Hematopoietic Cell Transplantation Comorbidity Index Score Research Articles

Outcomes in Patients Age 70 or Older Undergoing Allogeneic Hematopoietic Stem Cell Transplantation for Hematologic Malignancies

Allogeneic hematopoietic stem cell transplantation (HSCT) can achieve durable remissions in a number of patients with advanced hematologic malignancies. Little is known about the safety of HSCT in patients age 70 or older. Consecutive patients (n = 54) age 70 or older underwent HSCT between 2007 and 2012. Diseases included acute myelogenous leukemia (n = 25), myelodysplastic syndrome (n = 12), chronic lymphocytic leukemia (n = 5), non-Hodgkin lymphoma (n = 4), acute lymphoblastic leukemia (n = 3), myeloproliferative neoplasm (n = 4), and chronic myelogenous leukemia (n = 1). Median follow-up for survivors was 21 months. All patients received reduced-intensity conditioning regimens, primarily busulfan/fludarabine. All patients received unmanipulated peripheral blood stem cell grafts: 44 from 8/8 matched unrelated donors, 8 from matched related donors, and 2 from 7/8 matched unrelated donors. Graft-versus-host disease (GVHD) prophylaxis was calcineurin inhibitor–based in all patients. The median age at transplantation was 71 years (range, 70 to 76); the median HCT comorbidity index score was 1 (range, 0 to 5). Two patients died before hematopoietic recovery (1 with graft failure and 1 with disease progression), and 1 patient relapsed before hematopoietic recovery; otherwise, all engrafted with median donor chimerism of 94% at 1 month. Cumulative incidence of grades II to IV acute GVHD was 13% and of grades III to IV acute GVHD, 9.3%. At 2 years, the cumulative incidence of chronic GVHD was 36%, progression-free survival was 39%, overall survival was 39%, and relapse was 56%. Nonrelapse mortality was 3.7% at day +100 and 5.6% at 2 years. We conclude that allogeneic HSCT is a safe and effective option for carefully selected patients age 70 or older.

Pretherapy and posttherapy 18F-FDG PET/CT in isolated nasoseptal diffuse large B-cell lymphoma

The hematopoietic cell transplantation comorbidity index (HCT-CI), a weighted index of 17 pretransplantation comorbidities, has been validated in nonmyeloablative and myeloablative allogeneic hematopoietic stem cell transplantation (HSCT) studies, but it has not been specifically tested in patients with non-Hodgkin lymphoma (NHL) receiving reduced-intensity conditioning (RIC). We performed a retrospective analysis to assess the impact of the HCT-CI on outcomes of NHL patients treated with HSCT relative to treatment-related mortality (TRM), disease-related mortality (DRM), with a specific emphasis on overall survival (OS). Individual pretransplantation and disease-related factors also were analyzed with HCT-CI relative to their impact on OS. All patients were uniformly treated with an identical pretransplantation induction regimen and an identical RIC regimen (cyclophosphamide [Cy]/fludarabine [Flu]), and received T cell–replete allografts from HLA-matched siblings. The analysis included 63 NHL patients with a median HCT-CI score of 2 (range, 0 to 11). The HCT-CI (0 to 2 comorbidities vs 3+ comorbidities) demonstrated a potential association with TRM, but not with DRM, at 100 days (4.5% vs 26.3%) and at 1 year (13.6% vs 36.8%) posttransplantation. The factor most strongly associated with OS was response to pretransplantation chemotherapy (P = .0001), based on a composite measure. In a Cox model, pretransplantation chemotherapy response remained the most important factor (P < .0001) relative to OS, and there was a trend (P = .056) toward HCT-CI adding predictive value for OS. Although HCT-CI may be useful for predicting TRM, our data further underscore the importance of response to chemotherapy before transplantation as a predictor of overall transplantation outcome in NHL patients being considered for RIC allogeneic HSCT.

The Combination of the EBMT Score and the HCT-CI Is Not Better Than the HCT-CI Alone in the Prediction of NRM and OS in Patients Undergoing Allogeneic Hematopoietic Transplantation with Reduced-Toxicity Conditioning

AbstractAbstract 1925In recent years, several pre-transplant models have been developed to predict the outcome after hematopoietic cell transplantation (HCT) through the selection of the best candidates and conditioning regimens. Two models are the most popular one each side of the Atlantic: the HCT Comorbidity Index (HCT-CI) and the European Blood and Marrow Transplantation (EBMT) score. Their predictive capacity has been demonstrated in several studies. Since these models are focused on different pre-HCT characteristics (HCT-CI on comorbidities and the EBMT score on more classical risk factors) we hypothesized that the combination of the two could improve their individual predictive capacity.To that end, we retrospectively analyzed pre-HCT characteristics of all consecutive patients receiving a reduced-toxicity allogeneic HCT (allo-HCT) in 4 Spanish centers from 1999–2008. The HCT-CI and the EBMT scores were calculated as originally defined. Patients were then classified according to the HCT-CI in the original categoriesas originally defined and regardingto the EBMT score in two groups according to the median score of the whole cohort. Multivariate analyseis including pre-HCT characteristics were performed using Cox proportional Hazard models and taking into account the competitive risk structure. The predictive capacity of each model was calculated using the c-statistics. Patients were included in the same protocol of reduced-toxicity allo-HCT with fludarabine-based conditioning in combination with melphalan (70–140 mg/m2) or busulfan (8–10 mg/kg). The median follow-up for survivors was 51 months (range 3–123).A total of 442 recipients (80% transplanted from HLA identical siblings) were included. Most frequent diseases were acute leukemia/MDS (n=156, 35%) and non-Hodgkin lymphoma/chronic lymphocytic leukemia (n=125, 28%). The HCT-CI score distribution was: score 0 (n=87, 20%), score 1–2 (n=130, 29%) and score ≥3 (n=225, 51%) while for the EBMT score was 0–2 (n=62, 14%), 3–4 (n=194, 44%) and >4 (n=187, 42%). The probability of 100-day Non-Relapse Mortality (NRM), 4y-NRM and 4y-overall survival (OS) for the whole cohort were 12% (95%CI 11–14), 35% (95%CI 33–38) and 45% (95%CI 48–50), respectively. In the multivariate analysis, the HCT-CI had and impact on 4y-NRM (score 0: HR 1.0; scores 1–2: HR 1.6 [95%CI 0.9–3], p=0.09; scores ≥ 3: HR 2.3 [95%CI 1.3–3.8], p=0.003) and 4y-OS (score 0:HR of death 1.0; scores 1–2: HR 1.3 [95%CI 0.8–2], p=0.2; scores >2: HR 1.9 [95%CI 1.3–2.8], p=0.002) while the EBMT score did not (p=0.4 and p=0.5, respectively).Using the two models we classified the patients were classified into 3 groups: patients with low HCT-CI (0–2) and low EBMT score (<4) (Group 1), patients with high HCT-CI or high EBMT score (Group 2) and patients with both high HCT-CI and EBMT score (Group 3). The HR for 4y-NRM were: group 1 (HR 1.0), group 2 (HR 1.1 [95%CI 0.6–2], p=0.7), group 3 (HR 1.8 [95%CI 1–3], p=0.04) and for 4y-OS was: group 1 (HR 1.0), group 2 (HR 1 [95%CI 0.6–1.5], p=0.8), group 3 (HR 1.6 [95%CI 1–2.3], p=0.04).Regarding the predictive capacity of each model, the HCT-CI alone captured 58% (c- 95%CI: 53–62), the EBMT score 54% (c- 95%CI: 51–58) while the combination of the two models captured 57% (c- 95%CI: 53–61) of the patients.Finally, the impact of EBMT score was explored in each HCT-CI group. In patients with HCT-CI scores of 0 and 1–2, the EBMT score did not have an impact on NRM and OS. In the cohort of high HCT-CI score (>2), patients with low EBMT score showed a trend to lower risk of NRM (HR 0.6 [95%CI 0.3–1], p=0.08) with a similar risk as for patients with HCT-CI of 1–2 (Figure 1).In conclusion, high HCT-CI scores but not high EBMT scores are associated with worse outcome in patients undergoing reduced toxicity allo-HCT. The addition of the EBMT score contributes little to the HCT-CI, except maybe for patients with more and severe comorbidities. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Prospective Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for HCT Outcomes At US Transplant Centers: A Center for International Blood and Marrow Transplant Research (CIBMTR) Study

