Roger D. Gingrich

Nosocomial pneumonia in patients having bone marrow transplant attributable mortality and risk factors

The authors performed a matched historic cohort study to determine the attributable mortality and risk factors for nosocomial pneumonia in bone marrow transplant (BMT) recipients. All patients with nosocomial pneumonia at a university tertiary care center were identified by a prospective surveillance system between 1980 and 1988. Control patients were selected from the population of BMT patients. The crude mortality for 55 patients with nosocomial pneumonia was 74.5% (95% confidence interval [CI95], 63% to 86%). The excess or attributable mortality was 61.8% (CI95,43.7% to 80%). Aspergillus species represented the most frequent etiologic agent in this series, causing 20 of the 55 (36%) episodes. The attributable mortality of Aspergillus species pneumonia alone was 85% (CI95, 58.6% to 100%). For death in the hospital, the risk ratio for all 55 case patients relative to control patients was 9.5 (CI95, 4.1 to 22.1). To evaluate several risk factors simultaneously, a multiple logistic regression analysis using a conditional likelihood method was performed. A mathematical model with three variables best predicted nosocomial pneumonia in our patients: the occurrence of other nosocomial infections before the diagnosis of pneumonia, allogeneic BMT, and the use of methotrexate. The presence of other nosocomial infections before the diagnosis of pneumonia remained a significant independent risk factor, with an odds ratio of 13.27 (CI95, 2.51 to 70.2) after adjustment for the use of methotrexate and allogeneic BMT. Most importantly, effective methods for preventing nosocomial pneumonias in BMT recipients will have an enormous effect on crude mortality. Cancer 1992: 69:2653‐2662.

A Fatal Case of West Nile Virus Infection in a Bone Marrow Transplant Recipient

West Nile virus (WNV) can cause severe, potentially fatal neurological illnesses, which include encephalitis, meningitis, Guillain-Barré syndrome, and anterior myelitis. Because of the short viremic phase, WNV infection is most commonly diagnosed by detection of immunoglobulin M antibody to WNV in serum or cerebrospinal fluid (CSF). We describe a patient with T cell lymphoma who had undergone a T cell-depleted bone marrow transplantation and developed fatal WNV infection. The results of serological tests of blood samples and of CSF tests were negative. Diagnosis was made postmortem by a positive result of reverse-transcriptase polymerase chain reaction (ABI 7700; TaqMan) for WNV in stored CSF and serum samples.

THE USE OF PARTIALLY MATCHED, UNRELATED DONORS IN CLINICAL BONE MARROW TRANSPLANTATION

It is estimated that 60–70% of patients who might benefit from a bone marrow transplant will not have a suitably matched, related donor. We have, therefore, designed a clinical experiment to test the safety and feasibility of using marrow from partially matched, unrelated donors. This paper details our transplant experience in the first eight patients with leukemia. The first four patients had advanced leukemia at the time of transplantation. Each showed hematopoietic recovery, but all died from septic complications largely related to extended neutropenia encompassing both the pre-marrow-grafting and the post-marrow-grafting period. The next four patients were in remission at the time of transplantation. Each showed prompt and sustained hematopoiesis with variable graft-versus-host disease (GVHD). No acute or chronic GVHD was seen in two patients, grade II (skin only) was seen in one patient, and grade IV (skin, liver, and gut) was seen in one patient. One patient has died from sepsis five-and-one-half months following transplantation, and three are alive and well six-and-one-half to nine-and-one-half months postengraftment. This preliminary experience, together with several case reports in the literature, leads us to conclude that bone marrow transplantation with partially matched, unrelated marrow is a safe and feasible approach. If these results are confirmed by longer follow-up in a larger group of patients, the development of marrow donor pools would appear to be justified.

