Relapse-related Mortality Research Articles

Conditional Survival and Cause-Specific Mortality in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation (alloHCT) for Hematologic Malignancy Over Three Decades

AbstractAbstract 606 Background:alloHCT is offered with curative intent to patients with hematologic malignancies, and conventionally-computed survival estimates are offered for prognosticating outcomes. However, conventionally-computed survival estimates do not take into account elapsed time (and changing hazards with time survived); conditional survival overcomes these limitations, by calculating the probability of survival after having already survived a certain period of time – such data are unavailable for alloHCT recipients. We describe cause-specific (relapse-, GvHD-, treatment-related) conditional survival after alloHCT, providing clinically relevant information for patients who have survived 6 mos, 1, 2, and 5y after alloHCT. Methods:From 1976 to 2006, 2,427 consecutive patients received alloHCT for a hematologic malignancy at a single institution (median age: 34.7y [0.6–72.5]). Vital status and cause of death were determined using National Death Index, Social Security Death Index and medical records. Results:As of 12/31/2007, a total of 1413 deaths (58% of the cohort) were observed; 39% attributed to recurrent disease; 34% to GvHD; 12% to infection; 5% to cardiopulmonary disease; 2% to subsequent malignant neoplasm (SMNs); and 8% to other causes. Conventionally-computed probability of survival was 44.6% at 5y and 41.2% at 10y from alloHCT. On the other hand, conditional on survival for 6 mo, 1, 2, and 5y after alloHCT, 5-y survival rates were 62%, 75%, 83%, and 93%, respectively (Figure A). The cohort was at a 40-fold increased risk of any death compared with the general population (95%CI=38.2–42.4); at a 25.6-fold increased risk of death due to pulmonary complications, 3.3-fold risk due to SMNs, and 2.3-fold risk due to cardiovascular complications. Among patients followed for 15+y after HCT, the risk of all-cause mortality was 2.6-fold that of the general population (95%CI=1.8–3.7). Standardized mortality ratios (SMR) and cause-specific conditional mortality rates by primary diagnosis are summarized in the Table.Individuals who survived the first 5y had negligible (≤5%) risk of relapse- and GvHD-related mortality over the subsequent 5y. Treatment-related mortality increased over time; among those who survived 5y, treatment-related mortality rates exceeded relapse-related mortality (Figure B). After adjustment for demographics, underlying diagnosis and treatment era, individuals with chronic GVHD (cGVHD) had a significantly lower risk of relapse-related mortality (RR=0.43, 95%CI=0.4–0.5) compared to those without cGVHD. Conclusions:The projected 5-y survival rates improve conditional on time survived from alloHCT; 5-y survival exceeds 93% for those who have already survived 5y. However, alloHCT recipients who have survived 15+y continue to remain at increased risk of death compared to the general population. cGVHD is associated with decreased risk of relapse-related mortality. Both relapse-related and GvHD-related mortality rates decline with time, such that, among those who have survived 5y, treatment-related mortality exceeds relapse-related mortality. Conditional survival estimates provide clinically relevant prognostic information, helping inform preventive and interventional strategies. [Display omitted] [Display omitted] TableCause-specific mortality in patients undergoing allogeneic HCTFrom alloHCT1 yr survivors2 yr survivors5 yr survivors5-y mortality (%)SMR (95%CI)5-y mortality (%)SMR (95%CI)5-y mortality (%)SMR (95%CI)5-y mortality (%)SMR (95%CI)All PatientsRelapse18.640.3 (38.2–42.4)11.912.2 (11.1–13.4)6.57.6 (6.7–8.6)1.43.5 (2.9–4.3)GvHD16.48.76.62.0TRM11.53.35.02.1ALL (n=635)Relapse25.663.9 (57.7–70.0)18.721.1 (17.5–24.8)12.311.8 (9.2–14.8)1.84.0 (2.0–6.0)GvHD17.310.97.10.8TRM13.33.00.92.1AML (n=749)Relapse22.548.3 (43.9–52.7)12.814.1 (11.7–16.5)7.09.3 (7.4–11.4)1.14.6 (3.3–6.4)GvHD12.29.06.91.5TRM12.23.45.72.1CML (n=596)Relapse7.622.3 (19.7–24.9)4.67.4 (5.9–8.9)1.64.9 (3.8–6.3)0.72.8 (1.9–3.9)GvHD18.97.76.92.2TRM7.32.73.62.4NHL (n=235)Relapse21.445.9 (38.2–53.6)16.913.3 (9.1–17.6)12.68.6 (5.6–12.7)5.02.6 (0.9–5.6)GvHD17.76.25.60TRM11.06.43.53.3MDS (n=212)Relapse12.535.3 (28.8–41.8)7.17.5 (4.4–10.6)2.14.2 (2.3–7.1)2.03.5 (1.5–6.7)GvHD20.58.710.79.8TRM16.43.12.00TRM=Treatment related mortality Disclosures:No relevant conflicts of interest to declare.

Comorbidity and Outcomes for Patients Over Age 65 Years Treated with Allogeneic Stem Cell Transplantation for Acute Myelogenous Leukemia and Myelodysplastic Syndrome

AbstractAbstract 2032▪▪This icon denotes a clinically relevant abstract Background:Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) preferentially afflict patients 65 years of age and older. Patients in this age group are likely to have underlying comorbid conditions. These comorbidities affect treatment planning decisions and clinical outcomes. Here we report comorbidity-stratified outcomes of patients older than 64 treated at MD Anderson Cancer Center from 1996 until 2011, inclusive, treated with allogeneic stem cell transplant (ASCT). Methods:182 patients older than 64 received an ASCT for AML (n=143) or MDS (n=39). Patient charts were reviewed and comorbidity data abstracted using a standardized form. Burden of comorbidity was assessed using the Hematopoetic Stem Cell Transplant-Specific Comorbidity Index (HSCT-CI). Low-risk, intermediate-risk, and high-risk patients were categorised at 0, 1–2, and >=3 points as per the HSCT-CI. 157 patients were evaluable for pre-transplant comorbidity. Outcomes of interest were cumulative incidence of transplant-related mortality (TRM), cumulative incidence of relapse-related mortality (RRM), incidence of acute and chronic graft-versus-host disease (GVHD), and overall survival (OS). These were estimated from the date of transplantation. Results:The median age of transplanted patients was 67 (range 65–79), and 37 patients age 70 and older were treated. The majority of patients were intermediate-risk and high-risk patients (table), 9 patients had HSCT-CI scores of >=5. Median follow-up for alive patients was 12.6 months (n=63; range 0–118). Cumulative incidence of TRM was 6% at 100 days, 14% at 1 year, 23% at 2 years, and 36% at 5 years (figure). Cumulative incidence of RRM was 36% at 1 year, 42% at 2 years, and 47% at 5 years. HSCT-CI did not independently predict for either TRM or RRM (log-rank test p=0.95). The incidence of grade III and IV acute GVHD was 10% of all patients. The cumulative incidence of chronic GVHD was 25% at 1 year, 27% at 2 years, and 30% at 5 years, with no association between GVHD and HSCT-CI comorbidity. Conclusion:ASCT is a curative option for selected patients over age 64. HSCT-CI did not predict TRM or survival on this cohort of high-risk patients. Disease relapse was of greater concern than TRM, and so novel approaches to relapse prevention are needed.TablePatient characteristicsCategoryParameterNumber (%)HSCT comorbidity indexLow risk (0)34 (22)Intermediate risk (1)67 (37)High Risk (2)56 (36)Donor typematched related donor87 (48)matched unrelated donor73 (40)mismatched unrelated donor17 (9)Preparative regimensfludarabine/melphalan85 (47)fludarabine/busulfan61 (34)fludarabine/idarubicin13 (7)Immunosuppressiontacrolimus/mini-methotrexate147 (81)tacrolimus/mycophenolate8 (4)post-transplant cyclophosphamide16 (9)Cell sourcePeripheral blood122 (67)Marrow53 (29)Cord7 (4)CytogeneticsGood risk14 (8)Intermediate risk86 (42)Poor risk71 (50)Disease status at ASCTprimary induction failure21 (12)complete remission 138 (21)complete remission 2 or 315 (8)refractory/untreated disease120 (66) [Display omitted] Disclosures:No relevant conflicts of interest to declare.