AbstractAbstract 733In 2005, the HCT-CI was introduced by a single institution as a weighted scoring system to predict mortality risk following allogeneic HCT. Since then, not all investigators were able to validate the HCT-CI after testing in their respective institutions. In 2007, a new prospective multi-institutional observational study was initiated at the CIBMTR to collect comorbidities from all transplant centers by their respective evaluators and to validate the predictive power of the HCT-CI in a large sample of patients (pts). The HCT-CI was adapted into the Pre-Transplant Essential Data (pre-TED) collection form #2400. Data managers from all institutions attended an education session on comorbidity coding per the HCT-CI at the 2007 Tandem BMT Meeting in Keystone, Colarodo. This session was then made public to all data managers at the CIBMTR website. <>The study accrued 8115 consecutive pts treated with allogeneic HCT from 12/2007 to 12/2009 from related (47%) or unrelated (53%) donors. Median age was 52 [range 1–78) years. Conditioning regimens were high-dose (67%) or either reduced-intensity (RIC) or nonmyeloablative (NST) regimens (34%). Diagnoses were acute (54%) or chronic (12%) leukemia, myelodysplastic syndromes (16%), lymphomas (16%), and others (2%). GVHD prophylaxis regimens were cyclosporine-based (22%), tacrolimus-based (68%), or others (10%). Stem cell source was marrow (17%) or peripheral blood mononuclear cells (83%). Karnofsky performance status scores were <90% (33%), ≥ 90% (62%), or missing (5%). HCT-CI scores were 0 (47%), 1 (15%), 2 (11%), 3 (12%), 4 (7%), 5 (3%), ≥6 (4%), or missing (1%). About 11% of pts with score 0 had other comorbidities listed.Overall, pts experienced cumulative incidence of transplant-related mortality (TRM) of 28% and a survival rate of 48% at 3-years. Pts with HCT-CI scores of 0 vs. 1–2 vs. ≥3 had 3-year TRM incidences of 24%, 28%, and 35% (p <0.001) and 3-year overall survival (OS) rates of 54%, 47%, and 38%, respectively (p <0.001, Figure). Proportional hazards models were used to estimate the hazard ratio (HR) for TRM and OS associated with HCT-CI scores. The models were adjusted for all previously mentioned covariates in addition to disease status, CMV serology status, gender, and race. Increasing HCT-CI scores (1–2 and ≥3 vs. 0) were associated with increases in the HR [95% confidence interval (CI)] for TRM [1.12 (1.00–1.26) and 1.47 (1.31–1.65), respectively, p<0.0001] and OS [1.12 (1.03–1.22) and 1.36 (1.25–1.48), respectively, p<0.0001] in the overall pt population. No statistically significant difference could be detected between pts with score 0 + other comorbidities vs. score 0 for TRM (HR 0.93, p= 0.385) or OS (HR 0.96, p= 0.474). When the HCT-CI was modeled as scores of 0, 1, 2, 3, 4, and ≥5 the HR for TRM were 1.00 vs. 1.12 vs. 1.13 vs. 1.31 vs. 1.52 vs. 1.77, respectively (, p<0.0001) and for OS were 1.00 vs. 1.13 vs. 1.12 vs. 1.22 vs. 1.39 vs. 1.62 (p<0.0001). Likewise, the HCT-CI could discriminate outcomes well among pts given high-dose or RIC/NST regimens and those diagnosed with lymphoid or myeloid diseases (Table 1).The inter-rater reliability (IRR) rate among data managers versus their respective investigators was assessed in 3 institutions. Weighted kappa statistics were 0.54, 0.81, and 0.47 respectively, indicating fair-moderate agreement rate among evaluators.The HCT-CI is a valid tool to discriminate relative risks for TRM and OS after HCT across different institutions, different conditioning intensities, and different diagnoses. The HCT-CI should be used as a standard-of-care health measure in counseling pts for HCT, in clinical trial design, and in adjusting statistical analyses for HCT outcomes. Future efforts will focus on improving the IRR of the HCT-CI.Table 1:Multivariate analysesTRMOSHCT-CI scoresHRp-valueHRp-valueHigh-dose regimens01.00<0.00011.00<0.000111.191.1421.121.1031.341.1941.531.415+1.881.64RIC/NST regimens01.000.0011.00<0.000110.951.1221.101.1231.271.2741.461.395+1.661.65Lymphoid diseases01.00<0.00011.00<0.000111.161.1521.241.1231.371.3242.131.675+2.151.88Myeloid diseases01.00<0.00011.00<0.000111.121.1321.001.0631.251.1441.291.275+1.631.52 [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) Can Prospectively Discriminate Risks Affecting Overall Survival in Pediatric and Adult Patients with Non-Malignant Diseases

AbstractAbstract 737The HCT-CI was developed to summate the effect of 17 weighted comorbidities on non-relapse mortality and overall survival (OS) in the allogeneic HCT setting. However, only 3% of patients included in the initial HCT-CI study had non-malignant diseases (Sorror M. et al, Blood 2005). In an attempt to broaden the application of HCT-CI by assessing its prognostic effect on overall mortality in patients with nonmalignant diseases, we conducted a prospective observational study collecting comorbidities on all patients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) from December 2007 to December 2009. A total of 853 patients with non-malignant diseases were identified, including severe aplastic anemia (SAA, n=404); inherited disorders of erythrocytes (n=180), histiocytes (n=68), metabolism (n=41), and platelets (n=6); primary immune deficiencies (n=149); and autoimmune diseases (n=5). Patients were transplanted at a median of 12 (<1–70) years of age (72% of patients were less than 20 years of age at HCT), and a median of 10 (<1–500) months from diagnosis. Donors were unrelated (n=414), HLA-matched siblings (n=356), other relatives (n=76), or syngeneic (n=7). Transplant regimens were predominantly fludarabine (Flu) and total body irradiation (n=144); Flu and melphalan (n=140); busulfan and cyclophosphamide (CY, n=138); CY and antithymocyte globulin (n=137) for conditioning, and methotrexate with cyclopsporine (n=279) or tacrolimus (n=160) for post-grafting immunosuppression, respectively. Karnofsky/Lansky scores were ≥90% in 77% of patients. HCT-CI scores were 0 (64%), 1 (13%), 2 (6%), 3 (8%), 4 (5%), and ≥5 (4%). The top three HCT-CI comorbidities reported were active infection (8%) and pulmonary disease (severe 8% and moderate 7%). With a median follow-up of 27 (1–51) months, the OS for HCT-CI 0 (n=546), 1–2 (n=161), and ≥3 (n=144) at 3 years was 85%, 81%, and 63%, respectively (figure, p<0.001). Multivariate analyses were adjusted for age, conditioning regimen, donor type and HLA-match status. In these analyses, higher HCT-CI scores were associated with increased overall mortality as judged by increasing hazard ratios (HR, p<0.001) compared to patients with HCT-CI of 0. This was mostly a result from the effect of HCT-CI scores of ≥3 (HR 2.54, 95% Confidence Interval [CI] 1.68–3.83; p<0.0001) than from HCT-CI scores of 1–2 (HR 1.15; 95% CI 0.72–1.82 p=0.56). The negative effect of HCT-CI scores ≥ 3 on OS was preserved in subgroup analyses of pediatric (<20 years old; HR 2.43, 95% CI 1.30–4.54, p<0.005) and adult patients (≥20 years old; HR 2.91, 95% CI 1.56–5.41, p<0.001), and in SAA (HR 2.91, 95% CI 1.56–5.41, p<0.001). In conclusion, in a relatively large sample size, this study demonstrates that HCT-CI can also be used to predict OS in patients with non-malignant diseases. In particular, patients with HCT-CI scores of ≥3 experienced higher overall mortality independent of age group, conditioning regimen, donor type and HLA matching. HCT-CI is an important instrument to assist in patient counseling and transplant associated risk assessment in patients with nonmalignant diseases. [Display omitted] Disclosures:Pasquini:Miltenyi Biotec: Consultancy, Honoraria.