Neuropsychological and psychiatric functioning pre- and posthematopoietic stem cell transplantation in adult cancer patients: A preliminary study

The current study characterizes cognitive and psychiatric status in hematopoietic stem cell transplantation (HSCT) patients shortly before and after transplant. Thirty adult patients were assessed prospectively 1-2 weeks before transplantation and 100 days posttransplantation on neuropsychological and psychiatric measures. Before transplant, participants showed mild impairments on several neuropsychological measures, with the poorest performances occurring on learning and attention. Psychiatric functioning was significantly elevated compared with normative data. Significant improvements, however, were observed on neuropsychological measures by 100 days after transplant. Depression and anxiety scores also improved. Candidates for HSCT experienced mild diffuse cognitive dysfunction and psychiatric morbidity before the procedure, but these symptoms significantly improved by 3 months following their transplant in this small sample. Education about these possible pretransplant sequelae and the potential for rebound may be helpful to patients and families as they prepare for this treatment and the recovery period.

Donor T-lymphocyte infusion for unrelated allogeneic bone marrow transplantation with CD3+ T-cell-depleted graft

Summary:In T-cell-depleted allogeneic bone marrow transplantation (TCD-BMT) using unrelated donors, the role of donor lymphocyte infusion (DLI) for survival and disease control has not been defined. In a study of 116 patients (92 matched, 24 mismatched) who received CD3+ T-cell-depleted marrow graft, sequential infusions of escalated doses of donor T lymphocytes up to 1×106 CD3+ cells/kg were prospectively investigated. T cells were administered while patients were on cyclosporine, provided ≥grade II acute graft-versus-host-disease (GVHD) had not occurred. Acute GVHD of ≥grade II occurred in 27 of 110 (25%) patients before DLI and in 39 of 79 (49%) patients after DLI. In total, 12 of 27 (44%) patients without DLI and 44 of 72 (61%) patients who received DLI developed chronic GVHD. A total of 19 patients died of GVHD, with 17 of acute and two of chronic GVHD. Overall survival (OS) and event-free survival (EFS) at 5 years were 27 and 21%, respectively. The 2-year incidence of relapse was 14%. In multivariate analysis, only chronic GVHD was a good prognostic factor for both OS: hazard ratio (HR) 1.4, P=0.04, and EFS: HR 1.6, P=0.01. Both acute and chronic GVHD were favorable prognostic factors for relapse probability: HR 1.9 for both, P=0.02, 0.01, respectively. The 1-year cumulative incidence of transplant-related mortality (TRM), excluding cases of GVHD, was 42%. The two most common causes of 1-year non-GVHD death were viral infection (9%) and idiopathic pneumonia syndrome (12%). Although the incidence of relapse was low, the study suggests that the current scheme of DLI in unrelated TCD-BMT would not improve survival unless TRM decreases significantly.

18-Fluoro-deoxyglucose positron emission tomography report interpretation as predictor of outcome in diffuse large B-cell lymphoma including analysis of ‘indeterminate’ reports

This study evaluates the predictive value of post-therapy 18-fluoro-deoxyglucose positron emission tomography (FDG-PET), including indeterminate studies, following curative-intent therapy in diffuse large B-cell lymphoma (DLBCL). Consecutive patients from September 2002 to December 2005 were prospectively offered enrollment in an observational registry. Available FDG-PET reports after primary therapy were interpreted by hematologist–oncologists as positive, negative, or indeterminate. One hundred twenty-five patients with DLBCL had a median follow-up of 35.2 months. Ninety-three percent were treated with R-CHOP-like therapy. Twenty percent of PET reports were judged indeterminate. Event-free survival (EFS) at 3 years for the negative and indeterminate groups was 85% and 71%, respectively (p = 0.28 by log-rank). Overall survival (OS) at 3 years for negative, indeterminate, and positive groups was 89%, 88%, and 48%. Combining the pre-therapy International Prognostic Index (IPI) with the post-therapy FDG-PET result added to the predictive value of the study for patients. Three-year EFS for patients with low or low-intermediate IPI risk and an indeterminate FDG-PET report was 93%, while for those with high or high-intermediate pre-therapy IPI the 3-year EFS was 45% (p < 0.02). Interpreting FDG-PET reports following curative-intent chemotherapy in patients is informative but imprecise, and incorporation of pre-therapy prognosis can improve predictive utility.

