cutoff for classifying into high and low groups for each risk measure, first the association between the measure and clinical outcomes was determined to obtain the logistic regression. Then area under the curve (AUC) of the receiver operating characteristic (ROC) curve for each clinical outcome against the risk measure was calculated. The cutoff that maximized the sum of the ROC-AUC across all measured was selected. Patients with HCT-CI > 4, (cut off 4), had a less likelihood of survival than those with HCT < 4 OR 4.3 (95% CI: 1.6-11.2) (p=.0033). Similarly, patients with low albumin, (cutoff 4.1), were less likely to than those with high albumin survive OR 0.4 (95% CI: 0.2-0.9) (p=0.02). Patients in the high ferritin group, (cut off 2425) were less likely to survive than those with low ferritin OR 4.0 (95% CI:1.3-2.3) (p=0.016). The high HCT-CI group, (cut off 4) was more likely to relapse than lower HCT-CI OR 2.9, (95% CI: 1.1-8.1) (p=0.04) and patients with a high KPS, (cutoff 81), were less likely to relapse than lower KPS OR 0.3 (95% CI: 0.1-0.8) (p=0.22). In the high ferritin group, (cutoff 2020) patients were more likely to have GVHD than low ferritin group OR 0.2 (95% CI: 0.1-0.7) (p=0.005). (Table 2) We conclude that HCT-CI was more predictive of mortality than the PAM score in our cohort or patients with median age 65 years old. Our results are concordant with previously reported data showing serum ferritin and albumin is useful biomarkers to predict GVHD, relapse and survival. We are now incorporating objective markers such as ferritin, albumin, and other functional assessments to objectively quantify risk in our current patients presenting for allogeneic HSCT.Table 1Patient CharacteristicsAll Patients (N = 94)N (%)Patient Age< 5033 (35)50-5935 (37)60-7026 (28)RaceCaucasian76 (81)African American14 (15)Other4 (4)DonorRelated40 (43)Unrelated54 (57)HLA MismatchNo71 (76)Yes10 (11)Missing13Stem Cell SourceBM5 (5)PBSC89 (95)ConditioningMyeloablative47 (50)Reduced Intensity47 (50)ATGNo13 (14)Yes81 (86)Patient CMV Sero statusNegative41 (44)Positive48 (51)Missing5KPS< 9017 (18)90-10077 (82)BM indicates bone marrow; PBSC, peripheral blood stem cells; CMV, cytomegalovirus.Table 2Biomarkers and Clinical OutcomesBiomarkersGVHDRelapseSurvivalCut-offp-valueCut-offp-valueCut-offp-valuePAM240.1222240.4911210.2077HCT-CCI20330840.049540.0033Ferritin20200.005410700.381824250.0164KPS810.1679810.0226910.1289Albumin4.20.11034.20.27504.10.0220 DisclosuresNo relevant conflicts of interest to declare.

Pre-Transplant Autonomic Nervous System Malfunction Is a Powerful Predictor for Survival after Allogeneic Hematopoietic Cell Transplantation