A Novel Reduced Intensity Conditioning Regimen Induces a High Incidence of Sustained Donor Neutrophil and Platelet Engraftment After Double-Unit Cord Blood Transplantation

AbstractAbstract 4155 Introduction:Cord blood (CB) transplant (CBT) can be curative for patients with high-risk hematologic malignancies. However, patients of older age and/or with significant co-morbidities do not tolerate CBT with high-dose myeloablative conditioning. Non-myeloablative (NMA) conditioning can reduce transplant-related mortality (TRM) and extend transplant access to older or infirm patients, but it is limited by the risks of graft rejection in patients without extensive prior chemotherapy and relapse. While the addition of anti-thymocyte globulin (ATG) may reduce rejection, it increases the risk of viral infections, including Epstein-Barr virus lymphoproliferative disease, and may also increase relapse risk. Methods:We investigated the safety and efficacy of an ATG-free regimen of intermediate intensity prior to double-unit CBT in 30 patients with acute leukemias and myelodysplasia. Units were 4–6/6 HLA-A, B antigen, DRB1 allele matched to the patient. The conditioning regimen included cyclophosphamide 50 mg/kg (day -6), fludarabine 30 mg/m2/day × 5 (days -6 to -2), thiotepa 5 mg/kg/day × 2 (days -5 and -4), total body irradiation 200 cGy × 2 (days -2 and -1), and cyclosporine-A/mycophenolate mofetil immunosuppression. The indication for this regimen was one or more risk factors for TRM including age > 50 years, extensive prior therapy, and/or significant co-morbidities. The hematopoietic cell transplant co-morbidity index (HCT-CI) score of Sorror was retrospectively assigned. Results:The median age was 56 years (range 18–69). All but one patient had high-risk disease. Twenty-one had AML (16 CR1, 5 CR2) with all CR1 patients having high-risk features, including high-risk cytogenetics (n = 3), FLT-3 ITD mutation (n = 5), therapy-related disease or prior MDS (n = 6), and/or > 3 consecutive induction chemotherapies (n = 2). Five had ALL (4 CR1, 1 CR3); the 4 in CR1 had BCR/ABL mutations (n = 3) or prior refractory CNS disease (n = 1). Four patients had MDS with 3 having an IPSS score > 2. The median HCT-CI score was 2.5 (range 1–5). Median infused TNC doses were 2.6 (larger unit) and 1.9 (smaller unit) × 107/kg, respectively. Ninety-seven percent of patients engrafted (95%CI: 87–100) at a median of 26 days (range 13–43). The median day 21 total donor bone marrow chimerism was 100% (range 71–100). All surviving patients were 100% donor by day 100, and sustained hematopoiesis has been mediated by a single unit in all but one patient. The cumulative incidence of platelet recovery > 20 × 109/L by day 180 was 93% (95%CI: 83–100), and occurred at a median of 46 days (range 30–79). Day 180 TRM and 2-year relapse incidences were 20% and 11%, respectively. With a median 26.5 months (range 9–53) follow-up of survivors, the 2-year overall survival and disease-free survival (DFS) are both 60% (95%CI: 44–82). There was a hierarchy in 2-year DFS according to the Sorror HCT-CI score (Figure): the 11 patients (median age 55 years) with a score of 1 had a DFS of 82%. This compared with a 2-year DFS of 62% in the 9 patients (median age 51 years) with a score of 2–3, and 40% in the 11 patients (median age 58 years) with a score of 4–5 (p = 0.13). Discussion:This reduced intensity regimen combined with double-unit CBT reliably facilitates sustained donor engraftment without ATG. This regimen is associated with less toxicity than high-dose myeloablative conditioning. While other approaches are needed in patients with high comorbidity scores, this regimen is highly effective in older patients who are otherwise reasonably fit, as evidenced by the 82% 2-year DFS in patients with a median age of 55 years. Given the relatively low risk of relapse, it also represents a promising alternative to high-dose conditioning in younger patients. [Display omitted] Disclosures:Giralt:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Membership on an entity's Board of Directors or advisory committees.

Prediction of Non-Relapse Mortality in Recipients of Reduced Intensity Conditioning Allo-HSCT with Acute Myeloid Leukemia in First Complete Remission: Integrating the Seattle Comorbidity Index (HCT-CI) and EBMT Scoring Systems

AbstractAbstract 734Acute myeloid leukemia (AML) in first complete remission (CR1) has become the dominant indication for alloHSCT and an increasing number of patients currently receive reduced- intensity conditioning (RIC), because of age or pre-existing comorbidities. While relapse after alloHSCT is mainly determined by the underlying cytogenetic and molecular AML profile, non-relapse mortality (NRM) is mainly determined by pre-existing comorbidities in addition to patients' characteristics and transplant-related complications. In order to assess the risk of NRM prior to transplantation, predictive scores, including the Seattle hematopoietic cell transplantation comorbidity index (HCT-CI) and the European Group for Blood and Marrow Transplantation (EBMT)-score, were developed. In the present study, the EBMT acute leukemia working party set out to evaluate the predictive value of both scores and, next, to integrate the predominant parameters of each score into a novel score.Five hundred and sixty recipients of RIC-alloHSCT between 2000 and 2010 with AML in CR1, for whom both scores were assessed prior to transplantation, were included. The median follow-up was 35 (range 2–124) months. In this cohort, leukemia free survival (LFS) at 2 years was 55±2%, and the cumulative incidences (CI) of relapse, and NRM were 29%±2% and 16±2%, respectively. Of note, NRM continued to increase beyond 2 years and reached 21±2% at 5 years. The 2-year NRM split by HCT-CI score estimated 13±3%, 16±2%, and 17±3%, for patients with scores 0, 1–2, and >3, respectively, with relatively poor predictive value. The 2-year NRM split by EBMT-score estimated 13±2%, 17±2%, and 27±8% for patients with scores 2, 3, and >4, respectively, also bearing weak predictive value.Next, we assessed the relative value of each of the contributing individual parameters by multivariable analysis (according to the Fine & Gray method), which resulted in the identification of 13 parameters with a Hazard Ratio (HR) >1. These parameters included 9 specific comorbidities from the Seattle HCT-CI, but also age, donor-type, interval from diagnosis to transplant, and CMV-serology as delineated in the EBMT scoring system. The integration of these parameters into a novel score was evaluated first in a development cohort of 373 patients and subsequently validated in the remaining 187 patients. Patient’s characteristics in the development and validation cohorts were not statistically different.Overall, the median age was 58 (range 23–76) years, and median interval from diagnosis to transplant was 164 days. 229 patients received grafts from HLA-identical sibling donors and 144 patients from unrelated donors. 268 patients had a positive CMV-serology. Comorbidities with HR >1 included infection history (n=142), peptic ulcer (n=15), cerebrovascular disease (n=17), arrhythmia (n=25), severe liver function abnormalities (n=15), obesity (n=25), rheumatological disease (n=15), heart valve disease (n=29), and renal disease (n=23). Of note, co-occurrence of comorbidities was observed frequently in patients with a history of infection, pulmonary disease and cardiac disease, occurring in 161, 100, and 82 patients respectively, in addition to one or more comorbidities.Per study definition, each significant parameter was attributed 1, 2 or 3 points, as determined by its quantified HR. Combining all significant parameters into an integrated score, NRM estimated 9±2% at 2 years for low-risk patients with scores 0–2, 15±4% for intermediate-risk patients with score 3, and 28±4% for high-risk patients with a score of 4 points or more. NRM increased to 11±2%, 24±4% and 36±4% in the low-, intermediate- and high-risk cohorts, respectively, at 5 years from transplant. A further refined statistical analysis indicated relatively strong predictive values both in the sample and validation cohort. The integrated score did not predict for relapse, but proved to be significantly associated with LFS.Collectively, this analysis demonstrates that both HCT-CI and EBMT risk scores were relatively weak predictors of NRM in a large cohort of 560 AML-CR1 patients receiving RIC-alloHSCT. However, integration of the most dominant parameters from each score into a new, integrated score yielded a stronger risk categorization that significantly predicted for NRM at 2 years post-transplantation, and also at 3 and 5 years post-transplantation with increasing NRM at those time points. Disclosures:No relevant conflicts of interest to declare.