Prophylactic T cell infusion after T cell-depleted bone marrow transplantation in patients with refractory lymphoma.

Fifty-two patients with refractory lymphoma were prospectively treated with prophylactic T lymphocyte infusion after T cell-depleted allogeneic bone marrow transplantation, to induce graft-versus-lymphoma effect. Thirty-three patients had related donors; 19 had unrelated donors. After transplantation with marrow that had 0.8 ± 0.4 × 105CD3+ cells/kg, T cells up to 1.75 × 106 CD3+ cells/kg were given over 3 months provided ⩾ grade II acute graft-versus-host disease (GVHD) was not seen. The cumulative incidence of grades II–IV acute GVHD was 69%. Twenty of 32 evaluable patients (63%) developed chronic GVHD. Ten patients (19%) died of GVHD. The Kaplan–Meier 5-year overall survival of all patients was 34%. On multivariate analyses, chronic GVHD was significant for relapse (hazard ratio of 1.7, P < 0.05), and for overall survival (hazard ratio 1.4, P < 0.001). Chemosensitivity was significant for relapse only on univariate analysis. Patients who developed chronic GVHD had 4 years median survival, compared with 9 months in patients without chronic GVHD, P < 0.001. The study shows that patients with chronic GVHD have superior survivals, most probably related to a graft-versus-lymphoma effect, which could be modulated by prophylactic T cell infusion.

Clinical and Ultrasonic Evaluation of Spleen Size during Peripheral Blood Progenitor Cell Mobilization by Filgrastim: Results of an Open-Label Trial in Normal Donors

Rare reports of splenic rupture have been associated with filgrastim treatment during peripheral blood progenitor cell (PBPC) mobilization in allogeneic donors. We performed a prospective study of spleen volume change in 309 normal donors who received filgrastim according to local institutional practices. Splenic assessments consisted of ultrasonography and clinical examination at baseline and on the first day of leukapheresis in 304 donors. Of these, 90 donors were also examined 2 and 4 days after the first leukapheresis and 7 days after the last leukapheresis. Median spleen volume increased 1.47-fold (range: 0.63 to 2.60) on the first leukapheresis day and declined to near pretreatment levels at 7 days after last leukapheresis. Nine percent of donors had > or =2-fold increase in splenic volume. Spleen palpability did not correlate with change in spleen volume. No donors experienced a splenic rupture. There was no correlation between change in spleen volume and filgrastim dosage, number of doses/day, peak absolute neutrophil count (ANC), CD34+ yield, or donor baseline weight. Most donors experienced > or =1 adverse event, with 6 donors reporting serious adverse events. We conclude that the increase in splenic volume during PBPC mobilization in donors was transient, and that filgrastim was well tolerated in this study. This trial was registered at www.ClinicalTrials.gov as NCT00115128.

Outcome of allogeneic stem cell transplantation in myelodysplastic syndrome patients: prognostic implication of monosomal karyotype

Monosomal karyotype (MK) is defined as the presence of two or more autosomal monosomies or a single monosomy associated with a structural abnormality. It was first described as a high‐risk cytogenetic abnormality for acute myeloid leukemia and more recently in myelodysplastic syndromes (MDS). However, allotransplant outcome in MDS with MK has not been described.

Disseminated coagulopathy in chronic myelomonocytic leukemia

The clinical and laboratory features of nine patients with chronic myelomonocytic leukemia are described. Hepatic or splenic enlargement accompanied by an absolute monocytosis in an older patient with an elevated serum or urine lysozyme and serum vitamin B12 levels were characteristic of the majority of patients in this series. No single clinical or laboratory finding was diagnostic for the disease. Most importantly, seven of nine patients had abnormal coagulation values; in two cases the abnormalities were consistent with disseminated intravascular coagulation and correlated with a hemorrhagic diathesis. It is concluded that patients with chronic myelomonocytic leukemia who have thrombocytopenia or a bleeding tendency should be evaluated for evidence of disseminated intravascular coagulation.