Factors associated with second-line triplet therapy in routine care in relapsed/refractory multiple myeloma.

WHAT IS KNOWN AND OBJECTIVE: Second-line therapy (SLT) trials in relapsed/refractory multiple myeloma (RRMM) report superior outcomes with triplet combinations. We sought to determine factors associated with triplet SLT in routine practice. METHODS: A retrospective cohort with claims for MM between 01/01/2008 and 03/31/2015 was grouped by 1-2 ("doublet") or 3+ ("triplet") agent therapy. Charlson comorbidity index (CCI) and disability status; CRAB symptoms (hypercalcaemia, renal/bone disease, anaemia); and relapse risk were determined. RESULTS: Among 623 patients, the triplet group (n=146 [23%]) was younger (65.2 vs 69.8 years) and more likely to have high-risk relapse (67% vs 50%), CRAB symptoms (94.5% vs 81.1%), triplet first-line treatment (75% vs 51%) and frontline stem cell transplant (38% vs 20%) (P<0.001 for all). In multivariate analyses, CRAB symptoms (OR: 3.22, 95% CI: 1.47, 7.10), high-risk relapse (OR: 1.71, 95% CI: 1.12, 2.62) and prior triplet therapy (OR: 2.16, 95% CI: 1.38, 3.40), but neither CCI nor disability, were associated with triplet SLT. A trend towards triplets among younger patients (<65 vs >75 years, OR: 1.73, 95% CI: 0.99, 3.04) was observed. WHAT IS NEW AND CONCLUSION: The majority of patients did not receive triplet regimens. Treatment selection with triplet therapy for RRMM should carefully consider comorbidities and patient-specific characteristics.

Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force.

Chronic lymphocytic leukemia (CLL) mainly affects older people: the median age at diagnosis is > 70 years. Elderly patients with CLL are heterogeneous with regard both to the biology of their disease and aging. Following the diagnosis of CLL in an elderly individual, careful risk assessment is essential when treatment options are evaluated. This includes not only clinical staging and evaluation of disease-specific prognostic biomarkers such as 17p deletion and TP53 mutation, but also of comorbidities, physical capacity, nutritional status, cognitive capacity, ability to perform activities of daily living and social support. Comorbidity scoring and geriatric assessment tools are helpful in achieving such multidimensional evaluation in a systematic manner. The introduction of new drugs including novel monoclonal antibodies and kinase inhibitors offers enhanced opportunities for the treatment of elderly patients with CLL. This position paper of a Task Force of the International Society of Geriatric Oncology (SIOG) reviews currently available evidence relevant to such patients. All types of elderly patient (i.e. chronological age > 65-70 years) are considered, from robust (fit) to vulnerable (unfit) to the terminally ill. Among the topics covered are the following: (i) the relationship between chronological age, prognosis and survival, (ii) assessment of biological aging, (iii) biological age as a determinant of treatment feasibility and tolerance and (iv) tailoring of both first and further-line treatment to the circumstances of the individual patient.

Approach to therapy of diffuse large B-cell lymphoma in the elderly: the International Society of Geriatric Oncology (SIOG) expert position commentary.

Diffuse large B-cell lymphoma (DLBCL) is a treatable and potentially curable malignancy that is increasing in prevalence in the elderly. Until recently, older patients with this malignancy were under-represented on clinical treatment trials, so optimal therapeutic approaches for these patients were generally extrapolated from the treatment of younger patients with this disorder. Because of heightened toxicity concerns, older patients were sometimes given reduced dose therapy, potentially negatively impacting outcome. Geriatric considerations including functional status and comorbidities often were not accounted for in treatment decisions. Because of these issues as well as the lack of treatment guidelines for the elderly population, the International Society of Geriatric Oncology convened an expert panel to review DLBCL treatment in the elderly and develop consensus guidelines for therapeutic approaches in this patient population. The following treatment guidelines address initial DLBCL therapy, in both limited and advanced stage disease, as well as approaches to the relapsed and refractory patient.

The role of body mass index in survival outcome for lymphoma patients: US intergroup experience.