Intermittent Zolendronic Acid (ZA) for the Prevention of Osteoporosis After Allogeneic Hematopoietic Cell Transplantation (HCT)

AbstractAbstract 1965Bone mineral density (BMD) loss, osteoporosis, and avascular necrosis (AVN) of bone are relatively common in long term survivors of HCT with up to one half of recipients suffering post HCT bone loss. We performed a multi center phase II randomized open label trial of intravenous zolendronic acid (ZA) to prevent BMD loss in recipients of allogeneic HCT with pre-existing osteopenia prior to HCT. Methods:Eligible adult (>18 years) patients had baseline pre-transplant osteopenia defined as a T-score < −1 SD and > −2.5 SD (WHO definifition) at either the lumbar (L) spine and/or the proximal femur at a pre HCT screening evaluation with a dual energy X-Ray absorptiometry (DEXA) scan. Patients were eligible irrespective of donor source, stem cell type, or conditioning regimen intensity. Patients with myeloma, baseline renal dysfunction or concomitant active dental or endocrine issues precluding the use of ZA were excluded. Subjects were allocated by block randomization stratified by center and type of conditioning (myeloablative vs. non-myeloablative) to the treatment or control arms.Both treatment and control groups received 1000 mg of calcium and 400 – 500 IU of vitamin D orally daily and were encouraged to remain active and refrain from tobacco smoking and alcohol. Additionally subjects randomized to the treatment arm received ZA 4 mg iv over 15 minutes within 28 days pre-HCT and at 3 and 6 months (mo) after HCT. Control subjects did not receive ZA or other additional therapy for bone strength. ZA dose was modified for post HCT renal dysfunction.Primary outcome measure was change in BMD from baseline to 12 mo after HCT. Serum osteocalcin, serum bone specific alkaline phophatase (BSAP), and urinary N telopeptide (UNTX) were measured at baseline and at 6 and 12 mo. Results:Between 2006 and 2010, 61 patients were randomized – 32 to the ZA treatment cohort and 29 to the control arm. Cohorts were balanced for age, sex, performance score, donor type, diagnoses and conditioning regimen intensity. HCT co-morbidity index (HCTCI) was significantly worse in the ZA arm (50% with high risk scores > 3). Baseline BMD, T scores at the femoral neck and lumbar spine, urinary NTX, serum osteocalcin and BSAP were similar in both cohorts.Differences between cohorts in bone density and bone specific laboratory parameters at 12 mo post HCT are summarized in Table 1. There was significant increase in BMD at the femoral neck and lumbar Spine; with concomitant decease in bone resorption markers for the treatment group (ZA cohort). Incidences of acute and chronic graft vs. host disease and relapse rates were similar between cohorts. There was significantly higher 1 year mortality in the ZA cohort (15 deaths vs. 6 in the control cohort). Thus overall survival was inferior in the ZA cohort 43% vs. 75% at 2 years post HCT. Grade 3–4 adverse events were similar. Conclusions:We randomized HCT recipients at high risk of post transplant bone loss to receive 3 doses ZA starting prior to HCT. ZA prevented further bone loss and resulted in improvement in BMD and T scores as well the bone resorption marker, urinary NTX. Lower survival was observed in the ZA cohort likely related to baseline imbalance in pretransplant HCTCI scores. ZA was well tolerated and not associated with any cases of osteonecrosis of jaw, renal impairment or other serious adverse events. We conclude that intermittent ZA is effective in preserving long term bone health in HCT recipients at risk for osteoporosis.Table 1ParameterDifference from baseline to 12 moP ValueZA cohortStandard of CareBMD L Spine0.048−0.057<0.01T score L Spine0.55−0.45<0.01Z score L Spine0.50−0.200.06BMD Femoral0.018−0.0540.04T score Femoral0.20−0.400.02Z score Femoral0.30−0.300.03S. Osteocalcin−11−4.10.44S.BSAP−3−30.66Urine NTX−56−90.04 Disclosures:Hari:Novartis: Research Funding. Vesole:Novartis: Research Funding. Burns:Novartis: Research Funding.

Prognostic factors in patients aged 50 years or older undergoing allogeneic hematopoietic stem cell transplantation for hematologic malignancy

We retrospectively analyzed patients aged C 50 years with hematologic malignancies who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) to identify preoperative variables predicting the outcome. There were 71 patients with a median age of 57 years (range: 50-63 years) who had acute leukemia (n = 53) or myelodysplastic syndrome (n = 18). Myeloablative conditioning was done in 35 patients and 36 patients had reduced-intensity conditioning. The 5-year overall survival rate (OS), cumulative relapse rate, and non-relapse mortality rate (NRM) were 45, 24, and 33%, respectively. According to multivariate analysis, high-risk disease (HR 3.50, 95% CI 1.43-8.56, P = 0.006), a hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥ 3 (HR 4.41, 95% CI 1.31-14.77, P = 0.016), and an HLA-mismatched unrelated donor (HR 4.03, 95% CI 1.46-11.10, P = 0.007) were significant predictors of worse OS. Highrisk disease was also significantly associated with a higher cumulative relapse rate (HR 4.59, 95% CI 0.94-6.92, P = 0.065). Furthermore, an HCT-CI score ≥ 3 (HR 3.02, 95% CI 1.01-20.78, P = 0.048) and an HLA-mismatched unrelated donor (HR 3.02, 95% CI 1.04-8.74, P = 0.042) were risk factors for NRM. These results suggest that the disease risk, HCT-CI score, and donor type/histocompatibility are prognostic factors for elderly patients, while the conditioning regimen and age are not predictors.

The hematopoietic cell transplantation comorbidity index is a predictor of early death and survival in adult acute myeloid leukemia patients

The hematopoietic cell transplantation comorbidity index (HCT-CI) is predictive of early death and survival in elderly patients with acute myeloid leukemia (AML). The aim of this study was to determine the prognostic role of the HCT-CI for early death and survival in adult AML patients. In the single-center retrospective study, we analyzed the outcome of 233 adult AML patients. The results indicated that the HCT-CI score is an independent predictor of early death in entire cohort of adult patients with AML. In subgroup analysis, HCT-CI is an independent predictor for early death in elderly patients but not in patients younger than 60 years. A high HCT-CI score predicts shorter survival in adult patients with AML.

Multi-Institutional Validation of the Predictive Power of the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) for HCT Outcomes