Background: Autonomic nerve function can be affected by various factors such as patient activity of daily living, disease status, treatment history and/or comorbidity. Indeed, autonomic nervous system dysfunction, as indexed by heart rate variability (HRV), has shown prognostic value for various disease outcomes, but its influence on outcomes following allogeneic hematopoietic cell transplantation (allo-HCT) is unclear. We therefore conducted a prospective observational study to determine the impact of autonomic nervous system dysfunction on outcomes following allo-HCT.Methods: From July 2011 to July 2013, we prospectively registered patients who had received allo-HCT in our institute. We also applied well-established examination of HRV as a surrogate maker of the autonomic nervous system. HRV data were collected from 24-hour ambulatory ECG recordings within 28 days of the starting day of the conditioning regimen for allo-HCT. Obtained data were analyzed with RR data analysis software (MemCalc/CHIRAM version 3, GMS Co., LTD., Tokyo, Japan). The following parameters were employed as markers of HRV: standard deviation of NN interval (SDNN) and the squares of the differences between adjacent normal-to-normal RR intervals (r-MSSD) in time domain analysis, and low-frequency (LF) and high-frequency (HF) power in frequency domain analysis. Δ Akaike's information criterion (Δ AIC) was used to compare the HRV components-added model to the basic model by the Pre-transplantation Assessment of Mortality (PAM) score, HCT-specific comorbidity index (HCT-CI), or disease risk index (DRI) in a Cox proportional hazards model.Results: We registered 112 consecutive allo-HCTs (103 patients) who agreed to participate in this study. The median age of the patients was 45.5 years (range: 18-66) and the median follow-up period for survivors (76 patients) was 961 days (range: 159-1654). Diagnoses included acute myeloid leukemia (n=55, 49%), acute lymphoid leukemia/lymphoblastic lymphoma (n=13, 12%), mixed phenotype acute leukemia (n=3, 3%), myelodysplastic syndrome (n=15, 13%), adult T cell leukemia/lymphoma (n=7, 6%), aggressive lymphomas (n=6, 5%), indolent lymphoma/chronic lymphoid leukemia (n=3, 3%), chronic myeloid leukemia/other myeloproliferative neoplasms (n=5, 4%), aplastic anemia (n=2, 2%), and others (n=3, 3%). Stem cell sources consisted of HLA-matched related donors for 18 transplants (16%), mismatched related donors for 24 transplants (22%), matched unrelated donors for 32 transplants (29%), mismatched unrelated donors for 8 transplants (7%), and cord blood for 30 transplants (27%). Myeloablative conditioning was employed for 84 transplants (75%).Median value of LF, HF, SDNN, and r-MSSD was 409 msec2 (range: 27-1279), 103 msec2 (range: 5-1309), 122 msec (range: 48-231), and 20 msec (range: 4-95), respectively.From univariate analysis, the reduction of LF, HF, SDNN, or r-MSSD was significantly associated with decreased probability of OS (hazard ratio (HR): 0.7 for LF per 100 msec2 (p<0001), 0.5 for HF per 100 msec2 (p=0.001), 0.2 for SDNN per 100 msec (p=0.004), and 0.6 for r-MSSD per 10 msec(p=0.01), respectively). Of these four HRV components, the LF-added model for PAM, HCT-CI, and DRI had the highest values of Δ AIC (16.5, 22.2 and 11.4, respectively). From the analysis with stratification into four LF groups divided equally by the number of transplants (n=28), two-year OS was 92.9, 84.5, 59.7, and 33.2%, respectively (p <0.0001). LF solely represented a better discriminating variable for the prediction of survival. Additionally, from bivariate analysis for OS on each LF-added model to PAM, HCT-CI, or DRI, decreased LF was found to be an independent predictor for lower OS (adjusted HR for LF per 100 msec2: 0.7 (p=0.0003), 0.7 (p<0.0001), or 0.7 (p=0.001), respectively).Conclusions: Pre-transplant autonomic nervous system dysfunction is a powerful predictor of survival likely because it reflects the comprehensive physiological or pathological status of the patient. Of note, LF was a powerful predictor for survival and statistically independent from well-known prognostic indexes or scoring systems such as PAM, HCT-CI, and DRI. DisclosuresNakane:Otsuka: Honoraria. Nakamae:Otsuka: Other: My spouse receives research funding from Otsuka; Kyowa Kirin: Other: My spouse receives research funding from Kyowa Kirin. Nishimoto:Otsuka: Honoraria. Hino:Celgene: Honoraria. Nakamae:Otsuka: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding.

Reevaluation of the Pretransplant Assessment of Mortality Score after Allogeneic Hematopoietic Transplantation

The Pretransplant Assessment of Mortality (PAM) score was developed in 2006 to predict risk of mortality after allogeneic hematopoietic cell transplantation (HCT). Transplant practices have evolved during the past decade, suggesting the need to reevaluate the performance of the PAM score. We used statistical modeling to analyze and recalibrate mortality based on overall PAM scores, its components, and conditioning regimen in a retrospective cohort of 1549 patients who had HCT from 2003 through 2009. PAM scores correlated with mortality, but the effect size was smaller in the current study than in previous studies. PAM scores also demonstrated a stronger association with mortality in patients who received myeloablative conditioning than in those who received reduced-intensity conditioning. In contrast to the original study, carbon monoxide diffusing capacity, serum alanine aminotransferase, and serum creatinine concentrations were no longer significantly associated with 2-year mortality, whereas patient and donor cytomegalovirus serology was associated with mortality in the current cohort. Based on our findings, we developed and tested a revised PAM score for clinicians to estimate survival after allogeneic HCT with myeloablative conditioning regimens for patients with hematologic malignancy. Prognostic models such as the PAM score should be updated and recalibrated periodically to accommodate changes in clinical practice.