BK Virus (BKV) Associated Haemorrhagic Cystitis Is Associated with Graft Versus Host Disease (GVHD) and Significant Morbidity Post Haematopoietic Stem Cell Transplant (HSCT).

AbstractAbstract 3040The Polyomavirus hominis 1 BK virus (BKV) is a non-encapsulated DNA virus, which infects up to 90% of the world's population, and may reactivate at times of severe immunosuppression, including post haematopoietic stem cell transplantation (HSCT).The significance of BK virus reactivation post Haematopoietic Stem Cell Transplant (HSCT) remains unclear. We collected retrospective data on viruria, viraemia, haemorrhagic cystitis (HC) and acute/chronic graft versus host disease (a/cGVHD) in patients at our institution over the period 2006 to 2011. We compared with a multivariate matched control group of 38, who did not reactivate BK. The groups were matched for age, sex, donor source and conditioning regimen including use of Alemtuzumab. Global BK reactivation incidence was 32% (38/118) of allogeneic HSCT during this period. 73% (28/38) of those who reactivated received volunteer unrelated donor (VUD) grafts, and 50% (18/38) received Alemtuzumab.Patients were sub-divided into those with high grade viraemia (HGV, VL >104 copies/ml), 47% (18/38) or low grade viraemia (LGV, VL<104 copies/ml), 53% (20/38). HGV was present in 57% of VUD transplants and 20% of sibling recipients, compared to LGV in 29% of VUDs and 70% of siblings. HGV influenced 1 year EFS; 18% versus 55% in LGV. Median OS was 173 days in HGV versus 345 days in LGV.Cumulative mortality rate in the BK group was 71% (27/38) as compared to 55% (21/38) in the control group (not significant). Relapse related mortality in the BK group was 22% (6/27) versus 57% (12/21) in the control group, at a median follow up of 229 days (p=0.088), indicating the high incidence of non-relapse causes of mortality in the BK group.79% (30/38) of patients reactivating BK developed aGVHD, including 83% (15/18) with HGV, compared to 57% (21/37) in the control group (p=0.039). The number of patients who developed grade II-IV aGVHD in the BK group was 30/38 (79%) and 11/37 (20%) in the control group (p <0.001), figure 1. In 33% of patients BK reactivation preceded aGVHD by a mean of 12 days. 84% (27/32) of patients developed cGVHD, compared to 30% (18/30) in control group (p=0.05). Moderate-severe (NIH grade) cGVHD was more prevalent in patients reactivating BK, compared to control group; 75% (24/32) versus 3% (1/30) (p<0.001), figure 2.This data suggests the association of BK with an increased incidence of acute and chronic GVHD, and significant morbidity. Notably 10 patients developed severe complications including grade 4 HC (5/10), obstructive hydronephrosis and bladder wall dysfunction requiring invasive intervention. 7/10 (70%) of these patients had HGV; 2 patients reactivated early, failed treatment, developed obstructive renal failure and died. These patients had an increased rate of mortality compared to the whole study group (p=0.005), and all failed to achieve an EFS of over 1 year. Of note, 8.5% of all allografts developed grade 4 HC and 90% of these subsequently died.BK reactivation strongly correlates with acute and chronic GVHD and an increase in non relapse mortality. Routine surveillance for BK with risk scoring may allow earlier detection and reduced morbidity of BK and GVHD. Further prospective studies are required to understand the impact of the reactivation of the virus. [Display omitted] p <0.001 [Display omitted] p <0.001 Disclosures:No relevant conflicts of interest to declare.

Matched Cohort Analysis of Allogeneic Hematopoietic Cell Transplantation (HCT) with Total Marrow Irradiation/Fludarabine/Melphalan (TFM) Versus Fludarabine/Melphalan (FM) Conditioning for Acute Leukemia

AbstractAbstract 222We have previously reported the feasibility and safety of augmenting the reduced-intensity regimen (RIC) of FM by addition of total marrow irradiation, a targeted form of TBI, using a helical tomotherapy (HT) device (Rosenthal, Blood. 2011;117(1):309–315). In this study we compared outcomes in patients with acute leukemia undergoing HCT receiving either TFM or FM. Patients and Methods:We analyzed 72 patients with acute leukemia or MDS who received either FM (N=36) or TFM (N=36) HCT. Eligibility criteria for TFM were age > 50 years of age or compromised organ function (COF); high-risk remission or marrow blasts ≤10%. TFM patients were matched to a set of FM patients based on age, gender, diagnosis and disease risk (low, intermediate, high). All patients received FM with fludarabine 25 mg/m2/d × 5 days and melphalan140 mg/m2/d × 1 day, and TMI was delivered at 150cGy/fraction in 8 fractions over 4 days in the TFM group. Supportive care and treatment for prevention of GVHD were given according to our institution standard guidelines for both groups. Results:Demographic characteristics were similar, including gender (20 females, 55.6%) and age (median 58 years, range: 22–68 in TFM and 20–68 in FM). The proportions of patients by diagnoses were similar: AML (n=27), ALL (n=7), MDS (n=2). Disease risk assignments in both groups were: Low risk (n=15), intermediate (n=6), high (n=15). There were 15 and 13 pts with active disease in FM and TFM, respectively. HLA-identical siblings (n=16, 44.4%) or matched unrelated donor (n=20, 55.6%) were used in each group. Outcomes are reported for the TFM and FM recipients, respectively as follows: myeloid recovery was documented on day 13.5 (9–24) and 15 (8–20). Transplant-related toxicities were limited to grade 3 or less in both groups. The most common grade 3 toxicities were: mucositis, n=9 and n=7 and bacterial infection, n=10 and n=11, respectively. Acute GvHD grade II-IV occurred in 20 pts (55%) and 19 (53%). Extensive chronic GVHD was documented in 24 (67%) and 20 (56%) pts. Twenty-one and 18 patients are alive at a median of 30.2 months and 35.3 months in the TFM and FM, respectively. The relapse cumulative incidence at 2 years post HCT was 11.1% (TFM) compared to 30.6% (FM) (p=0.06) (insert ). With a median follow-up of 31.7 months (4.1 – 62.5) for alive patients, the 2-year overall and progression-free survival estimates are 57.2 % (95% CI, 46.6–66.4) -TFM, and 62.8% (95% CI, 51.8–72.0) -FM, and 57.7% (95% CI, 47.2–67.0) -TFM, and 48.5% (95% CI, 40.2–56.3) -FM, respectively. Conclusion:The addition of TMI at a dose of 1200 cGy to FM is safe and tolerable and may decrease the risk of relapse related mortality. Disclosures:No relevant conflicts of interest to declare.

