Barry E. Storer

Transplantation of bone marrow as compared with peripheral-blood cells from HLA-identical relatives in patients with hematologic cancers.

BACKGROUND In recipients of allogeneic hematopoietic-cell transplants, peripheral-blood cells mobilized with the use of filgrastim (recombinant granulocyte colony-stimulating factor) engraft more rapidly than bone marrow. However, the relative effects of these techniques on the rates of acute and chronic graft-versus-host disease, overall survival, and disease-free survival have not been determined in randomized studies. METHODS Between March 1996 and July 1999, 172 patients (12 to 55 years of age) with hematologic cancer were randomly assigned to receive either bone marrow or filgrastim-mobilized peripheral-blood cells from HLA-identical relatives for hematopoietic rescue after the treatment of hematologic cancer with high doses of chemotherapy, with or without radiation. RESULTS The recovery of both neutrophils and platelets was faster with peripheral-blood cells than with marrow (P<0.001 for both comparisons). The cumulative incidence of grade II, III, or IV acute graft-versus-host disease at 100 days was 64 percent with peripheral-blood cells and 57 percent with marrow (hazard ratio, 1.21; 95 percent confidence interval, 0.81 to 1.81; P=0.35). The cumulative incidence of chronic graft-versus-host disease was 46 percent with peripheral-blood cells and 35 percent with marrow (hazard ratio, 1.16; 95 percent confidence interval, 0.71 to 1.90; P=0.54). The estimated overall probability of survival at two years was 66 percent with peripheral-blood cells and 54 percent with marrow (hazard ratio for death, 0.62; 95 percent confidence interval, 0.38 to 1.02; P=0.06). The rate of disease-free survival at two years was 65 percent with peripheral-blood cells and 45 percent with marrow (hazard ratio for relapse or death, 0.60; 95 percent confidence interval, 0.38 to 0.95; P=0.03). CONCLUSIONS In patients given high-dose chemotherapy, with or without radiation, for the treatment of hematologic cancer, allogeneic peripheral-blood cells used for hematopoietic rescue restore blood counts faster than allogeneic bone marrow, without increasing the risk of graft-versus-host disease.

Graft-Versus-Tumor Effects After Allogeneic Hematopoietic Cell Transplantation With Nonmyeloablative Conditioning

PURPOSE We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy. PATIENTS AND METHODS We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130). RESULTS Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003). CONCLUSION New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

Comorbidity and Disease Status–Based Risk Stratification of Outcomes Among Patients With Acute Myeloid Leukemia or Myelodysplasia Receiving Allogeneic Hematopoietic Cell Transplantation

PURPOSE Retrospective studies have shown similar survival among patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) after nonmyeloablative compared with myeloablative conditioning. Refined risk stratification is required to design prospective trials. PATIENTS AND METHODS We stratified outcomes among patients with AML (n = 391) or MDS (n = 186) who received either nonmyeloablative (n = 125) or myeloablative (n = 452) allogeneic hematopoietic cell transplantation (HCT) based on comorbidities, as assessed by a HCT-specific comorbidity index (HCT-CI), as well as disease status. Patients receiving nonmyeloablative conditioning were older, more frequently pretreated, more often received unrelated grafts, and more often had HCT-CI scores of 3 compared with patients who received myeloablative conditioning. RESULTS Patients with HCT-CI scores of 0 to 2 and either low or high disease risks had probabilities of overall survival at 2 years of 70% and 57% after nonmyeloablative conditioning compared with 78% and 50% after myeloablative conditioning, respectively. Patients with HCT-CI scores of 3 and either low or high disease risks had probabilities of overall survival of 41% and 29% with nonmyeloablative conditioning compared with 45% and 24% with myeloablative regimens, respectively. After adjusting for pretransplantation differences, stratified outcomes were not significantly different among patients receiving nonmyeloablative compared with myeloablative conditioning, with the exception of lessened nonrelapse mortality (hazard ratio, 0.50; P = .05) in the highest risk group. CONCLUSION Patients with low comorbidity scores could be candidates for prospective randomized trials comparing nonmyeloablative and myeloablative conditioning regardless of disease status. Additional data are required for patients with low-risk diseases and high comorbidity scores. Novel antitumor agents combined with nonmyeloablative HCT should be explored among patients with high comorbidity scores and advanced disease.

Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria

Risk factors for grades 2-4 acute graft-versus-host disease (GVHD) and for chronic GVHD as defined by National Institutes of Health consensus criteria were evaluated and compared in 2941 recipients of first allogeneic hematopoietic cell transplantation at our center. In multivariate analyses, the profiles of risk factors for acute and chronic GVHD were similar, with some notable differences. Recipient human leukocyte antigen (HLA) mismatching and the use of unrelated donors had a greater effect on the risk of acute GVHD than on chronic GVHD, whereas the use of female donors for male recipients had a greater effect on the risk of chronic GVHD than on acute GVHD. Total body irradiation was strongly associated with acute GVHD, but had no statistically significant association with chronic GVHD, whereas grafting with mobilized blood cells was strongly associated with chronic GVHD but not with acute GVHD. Older patient age was associated with chronic GVHD, but had no effect on acute GVHD. For all risk factors associated with chronic GVHD, point estimates and confidence intervals were not significantly changed after adjustment for prior acute GVHD. These results suggest that the mechanisms involved in acute and chronic GVHD are not entirely congruent and that chronic GVHD is not simply the end stage of acute GVHD.

Effect of Segment Length on Risk for Neoplastic Progression in Patients with Barrett Esophagus

In Barrett esophagus, the normal stratified squamous epithelium of the esophagus is replaced by specialized columnar epithelium in response to the tissue injury caused by chronic gastroesophageal reflux (1). Barrett esophagus is present in approximately 5% to 15% of persons with clinical indications for elective upper endoscopy (2-5). The results of several recent studies suggest that most patients with Barrett esophagus have short-segment (<3 cm) Barrett esophagus (2-7). Patients with long-segment ( 3 cm) Barrett esophagus are known to have a much greater risk for esophageal adenocarcinoma than members of the general population (8-11). Because investigators were initially uncertain whether short-segment Barrett esophagus predisposed persons to esophageal adenocarcinoma and because short-segment Barrett esophagus is more difficult to diagnose endoscopically (12), patients with short segments were often excluded from studies of the natural history of Barrett esophagus (8-11, 13, 14). Since the late 1980s, however, there have been several reports of esophageal adenocarcinoma in patients with short-segment Barrett esophagus (5, 15-18). Although this suggests that patients with short-segment Barrett esophagus are at increased risk for esophageal adenocarcinoma, the extent of the increase is largely unknown. The survival of patients who receive a diagnosis of esophageal adenocarcinoma is usually poor. More than 90% of patients with invasive disease die within 5 years of diagnosis (19). If tumors are resected at an early stage, however, survival improves substantially (20-22). Therefore, many authors have recommended regular endoscopic surveillance for patients with Barrett esophagus who are good surgical candidates (20, 21, 23-27) and prompt resection of the entire Barrett segment if cancer is identified (22, 28, 29). However, endoscopic surveillance has several disadvantages, including its high cost, procedure-related risks, inconvenience, and discomfort (30, 31). Because only a small percentage of patients with Barrett esophagus will develop cancer, it is reasonable to question the merits of frequent endoscopic surveillance for all such persons (11, 12, 23). We hypothesized that the risk for esophageal adenocarcinoma would increase with Barrett segment length. If this was true, it might be appropriate to perform endoscopic surveillance less frequently in patients with short-segment Barrett esophagus than in those with longer segments. To investigate this hypothesis, we conducted a prospective cohort study among patients who were participating in the Seattle Barretts Esophagus Project, which includes regular endoscopic surveillance. We determined the incidence of esophageal adenocarcinoma in patients with short-segment Barrett esophagus and examined the relation between segment length and cancer risk through multivariate analyses. We also examined the relation between segment length and aneuploidy, a genetic abnormality that usually precedes the development of esophageal adenocarcinoma and has been shown to predict progression to cancer (32). Aneuploidy was chosen as an outcome of interest primarily because it occurred more frequently than cancer in the study cohort, thus increasing statistical power for analyzing the relation between segment length and neoplastic progression. Methods Study Sample Study participants were selected from a cohort of patients who were enrolled in the Seattle Barretts Esophagus Project and underwent endoscopic surveillance between July 1983 and July 1998. Gastroenterologists who practice in Washington State have been the primary source of referrals to this cohort. All cohort members who met the following criteria as of 10 July 1998 were included in our study: 1) at least two endoscopies with histologic diagnoses, 2) presence of specialized columnar epithelium in the esophagus at the first endoscopy, 3) a record of Barrett segment length at the first endoscopy, 4) no esophageal cancer at the first endoscopy, and 5) no history of esophageal cancer. Three hundred nine persons qualified for the study. All of the study patients received counseling on lifestyle measures to reduce gastroesophageal reflux, and most used acid-reducing medication regularly. The