Predictive value of risk assessment scores in patients with hematologic malignancies undergoing reduced-intensity conditioning allogeneic stem cell transplantation.

Reduced-intensity conditioning allogeneic stem cell transplantation (RIC allo-SCT) is associated with less toxicity and is used for older patients. We retrospectively studied the predictive value of two risk assessment scores, which were the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) and the pre-transplantation assessment of mortality (PAM) score, for assessing the outcome of RIC allo-SCT. Seventy-eight patients underwent transplantation between 2005 and 2013 at a single institution. RIC was performed with fludarabine and melphalan with/without total body irradiation. The 3-year overall survival of patients with an HCT-CI >3 was significantly worse than that of patients with an HCT-CI 0-3 (31.6% vs. 59.6%, P = 0.020). Also, the 3-year overall survival of patients with a PAM score >24 was significantly worse than that of those with a PAM score ≤24 (29.2% vs. 61.4%, P = 0.005). The present findings suggest that changing the cut-off values of these risk assessment scores can improve prediction of outcomes in patients receiving RIC allo-SCT with this conditioning regimen and we need validation by large-scale study with other regimens.

Pre-Transplantation Assessment Of Mortality (PAM) Score Is a Poor Predictor For Survival In The Highest Risk Group When Used In T Cell Depleted Myeloablative Allogeneic Transplants

IntroductionPAM score is a simple tool for predicting mortality risk in patients undergoing allogeneic bone marrow transplantation. Originally developed and validated at Fred Hutchinson Cancer Research Center, Seattle, this has recently been validated in 276 patients from Japan. We retrospectively evaluated this in our cohort of T deplete myeloablative allogeneic transplants as there are no published studies validating PAM score in T deplete myeloablative setting. ResultsAfter a median follow up of 63 months 51% of the patients are alive. The predicted mortality for category 2, 3 and 4 patients via PAM score was 28%, 48% and 28% respectively. This was concordant with the predicted mortality at 2yrs for category 2 and 3. Category 4 was not concordant (Chi-square test, P=0.0035).CharacteristicsN=51Age-yrMedian35Range17-57Sex-No (%)Male29 (57)Female22 (43)Donor type-No (%)Related29 (57)Unrelated22 (43)Disease type-No (%)ALL12 (24)AML24 (48)CML3 (6)MDS4 (7)Others8 (15)Disease risk category-No (%)Low3 (6)Intermediate32 (63)High16 (31)Conditioning Regimen-No (%)TBI >12Gy43 (84)TBI<123 (6)Non TBI5 (10)Alemtuzumab dose in stem cell bag (mg)047.5610181542019PAM score categories (2 yr probability of mortality)Predicted(%)Observed(%)11<25021425-502832950-754847>7528Follow up (months)Median63Range1-162 [Display omitted] [Display omitted] [Display omitted] Disclosures:Milligan:Celgene:unrestricted educational grant Other.

Validation of pretransplantation assessment of mortality risk score in the outcome of hematopoietic SCT in non-Caucasians

The Pretransplantation Assessment of Mortality (PAM) score is a risk score for mortality after allogeneic hematopoietic SCT (HSCT). Ethnicity is a genetically determined factor that correlated with immune-mediated outcomes of allogeneic HSCT. We evaluated the predictive value of the PAM score for transplant outcome in 276 Japanese populations in which transplant-related complications occur less frequently than Caucasians. The PAM score effectively risk-stratified these patients for survival; overall survival (OS) at 2 years was 100%, 80.2%, 49.4%, and 13.9% in the categories 1, 2, 3, and 4, respectively, showing a clear distinction of OS by categories (P<0.001). In addition, the PAM score is useful for the prediction of transplant outcomes both in patients with standard-risk underlying diseases and those with high-risk diseases. The PAM score developed in Caucasian populations is thus useful in non-Caucasian populations.