Conditional survival and cause-specific mortality after autologous hematopoietic cell transplantation for hematological malignancies

The probability of survival is conventionally calculated from autologous hematopoietic cell transplantation (aHCT). Conditional survival takes into account the changing probability of survival with time survived, but is not known for aHCT populations. We determined disease-, and cause-specific conditional survival for 2388 patients treated with aHCT over a period of 20 years at a single institution. A total of 1054 deaths (44% of the cohort) were observed: 78% attributed to recurrent disease; 9% to subsequent malignancies; and 6% to cardiopulmonary disease. Estimated probability of relative survival was 62% at 5 and 50% at 10 years from aHCT. On the other hand, 5-year relative survival was 70%, 75%, 81%, and 88% after having survived 1, 2, 5, and 10 years after aHCT, respectively. The cohort was at a 13.9-fold increased risk of death compared with the general population (95%CI=13.1–14.8). The risk of death approached that of the general population for 10-year survivors (SMR=1.4, 95%CI=0.9–1.9), with the exception of female Hodgkin lymphoma patients transplanted before 1995 at age 40 years or younger (SMR=6.0, 95%CI=1.9–14.0). Among those who had survived 10 years, non-relapse-related mortality rates exceeded relapse-related mortality rates. This study provides clinically relevant survival estimates after aHCT, and helps inform interventional strategies.

Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults.

Allogeneic haematopoietic stem cell transplantation (HSCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after HSCT, is the result of host tissues being attacked by donor immune cells. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATG), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation. To assess the effect of ATG used for the prevention of graft-versus-host disease (GVHD) in patients undergoing allogeneic HSCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, incidence of infectious complications, non-relapse mortality, early mortality within 100 days of transplantation, progression-free survival, quality of life and adverse events. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (January 1950 to February 2012), trials registries and conference proceedings. The search was conducted in October 2010 and was updated in July 2011 and February 2012. We did not apply any language restrictions. We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic HSCT. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen. Two review authors screened abstracts, extracted data and analysed the data independently. We contacted study authors for additional information. We included in the meta-analysis six RCTs which met the pre-defined selection criteria, involving a total of 568 participants. Quality of data reporting was heterogeneous among these studies with a lack of detailed information in the early studies.The primary outcome of overall survival was not significantly changed by the addition of ATG for the prophylaxis of GVHD (harms ratio (HR) 0.88; 95% CI 0.67 to 1.15, P = 0.33).The incidence of treatment-requiring or severe acute GVHD (grade II to IV) was significantly lower in patients who received ATG (risk ratio (RR) 0.68; 95% CI 0.55 to 0.85, P = 0.009; number needed to treat (NNT) 8). Also, the incidence of severe acute GVHD (grade III to IV) was significantly reduced (HR 0.53; 95% CI 0.33 to 0.85, P = 0.0005; NNT 7) but comparable data were available for rabbit ATG only. However, pooled study results regarding the incidence of acute GVHD of all grades (I to IV) showed no significant benefit of ATG treatment (RR 0.89; 95% CI 0.74 to 1.06, P = 0.20).Meta-analysis of data regarding the incidence of overall chronic GVHD (both, limited and extensive) was not possible. Nevertheless, studies reporting on extensive chronic GVHD (only studies evaluating rabbit ATG) suggested a lower incidence of extensive chronic GVHD whereas others that only reported on overall chronic GVHD did not show an advantage for ATG.Pooled results regarding the incidence of relapse were not significantly different (RR 1.13; 95% CI 0.75 to 1.68, P = 0.56), as well as pooled results regarding non-relapse mortality (HR 0.82; 95% CI 0.55 to 1.24, P = 0.35).Due to the lack of comparable data, we could not perform meta-analysis of data regarding the incidence of chronic GVHD, relapse-related mortality, progression-free survival, quality of life, adverse events and engraftment. Our systematic review suggests that the addition of ATG during allogeneic HSCT significantly reduces the incidence of severe grades (II to IV) of acute GvHD, whereas the incidence of overall acute GVHD (grades I to IV) was not significantly lowered. This indicates a reduction of the severity but not the incidence of acute GVHD. However, this effect did not lead to a significant improvement of overall survival, which may be due to the severe potential side effects of the consecutively increased immunosuppression.Furthermore, future research is needed to clarify the effect of ATG on the incidence and severity of chronic GVHD and consequently on all aspects of quality of life.From the currently available data, no recommendation on the general use of ATG in allogeneic HSCT can be supported. Therefore, a careful consideration of the use of ATG based on the patient's condition and the risk factors of the transplantation setting should be made.

Differential impact of inhibitory and activating Killer Ig-Like Receptors (KIR) on high-risk patients with myeloid and lymphoid malignancies undergoing reduced intensity transplantation from haploidentical related donors

The impact of activating KIR (aKIR) and inhibitory KIR (iKIR) on OS, relapse-related mortality (RRM) and acute GVHD (aGVHD) was prospectively studied in 84 adults with high-risk hematologic malignancies receiving reduced intensity conditioning (RIC) T-cell depleted hematopoietic SCT (HSCT) from haploidentical related donors. In this clinical model, freedom from RRM is dependent on GVL effect. Patients were divided into myeloid (n=49) and lymphoid (n=35) malignancy groups. KIR-ligand and ligand-ligand models were studied in both GVH and rejection directions and statistically correlated with outcome measures. In the myeloid group, OS was higher (P=0.009) and RRM was lower (P=0.036) in patients missing HLA-C group2 ligand to donor iKIR. OS was higher if patients had >1 missing ligand (P=0.018). In lymphoid malignancy, missing ligand to donor KIR had no impact on OS or RRM. However, OS was better with donor aKIR 2DS2 (P=0.028). There was a trend towards shorter OS in recipient with KIR 2DS1, 2DS5 and 3DS1, although sample sizes were too small to provide inferential statistics. Findings in lymphoid malignancy patients should be further studied. These results suggest that the absence of appropriate HLA ligands in the recipient to donor iKIR may induce GVL without aGVHD in myeloid malignancy patients undergoing TCD-RIC transplants.

