George B. Selby

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome following allogeneic HPC transplantation: A diagnostic dilemma

BACKGROUND: Thrombotic thrombocytopenic purpura‐hemolytic uremic syndrome (TTP‐HUS) has been described as a specific sequela of allogeneic HPC transplantation (HPCT). Nevertheless, because multiple transplant‐related sequela can cause the characteristic clinical features of TTP‐HUS, the diagnosis is difficult.

HLA-Identical Sibling Compared With 8/8 Matched and Mismatched Unrelated Donor Bone Marrow Transplant for Chronic Phase Chronic Myeloid Leukemia

PURPOSE Transplantation of hematopoietic stem cells from an unrelated donor (URD) is an option for many patients who do not have an HLA-identical sibling donor (MSD). Current criteria for the selection of URDs include consideration for HLA alleles determined by high resolution typing methods, with preference for allele-matched donors. However, the utility and outcome associated with transplants from URDs compared with those from MSDs remains undefined. PATIENTS AND METHODS We examined clinical outcome after patients received bone marrow transplants (BMTs) from MSDs; HLA-A, -B, -C, and DRB1 allele-matched URDs (8/8); and HLA-mismatched URDs in a homogeneous population of patients with chronic myeloid leukemia (CML) in first chronic phase (CP1) where a strong allogeneic effect and hence a lower risk of relapse is anticipated. Transplantation outcomes were compared between 1,052 URD and 3,514 MSD BMT recipients with CML in CP1. RESULTS Five-year overall survival and leukemia-free survival (LFS) after receipt of BMTs from 8/8 matched URDs were worse than those after receipt of BMTs from MSDs (5-year survival, 55% v 63%; RR, 1.35; 95% CI, 1.17 to 1.56; P < .001; LFS, 50% v 55%; RR, 1.21; 95% CI, 1.06 to 1.40; P = .006). Survival was progressively worse with greater degrees of mismatch. Similar and low risk of relapse were observed after receipt of transplant from either MSD or URD. CONCLUSION In this homogeneous cohort of good risk patients with CML in CP1, 5-year overall survival and LFS after receipt of transplant from 8/8 allele-matched donors were modestly though significantly worse than those after receipt of transplant from MSDs. Additive adverse effects of multilocus mismatching are not well tolerated and should be avoided if possible.

Microbial contamination of hematopoietic progenitor cell grafts—incidence, clinical outcome, and cost-effectiveness: an analysis of 735 grafts

BACKGROUND: Screening of progenitor cell grafts (marrow, peripheral blood, and cord blood) for microbial contamination is required by the standards of AABB. Clinical sequelae from infusion of these contaminated grafts, however, is uncommon.

Thrombotic Microangiopathy After Allogeneic Hematopoietic Stem Cell Transplantation : An Autopsy Study

Background. Posttransplantation thrombotic microangiopathy (PTMA) is a complication of allogeneic hematopoietic stem cell transplantation (HSCT). However, limited autopsy data are available, and it remains unclear whether PTMA is a discrete clinical and pathologic entity. The aims of this autopsy study were to determine the correlation between clinical and pathologic diagnosis of PTMA, to define the precise morphologic spectrum of PTMA, and to seek for potential etiologic factors. Methods. The study included 20 consecutive patients with HSCT autopsied at the University of Oklahoma, between 1994 and 2005. Applying strict clinical-laboratory criteria, 6 patients were diagnosed clinically with PTMA and treated with plasma exchange. Clinical variables, including underlying disease, conditioning regimen, stem cell donor status, duration and serum level of cyclosporine, infections, and acute graft versus host disease were compared statistically in patients with histologic signs of PTMA (n=8) with those without PTMA (n=12). Results. PTMA was verified histologically in all 6 patients with a clinical diagnosis of PTMA but only 2 of the 14 patients who were not clinically diagnosed had histologic evidence of PTMA (P<0.0001). Kidneys were affected in all 8 patients with PTMA, and limited extrarenal involvement by PTMA was observed in 3 of these 8 patients. No statistically significant differences in relevant clinical and morphologic variables were identified between the PTMA and non-PTMA groups. Conclusions. This study documents a strong correlation between the clinical and morphologic diagnosis of PTMA. The kidney is the primary target of PTMA, with dominant glomerular and arteriolar involvement. The etiology is likely to be multifactorial.

