Hematopoietic Cell Transplantation Cohort Research Articles

Feasibility of Frequent Patient-Reported Outcome Surveillance in Patients Undergoing Hematopoietic Cell Transplantation

Patient-reported outcomes (PROs), including symptoms and health-related quality of life (HRQOL), provide a patient-centered description of hematopoietic cell transplantation (HCT)-related toxicity. These data characterize the patient experience after HCT and may have prognostic usefulness for long-term outcomes after HCT. We conducted a study of 32 patients after HCT (10 autologous HCT recipients, 11 full-intensity conditioning allogeneic HCT recipients, and 11 reduced-intensity conditioning allogeneic HCT recipients) to determine the feasibility of weekly electronic PRO collection from HCT until day (D) +100. We used questions from the PRO version of the Common Terminology Criteria for Adverse Events to capture symptoms, and the Patient-Reported Outcomes Measurement Information System Global Health scale to measure physical and mental HRQOL. The vast majority (94%) of patients used the electronic PRO system, with only 6% opting for paper-and-pencil only. The median weekly percentage of participants who completed the surveys was 100% in all cohorts through hospital discharge, and remained 100% for the autologous HCT and reduced-intensity allogeneic HCT cohorts through D+100. Patients were satisfied with the electronic system, giving high marks for readability, comfort, and questionnaire length. Symptom severity varied by absolute level and type of symptom across the 3 cohorts, with the full-intensity allogeneic HCT cohort exhibiting the greatest median overall symptom severity, peaking at D+7. Median physical health HRQOL scores decreased with time in the 3 cohorts, and HRQOL was generally correlated with overall symptom severity. Our results demonstrate the feasibility of frequent electronic PROs in the early post-HCT period. Future studies in larger populations to explore predictive models using frequent PRO data for outcomes, including long-term HRQOL and survival, are warranted.

Autologous and Allogeneic Transplantation for Burkitt Lymphoma Outcomes and Changes in Utilization: A Report from the Center for International Blood and Marrow Transplant Research

Trends in utilization and outcomes after autologous or allogeneic hematopoietic cell transplantation (HCT) for Burkitt lymphoma were analyzed in 241 recipients reported to the Center for International Blood and Marrow Transplant Research between 1985 and 2007. The autologous HCT cohort had a higher proportion of chemotherapy-sensitive disease, peripheral blood grafts, and HCT in first complete remission (CR1). The use of autologous HCT has declined over time, with only 19% done after 2001. Overall survival at 5 years for the autologous cohort was 83% for those in CR1 and 31% for those not in CR1. Corresponding progression-free survival (PFS) was 78% and 27%, respectively. After allogeneic HCT, overall survival at 5 years was 53% and 20% for the CR1 and non-CR1 cohorts, whereas PFS was 50% and 19%, respectively. The most common cause of death was progressive lymphoma. Allogeneic HCT performed in a higher-risk subset (per National Comprehensive Cancer Network guidelines) resulted in a 5-year PFS of 27%. Autologous HCT resulted in a 5-year PFS of 44% in those undergoing transplantation in the second CR.

Cardiac QTc Interval Characteristics and Behavior in 995 Consecutive Hematopoietic Cell Transplantation Patients At a Single Institution