Kinetics of Engraftment and Predictors of Outcome in Patients with Advanced Chronic Lymphocytic Leukaemia (CLL) After Treatment with Low Dose Total Body Irradiation (TBI) Followed by related or unrelated hematopoietic Stem Cell Transplantation

Abstract 4532 Introduction:In an unicenter analysis we investigated the impact of allogeneic hematopoietic cell transplantation (RIC-HCT) after reduced intensity conditioning on the kinetics of engraftment and predictor of outcome in 50 patients with advanced CLL. Patient and Methods:Patients in advanced stage CLL (n=50) received Fludarabine 30mg/m2 on day -4 to -2 and 2Gy TBI on day 0 followed by cyclosporine and MMF from unrelated (n=40) or related (n=10) donors between June 1999 and March 2010 at the University of Leipzig. The majority of patients (n= 35) were male, had Binet C (n=37, 74%) at RIC-HCT. The median age was 58 (range 44–69) years. Of 48 patients for whom cytogenetic analyses were available, 22 (46%) had unfavourable cytogenetics including del 17 or del 11q. Three (6%) patients had CR, 27 (54%) PR, 7 (14%) progressive disease, 12 (24%) stable disease and one (5%) relapse at RIC-HCT. Resistance to first line therapy was present in 25 (50%) patients, whereas 12 (24%) were resistant to Fludarabine. Richter's transformation was found in six patients (12%). Chimerism was detected in bone marrow and peripheral blood on T-lymphocytes and B-lymphocyte subpopulation after sorting at monthly intervals in the posttransplant period and than in 6 months interval. Results:Hematological toxicities after RIC-HCT were moderate. The majority of patients (96%) engrafted with neutrophiles >500/μ L median at day 22 after HCT. Six (12%) and 15 (30%) patients maintained absolute neutrophil counts (ANC) >0,5 × 109/L and platelet counts >50 × 109/L, respectively. T-cell donor chimerism increased to >95% at day 56 and B-cell donor chimerism to 94% at day +360, respectively. B-CLL cells disappeared completely on day +360 (median 0%). Overall survival (OS) at 4 years was 51%, Non relapse related mortality (NRM) 30%, Progression-free survival 33% and progression/relapse 37%. The most common causes of NRM were GvHD (n= 7; 14%) and sepsis (n=3, 6%). Factors significantly associated with increased risk of relapse/progression were intermediate/advanced disease vs. CR/PR1 (p=0.022) and lymphocytes ≥ 5 × 109/L vs. < 5 × 109/L (18% vs. 58%, p= 0.00) at 12 months in univariate analysis. Conclusion:Full donor T-cell chimerism was reached early after HCT, while B-cell reconstitution was observed only 1.5 years after RIC-HCT despite the absence of evident disease by 360 days after RIC-HCT. Best predictor for Progression-free survival (PFS) was CR or PR1. Disclosures:Pönisch:Mundipharma: Honoraria, Research Funding.

Combining Early Heat Shock Protein Vaccination with Directed IL-2 Leads to Effective Anti-Tumor Immunity in Autologous Hematopoietic Cell Transplantation Recipients

Abstract 998Tumor relapse is still the major cause of morbidity and mortality in patients with hematologic cancers that undergo aggressive chemo-radiotherapy followed by autologous hematopoietic cell transplantation (auto-HCT). Hence, there is a critical need for new anti-tumor therapies. Heat shock protein (HSP) based vaccines elicit innate and adaptive immune responses in murine studies and have shown promise in clinical trials. The pre-clinical studies here investigated the efficacy of vaccination with tumor cells secreting the HSP fusion gp96-Ig together with directed IL-2 in tumor bearing auto-HCT recipients. To mimic clinical T cell replete auto-HCT, transplanted donor T cells were obtained from congenic tumor bearing mice (C57BL/6 CD45.2+ CD90.1+) that had been previously inoculated intraperitoneally (ip) with 4×106 OVA expressing lymphoma cells (E.G7). Some of these donor mice received 0.5×106 CD8 T cells specific for OVA257–264 (OT-I) to allow for tumor antigen specific T cell monitoring. Three weeks later, T cells were harvested from these animals bearing progressively growing tumor for use in T cell replete auto-HCT. Recipient mice (C57BL/6 CD45.2+ CD90.2+) received 9.5 Gy TBI with subsequent infusion of 5×106 congenic T cell depleted bone marrow cells (C57BL/6 CD45.1+ CD90.2+) supplemented with 2×106 enriched T cells from the tumor bearing donors. The following day, recipients were inoculated ip with 1×105 viable E.G7 lymphoma cells. Based on our prior findings, a multiple vaccination protocol was employed utilizing 1×107 irradiated E.G7 cells transfected to secrete the HSP fusion gp96-Ig (E.G7-gp96-Ig). Some recipients were administered IL-2 via specific antibody-cytokine complexes comprised of IL-2 and αIL-2 mAb clone S4B6 (IL-2/αIL-2CD122). This specific IL-2 complex has been shown to interact with cells expressing the β chain (CD122) of the IL-2 receptor, such as memory CD8 T cells and NK cells, but not with cells expressing the α chain (CD25).Compared to recipients of T cell replete auto-HCT vaccinated with parental E.G7 tumor cells who exhibited virtually no increase in antigen-specific CD8 T cells, marked expansion was detected in the blood after 2 vaccinations with E.G7-gp96-Ig, i.e. within 1 week of auto-HCT. This response reached a plateau after 3 vaccinations, and persisted throughout the 5 vaccine protocol. To quantitate this vaccine induced CD8 T cell expansion, analysis of the vaccine site, splenic and lymph node compartments was performed following 3 vaccinations, i.e. 2 weeks post-HCT. In contrast to the modest 25× increase observed after vaccination with parental E.G7 cells, a 175× expansion was detected following E.G7-gp96-Ig vaccination (6.8×106 vs. 3.8×104 input). Moreover, 75% of these gp96-Ig expanded CD8 T cells at the vaccine site were bifunctional, expressing IFN-γ and TNF-α following antigen specific stimulation ex vivo. Strikingly, combined treatment with vaccine cells secreting gp96-Ig together with IL-2/αIL-2CD122 complex resulted in a 1000× enhancement of antigen specific CD8 T cell numbers in all compartments analyzed. Tumor bearing auto-HCT recipients exhibited a median survival time (MST) of 1 month if not vaccinated or if vaccinated with parental E.G7 cells (Figure). However, vaccination with E.G7-gp96-Ig extended the MST by more than 2 weeks and ∼20% of recipients survived long term (>100 days). This effect was dependent on T cells since gp96-Ig vaccination alone without donor T cells resulted in no MST extension. Combination therapy with tumor cells secreting gp96-Ig and IL-2/αIL-2CD122 complex markedly elevated total CD8 T cells as well as NK cells at the vaccine site and in secondary lymphoid tissues, two populations that have been shown to facilitate HSP based vaccines. Notably, this strategy resulted in a MST >100 days with ∼60% of mice surviving indefinitely. We propose that 3 components are required together with auto-HCT to avoid relapse related mortality: (1) transplanted autologous T cells, (2) a pan-antigen vaccination approach that induces potent antigen presentation and activation of multiple antigen specific T cells, i.e. tumor cells secreting gp96-Ig, and (3) an adjuvant that potentiates this vaccine induced response, i.e. IL-2 delivered in the form of an antibody-cytokine complex. In total, this combinatorial protocol represents a promising regimen that could be translated into the clinic for patients with hematologic cancers. [Display omitted] Disclosures:Podack:Heat Biologics, Inc.: Consultancy, Equity Ownership, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties, Research Funding.