Human Subjects Review Committee at the University of Washington approved the study. To evaluate the relation between segment length and aneuploidy, it was necessary to have information about the presence or absence of aneuploidy from at least two endoscopies. Of the 208 patients for whom this information was available, 37 had aneuploidy at the first qualifying endoscopy and were therefore excluded, leaving 171 for analyses with the aneuploidy end point. Endoscopy Barrett segment length was defined as the distance between the esophagogastric junction and the squamocolumnar junction. The esophagogastric junction was defined as the endoscopic lower esophageal sphincter or, if this was not apparent, the location at which the tubular esophagus joined the proximal margin of the gastric folds. The squamocolumnar junction was defined as the location at which the light-pink mucosa of the squamous-lined esophagus joined the red mucosa of the columnar-lined esophagus. The locations of these landmarks were determined as the endoscope was withdrawn from the stomach to the upper esophagus. Air was always removed from the stomach before this assessment. Tissue samples were obtained by using the turn and suction technique and jumbo biopsy forceps, as described elsewhere (33, 34). Until 1992, four biopsies (one per quadrant of the esophagus) were obtained from every other centimeter of the Barrett segment in all patients. From 1992 through 1998, four biopsies (one per quadrant of the esophagus) were obtained from every centimeter of the Barrett segment in patients with a history of high-grade dysplasia. In all patients, at least one control biopsy specimen was also taken from the gastric fundus and several biopsy specimens were taken from any visible mucosal abnormality. Each biopsy specimen was oriented on plastic mesh, epithelial surface upward, as soon as it was obtained. The gastric biopsy specimen and half of the first biopsy specimen from every level were placed in separate vials containing minimum essential medium with 5% serum and 10% dimethyl sulfoxide. The specimens were then immediately placed on wet ice and were stored at 70 C for subsequent flow cytometric analysis. The other half of the first biopsy specimen and the remaining three biopsy specimens from each level were placed in Hollande solution (one vial per level) for subsequent histologic examination. The most advanced histologic diagnosis at a given endoscopy was used to select the follow-up interval to the next endoscopy and the biopsy protocol for that endoscopy. The median interval between endoscopies was 25 months for patients with a baseline diagnosis of metaplasia, 18 months for patients with a baseline diagnosis of indefinite for dysplasia or low-grade dysplasia, and 5 months for patients with a baseline diagnosis of high-grade dysplasia. Histologic Examination The fixed biopsy specimens were serially cut into 4-m sections, mounted onto slides, and stained with hematoxylin and eosin alone or with hematoxylin and eosin, saffron, and Alcian blue at a pH of 2.5. The slides were examined by an experienced gastrointestinal pathologist, as described elsewhere (35). A histologic diagnosis of negative for dysplasia, indefinite for dysplasia, low-grade dysplasia, high-grade dysplasia, or intramucosal carcinoma was assigned to each slide by using established criteria (36). Because pathologists cannot consistently differentiate between the diagnoses of indefinite for dysplasia and low-grade dysplasia (36), these histologic diagnoses were combined into one category for all statistical analyses. DNA Content Flow Cytometry The methods used to prepare biopsy specimens for cell sorting, to perform flow cytometry, and to analyze the resulting data have been described elsewhere (34). Aneuploidy was diagnosed if, in at least one biopsy specimen from a particular endoscopy, two discrete peaks were observed on the histogram (one reflecting the presence of an aneuploid population and the other reflecting the presence of a diploid population) and the aneuploid peak represented at least 2.5% of the cells in the biopsy specimen (32). Tetraploid DNA contents in the range of 3.85N to 4.1N were also excluded. Demographic, Lifestyle, and Anthropometric Data Trained staff used a standard questionnaire to interview 71% (220 of 309) of the patients in this study in person between January 1995 and July 1998. Collected data included information on cigarette use, usual weight, height, ethnicity, annual income, education, and symptoms of gastroesophageal reflux. Information on age at study entry and sex was extracted from electronic patient records. Statistical Analysis Incidence rates were calculated by dividing the total number of cases by the total follow-up time (in person-years) in the full study sample or in defined subsets of the study sample. For each patient, follow-up time within the cohort began on the date of the first endoscopy that met the eligibility criteria. In analyses in which cancer was the outcome of interest, follow-up time ended on the date of the last endoscopy before the end of our study (10 July 1998) or on the date of the endoscopy that led to a diagnosis of cancer, whichever occurred first. Similarly, in analyses in which aneuploidy was the outcome of interest, follow-up time ended on the date of the last endoscopy before the end of the study or on the date of the endoscopy that led to a diagnosis of aneuploidy. In the analyses in which aneuploidy was the disease end point, a small number of participants (n=10) received a diagnosis of cancer at an endoscopy for which no flow cytometry data were available. Because approximately 90% of esophageal adenocarcinomas contain aneuploid cell p