Abstract 145▪▪This icon denotes a clinically relevant abstractIn 2005, the HCT-CI was introduced as a weighted scoring system to predict mortality risk following allogeneic HCT. Since then, not all investigators were able to validate the HCT-CI after testing in their respective institutions. In 2007, a collaborative multi-institutional study was initiated to investigate 1) whether the HCT-CI was predictive of outcomes across different institutions, 2) the degree of homogeneity of outcome prediction, and 3) the reasons for lack of agreement among investigators. To this end, data were collected from 3347 consecutive patients (pts) treated with allogeneic HCT between 2000 and 2006 from HLA-matched related or unrelated donors at 5 institutions. All data were collected by a single investigator, blinded from the final outcomes of pts, to ensure consistent comorbidity coding. Numbers of pts, percentages of available comorbidity data, and other transplant and pt characteristics were statistically significantly different among institutions (Table 1). Pts missing comorbidity or other covariate data were excluded from further analyses, yielding a final sample size of 2523.Table 1:Pre-transplant risk factors among the five institutionsInstitutionsA (n=1073), %B (n=973), %C (n=336), %D (n=237), %E (n=206), %pMissing comorbidity data<1202623<0.001HCT-CI scores02930324232<0.0011,23428292822≥33743393046DonorUnrelated5038514031<0.001Age, years≥504229472151<0.001Conditioning RegimensHigh-dose5367796746<0.001Reduced-intensity1329101331Nonmyeloablative344102123ATG in regimen11431514<0.001DiagnosesMyeloid6356595751<0.001Lymphoid2841382546Other cancers23131Non-malignant diseases702154Disease riskHigh5962675167<0.001Stem cell sourceMarrow1919245610<0.001Pt CMVPositive5673706551<0.001KPS≤802918303825<0.001Prior regimens≥423222420300.25Overall, pts with HCT-CI scores of 0 vs. 1–2 vs. ≥3 had 2-year non-relapse mortality (NRM) rates of 14%, 23%, and 39% (p <0.0001), respectively, and 2-year overall survival (OS) rates of 74%, 61%, and 39% (p <0.0001), respectively. Proportional hazards models were used to estimate the hazard ratio (HR) for NRM and OS associated with HCT-CI scores in each of the 5 institutions (Table 2). The models were adjusted for covariates in Table 1. Increased HCT-CI scores were associated with increases in the HR for NRM and OS across all 5 institutions and these increases were highly statistically significant except for institution E, which had the smallest sample size. Of note, the magnitudes of increases in HRs were not entirely comparable across institutions. In a unified model including all institutions, we found a statistically significant lack of homogeneity across institutions for the HRs associated with scores 1–2 (p=0.03) and ≥3 (p=0.04) for NRM and with scores ≥3 (p=0.01) for OS but not with scores 1–2 for OS (p=0.18). We also found a statistically significant, independent impact of institution on NRM (p=0.001) and OS (p<0.001).Table 2:Multivariate risk modelInstitutionsNRM HROverall survival HRHCT-CI scores01–2≥3p01–2≥3pA1.01.42.5<0.00011.01.362.23<0.0001B1.02.884.15<0.00011.01.882.77<0.0001C1.01.33.62<0.00011.01.333.28<0.0001D1.01.656.89<0.00011.01.845.81<0.0001E1.01.762.660.091.01.132.280.09We then assessed, among 80 pts from institution A, the inter-observer variability in scoring comorbidity between two individual investigators and between each of them and unknown individuals from a pool of other evaluators. Weighted kappa statistics were highest (0.59) between two single evaluators and lowest between each and multiple evaluators (0.43 and 0.55, respectively). The principal investigator then developed a comprehensive guideline to code comorbidities and used it to train the other single investigator in a single session. Additional evaluation of inter-observer agreement demonstrated marked improvement of the weighted kappa statistic to 0.78. The reported disagreements on the validity of the HCT-CI may be explained by different institutional experiences in managing transplant pts, small number of pts at some institutions, and inter-observer variability in score assignment.The HCT-CI is valid to discriminate relative risks of mortalities after HCT across different institutions and should be used regularly for counseling pts and clinical trial design. Efforts to improve methods for coding comorbidity are in progress. Disclosures:No relevant conflicts of interest to declare.

T-Cell Replete Haploidentical Transplantation Using Post-Transplant Cyclophosphamide Results in Equivalent Non-Relapse Mortality and Disease-Free Survival Compared to Transplantation From HLA-Identical Sibling and Matched Unrelated Donors: A Stratified Cox Model Analysis of Two Hundred and Sixty Contemporaneous Allogeneic Transplants From a Single Center

Abstract 833HLA-identical siblings (MRD) or 10 of 10 HLA - A, B, C, DRB1 and DQB1 matched unrelated volunteers (MUD) are considered optimal donors for patients who may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). However, many patients, particularly those from ethnic minorities and mixed race backgrounds, will lack such donors.HLA-haploidentical (Haplo) relatives are available for virtually all patients. Traditional approaches to allo-HCT using Haplo donors have entailed stringent ex-vivo T-cell depletion and intense preparative regimens. Such transplants have been associated with slow immune reconstitution and a high-risk of opportunistic infections and non-relapse mortality (NRM). Recently, another approach to haploidentical transplantation using T-replete grafts and post-transplant cyclophosphamide (Cy) to prevent graft versus host disease (GVHD) and rejection has demonstrated promising results (Brunstein et al Blood 2011, vol118, p 282).Forty-Five patients underwent first allografts with a Haplo donor at our center between 02/05 and 08/10 (median age=46, range 20–73; diagnoses were AML 14, ALL 6, CML 4, MDS 4, CLL 7, NHL 4, HD 6; median KPS 90, range 70–90; CIBMTR disease risk score low 14, intermediate 7, high 24; median hematopoietic cell transplant co-morbidity index (HCTCI) score = 1, range 0–5; prior autotransplant = 7). Twenty-seven patients received a reduced-intensity conditioning regimen (RIC): fludarabine 30 mg/m2/d d −6 to −2; TBI 200cGy d-1, Cy 14.5 mg/kg/d on d-6,-5 and 50mg/kg/d on d+3,+4 with a bone marrow graft. Eighteen patients received myeloablative conditioning where the above regimen was modified by replacing low-dose TBI with iv busulfan 110–130 mg/m2/d × 4 days and bone marrow was replaced with G-CSF mobilized PBSC as the graft. Two patients receiving RIC failed to engraft and developed autologous hematopoietic recovery. All other patients engrafted with median 100% donor T-cell chimerism from initial testing at d+30. Outcomes of the Haplo transplants were compared to contemporaneous first allografts from MRD (n=115) and MUD (n=99) at our center. Median follow-up for surviving patients was 36 months (range 9–74.5 months). Cumulative probability of NRM at 36 months was 16%, 19% and 8% for MRD, MUD and Haplo respectively (p=NS) (see Fig). For both overall survival (OS) and disease-free survival (DFS), the effects of patient and disease characteristics were evaluated in Cox models with three transplant groups as strata. HCTCI score, CIBMTR risk category, type of diagnosis were identified as significant covariates on both OS and DFS, while age was significant on DFS only. The adjusted probabilities of OS and DFS were estimated from the stratified Cox models, weighted by the proportions of the significant covariates in the pooled sample. MRD had statistically superior OS to Haplo at 18 months (79% vs. 61%, p=0.033 in point wise comparison). However, adjusted OS was not significantly different between the three types of transplant at 36 months (71%, 58% and 58% for MRD, MUD and Haplo respectively (p=NS)). Adjusted DFS at 36 months was 47%, 46% and 55% respectively (p=NS) (see Fig). Ninety-three patients (35.7%) suffered relapse or progression of their malignancy at a median of 154 days post transplant (range 12–1445 days). Estimated cumulative incidence of relapse at 36 months was 35%, 38% and 36% respectively for MRD, MUD and Haplo (p=NS) (see Fig). The inverse probability of censoring weighted (IPCW) method was used to determine survival following relapse/progression in each group. Estimated survival at 1 year following relapse was 71%, 64% and 15% (p<0.0001 pointwise comparison for MRD vs. Haplo and MUD vs. Haplo).This study demonstrates that excellent NRM and DFS can be achieved using haploidentical donor transplantation with the above regimens. These outcomes are equivalent to those obtained in contemporaneously transplanted MRD and MUD at our center. T-cell replete haploidentical transplant is therefore a valid alternative for patients who lack a conventional donor. Survival following relapse/progression is inferior following haploidentical than conventional donor transplants. This may at least partly be related to the difficulty in using DLI following relapse in haploidentical transplants. Future strategies to improve outcomes following haploidentical transplants should focus on treatment approaches following relapse. [Display omitted] [Display omitted] Disclosures:Bashey:Otsuka America Pharmaceuticals, Inc: Research Funding. Sizemore:Otsuka America Pharmaceuticals, Inc: Research Funding. Manion:Otsuka America Pharmaceuticals, Inc: Research Funding. Brown:Otsuka America Pharmaceuticals, Inc: Research Funding. Holland:Otsuka America Pharmaceuticals, Inc.: Research Funding. Solomon:Otsuka America Pharmaceuticals, Inc: Research Funding. Morris:Otsuka America Pharmaceuticals, Inc: Research Funding.