A 2-step approach to myeloablative haploidentical stem cell transplantation: a phase 1/2 trial performed with optimized T-cell dosing

AbstractStudies of haploidentical hematopoietic stem cell transplantation (HSCT) have identified threshold doses of T cells below which severe GVHD is usually absent. However, little is known regarding optimal T-cell dosing as it relates to engraftment, immune reconstitution, and relapse. To begin to address this question, we developed a 2-step myeloablative approach to haploidentical HSCT in which 27 patients conditioned with total body irradiation (TBI) were given a fixed dose of donor T cells (HSCT step 1), followed by cyclophosphamide (CY) for T-cell tolerization. A CD34-selected HSC product (HSCT step 2) was infused after CY. A dose of 2 × 108/kg of T cells resulted in consistent engraftment, immune reconstitution, and acceptable rates of GVHD. Cumulative incidences of grade III-IV GVHD, nonrelapse mortality (NRM), and relapse-related mortality were 7.4%, 22.2%, and 29.6%, respectively. With a follow-up of 28-56 months, the 3-year probability of overall survival for the whole cohort is 48% and 75% in patients without disease at HSCT. In the context of CY tolerization, a high, fixed dose of haploidentical T cells was associated with encouraging outcomes, especially in good-risk patients, and can serve as the basis for further exploration and optimization of this 2-step approach. This study is registered at www.clinicaltrials.gov as NCT00429143.

Outcome of allogeneic stem cell transplantation with a conditioning regimen of busulfan, cyclophosphamide and low-dose etoposide for children with myelodysplastic syndrome

Allogeneic stem cell transplantation (SCT) offers the best chance of cure and long-term survival for children with myelodysplastic syndromes (MDS). Retrospective analysis of pediatric patients with primary MDS treated with allogeneic SCT at a single institution treated between January 1993 and December 2008. Of 16 consecutive children who received allogeneic SCT for treatment of MDS in our center, 14 patients met the criteria of MDS according WHO I and II criteria. The median age was 4.8 years (range, 1-14 years) and 64% were male. The median time from diagnosis to transplant was 6 months. MDS stage was refractory cytopenia (RC) in 9, refractory anemia with excess blasts (RAEB) in 5. Monosomy 7 was present in 35% of the patients. The majority of patients (11/14) were conditioned with a busulfan-based myeloablative (MA) regimen with addition of low-dose of etoposide (30 mg/kg). All but one received a bone marrow graft. Nine patients achieved complete remission (CR), and seven remain alive. At a median follow-up of 3 years (range, 2-14 years) the OS and EFS was 57% (95%CI, 0.28-0.78). Cumulative EFS at 10 years was 43% (95% CI, 0.14-0.70). Relapse-related mortality was 21.4%; nonrelapse mortality (NRM) was 28.57%. All the survivors had etoposide in their conditioning regimen. Patients younger than 10 years had better survival (P=.001). Children with MDS achieve encouraging OS and EFS following allogeneic SCT. A busulfan-based regimen with a lower dose of etoposide is an effective and less toxic regimen. The outcomes are best in younger patients.

The Prognostic Value of YKL-40 Concentrations in Nonmyeloablative Conditioning Allogeneic Hematopoietic Cell Transplantation

Increased plasma concentrations of YKL-40, also called chitinase-3-like-1 protein (CHI3L1), have been correlated with disease severity in a variety of malignant and inflammatory diseases. The objective of the current study was to assess pretransplant recipient and donor CHI3L1 polymorphisms and plasma YKL-40 concentrations as prognostic biomarkers in a cohort of 149 patients treated with hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies. Recipients with pretransplant YKL-40 concentrations above the age-adjusted 95th percentile (high) had higher relapse-related mortality (33% versus 18%, P = .04; hazard ratio (HR) = 4.41, P = .01), lower progression-free survival (38% versus 64%, P < .01; HR = 2.84, P = .01), and overall survival (42% versus 69%, P = .01; HR = 3.09, P = .01). Recipients transplanted with donors with high YKL-40 concentrations had an increased probability and risk of grade 2-4 acute graft-versus-host disease (aGVHD) (93% versus 62%, P < .01; HR = 2.25, P = .02). CHI3L1 polymorphisms were associated with plasma YKL-40 concentrations, but not with clinical outcomes. In conclusion, our study suggests that plasma YKL-40 could function as a biomarker for relapse risk and treatment-related toxicity, and possibly as a tool complementing clinical risk scores such as the HCT comorbidity index.

Phase 1/2 trial of total marrow and lymph node irradiation to augment reduced-intensity transplantation for advanced hematologic malignancies

AbstractThis phase 1/2 study assessed the augmentation of reduced-intensity conditioning (RIC) with total marrow and lymph node irradiation (TMLI), for peripheral blood stem cell transplantation, in patients with advanced hematologic disease. The regimen consisted of fludarabine 25 mg/m2 per day for 5 days, melphalan 140 mg/m2 for one day, and TMLI radiation at 150 cGy/fraction in 8 fractions over 4 days. Eligible patients were over 50 years old and/or had compromised organ function. Median age of the 33 evaluable patients was 55.2 years. Eighteen events of nonhematologic grade III or higher toxicities occurred in 9 patients. Day 30 and day 100 mortalities were 3% and 15%, respectively. Patients achieved myeloid and platelet engraftment at a median of 14 days after transplantation. Long-term toxicities occurred in 2 patients: hypokalemia and tremor, both grade III, on days 370 and 361 after transplantation. Fourteen patients died, 7 of relapse-related causes and 7 of non–relapse-related causes. With a median follow-up for living patients of 14.7 months, 1-year overall survival, event-free survival, and non–relapse-related mortality were 75%, 65%, and 19%, respectively. Addition of TMLI to RIC is feasible and safe and could be offered to patients with advanced hematologic malignancies who might not otherwise be candidates for RIC.

Hematopoietic Stem Cell Transplantation for Treatment of Myleodysplastic Syndromes

Allogeneic stem cell transplantation is a potentially curative treatment for myelodysplastic syndromes. Transplants are clearly indicated in patients with intermediate-2 and high risk disease; there is controversy regarding when transplantation should be performed in patients with low and intermediate-1 risk disease. Most patients with MDS are over age 65 and Medicare has recently provisionally approved transplants, but only when performed as part of a comparative clinical trial which still must be finalized. Nonmyeloablative preparative regimens allow treatment of older patients with MDS, and novel approaches are under evaluation to reduce the risk of relapse and treatment related morbidity and mortality.