Reduced Mortality after Allogeneic Hematopoietic-Cell Transplantation

Over the past decade, advances have been made in the care of patients undergoing transplantation. We conducted a study to determine whether these advances have improved the outcomes of transplantation. We analyzed overall mortality, mortality not preceded by relapse, recurrent malignant conditions, and the frequency and severity of major complications of transplantation, including graft-versus-host disease (GVHD) and hepatic, renal, pulmonary, and infectious complications, among 1418 patients who received their first allogeneic transplants at our center in Seattle in the period from 1993 through 1997 and among 1148 patients who received their first allogeneic transplants in the period from 2003 through 2007. Components of the Pretransplant Assessment of Mortality (PAM) score were used in regression models to adjust for the severity of illness at the time of transplantation. In the 2003-2007 period, as compared with the 1993-1997 period, we observed significant decreases in mortality not preceded by relapse, both at day 200 (by 60%) and overall (by 52%), the rate of relapse or progression of a malignant condition (by 21%), and overall mortality (by 41%), after adjustment for components of the PAM score. The results were similar when the analyses were limited to patients who received myeloablative conditioning therapy. We also found significant decreases in the risk of severe GVHD; disease caused by viral, bacterial, and fungal infections; and damage to the liver, kidneys, and lungs. We found a substantial reduction in the hazard of death related to allogeneic hematopoietic-cell transplantation, as well as increased long-term survival, over the past decade. Improved outcomes appear to be related to reductions in organ damage, infection, and severe acute GVHD. (Funded by the National Institutes of Health.).

Retrospective analysis of common scoring systems and outcome in patients older than 60 years treated with reduced-intensity conditioning regimen and alloSCT

In this retrospective study, 63 patients >60 years with hematological malignancies and treated with allo-SCT and with reduced-intensity conditioning (RIC) were reviewed. A total of 51% of patients suffered from AML or myelodysplastic syndromes. Disease status before transplantation was CR or PR 71 with 29% transplanted with active disease. Patients were classified according to three published prognostic indexes: (1) hematopoietic cell transplantation comorbidity index (HCT-CI); (2) European BMT (EBMT) score; and (3) Pretransplantation Assessment of Mortality (PAM) score. The 100-day and 1-year treatment-related mortality (TRM) were 6 and 22%, respectively, for the entire group. The 2-year OS and PFS were 60 and 58%, respectively. The incidence of grade II-IV acute GVHD (aGVHD) and extensive chronic GVHD was 46 and 48%, respectively. In a univariate analysis, neither the HCT-CI nor the EBMT score, nor the PAM score were predictive of TRM and OS. Only the occurrence of aGVHD affected the TRM and OS. ALLO-RIC is feasible in elderly patients. Even if those prognostic scores were not adapted to elderly patients, they did not predict for TRM and OS. aGVHD is the main cause of TRM and more efforts should be made to reduce its incidence without sacrificing graft vs tumor effect.

Comparison of Two Pretransplant Predictive Models and a Flexible HCT-CI Using Different Cut off Points to Determine Low-, Intermediate-, and High-Risk Groups: The Flexible HCT-CI Is the Best Predictor of NRM and OS in a Population of Patients Undergoing allo-RIC