BACKGROUND: The role of body mass index (BMI) in survival outcomes is controversial among lymphoma patients. We evaluated the association between BMI at study entry and failure-free survival (FFS) and overall survival (OS) in three phase III clinical trials, among patients with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin's lymphoma (HL). PATIENTS AND METHODS: A total of 537, 730 and 282 patients with DLBCL, HL and FL were included in the analysis. Baseline patient and clinical characteristics, treatment received and clinical outcomes were compared across BMI categories. RESULTS: Among patients with DLBCL, HL and FL, the median age was 70, 33 and 56; 29%, 29% and 37% were obese and 38%, 27% and 37% were overweight, respectively. Age was significantly different among BMI groups in all three studies. Higher BMI groups tended to have more favorable prognosis factors at study entry among DLBCL and HL patients. BMI was not associated with clinical outcome with P-values of 0.89, 0.30 and 0.40 for FFS, and 0.64, 0.67 and 0.09 for OS, for patients with DLBCL, HL and FL, respectively. The association remains non-significant after adjusting for other clinical factors in the Cox model. A subset analysis of males with DLBCL treated on R-CHOP revealed no differences in FFS (P = 0.48) or OS (P = 0.58). CONCLUSION: BMI was not significantly associated with clinical outcomes among patients with DLBCL, HD or FL, in three prospective phase III clinical trials. The findings contradict some previous reports of similar investigations. Further work is required to understand the observed discrepancies.

Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET).

BACKGROUND: Invasive fungal infections are a major cause of morbidity and mortality among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients, but few data have been reported on the epidemiology of endemic fungal infections in these populations. METHODS: Fifteen institutions belonging to the Transplant-Associated Infection Surveillance Network prospectively enrolled SOT and HCT recipients with histoplasmosis, blastomycosis, or coccidioidomycosis occurring between March 2001 and March 2006. RESULTS: A total of 70 patients (64 SOT recipients and 6 HCT recipients) had infection with an endemic mycosis, including 52 with histoplasmosis, 9 with blastomycosis, and 9 with coccidioidomycosis. The 12-month cumulative incidence rate among SOT recipients for histoplasmosis was 0.102%. Occurrence of infection was bimodal; 28 (40%) infections occurred in the first 6 months post transplantation, and 24 (34%) occurred between 2 and 11 years post transplantation. Three patients were documented to have acquired infection from the donor organ. Seven SOT recipients with histoplasmosis and 3 with coccidioidomycosis died (16%); no HCT recipient died. CONCLUSIONS: This 5-year multicenter prospective surveillance study found that endemic mycoses occur uncommonly in SOT and HCT recipients, and that the period at risk extends for years after transplantation.

A second-generation screen of the human genome for susceptibility to insulin-dependent diabetes mellitus.

During the past decade, the genetics of type 1 (insulin-dependent) diabetes mellitus (IDDM) has been studied extensively and the disorder has become a paradigm for genetically complex diseases. Previous genome screens and studies focused on candidate genes have provided evidence for genetic linkage between polymorphic DNA markers and 15 putative IDDM susceptibility loci, designated IDDM1-IDDM15. We have carried out a second-generation screen of the genome for linkage and analysed the data by multipoint linkage methods. An initial panel of 212 affected sibpairs (ASPs) was genotyped for 438 markers spanning all autosomes, and an additional 467 ASPs were used for follow-up genotyping. Other than the well-established linkage with the HLA region at chromosome 6p21.3, there was only one region, located on chromosome 1q and not previously reported, where the log likelihood ratio (lod) was greater than 3. Lods between 1.0 and 1.8 were found in six other regions, three of which have been reported in other studies. Another reported region, on chromosome 6q and loosely linked to HLA, also had an elevated lod. Little or no support was found for most reported IDDM loci (lods were less than 1), despite larger sample sizes in the present study.

A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2.

Non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is a common disorder of middle-aged individuals characterized by high blood glucose levels which, if untreated, can cause serious medical complications and lead to early death. Genetic factors play an important role in determining susceptibility to this disorder. However, the number of genes involved, their chromosomal location and the magnitude of their effect on NIDDM susceptibility are unknown. We have screened the human genome for susceptibility genes for NIDDM using non-and quasi-parametric linkage analysis methods in a group of Mexican American affected sib pairs. One marker, D2S125, showed significant evidence of linkage to NIDDM and appears to be a major factor affecting the development of diabetes mellitus in Mexican Americans. We propose that this locus be designated NIDDM1.