Comparison of Single Versus Multiple Unit Umbilical Cord Blood Transplantation for Adult Hematologic Malignancy Patients

AbstractAbstract 3545Umbilical cord blood transplantation (UCBT) is an alternative donor transplant approach for adult hematologic malignancy patients. Although UCBT was initially performed using single cord blood units (SCBU), a major limitation of this approach has been the low infused total nucleated cell (TNC) and CD34+ cell doses at the time of transplant. This accounts for delayed hematopoietic recovery post-transplant that increases the risk for infections and transplant-related mortality (TRM). Multiple unit (MU) UCBT has become an acceptable approach to increase the cell doses available for transplantation. We retrospectively compared outcomes for 38 consecutively treated adult hematologic malignancy patients who underwent SCBU (n=6) or MU (n=32) UCBT at our institution from October 1999 through April 2010. The median age was 49 years (range, 18–71) and 20 (53%) were men. Diagnoses included: 21 AML, 5 CML, 3 MDS, 5 ALL, 2 CLL, 1 NHL and 1 myelofibrosis. The majority of patients received myeloablative conditioning (n=32) most commonly with total body irradiation, etoposide and ATG (Sobecks et al, Br J Haematol 2010, in press) while those treated with reduced-intensity conditioning received fludarabine 40 mg/m2/day × 5 (days -6 through -2), cyclophosphamide 50 mg/kg (day -6), ATG 30 mg/kg/day × 5 (days -3 through +1) and total body irradiation 200 cGy (days -1 and 0; total dose 400 cGy). GVHD prophylaxis included a calcineurin inhibitor for all patients and most MU patients received mycophenolate mofetil. Among the SCBU group there were three 4/6 and three 5/6 HLA matches with the patient. For the MU group when considering the best matched UCB unit with the patient there were seven 4/6, nineteen 5/6 and six 6/6 HLA matches while for the worst matched UCB unit there were one 3/6, eleven 4/6, sixteen 5/6 and four 6/6 HLA matches with the patient. The SCBU group included more women than the MU group (100% vs. 38%, p<0.001). When comparing both groups there were no differences regarding age at transplant, race, CIBMTR comorbidity index score, median number of prior chemotherapy regimens, myeloid vs. lymphoid diagnosis, myeloablative vs. reduced-intensity conditioning, use of ATG, median TNC and CD34+ cell doses infused, time for neutrophil and platelet engraftment, graft failure or length of transplant hospitalization. However, as compared to the MU group the SCBU group had more grade 3–4 acute GVHD (HR 11.4, 95% CI 2.07–62.6, p=0.005) and a trend for more grade 2–4 acute GVHD (HR 2.80, 95% CI 0.85–9.22, p=0.09). There were no differences between the groups regarding the number of HLA disparities with the recipient when considering the worst matched, best matched or engrafting UCB unit. There also was no difference between the groups with regards to chronic GVHD. CMV infection developed in 2 (33%) SCBU patients and in 8 (25%) MU patients while other infections occurred in 5 (83%) SCBU patients and 30 (94%) MU patients. There has been 1 (17%) relapse in the SCBU group (ALL patient) and 3 (9%) in the MU group (1 MDS, 1 AML and 1 CML). One (17%) SCBU and 14 (44%) MU patients remain alive at a median follow-up of 15 months (range, 3–92 months). Deaths in the SCBU group included 2 acute GVHD, 2 disease relapses and 1 hemorrhage while in the MU group there were 10 infections, 2 pulmonary toxicities, 1 acute GVHD, 1 relapse, 1 hemorrhage, 1 graft failure, 1 multi-organ failure and 1 secondary malignancy. The respective 100 day mortality was 50% vs. 42%; 1 and 2 year transplant-related mortality 50% vs. 46% and 50% vs. 57%; 1 and 2 year relapse-related mortality were both 33% vs. 3% for the SCBU and MU groups. The greater amount of grade 3–4 acute GVHD in the SCBU patients could not be attributed to HLA disparities, conditioning regimen intensity, use of ATG, infused TNC or CD34+ cell doses. Further follow-up with more patients is required to confirm this finding and to adequately assess for a survival benefit between the groups. Novel approaches to enhance immune reconstitution and prevent infection after UCBT are warranted. Disclosures:No relevant conflicts of interest to declare.

Early Mortality After Hematopoietic Cell Transplantation (HCT) for Hematologic Malignancies Performed In the Recent Era