Hematopoietic Cell Transplantation Co-Morbidity Index (HCT-CI) to Predict Non Relapse Mortality After Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Abstract 4561 Introduction:In recent decades, several advances were made in the management of patients (pts) who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Despite that, the transplant related mortality (TRM) is not negligible. Tools that could predict TRM, based on pre HSCT characteristics and co-morbidities were always sought. Some of these tools are the modified hematopoietic cell transplantation co-morbidity index (HCT-CI). Objectives:To apply the modified HCT-CI and correlate it with overall survival (OS) and non-relapse mortality (NRM). Pts and Methods: This analysis include patients who received allogeneic HSCT, for malignant and non malignant hematological diseases, after high or low dose conditioning regimens, from related and unrelated donor, at the HSCT unit of the University Hospital of Campinas between 1993 to 2010. The conditioning regimens and graft versus host disease (GVHD) prophylaxis were selected according to ongoing protocols at the University Hospital. Informed consent for transplant was obtained from all patients. We defined low dose conditioning regimen as follow: busulfan dose < 9 mg/kg, melphalan dose < 150mg/m2, and total body irradiation dose of 2Gy. All patients received cyclosporine-A (CsA) with methotrexate or CsA with mycophenolate mofetil as GVHD prophylaxis. Screening for cytomegalovirus with antigenemia and preemptive treatment with ganciclovir were made for all patients. Prophylaxis for Candida infections was made with fluconazole; for bacterial infections ciprofloxacin was used. Prophylaxis for Pneumocystis jirovecii was made with sulfamethoxazole and trimethoprim. For viral agents as herpes simplex virus and varicella zoster virus, acyclovir was used. The diagnosis and clinical grading of acute and chronic GVHD were performed using standard criteria. Information on co morbidities was extracted, retrospectively, from medical charts. Each co-morbidity was assigned an integer weight, based on derived scores from Sorror et al. The HCT-CI score was the sum of this integer weights, and the patients were then assigned to one of the risk groups: 0, 1, 2 and 3 or more. Kaplan-Meier was applied for estimation of overall survival. NRM was estimated by cumulative incidence considering primary relapse disease as competing risk. Results:457 pts were analyzed at the beginning. However, 331 (72.4%) were evaluable, 126 (27.6%) were excluded when at least one parameter was missing. 208 (63%) were male with a median age of 36.5 (5–65) years, 249 (75%) pts received high dose (HD) conditioning and 82 (25%) low dose (LD). Distribution of diseases in the HD was: 110 (44%) acute leukemias; 109 (43%) CML and 30 (13%) others; LD was: 42 (51%) severe aplastic anemia; 14 (17%) lymphomas; 12 (15%) myeloma and 14 (17%) others. HCT-CI in HD was: 127 (51%) score 0; 39 (16%) score 1; 19 (7%) 2 and 64 (26%) score ≥ 3; in LD 33 (40%) score 0; 14 (17%) score 1; 8 (10%) score 2 and 27 (33%) score ≥ 3. The median follow up in HD was 22 months (0–201) and 9 (0–203) in LD. The adjusted OS at 10 year for HD conditioning according to the HCT-CI was 55% for score 0, 34% for score 1–2 & 34% for score ≥ 3 and for LD conditioning was 58% for score 0, 53% for score 1–2 & 15% for score ≥ 3 (P< 0.0001). The NRM rate in the HD cohort was 32% in the pts with a score 0, 42% for score 1–2 and 53% in the score ≥ 3. In the LD cohort, the NRM was 23% in the pts with a score of 0; 35% for score 1–2 and 54% in the score ≥ 3 (P= 0.002). The adjusted OS for conditioning type in patients with cardiac valve disease was associated to a lower OS (29% and 33% P= 0.002) whereas mild hepatic involvement was just significant in the HD cohort. Conclusion:The OS and NRM were worse for score ≥ 3 either in HD and LD groups. The heart valve disease emerged as a worse outcome in both conditioning type and mild hepatic involvement only in HD group. The HCT-CI showed to be a valid tool to predict outcome after allogeneic HSCT. Disclosures:No relevant conflicts of interest to declare.

Hematopoietic Cell Transplantation After Reduced Intensity Conditioning for Severe Paroxysmal Nocturnal Hemoglobinuria:

Abstract 2047 Objectives:Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare acquired clonal hematopoietic stem cell disease. Patients may present with intermittent hemolysis, thrombotic events or cytopenias. The manifestations can be life threatening. Hematopoietic Cell Transplantation (HCT) is still the only curative therapy. Hegenbart et al reported early results in 7 patients with PNH with high risk features who received transplants from matched related (n=2) or unrelated donors (n=5) after conditioning with a fludarabine / total body irradiation (TBI) based regimen (Biol Blood Marrow Transplant 2003; 9: 689–697). Here we update the data and report outcomes in 12 additional patients. Patients:Nineteen patients diagnosed with severe PNH underwent allogeneic HCT after a reduced intensity conditioning (RIC) regimen. Patients were treated at 9 centers. Eighteen patients had at least 1 high-risk feature (Table), 1 patient had none but underwent transplant because of severe hemolysis prior to the era of eculizumab. Conditioning consisted of fludarabine (30 mg/m2/d) on days −4 to −2 before HCT and 2 Gy (n=16) or 4 Gy (n=3) of TBI on day 0 (n=16) followed by treatment with mycophenolate mofetil and cyclosporine or tacrolimus. All patients received peripheral blood stem cells (PBSC). Donors were HLA-matched related (n=3), HLA-matched unrelated (n=12) or HLA-mismatched unrelated (n=4). Results:The follow-up period ranges between 2 months and almost 10 years (median 27.5 months) after HCT. Neutropenia (absolute neutrophil count<500/μl) developed in 15 of 19 patients after transplantation. The median time to neutrophil recovery in patients who engrafted was 16 days (range 0–29) with a median duration of neutropenia of 12 days (range 0–17, n=12). The median duration of thrombocytopenia (platelet count <20,000/μl) was 3 days (range, 0 to 10 days, n=12). All but 2 patients (89.5%) had a sustained engraftment. One patient experienced primary graft failure and remained neutropenic. He received a second nonmyeloablative HLA-matched unrelated PBSC transplant, 47 days after the first transplant, from a different donor, with 3 Gy TBI and 90mg/m2 fludarabine, and had sustained engraftment. The second patient experienced after engraftment, late graft failure 6 months after HCT. She underwent, 7 months after the first transplant, a second nonmyeloablative, HLA- matched unrelated PBSC transplant, from a different donor, with 4 Gy TBI and 150mg/m2 fludarabine, and had sustained engraftment. Eighteen patients were assessable for acute graft-versus-host disease (GvHD). The incidence of grades 2, 3, and 4 acute GvHD were 22% (4/18), 17% (3/18), and 5% (1/18), respectively. Chronic GvHD developed in 78% (14/18) of evaluable patients. Fifteen patients (78.9%) are alive at the time of last follow-up (Fig.). None of the 15 patients still alive has any evidence of relapse, clinically nor by flow cytometry. Four patients died (21.1%) of complications (necrotizing pancreatitis of unknown cause, pseudomonas infection during treatment of chronic GvHD, hemorrhage after liver biopsy with subacute/chronic liver GvHD, intracerebral bleed). All 15 surviving patients have an ECOG performance status of 0 or 1. [Display omitted] Conclusion:The RIC regimen reported here is well tolerated and leads to a high rate of successful engraftment. The graft-versus-host effect seems to be sufficient to eradicate the PNH clone. This regimen may be equally effective in medically fit PNH patients to eradicate the PNH clone while reducing treatment related complications of higher intensity conditioning regimens. Note:1st 3 authors contributed equally.TablePatient and disease characteristicsCharacteristicNumber (n=19)PercentageSexMale526Female1474Age, yearsMedian34Range19–67Number of high risk features1015110632726315ThrombosisYes1047No953Treatment prior to transplantSteroids1684CSP842ATG2516MMF15Azathioprine15Danazol15IVIG315Eculizumab210MyelodysplasiaYes626No1374HCT-CI40-16233+6Not available4[1]High risk features are occurrence of thrombosis (relative risk [RR] 10.2), evolution to pancytopenia (RR 5.5), myelodysplastic syndrome or acute leukemia (RR 19.1), age over 55 years at diagnosis (RR 4), more than one treatment (RR 2.1), and thrombocytopenia at diagnosis (RR 2.2).2Antithymocyte globulin.3Intravenous immunoglobulin.4Hematopoietic Cell Transplant-Comorbidity Index score. Disclosures:No relevant conflicts of interest to declare.