Autologous Is Superior to Allogeneic Hematopoietic Cell Transplantation for Acute Promyelocytic Leukemia in Second Complete Remission

To identify favored choice of transplantation in patients with acute promyelocytic leukemia (APL) in second complete remission, we studied 294 patients with APL in second complete remission (CR2) receiving allogeneic (n = 232) or autologous (n = 62) hematopoietic cell transplantation (HCT) reported to the Center for International Blood and Marrow Transplantation Research (CIBMTR) from 1995 to 2006, including 155 with pre-HCT PML/RAR∝ status (49% of allogeneic and 66% of autologous). Patient characteristics and transplantation characteristics, including treatment-related mortality, overall survival (OS), and disease-free survival, were collected and analyzed for both univariate and multivariate outcomes. With median follow-up of 115 (allogeneic) and 72 months (autologous), 5-year disease-free survival (DFS) favored autologous with 63% (49% to 75%), compared with allogeneic at 50% (44% to 57%) (P = .10). OS was 75% (63% to 85%) versus 54% (48% to 61%) (P = .002), for autologous and allogeneic transplantation, respectively. Multivariate analysis showed significantly worse DFS after allogeneic HCT (hazard ratio [HR], 1.88; 95% confidence interval [CI], 1.16 to 3.06; P = .011) and age > 40 years (HR, 2.30; 95% CI, 1.44 to 3.67; P = .0005). OS was significantly worse after allogeneic HCT (HR, 2.66; 95% CI, 1.52 to 4.65; P= .0006); age > 40 (HR, 3.29; 95% CI, 1.95 to 5.54; P < .001), and first complete remission < 12 months (HR, 1.56; 95% CI, 1.07 to 2.26; P = .021). Positive pre-HCT PML-RAR∝ status in 17 of 114 allogeneic and 6 of 41 receiving autologous transplantation did not influence relapse, treatment failure, or survival in either group. The survival advantage for autografting was attributable to increased treatment-related mortality (TRM) in the allogeneic group of 30% compared to 2% in the autologous group, in addition to the added mortality associated with GVHD. We conclude that autologous HCT yields superior OS for APL in CR2. Long-term DFS in autologous recipients, even with minimal residual disease-positive grafts, remains an important subject for further study.

Cytomegalovirus surveillance and prevention in allogeneic bone marrow transplantation: Examination of a preemptive plan of ganciclovir therapy

Forty‐two cytomegalovirus (CMV)‐seropositive allogeneic marrow transplant patients or recipients of CMV‐seropositive marrow allografts were entered into a surveillance program to detect and treat CMV infection during the first 120 days posttransplant. CMV infection was detected at a mean time of day 50 in 21/37 (58%) patients who had surveillance cultures. Twelve of 42 (28%) received preemptive ganciclovir treatment for virus isolated from blood (9 patients) or from bronchoalveolar lavage fluid (3 patients), and all had no CMV‐associated sequelae. CMV disease was diagnosed in 5 patients (4 with pneumonia, 1 with gastroenteritis) who did not have positive cultures until the onset of their disease. CMV‐related mortality was 4/42 (10%). Patients who earlier manifested lung injury or diffuse alveolar hemorrhage (DAH) were significantly predisposed to subsequent CMV pneumonia (P = 0.0013, Fishers exact test) at a median onset of day 42. Restricted prophylactic use of ganciclovir in such patients may be indicated. Fifty percent of all patients never required ganciclovir during the surveillance period. When compared to a universal prophylaxis program of ganciclovir for the prevention of CMV disease, the use of ganciclovir in a preemptive strategy could avoid unnecessary therapy for a substantial number of patients and earn significant cost‐savings.

Challenges and Potential Solutions for Recruitment and Retention of Hematopoietic Cell Transplantation Physicians: The National Marrow Donor Program’s System Capacity Initiative Physician Workforce Group Report

Hematopoietic cell transplantation (HCT) remains the only known curative therapy for many patients with hematologic, metabolic, and immunologic disorders. Furthermore, the use of HCT has increased with the emergence of HCT as a viable therapeutic option for older patients, those with significant comorbidities, and, with the demonstrated clinical effectiveness of alternative allogeneic donor sources, for those patients without a suitable sibling donor. The National Marrow Donor Program (NMDP) estimates that by 2020, it will facilitate 10,000 transplantations per year, double the number in 2010. To understand the needs of the HCT infrastructure to facilitate this number of transplantations, the NMDP organized the System Capacity Initiative 2020, centered on 6 working groups representing a diverse group of stakeholders. The Physician Workforce Group was tasked with addressing issues relating to recruitment and retention of transplantation physicians. We report here the results of our efforts and future initiatives.