AbstractAbstract 902 Background:HCT is a curative option for patients with hematologic malignancies. However, the procedure carries a high risk of death in the immediate post-HCT period in part due to disease recurrence (relapse-related mortality [RM]), but also due to treatment-related mortality (TRM) resulting from the following: i) toxicity due to high intensity treatment; ii) graft vs. host disease (GvHD) and its management; and iii) infections. Previous studies utilizing data from HCTs performed in 1980s and 1990s indicate that the 1-yr cumulative incidence of TRM exceeds 20% for related donor and 30% for unrelated donor HCTs. However, gaps in knowledge remain related to the cause-specific cumulative incidence of TRM and RM after autologous and allogeneic HCT performed in the more recent eras. Methods:Between 2005 and 2008, a total of 1,673 consecutive patients received HCT at City of Hope at a median age of 50 years for AML (n=433), NHL (n=428), MM (n=369), ALL (n=176), and HL (n=154); 913 patients received autologous HCT; 382 allogeneic related donor; and 378 unrelated donor HCT. Reduced intensity conditioning was used for 268 patients. Early mortality was defined as death in the first year after HCT due to disease (RM) or treatment (TRM). Information regarding vital status and cause of death were obtained from medical records, supplemented with Social Security Death Index. Overall survival (OS) and cumulative incidence of TRM and RM were calculated for 30 d, 6 mo and 1 yr after HCT for i) the entire cohort, and by ii) diagnosis and iii) type of HCT. Multivariable models identified predictors of TRM and RM. Results:A total of 323 deaths (19.3% of the entire cohort) were observed within the first year after HCT; 55.5% attributed to TRM and 44.5% to RM. Among deaths due to TRM, 59% were attributed to infections, 12.9% to acute or chronic GvHD, and 9.5% to organ toxicity. Among autologous, related and unrelated donor HCT recipients, overall survival (OS) was 87.2%, 76.6% and 63.5% at 1 yr (p<0.001) (Figure 1A). Among autologous, related donor, and unrelated donor HCT recipients, 1-yr cumulative incidence of TRM was 1.6%, 12.1%, and 25.6% respectively (p<0.001) (Figure 1B), and cumulative incidence of RM was 8.2%, 6.9%, and 8.7% respectively (p=0.73) (Figure 1C). OS and cumulative incidence of TRM and RM by disease and type of HCT are summarized in Table. Predictors of increased RM included age at HCT 40–60 yr (HR: 1.6, p=0.04; referent group: <40 yr), and diagnosis of NHL (HR=2.0, p=0.008; referent group: AML); receipt of HCT in the later years was associated with decreased RM (2007: HR=0.5, p=0.02; 2008: HR=0.5, p=0.04; referent group: HCT in 2005). Of note, RM for NHL and AML did not differ by type of HCT (p=0.94). Predictors of TRM included allogeneic HCT (related: HR=4.3, p=0.0003; unrelated: HR=10.2, p<0.0001; referent group: autologous HCT). Among related and unrelated HCT recipients, use of reduced intensity conditioning did not have a significant impact on TRM (HR=1.2, p=0.6) or RM (HR=1.2, p=0.7). Conclusion:For patients with NHL and AML, cumulative incidence of RM does not differ by HCT type. Unrelated donor HCT continues to be associated with the highest risk of TRM. Infection is the most frequent cause of TRM, accounting for 62% of deaths due to TRM in unrelated donor, 52% in related donor, and 46% in autologous HCT recipients – reinforcing the need for aggressive measures for prevention and treatment of infections in this immune compromised population.Overall survivalCum incidence: TRMCum incidence RRM30 d6 mo1 yr30 d6 mo1 yr30 d6 mo1 yrEntire cohort (n=1673)98.7%88.8%79.1%1.2%6.7%9.7%0.1%3.7%8%Autologous HCT (n=913)99.6%94.8%87.2%0.5%1.1%1.6%02.9%8.2%Allogeneic HCT (n=382)98.7%87%76.6%0.8%8.2%12.1%0.6%4.3%6.9%URD HCT (n=378)96.6%77%63.5%3.6%17.9%25.6%0%5%8.7%Autologous (AML: n=67)98.5%95.2%85.3%1.5%4.8%6.4%0%0%8.2%Related donor (AML: n=175)98.9%85.3%72.4%0.6%10.1%14%0.6%4.4%8.3%URD HCT (AML: 191)97.4%75%62.9%2.7%19.3%25.1%05%9.1%Related donor (ALL: n=89)97.8%89.7%80.3%2.4%8.5%13.6%0%0%0%URD HCT (ALL: n=87)93.3%72.8%57.8%6.7%21.5%33.1%05.7%9.2%Autologous (NHL: n=313)100%91.2%82%0%0%0.4%0%6.6%13.7%Related donor (NHL: n=63)98.4%81.6%68.9%0%8.5%14.2%0%10.5%14.3%URD HCT (NHL: n=52)98.1%82.4%70.7%1.9%9.9%16.5%0%7.9%11.9%Autologous (HL: n=147)99.3%94.2%87.2%0.7%2.2%2.2%0%2.2%7%Autologous (MM: n=358)99.7%98.4%92.6%0.3%0.6%1.3%0%0.7%3.9% [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Phase II Study Evaluating Busulfan and Fludarabine as Preparative Therapy In Adults with Hematopoietic Disorders Undergoing Matched Unrelated Donor Stem Cell Transplantation.

AbstractAbstract 1317 Introduction:Allogeneic stem cell transplantation offers potentially curative therapy for selected patients with hematopoietic malignancies or bone marrow failure states. Only 20–25% of transplantation candidates have compatible related donors, and thus the majority of patients require stem cells from unrelated individuals matching their human leukocyte antigen (HLA) genes. Unrelated donor transplantation (NMUDT) is associated with higher rate of acute and chronic graft versus host disease (aGVHD and cGVHD, respectively) resulting in significant treatment related morbidity and mortality. Severe aGVHD (grade III/IV) occurs in 30–40% of patients and many of these patients eventually die from the complications. The incidence of cGVHD following unrelated transplantation was reported to occur up to 80%. Treatment-related mortality in the first 100–180 days post-transplant ranges from 30–60% depending on the patient/donor age, disease status at time of transplant and HLA mismatch. This compares to a treatment-related mortality of approximately 20–30% for patients receiving sibling-donor transplants. More aggressive conditioning including total body irradiation is believed to result in severe organ toxicities fueling subsequent GVHD in the NMUDT patients. In this study we evaluated chemotherapy only based preparative therapy (busulfan and fludarabine) and tacrolimus plus methotrexate as the GVHD prophylaxis. Also the donors and recipients were matched with strict HLA compatibility. Patients and Method:Thirty-five patients meeting eligibility criteria for NMUDT were prospectively enrolled. Diagnoses included:14 AML, 6 NHL, 6 MDS, 5 ALL, 2 MPD, 2 CML. The median age was 46 years (18-61); 20 males and 15 females. Preparative therapy consisted of Fludarabine (F) 30mg/m2 daily for 5 doses, Busulfan (Bu) 0.8mg/kg IV q6 hrs for 16 doses. All patients received stem cells from allele-matched unrelated donors; 7/8 (n=1), 8/10 (n=1), 9/10 (n= 7) or 10/10 (n= 26) at HLA A, B, C, DR and DQ. 9 patients received bone marrow and 26 patients received G-CSF mobilized peripherial blood stem cells. All patients received TAC (target 5–10 ug/L), MTX (5mg/m2 d1,3,6,11) for GVHD prophylaxis. Infectious disease prophylaxis included; G-CSF, acyclovir, anti-bacterials, voriconazole, and CMV pre-emptive therapy. Results:The engraftment was documented as follows: ANC >1.0 median: day 12 (SD3.5), Plt >50×10e9/L median: day 16 (SD 7.2), Plt >100×10e9/L median: day 20 (SD 40.7). The frequent (>20%) toxicities included bone marrow suppression (grade 4 100%) mucositis (gr≥1 91%), enteritis (gr≥1 43%); elevated AST (gr 1 27%), elevated total bilirubin (gr 1 20%) and alkaline phosphatase (gr1 40%). Other significant toxicities (gr ≥3) included neutropenic fever (20%), bacteremia (11%), infections (including pneumonia, fungal pneumonia, CMV viremia) (26%), enteritis 6%, ARF 9%, rash 9%, respiratory failure 14%. The incidence of aGVHD (Gr II-IV) was 43%. The incidence of cGVHD was 60% (90% extensive cGVHD). The 100 day non-relapse mortality (NRM) was 9% (2 GVHD, 1 VOD). The late TRM (beyond 100 days) was 11% (3 GVHD, 1 infection). Cumulative relapse related mortality was 17% at 6 months, 26% at 9 months and 31% at 24 months. Overall mortality at 1 year was 44%. Overall survival is currently 40% with median follow-up of 4.4 years. Conclusions:In this prospective study of 35 patients undergoing matched unrelated donor transplantation, the busulfan/fludarabine preparative regimen is safe and resulting in reasonably low TRM and comparable GVHD rates. Disease relapse remains the most significant cause of death. Disclosures:No relevant conflicts of interest to declare.