Treatment for Acute Myelogenous Leukemia by Low-Dose, Total-Body, Irradiation-Based Conditioning and Hematopoietic Cell Transplantation From Related and Unrelated Donors

Purpose The use of low-dose, irradiation-based preparative regimens have allowed the extension of allografting to older and medically infirm patients. The study reported here assessed outcomes for patients with acute myeloid leukemia (AML) in different stages of their disease, who were not considered candidates for conventional hematopoietic cell transplantation (HCT) because of age and/or other known risk factors and were given minimal conditioning followed by HCT from related or unrelated donors. Patients and Methods The present study included 122 patients with AML, who were conditioned with 2 Gy total-body irradiation (TBI) on day 0 with or without preceding fludarabine (30 mg/m2/d from days −4 to −2), and given postgrafting cyclosporine at 6.25 mg/kg twice daily from day −3 and mycophenolate mofetil at 15 mg/kg twice daily from day 0. Results Durable engraftment was observed in 95% of the patients. Cumulative incidences of acute graft-versus-host disease grades 2 to 4 at 6 months were 35% after relate...

Five-Year Follow-Up of Patients With Advanced Chronic Lymphocytic Leukemia Treated With Allogeneic Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning

PURPOSE We reported encouraging early results of allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning in 64 patients who had advanced chronic lymphocytic leukemia (CLL). Here, we have extended the follow-up to a median of 5 years and have included data on an additional 18 patients. PATIENTS AND METHODS Eighty-two patients, age 42 to 72 years, who had fludarabine-refractory CLL were conditioned with 2 Gy total-body irradiation alone or combined with fludarabine followed by HCT from related (n = 52) or unrelated (n = 30) donors. RESULTS Complete remission (CR) and partial remission were achieved in 55% and 15% of patients, respectively. Higher CR rates were noted after unrelated HCT (67% v 48%). The 5-year incidences of nonrelapse mortality (NRM), progression/relapse, overall survival, and progression-free survival were 23%, 38%, 50%, and 39%, respectively. Among 25 patients initially reported in CR, 8% relapsed and 8% died as a result of NRM, whereas 84% have remained alive and in CR. Among 14 responding patients who were tested and who had molecular eradication of their disease, two died as a result of NRM, two relapsed, and 10 have remained negative. At 5 years, 76% of living patients were entirely well, whereas 24% continued to receive immunosuppression for chronic graft-versus-host disease; the median performance status in each group was 100% and 90%, respectively. Lymphadenopathy > or = 5 cm, but not cytogenetic abnormalities at HCT, predicted relapse. In a risk-stratification model, patients who had lymphadenopathy less than 5 cm and no comorbidities had a 5-year OS of 71%. CONCLUSION Nonmyeloablative HCT resulted in a median survival of 5 years for patients who had fludarabine-refractory CLL with sustained remissions and in the continued resolution of chronic graft-versus-host disease in surviving patients.

Hematopoietic Cell Transplantation After Nonmyeloablative Conditioning for Advanced Chronic Lymphocytic Leukemia