Introducing case management to a general medicine ward team of a teaching hospital

PURPOSE: To introduce case management to a general medicine ward team of a teaching hospital to improve patient care and ensure comprehensive longitudinal care. METHOD: The Department of Veterans Affairs Medical Center is one of four hospitals used by University of Oklahoma School of Medicine residents. There are five medicine teams, each comprising a second- or third-year resident, one or two interns, two medical students, and a faculty physician. The case-management program was initiated in November 1994. No attempt was made to limit the residents assigned to the case-managed team (i.e., many residents who worked with the case-managed team subsequently rotated through the other teams). Patients were assigned to the teams by rotation, and no attempt was made to adjust for the severity of illness among admissions. The teams were separated as follows: pre-case-management teams (all five teams prior to the case-management program), non-case-management teams (the four teams without case managers after the programs initiation), and the case-management team. The study periods were January-July 1994 (pre-case management) and January-July 1995 (after case management). RESULTS: The numbers of patients treated by the three groups were 1,305, 1,139, and 289, respectively. The median length of stay for pre-case-management patients was 5 days (interquartile range, 3-9 days); for non-case-management patients, 5 days (range, 3-8 days); and for case-management patients, 5 days (range, 3-7 days). The cumulative distribution of lengths of stay for case-management patients was significantly different from those of the other study groups by the Kolmogorov-Smirnov test (p = .02). More case-management patients were discharged by day 7. Rates of readmission were not significantly different between the teams. CONCLUSION: In this study a case-management program was effectively implemented in a teaching hospital, resulting in reduced lengths of stay for patients. As academic health centers become more concerned with efficiency and cost, case management should be seriously considered as a way to deal with such issues.

A phase II evaluation of fazarabine in high-grade gliomas: a Southwest Oncology Group study

Patients with high-grade gliomas, gl ioblastoma multiforme, and anaplastic astrocytomas have a median survival of approximately 1 year fol lowing resection and radiation therapy [6]. The addition of chemotherapy makes only a modest contribution to prolonging survival [1], and little progress has been made in the chemotherapy of these tumors since the introduction of the nitrosoureas [4]. Fazarabine (Ara-AC, 1-B-D-arabinofuranosyl-5-azacytosine) is an analog of both cytosine arabinoside (Ara-C) and 5-azacytidine (5-AC). Like Ara-C, fazarabine inhibits D N A synthesis and DNA methylation, albeit with little inhibition of R N A synthesis [2, 5]. Since activity of this agent against experimental tumor models, including TE671 medulloblastoma, has been documented and because fazarabine crosses the blood-brain barrier, achieving cerebrospinal fluid concentrations equal to 13%-18% of serum levels [3], a phase II trial of this agent as treatment for highgrade gliomas was undertaken.

Efficacy and safety of oral granisetron versus i.v. granisetron in patients undergoing peripheral blood progenitor cell and bone marrow transplantation

This randomized, controlled, double-blind pilot study assessed the efficacy and safety of oral versus i.v. granisetron, both in combination with non-5-HT3 antiemetics, in preventing emesis caused by high-dose chemotherapy. Fifty-one patients who underwent peripheral blood progenitor cell transplantation (PBPCT) or bone marrow transplantation (BMT) were evaluated. Efficacy was assessed by the number of emetic episodes during the worst 24 h period. A complete response (CR) was defined as no vomiting, partial response (PR) as less than three emetic episodes and failure as three or more emetic episodes. Patients who received oral granisetron experienced significantly (p<0.0008) fewer emetic episodes than those who received i.v. granisetron; however, the number of emetic episodes over the worst 24 h was similar between the oral and i.v. granisetron groups (13 and 15, respectively), as were the overall response rates (CR+PR, 54.5 and 41.4%, respectively). Both dosage forms were well tolerated. Based on these findings, further comparative studies of oral granisetron are warranted in patients undergoing PBPCT or BMT.