Cause-Specific Conditional Survival In 2603 Consecutive Patients Undergoing Autologous Hematopoietic Cell Transplantation (aHCT) Over a 20-Year Period

AbstractAbstract 933 Background:aHCT is offered with curative intent to patients with hematologic malignancies. However, survival estimates are conventionally computed from time of transplantation. These estimates provide initial prognosis, but do not reflect how prognosis changes with changing hazard rates over time. Conditional survival accounts for elapsed time since diagnosis, describing the probability of survival after having already survived a certain period of time after aHCT. We describe cause-specific conditional survival, providing clinically relevant information to inform preventive and interventional strategies for patients alive for differing lengths of time from aHCT. Methods:From 1986 to 2006, a total of 2,603 consecutive patients received aHCT at City of Hope at a median age of 48 yrs (NHL: n=1063; MM: n=625; HL: n=475; AML: n=330; other: n=110). Information regarding vital status and cause of death were determined using National Death Index Plus and medical records. Survival probabilities and standardized mortality ratios (SMRs) were calculated for the entire cohort as well as by diagnosis, conditional on survival for 1, 2, 5, and 10 yrs after aHCT. Results:A total of 1135 deaths (representing 44% of the cohort) were observed by December, 2007; 79% of deaths were attributed to recurrent disease (range: 88% after MM to 71% after HL); 8% to subsequent neoplasm (SMN: range: 4% after MM to 13% after HL); 6% to cardiopulmonary disease (range: 2% after MM to 10% after HL); and 7% to other causes. Using conventional survival estimates, overall survival (OS) was 60% at 5 yr and 48% at 10 yr from aHCT; and the cohort was at a 15.6-fold increased risk of premature death compared with the general population (95%CI=14.7-16.6). Females were at a higher risk of premature death (SMR=19.1) than males (SMR=12.3). The cohort was at a 4.9-fold (95%CI=3.9-5.9) increased risk of death due to SMNs, and at a 2.3-fold (1.5-3.2) increased risk of deaths due to late cardiac complications. Conditional survival estimates demonstrated that every additional yr survived was associated with an increase in the probability of surviving the subsequent 5 yrs. Thus, the 5-yr survival rate was 68% after surviving 1 yr, 73% after surviving 2 yr, 80% after 5 yr; and approaching 88% after having survived 10 yrs from aHCT (Figure). Cause-specific conditional survival rates and SMRs by primary diagnosis are summarized in the Table. The risk of premature death (due to any cause) was comparable to the general population for 10-yr survivors, with the exception of HL survivors (2.6-fold increased). With the exception of MM, individuals who had survived 10 years were projected to have a <5% risk of relapse-related mortality over the next 5 yrs (range: AML – 0% to HL: 5%). However, non-relapse mortality remained elevated long-term, indicating a need for extended surveillance. Conclusion:This study demonstrates that the projected 5-yr survival rates improve conditional on previous time survived from aHCT, and that the 10-year survivors of aHCT for AML, NHL, and MM have mortality rates that are comparable to the general population. HL survivors continue to experience a 2.6-fold increased risk of premature death, primarily because of the excess risk of non-relapse mortality (due to SMN and cardiac causes). Conditional survival estimates provide clinically relevant prognostic information and an accurate estimate of cause-specific survival, helping inform preventive and interventional strategies.TableCause-specific Conditional Survival in patients undergoing autologous HCTfrom aHCT1 yr survivors5 yr survivors10 yr survivors5 yr survivorsSMR (95%CI)5 yr survivorsSMR (95%CI)5 yr survivorsSMR (95%CI)5 yr survivorsSMR (95%CI)All patientsOverall6015.6(14.7–16.5)689.5(8.8–10.2)803.5(3.0–4.1)881.5(1.0–2.0)Relapse-related65748897Non-relapse-related92939291AMLOverall6215.7(13.1–18.3)748.8(6.8–10.8)862.8(1.4–4.0)911.1(0.02–2.1)Relapse-related647694100Non-relapse-related96999391NHLOverall6114.0(12.7–15.2)747.2(6.3–8.1)813.0(2.3–3.7)861.4(0.7–2.1)Relapse-related66809298Non-relapse-related92938988HLOverall5930.4(26.3–34.5)6619.4(16.1–22.7)846.5(4.4–8.5)902.6(0.9–4.3)Relapse-related68769195Non-relapse-related87889295MMOverall5910.9(9.5–12.3)569.1(7.8–10.3)633.8(2.6–4.9)841.1(0–2.6)Relapse-related63606684Non-relapse-related959595100 [Display omitted] Disclosures:Nademanee:Genzyme: Consultancy, Research Funding; Allos Therapeutics: Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees.

Multiple unit umbilical cord blood transplantation with total body irradiation, etoposide and antithymocyte globulin for adult haematological malignancy patients

Multiple unit umbilical cord blood transplantation with total body irradiation, etoposide and antithymocyte globulin for adult haematological malignancy patients

No Impact of Dectin-1 Polymorphism Y238X On the Outcome of Hematopoietic Stem Cell Transplantation, but a Role for Candida in Acute Graft-Versus-Host Disease.

Abstract 4498Dectin-1 is a C-type lectin receptor that recognizes b-1,3-glucan, and plays an important role in antifungal immunity. The recently discovered dectin-1 Y238X polymorphism, which results in “loss-of-function” has been shown associated with increased Candida colonization of stem cell transplantation (SCT) recipients. Besides its role in antifungal immunity Dectin-1 exhibits a broader function in immunity. Stimulation of Dectin-1 with β-glucan affects antigen presentation, modulates T-lymphocytic (CD4+, both Th1 and Th17, and CD8+) and B-lymphocytic responses, and induces cytokine production including interleukin (IL) 10, IL-12 and IL-23. These specific T-cell responses and cytokines are of particular interest in SCT because they are involved in graft-versus-leukemia (GvL) effects as well as in the pathogenesis of graft-versus-host disease (GvHD). Therefore we now performed a retrospective study in 140 patients on the impact of the Y238X polymorphism on the outcome of myeloablative T cell-depleted matched related SCT. The allele frequency of the Y238X polymorphism was 6.6%, with 10.7% of patients and 15.7% of donors bearing the polymorphism. All were heterozygous and at least one polymorphism was present in 28 of 140 (20%) patient-donor pairs. We found no impact of the polymorphism on the occurrence of acute and chronic GvHD, non-relapse and relapse related mortality, nor disease-free and overall survival. Interestingly, patients from patient-donor pairs bearing the wild-type allele who were colonized with Candida had an increased incidence of acute GvHD compared to non-colonized patients (41.9% vs. 20.4%, OR=2.6 95%CI:1.02-6.58, P=0.04). However, this seemed to be the other way round for patients from pairs with the Y238X polymorphism (23.5% colonized vs. 30% not colonized, OR=0.7, ns). Therefore we hypothesize that the loss-of-function of dectin-1 increases colonization through deficient mucosal immunity, but prevents inflammatory complications resulting from colonization (Figure 1). This might explain the lack of an effect of the Dectin-1 Y238X polymorphism on outcome measures of SCT. [Display omitted] In case of Candida colonization (left) activation of the dectin-1 receptor influences immune responses and allo-reactivity increasing the incidence of acute GvHD. In the presence of the loss-of-function polymorphism Y238X (right), although Candida colonization is increased, due to the loss-of-function of dectin-1, no changes in the allo-reactive T-cell responses occur. Disclosures:No relevant conflicts of interest to declare.