Survival benefits from reduced-intensity conditioning in allogeneic stem cell transplantation for young lower-risk MDS patients without significant comorbidities

The aim of this study was to determine the optimum conditioning intensity for allogeneic stem cell transplantation (SCT) in young (age ≤50), lower-risk (INT-1 by IPSS) Myelodysplastic syndrome (MDS) patients without significant comorbidities (hematopoietic cell transplantation-comorbidity index score ≤3). Transplant outcomes from 46 consecutive patients were retrospectively analyzed according to the conditioning intensity: reduced-intensity conditioning (RIC; n = 14), intensified RIC by adding low-dose total body irradiation (iRIC; n = 15), and myeloablative conditioning (MAC; n = 17). After a median follow-up of 73.7 months, RIC had a better 4-yr overall survival (OS) (92.9%) compared with the iRIC (64.2%) or MAC (70.6%). Multivariate analysis showed that RIC was associated with improved OS compared with the MAC [relative risk (RR) of 0.08, P = 0.022] because of a lower transplant-related mortality (TRM) (RR, 0.08, P = 0.035). iRIC failed to show survival benefits over the MAC (RR of 0.77, P = 0.689) because of similarly high TRM (RR of 0.41, P = 0.480). Cumulative incidence of acute and chronic graft-versus-host disease (GVHD) after RIC was higher, but GVHD-specific survival was significantly better (RIC 100% vs. iRIC 45.7% vs. MAC, P = 0.018). Relapse rate was not different among the three groups, but in the RIC group, azacitidine was available and useful for inducing remission in two patients. This study shows that RIC improved OS by directly lowering TRM and indirectly giving an additional chance for relapsed MDS in the era of hypomethylating treatment. RIC-SCT should be considered for relative healthy lower-risk MDS patients.

Analysis of Readmission After Autologous HCT: Predictive Factors and Clinical Consequences

AbstractAbstract 932With increasing scrutiny of healthcare expenditures, the reduction of hospital readmission rates has emerged as a targeted area of health reform; however, readmission rates following hematopoietic cell transplantation (HCT) have not been systematically examined. Whereas patients (pts) undergoing allogeneic HCT at increased risk of toxicity and mortality can be identified by their coexistent medical comorbidities as calculated by the HCT-comorbidity index (HCT-CI), the impact of such pre-HCT characteristics on outcome following high dose chemotherapy with autologous HCT is not known. We retrospectively analyzed the association of pre-transplantation HCT-CI with readmission rates and survival for all pts who underwent autologous HCT at a single institution from 1/2004 to 12/2008.Of 475 pts who underwent an autologous HCT, 62% were male and the median age was 52 years (range 20–75). Diagnoses were non-Hodgkin lymphoma (n=253, 53%), multiple myeloma (MM, 124, 26%), Hodgkin lymphoma (82, 17%), and other hematologic disorders (16, 3%). Forty-seven pts (10%) underwent a second autologous HCT as part of a planned tandem transplantation protocol; readmission and survival were calculated from the time of the first HCT. A total of 193 pts (41%) had a comorbidity score of 0, according to HCT-CI, 146 (31%) had a score of 1 to 2, and 136 (29%) had a score of 3 or greater. The preparative regimens included busulfan, cyclophosphamide, and etoposide (323, 68%), melphalan (86, 18%), and busulfan with cyclophosphamide (66, 14%). The median time to neutrophil recovery was 10 days and to platelet recovery was 14 days. The mean length of hospitalization was 20 +/− 4 days.Overall, 14% of patients were readmitted within 30 days of discharge, 21% within 100 days, and 30% within one year. Within the first 30 days post-HCT, infection (62%) and gastrointestinal disorders (22%) accounted for the majority of hospital readmissions. Infection (42%) was also the most frequent reason for readmission within one year, followed by gastrointestinal disorders (16%), relapsed malignancy (14%), and cardiopulmonary disease (9%). By stepwise logistic regression analysis, high pretransplantation HCT-CI (score ≥ 3) was predictive of hospital readmission within 30 days (odds ratio [OR] 2.08, 95% confidence interval [CI] 1.09–3.95, p=.026), 100 days (OR 1.93, 95% CI 1.14.-3.26, p=.014), and one year (OR 1.68, 95% CI 1.04–2.70, p=.034) of HCT discharge. Older age was also prognostic; each ten year increase in age at time of autologous HCT led to an increased likelihood of 30 day readmission (OR 1.36, 95% CI 1.07–1.73, p=.014). A model for probability of post-autologous HCT readmission was constructed using these multivariable risk factors (Table 1).Cox proportional hazards analysis was used to identify prognostic factors for overall survival. In univariable analysis, high HCT-CI, diagnosis, preparative regimen, and readmission were risk factors for mortality, but in stepwise multivariable analysis, only diagnosis (MM vs other diagnoses, hazard ratio [HR] .61, 95% CI .40-.92, p=.018) and readmission (HR 3.97, 95% CI 2.85–5.52, p<.001) remained prognostic for overall survival.We conclude that both age and comorbidity status influence readmission rates following autologous HCT. Importantly, readmission is strongly associated with a greater risk of mortality, a link that should be further investigated. HCT-CI scores should be calculated for all autologous HCT pts, which may allow for improved comparison of outcomes and readmission data between institutions and provide opportunities to further increase the safety of autologus HCT. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Geriatric Assessment Predicts Overall Survival Among Older Adults Receiving Induction Chemotherapy for Acute Myelogenous Leukemia.

AbstractAbstract 1535 Background:Acute myelogenous leukemia (AML) is a disease which largely affects older adults, for whom optimal therapy is unclear. Evidence-based strategies to identify those older adults who may tolerate and benefit from standard therapies are lacking. Objective:Evaluate the predictive value of bedside geriatric assessment (GA) on overall survival (OS) for older adults receiving induction therapy for AML. Methods:Ongoing prospective study of patients ≥60 years of age with newly diagnosed AML and planned induction chemotherapy admitted to Wake Forest University. Bedside GA was performed during inpatient work-up for AML. GA measures included the Modified Mini-Mental Status Exam (3MS), Center for Epidemiologic Studies Depression Scale (CES-D), Distress thermometer, Pepper Assessment Tool for Disability ([PAT-D], includes self- reported activities of daily living (ADL), instrumental activities of daily living (IADL), and mobility questions), Short Physical Performance Battery ([SPPB], includes timed 4-meter walk, chair stands, standing balance), and grip strength. Cox proportional hazards models were fit for each GA measure as a predictor of OS, controlling for age, gender, Eastern Cooperative Oncology Group (ECOG) score, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) score, and cytogenetic risk group. The median follow-up was 4.7 months. Results:Among 53 consecutive patients the mean age was 69 (SD 11.5) years, 59.3% were female, and 46.3% had significant comorbidity (HCT-CI score >1). The majority had intermediate (72.6%) or poor risk (23.6%) cytogenetics. Approximately two thirds (64.7%) received standard induction therapy with anthracycline, cytarabine ± etoposide. Mean baseline GA scores included: 3MS 82.4 (SD 9.6), CES-D 13.5 (SD 11.3), Distress 4.2 (SD 3.3), PAT-D 1.6 (SD 0.6), SPPB 6.4 (SD 4.2), grip strength 32.0 kilograms (SD 8.5). In adjusted analyses, better performance on the cognitive screen (3MS) was associated with improved OS (HR 0.94, 95% CI 0.89–0.99). There was a trend towards worse OS among individuals who screened positive for depression at baseline (CES-D>16) (HR 2.3, 95% CI 0.75–6.80) and among those with a slower gait speed (< 1 meter/second) (HR 5.9, 95% CI 0.80–45.3). Additional baseline GA measures were not associated with OS in this analysis. Conclusions:Geriatric assessment measures may independently predict OS among older adults receiving induction therapy for AML. If validated in future studies, these screening measures may improve risk stratification and inform interventions to improve outcomes for older adults with AML.Supported by the American Society of Hematology Scholar Award, Atlantic Philanthropies, the John A. Hartford Foundation, ASP, and the WFU Pepper Center (P30 AG-021332). Disclosures:No relevant conflicts of interest to declare.