Abstract 1967 Introduction:The cardiac QT interval (QT) has gained deserved scrutiny among electrophysiologists. Reflecting the duration of the ventricular myocardial depolarization/repolarization cycle, the QT depends upon ion exchange across cardiomyocyte membranes. Ion flux perturbations (due to abnormalities of membrane-bound ion channel number, structure or function) can predispose to QT prolongation that, in turn, is associated with linearly increasing risks of ventricular tachy-arrhythmias and sudden death. As both polypharmacy and dys-electrolytemia have been reported to affect QT, we studied the interval's behavior in the potentially at-risk population of children and adults undergoing hematopoietic cell transplantation (HCT). Methods:We retrospectively reviewed over 2600 cardiologist-evaluated electrocardiograms (ECG) and transplant-related data for 995 consecutive children and adults undergoing HCT between 2006 and 2010, inclusive. Patients underwent routine pre-HCT ECG screening; repeat studies were obtained for various clinical indications. Corrected QT intervals (QTc) were noted; any study demonstrating non-sinus rhythm was disregarded. Multivariate regression models tested the association between QTc and other patient or transplant-related covariates (including age, gender, primary diagnosis, intensity of conditioning, and donor relatedness/graft-versus host disease prophylaxis for allograft recipients); reference groups representing fixed covariate characteristics were defined among the cohort for comparison. Student's t-test was used to determine the significance of aggregate intra-patient change in QTc from pre- to post-HCT. Results:Pre-HCT: 952 patients had an evaluable pre-HCT maximum QTc observed at a median Day −22. Median QTc was 428 ms (range, 330 to 569; interquartile range [IQR], 409 to 447). Statistically significant QTc variability with age was observed and reflected widely accepted age-dependent phenomena in the population-at-large. Factors predicting shorter QTc included male gender (-11 ms compared to reference group [CRG], p < 0.01) and inherited metabolic disorder (IMD) as HCT indication (-10 ms CRG, p = 0.03). Factors predicting longer QTc were myeloproliferative disorder (+22 ms CRG, p = 0.01) and acute myeloid leukemia (+7 ms CRG, p = 0.02) as HCT indications.Post-HCT: 578 patients had an evaluable post-HCT maximum QTc observed at a median Day +69. Median QTc was 454 ms (range, 367 to 619; IQR, 433 to 476). Age was not significantly predictive of maximum QTc post-HCT. Factors predicting shorter QTc were male gender (-7 ms CRG, p = 0.05) and no exposure to mycophenolate mofetil (MMF) for graft-versus-host disease (GvHD) prophylaxis (-11 ms CRG; p = 0.05). Patients diagnosed with acute lymphoblastic leukemia (ALL) demonstrated longer QTc (+17 ms CRG, p = 0.03).δQTc: 559 patients had at least one evaluable pre- and one evaluable post-HCT ECG. The median δQTc (defined per patient as [mean post-HCT QTc] - [mean pre-HCT QTc]) was 15.7 ms (range, −72 to 142; IQR, −2 to 32). A highly significant difference between post-HCT and pre-HCT QTc per patient was observed in this cohort (p < 0.01).Very Long QTc: 92 (15%) males demonstrated QTc ≥ 480 ms and 39 (10%) females demonstrated QTc ≥ 500 ms on any ECG. Of patients with ≥ 2 evaluable ECGs, 306 (50%) demonstrated prolongation ≥ 40 ms. Factors significantly predicting extreme prolongation included age < 1 year (+39 ms CRG, p < 0.01) and diagnosis of ALL (+15 ms CRG, p = 0.04); a trend toward more extreme prolongation was seen in patients with myelodysplastic syndrome (+14 ms CRG, p = 0.05). The factor protecting from extreme QTc prolongation was treatment with a related allograft (-9 ms CRG, p = 0.03); trends toward less extreme prolongation were also seen in autologous HCT and those not receiving MMF for GvHD prophylaxis. Conclusion:Prolonged QTc is associated with life-threatening ventricular tachy-arrhythmias. This retrospective analysis of a large, diverse HCT cohort shows statistically significant prolongation during transplantation. Too, we identify sub-populations demonstrating very-long QTc and/or experiencing marked QT prolongation during HCT. Further analysis regarding pharmacologic, electrolytic and HCT-related predictors as well as outcomes for the cohort is underway. Disclosures:No relevant conflicts of interest to declare.

Interleukin-10 Promoter Polymorphisms Associating with Severe Acute Graft-Versus-Host Disease In HLA-Identical Sibling Transplants.