PURPOSE Patients with chemotherapy-refractory chronic lymphocytic leukemia (CLL) have a short life expectancy. The aim of this study was to analyze the outcome of patients with advanced CLL when treated with nonmyeloablative conditioning and hematopoietic cell transplantation (HCT). PATIENTS AND METHODS Sixty-four patients diagnosed with advanced CLL were treated with nonmyeloablative conditioning (2 Gy total-body irradiation with [n = 53] or without [n = 11] fludarabine) and HCT from related (n = 44) or unrelated (n = 20) donors. An adapted form of the Charlson comorbidity index was used to assess pretransplantation comorbidities. RESULTS Sixty-one of 64 patients had sustained engraftment, whereas three patients rejected their grafts. The incidences of grades 2, 3, and 4 acute and chronic graft-versus-host disease were 39%, 14%, 2%, and 50%, respectively. Three patients who underwent transplantation in complete remission (CR) remained in CR. The overall response rate among 61 patients with measurable disease was 67% (50% CR), whereas 5% had stable disease. All patients with morphologic CR who were tested by polymerase chain reaction (n = 11) achieved negative molecular results, and one of these patients subsequently experienced disease relapse. The 2-year incidence of relapse/progression was 26%, whereas the 2-year relapse and nonrelapse mortalities were 18% and 22%, respectively. Two-year rates of overall and disease-free survivals were 60% and 52%, respectively. Unrelated HCT resulted in higher CR and lower relapse rates than related HCT, suggesting more effective graft-versus-leukemia activity. CONCLUSION CLL is susceptible to graft-versus-leukemia effects, and allogeneic HCT after nonmyeloablative conditioning might prolong median survival for patients with advanced CLL.

THE IMPACT OF CO-MORBIDITY ON LIFE EXPECTANCY AMONG MEN WITH LOCALIZED PROSTATE CANCER

PURPOSE We evaluated 3 indexes used to assess patient co-morbidities to determine whether they could predict mortality among men with clinically localized prostate cancer. MATERIALS AND METHODS We measured the impact of co-morbidity classifications on all cause mortality using a parametric proportional hazards model based on a retrospective cohort analysis. RESULTS Each index tested is a highly significant predictor of mortality for patients dying of nonprostate cancer related causes after adjusting for age and Gleason score. CONCLUSIONS Each co-morbidity index provides significant, independent predictive information concerning patient mortality beyond that provided by age, Gleason score and clinical stage alone.

Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis.

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90 mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16 mg/kg (targeted to 800–900 ng/ml), and cyclophosphamide 120 mg/kg. Nonmyeloablative patients were older (median age 62 vs 52 years, P<0.001), more frequently had progressed to tAML (53 vs 31%, P=0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P=0.004), had higher transplant specific comorbidity indices (68 vs 42%, P=0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P=0.56)), progression-free survival (28%/44%, (P=0.60)), and nonrelapse mortality (41%/34%, (P=0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR=0.9, P=0.84) and progression-free survivals (HR=1, P=0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.