Patient comorbidities are being increasingly analyzed as predictors for outcome after hematopoietic stem cell transplantation (HSCT), especially in allogeneic HSCT (Allo-HSCT). Researchers from Seattle have recently developed several pretransplant scoring systems (hematopoietic cell transplantation comorbidity index [HCT-CI] and the Pretransplantation Assessment of Mortality (PAM) model) from large sets of HSCT recipients with the aim of improving non-transplant models, mainly the Charlson Comorbidity Index (CCI). The validation of these comorbidity indexes in other institutions and in different disease and conditioning-related settings is of interest to determine whether these models are potentially applicable in clinical practice and in research settings. We performed a retrospective study in our institution including 194 consecutive reduced-intensity conditioning (RIC) AlloHSCT (allo-RIC) recipients to compare the predictive value of the PAM score, CCI, the original HCT-CI, and the flexible HCT-CI using a different risk group stratification. The median patient pretransplant scores for the HCT-CI, PAM, and CCI were 3.5, 22, and 0, respectively. The flexible HCT-CI risk-scoring system (restratified as: low risk [LR] 0-3 points, intermediate risk [IR] 4-5 points, and high risk [HR] >5 points) was the best predictor for non-relapse mortality (NRM). The 100-day and 2-year NRM incidence in these risk categories was 4% (95% confidence interval C.I. 2%-11%), 16% (95% C.I. 9%-31%), and 29% (95% C.I. 19%-45%), respectively (P < .001), and 19% (95% C.I. 12%-28%), 33% (95% C.I. 22%-49%), and 40% (95% C.I. 28%-56%), respectively (P=.01). However, we found no predictive value for NRM using neither the original HCT-CI nor the PAM or CCI models. The better predictive capacity for NRM of the flexible HCT-CI than PAM and CCI was confirmed with the c-statistics (c-statistics of 0.672, 0.634, and 0.595, respectively). Regarding the 2-year overall survival (OS), the flexible HCT-CI score categories were also associated with the highest predictive HR. In conclusion, our single-center study suggests that the flexible HCT-CI is a good predictor of 2-year NRM and survival after an allo-RIC.

Carbon Monoxide Diffusion Capacity: How Low Can You Go for Hematopoietic Cell Transplantation Eligibility?

Current guidelines suggest that patients with a pretransplantation diffusion capacity of the lung for carbon monoxide (DLCO) ≤ 60% are not ideal candidates for hematopoietic cell transplantation (HCT); however, recent studies suggest this criterion may exclude patients who will benefit from the procedure. We conducted a study of all adult patients who underwent autologous or allogeneic HCT between 1990 and 2005, and had a DLCO < 60%, of predicted normal, to examine whether there is a lower limit for the DLCO threshold in the context of respiratory failure and nonrelapse mortality risk (NRM), and whether a comprehensive risk scoring system, such as the Pretransplant Assessment of Mortality (PAM) risk score, can more effectively risk stratify these patients with a very low pretransplantation DLCO. We found that among patients with a DLCO ≤ 60% the risk of respiratory failure or NRM was not significantly different; however, the PAM score effectively risk-stratified these patients for NRM risk. There was a stepwise relationship between PAM score category and NRM risk; the highest PAM score category was associated with a 4.38-fold increase in risk ( P < .001). These findings suggest that the pretransplantation DLCO should not be considered the sole eligibility criteria for allogeneic HCT.

Impact of comorbidity indexes on non-relapse mortality

Comorbidity indexes (CI) have been reported to predict non-relapse mortality (NRM) and overall survival after allogeneic hematopoietic stem cell transplantation (HSCT) (Charlson's comorbidity index (CCI), hematopoietic cell transplantation CI (HCT-CI) and the pre-transplantation assessment of mortality (PAM) score). Which of these indexes best predict survival is unknown yet. We retrospectively studied 286 patients who underwent allogeneic HSCT. HCT-CI and PAM scores required grading according to pre-transplant pulmonary function tests (PFTs), which were lacking for some patients. We thus designed a reduced HCT-CI and an adjusted PAM, without results of PFTs. Using CCI, 25% of patients had indexes of 1 or more; median reduced HCT-CI score was 1; median adjusted PAM score was 24. The discriminative properties of the three CIs were rather low in our population. Comparison of patients and transplant characteristics between our and Seattle group's cohorts, however, revealed significant differences in more children, in more cord blood HSCT and in HSCT for Fanconi anemia in St Louis. Finally, multivariate analysis of scoring items revealed that age, matched unrelated or mismatched donor and hepatic disease were associated with NRM in our cohort. Translating use for patient's counseling or decision to proceed to transplant of these CIs will need prospective studies in a large independent cohort.

309: Pretransplantation Assessment of Mortality (PAM) Risk Score can Predict Cost for Patients Submitted to Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

309: Pretransplantation Assessment of Mortality (PAM) Risk Score can Predict Cost for Patients Submitted to Autologous and Allogeneic Hematopoietic Stem Cell Transplantation