AbstractAbstract 4533Acute graft-versus-host disease (GVHD) remains the major complication of allogeneic hematopoietic-cell transplantation (HCT). Matching of donor and recipient for human leukocyte antigens (HLA) and minor histocompatibility antigens is important to optimize the outcome of allogeneic HCT. In addition donor and recipient polymorphisms in cytokine genes can influence immune responses, inflammation, and tissue injury and have been associated with the incidence and severity of GVHD in HLA-identical bone marrow transplantation.To gain further insights on the impact of these polymorphisms in allogeneic transplantation, we analyzed 7 polymorphisms located in four cytokine genes (interleukin-10 (IL10), interleukin-1 beta (IL1B), interleukin-1-receptor-antagonist (IL1RA) and tumor-necrosis-factor alpha (TNFa)) previously reported to have impact on outcome- in a group of 90 HLA-identical sibling donor-recipient pairs. Allele identification was realized using restriction enzyme digestion and high- resolution fragment analysis. Resulting genotypes were tested for an association with incidence and severity of GVHD by univariate and multivariate analysis.Three polymorphisms of the IL-10 promoter have been assessed: the microsatellites IL-10.G-1064 and IL-10.R and the single nucleotide polymorphism IL-10.G-1082. The allelic distribution was similar to that previously reported in Caucasian populations. In univariate analysis, recipients homozygous for longer IL-10.G-1064 microsatellite alleles were found associated with more severe GVHD (grade II to IV) when compared to the remaining genotypes (p=0.014). This result could be confirmed by multivariate analysis (p= 0.012; odds ratio (OR) 6.68). Patients homozygous for the shorter alleles (<12) and heterozygous individuals (<12)/(12-16) did not show an increased risk to develop significant acute GVHD (Figure 1). [Display omitted] In the donor IL-10 promoter region the IL-10.R3/R3 genotype was associated with an increased risk of grade II to IV acute GVHD in univariate and multivariate analysis (p=0.031; OR 12.33). There was no significant association between the recipients IL-10.R genotype and the incidence of acute GVHD. Previously described impact of the TNFd genotype, the IL-1B-511 and IL-10.G-1082 single nucleotide polymorphisms and the IL-1RA variable number of tandem repeat (VNTR) polymorphism could not be confirmed in this study. No significant differences were detected in the distribution of known GVHD risk factors, including age at transplantation, presence of sex mismatch between donor and recipient and use of total-body irradiation in the conditioning regimen.Our data support previously reported results that the IL-10 promoter genotype might be useful to detect patients at risk to develop severe acute GVHD after allogeneic HCT. However, before it can improve outcome prediction over standard clinical prognostic indicators additional studies in larger HCT cohorts and prospective clinical trials are needed. Disclosures:No relevant conflicts of interest to declare.

Population-Based Analysis of Late Cardiovascular Morbidity and Hospitalizations After Hematopoietic Cell Transplantation.

Abstract 517▪▪This icon denotes an abstract that is clinically relevant. BACKGROUND:There is growing evidence that recipients of hematopoietic cell transplantation (HCT) have increased risk of adverse long-term effects such as hypertension, dyslipidemia, and diabetes which may contribute to increased cardiovascular (CV) morbidity and mortality. METHODS:The Fred Hutchinson Cancer Research Center (FHCRC) performs the vast majority of HCTs in Washington State. We linked the medical records of all 2-year HCT survivors who were state residents treated at FHCRC from 1985-2005 (n=1405; 62% allogeneic; 38% autologous) to the state's hospital discharge and death registries beginning 2 years after HCT. Individuals randomly selected from state driver's license files (n=5964) served as a comparison group, frequency-matched by age, sex, and county of residence. Selected serious CV diagnoses (ischemic heart disease, dysrhythmia, cardiomyopathy/heart failure, stroke and other vascular disease) and related diseases (dyslipidemia, diabetes, chronic renal disease) were identified from these databases for the HCT and comparison cohorts. Odds ratio (OR) estimates of the relative risk were calculated using logistic regression adjusted for age and year of HCT/driver's license filing, sex, and race/ethnicity (HCT patients only). RESULTS:With a median age at HCT of 40 (0-73) years and follow-up time of 5 (2-22) years since HCT, survivors were significantly more likely to have subsequent CV and related diagnoses recorded in hospital discharge (28% vs. 10%; p<0.01) and death records (4% vs. 1%; p<0.01) vs. the comparison group. In particular, dysrhythmia, cardiomyopathy/heart failure, stroke and other vascular diseases, diabetes, and chronic renal disease were recorded more frequently among the HCT cohort. Rates of ischemic heart disease were not significantly different between the 2 groups (4% vs. 3%; p=0.14). In multivariable analyses, factors independently associated with increased CV hospitalizations included history of chronic graft vs. host disease (OR 2.0 [1.4-2.7]) and receiving >1 HCT of any type (OR 2.1 [1.4-3.0]). Receiving >1 HCT also was associated with statistically significant 2-3 fold increased risks of dysrhythmia, cardiomyopathy/heart failure, and chronic renal disease. Allogeneic transplants and preparative regimens containing total body irradiation (TBI) were not associated with an increased risk of CV hospitalization compared with autologous transplants and non-TBI containing regimens, respectively. While older age at baseline was associated with an increased risk of most CV outcomes in both groups, in age-stratified analysis, those who received HCT at a younger age had the greatest risk vs. similar-aged comparison subjects (e.g. <20 years at HCT, CV hospitalization OR=37.8 [16.5-86.2]; ≥60 years at HCT, OR=1.7 [1.1-2.6]). In contrast to the comparison group, among HCT survivors increased body mass index was not consistently associated with an increased risk of CV outcomes except for diabetes. CONCLUSIONS:CV-related hospitalizations and deaths occurred significantly more often among 2-year HCT survivors than the comparison group, as measured by hospital discharge and death registries. Similar risk was observed following allogeneic and autologous transplants. Patients who received HCT at a younger age and those who experienced multiple transplants of any type were at particularly increased risk. To more completely delineate risk factors, future analyses will examine the effects of pre-HCT anthracycline and chest radiotherapy exposures, and elapsed time since HCT.OutcomesHCT patientsComparison groupOR* 95%CIn=1405n=5964N(%)N(%)Ischemic heart disease523.7%1763.0%1.30.96-1.9Dysrhythmia906.4%1472.5%2.92.2-3.8Cardiomyopathy/heart failure705.0%1242.1%2.61.9-3.6Stroke271.9%641.1%1.81.1-2.8Other vascular disease382.7%851.4%2.01.3-2.9Lipid disorders694.9%2263.8%1.41.0-1.8Diabetes725.1%1702.9%1.91.4-2.5Chronic renal disease/failure745.3%430.7%8.15.5-12.0*Adjusted for age at HCT/driver's license filing, year of diagnosis/driver's license filing, and sex. Disclosures:No relevant conflicts of interest to declare.