Sequential Autologous Followed by Nonmyeloablative Allogeneic Hematopoietic Cell Transplantation (HCT) From HLA-Matched Related or Unrelated Donors Improves Outcomes of Patients (pts) with Bulky Lymphoma or Chronic Lymphocytic Leukemia (CLL)

AbstractAbstract 2365Large lymph node size or chemo-refractoriness limited the success of nonmyeloablative allogeneic HCT in eradicating CLL or lymphoma. We explored an approach of combining the cyto-reductive effect of high dose chemo/radiation therapy and autologous HCT with the graft-versus-tumor effect of nonmyeloablative allogeneic HCT for pts with rapidly progressive/refractory CLL or lymphoma. Between 4/2000 and 3/2010, 45 pts with advanced indolent (16%) or aggressive (54%) non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL, 18%), or CLL (11%) ineligible for myeloablative allogeneic HCT due to age and/or comorbidities were treated with the sequential approach. Autologous HCT alone was thought to be insufficient for disease control. Pts received high-dose therapy and autologous HCT followed [at a median of 65 (range 39–128) days] by nonmyeloablative conditioning and related (n=28) or unrelated donors (n=17) allogeneic HCT. Median pt age was 49 (range 20–71) years and number of prior regimens was 4 (range 1–12). Thirty-four percent of pts had disease responsive to the last chemotherapy before autografting [30% partial (PR) and 4% complete remission (CR)] while 44% and 22% had refractory and progressive disease, respectively. Most pts had aggressive disease (72%). Conditioning for autografts consisted of BEAM (49%) or Cyclophosphamide/12 Gy TBI±VP16 (51%). After auto-grafting, 58% of pts had CR/PR (29%/29%), 36% had responses <PR, 3% had relapse, and 3% had refractory disease. Conditioning for allografts consisted of 2 Gy TBI alone (53%) or combined with FLU (47%), 90 mg/m2. Pts received G-CSF mobilized allogeneic peripheral blood mononuclear cells. All 45 pts had sustained donor engraftment. Incidences of grades II, III, and IV acute and of chronic GVHD were 46%, 16%, 0%, and 52% respectively. With median follow up of 51 (range 5–116) months, the overall response rate was 60% (46% CR). Eighteen pts died, 12 from progression/relapse, 3 from pulmonary complications, 1 from GVHD, 1 from sepsis, and 1 from multi-focal leuko-encephalopathy. Estimated 5-year rates of non-relapse mortality, relapse, overall, and progression-free survivals from the time of autografting were 15%, 44%, 55%, and 42% respectively. Pts with CLL or indolent NHL had rates of relapse and PFS of 11% and 68% compared to 47% and 37% for those with aggressive NHL and 69% and 31% for those with HL, respectively. No statistical significant differences in outcomes were detected for lymph node size (Figure), disease status at allografting, donor type, conditioning regimens for autografts or allografts, HCT-comorbidity index scores, or time between autologous and allogeneic grafting (Table). Sequential Auto-Allo HCT resulted in relatively low NRM with median survival not yet reached among pts with rapidly progressive lymphoma/CLL. This sequential transplant approach overcame the previously reported high relapse risk of bulky lymphadenopathy. [Display omitted] Disclosures:Off Label Use: All discussions about therapeutics used for HCT preparative regimens are off-label.

Influence of comorbidities on transplant outcomes in patients aged 50 years or more after myeloablative conditioning incorporating fludarabine, BU and ATG

Non-myeloablative (MA) and reduced intensity allo-SCT regimens are offered to older patients and/or those with comorbidities because the morbidity and mortality attributable to fully MA conditioning is thought to be unacceptably high. A total of 207 patients aged 50-66 years were treated between 1999 and 2008 with SCT after MA conditioning with fludarabine 50 mg/m(2) daily × 5 and i.v. BU 3.2 mg/kg daily × 4.90 (43%) had additional TBI 200 cGy × 2. GVHD prophylaxis was CsA, MTX and thymoglobulin (4.5 mg/kg total dose). As defined by the hematopoietic cell transplantation co-morbidity index (HCT-CI) scoring system 117 (57%) pts scored 0 and 90 (43%) 1. At 5 years OS was 39 vs 54% (P=0.008), disease-free survival 38 vs 49% (P=0.03), TRM 39 vs 19% (P=0.003) and relapse 36 vs 39% (P=ns) in those with scores of 0 and 1, respectively. Multivariate analysis confirmed the influence of HCT-CI scores on TRM (subhazard ratios=2.29; 95% confidence interval=1.29-4.08; P=0.005). We conclude that comorbidities as assessed by the HCT-CI do influence TRM with this regimen but that age alone should not be an indication to prefer a less intense protocol.

Inpatient Geriatric Assessment Detects Impairment Among Older Adults Receiving Induction Chemotherapy for Acute Myelogenous Leukemia.

Abstract 1401Poster Board I-423 Background:Acute myelogenous leukemia (AML) is a disease which largely affects older adults, for whom optimal therapy is unclear. Evidence-based strategies to identify those older adults who may tolerate and benefit from standard therapies are lacking. Objective:Test the utility of a bedside geriatric assessment (GA) to detect impairment in multiple geriatric domains among older adults initiating induction chemotherapy for AML. Methods:Ongoing prospective study of patients ≥60 years of age with newly diagnosed AML and planned induction chemotherapy admitted to Wake Forest University. Bedside geriatric assessment (GA) was performed during inpatient work-up for AML. GA measures included the Modified Mini-Mental Status Exam (3MS), Center for Epidemiologic Studies Depression Scale (CES-D), Distress thermometer, Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI), Pepper Assessment Tool for Disability ([PAT-D], includes self- reported activities of daily living (ADL), instrumental activities of daily living (IADL), and mobility questions), Short Physical Performance Battery ([SPPB], includes timed 4-meter walk, chair stands, standing balance), and grip strength. Results:26 of 29 eligible patients enrolled between 1/2009 and 8/2009. The median age was 68 (range 60-82) years, and 42.3% were female. Prior myelodysplastic syndrome was present in 34.6%, with intermediate or poor-risk cytogenetics in 95.6%. Baseline laboratory measures included white blood cell count (mean 17.3×103/mm3, SD 25.0×103), hemoglobin (mean 9.2g/dl, SD 1.5), lactate dehydrogenase (mean 282.4 U/L, SD 168.8). Mean baseline GA scores included: 3MS 83.0 (SD 14.7), CES-D 9.4 (SD 9.3), Distress 3.8 (SD 3.4), HCT-CI 1.3 (SD 1.6), PAT-D 1.4 (SD 0.7), SPPB 7.1 (SD 3.9), grip strength 32.4 kilograms (SD 9.2). Although 84.6% of subjects had an Eastern Cooperative Oncology Group (ECOG) Performance score <2, a substantial proportion met criteria for impairment in multiple geriatric domains.Characteristic% impairedPoor performance status (ECOG≥2)15.4Comorbidity (HCT-CI score >1)38.5Impairment in instrumental activities of daily living (IADL)34.6Impairment in objective physical function (SPPB<9)60.0Cognitive impairment (3MS<77)15.4Depression (CES-D ≥16)23.1Distress (score ≥4)50.0 Conclusions:GA measures detect abnormalities which are not adequately reflected by the ECOG performance score in older adults with AML. Future analyses from this ongoing study will evaluate whether these abnormalities are independently associated with treatment-related morbidity and survival. Disclosures:No relevant conflicts of interest to declare.