Defective Neo-Antigen Response to Keyhole Limpet Hemocyanin (KLH) Vaccines in Patients after Hematopoietic Cell Transplantation.

Relapse is the most common cause of treatment failure for advanced cancer, even those treated with autologous hematopoietic cell transplantation (HCT). Effective tumor-specific immunotherapy may decrease relapse, however, this will fail if the immune system is not able to respond appropriately. To test the integrity of the immune response, we vaccinated 27 normal volunteers, 14 patients after HCT, and 19 patients with advanced cancer with a single injection of KLH, a neo-antigen that humans have not been exposed to previously. KLH (Intracel, Rockville, MD or Biosyn Corp, Carlsbad, CA) was given as a single 1 mg subcutaneous injection. Immune response was measured by ELISA, proliferation or ELISPOT (validated for cryopreserved cells) assays on blood 1 month after vaccination compared to preimmunization. Intracel KLH (containing the intact KLH molecule, 6000–8000 kDA) induced a potent IgM, IgG1 and IgG2 response as well as a cellular response measured by proliferation assay in normal volunteers (n=17). Because of sporadic availability, Biosyn KLH, produced as 350/390 kDA subunits of KLH, was then tested. Biosyn KLH alone failed to induce either a humoral or cellular response. We hypothesized that lack of a response to a single Biosyn KLH immunization was due to the product purity and decreased complexity of size resulting in loss of adjuvant properties compared to the intact KLH product. Biosyn KLH was then mixed with the oil/surfactant Montanide ISA-51, which completely restored immunogenicity to a single 1 mg KLH test vaccine in normal subjects (n=10) similar to the Intracel intact KLH product. In marked contrast to the normal response, humoral responses were significantly impaired in 11 patients 58–144 [median 103] days after autologous HCT and in 1 as late as 16 months after HCT. This latter patient was the only one who mounted a cellular response to KLH after HCT. Patients with metastatic melanoma and renal cell carcinoma exhibited an intermediate response (Table). The decreased KLH-specific IgG2 response after HCT was partially explained by the decreased total IgG2 levels after transplant as compared to normal volunteers and solid tumor patients. Total IgG1 and IgM immunoglubulin levels were not significantly different between groups. The defect in isotype switching correlated with decreases in absolute CD4 counts between the normal (891±58/mm3), solid tumor (501±73/mm3) and HCT (290±119/mm3) cohorts. We conclude that patients with cancer and especially those patients after autologous HCT have immune defects significantly impairing neo-antigen responses. This has important implications for tumor vaccine strategies in these settings. KLH vaccines are safe, and 100% of normal volunteers require only a single injection to test cellular and humoral neo-antigen responses including isotype switching, an optimal platform for definitive testing of strategies to promote immune reconstitution after HCT.Response to KLH 1 month after vaccination.ReadoutNormal (n=27)Solid Tumor (n=19)HCT (n=14)IgM*7.7 ± 1.37.6 ± 2.11.4 ± 0.28IgG1*234 ± 5037.3 ± 13.27.9 ± 4.5IgG2*34 ± 5.112.7 ± 4.10.67 ± 0.23ELISPOT#311 ± 61 (n=10)Not done14 ± 9 (n=7)* values are mean ± SEM in mcg/ml; # reported as spots/million cells