Persistence of the efficacy of zoster vaccine in the shingles prevention study and the short-term persistence substudy.

BACKGROUND: The Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Study 403) demonstrated that zoster vaccine was efficacious through 4 years after vaccination. The Short-Term Persistence Substudy (STPS) was initiated after the SPS to further assess the persistence of vaccine efficacy. METHODS: The STPS re-enrolled 7320 vaccine and 6950 placebo recipients from the 38 546-subject SPS population. Methods of surveillance, case determination, and follow-up were analogous to those in the SPS. Vaccine efficacy for herpes zoster (HZ) burden of illness, incidence of postherpetic neuralgia (PHN), and incidence of HZ were assessed for the STPS population, for the combined SPS and STPS populations, and for each year through year 7 after vaccination. RESULTS: In the STPS as compared to the SPS, vaccine efficacy for HZ burden of illness decreased from 61.1% to 50.1%, vaccine efficacy for the incidence of PHN decreased from 66.5% to 60.1%, and vaccine efficacy for the incidence of HZ decreased from 51.3% to 39.6%, although the differences were not statistically significant. Analysis of vaccine efficacy in each year after vaccination for all 3 outcomes showed a decrease in vaccine efficacy after year 1, with a further decline thereafter. Vaccine efficacy was statistically significant for the incidence of HZ and the HZ burden of illness through year 5. CONCLUSIONS: Vaccine efficacy for each study outcome was lower in the STPS than in the SPS. There is evidence of the persistence of vaccine efficacy through year 5 after vaccination but, vaccine efficacy is uncertain beyond that point.

Malassezia: is it a pulmonary pathogen in the stem cell transplant population?

Malassezia furfur is a yeast that can cause a variety of infections, most commonly in normal hosts, and also in immunocompromised hosts. This yeast typically colonizes the skin, and is the causative agent of tinea versicolor. However, in immunocompromised hosts, it can more commonly cause catheter-related fungemia or folliculitis. Pulmonary infections from Malassezia have not been commonly recognized. Unlike many other common opportunistic fungal infections in immunocompromised hosts, neutropenia and the use of broad-spectrum antibiotics do not appear to be significant risk factors for Malassezia infections in the stem cell transplant (SCT) population. Additionally, disseminated infection, despite fungemia, is uncommon. A series of patients who underwent SCT at the University of Minnesota between 2004 and 2006 were reviewed for the occurrence of suspected Malassezia infections in the post-transplant period. Four cases of possible pulmonary M. furfur infection were identified in our SCT recipients. The clinical characteristics of these patients, the infections, treatment, and outcome are described. In addition, we discuss the possible pathogenicity of this yeast in the pulmonary setting.

A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults.

BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.

Impact of therapy With chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011.

PURPOSE: We sought to determine whether therapy with single-agent fludarabine compared with chlorambucil alone or the combination of both agents had an impact on the incidence and spectrum of infections among a series of previously untreated patients with B-cell chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Five hundred fifty-four previously untreated CLL patients with intermediate/high-risk Rai-stage disease were enrolled onto an intergroup protocol. Patients were randomized to therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Data pertaining to infection were available on 518 patients. Differences in infections among treatment arms were tested with the Kruskal-Wallis, Wilcoxon, and chi(2) tests. RESULTS: A total of 1,107 infections (241 major infections) occurred in 518 patients over the infection follow-up period (interval from study entry until either reinstitution of initial therapy, therapy with a second agent, or death). Patients treated with fludarabine plus chlorambucil had more infections than those receiving either single agent (P <.0001). Comparing the two single-agent arms, there were more infections on the fludarabine arm (P =.055) per month of follow-up. Fludarabine therapy was associated with more major infections and more herpesvirus infections compared with chlorambucil (P =.008 and P =.004, respectively). Rai stage and best response to therapy were not associated with infection. A low serum immunoglobulin G was associated with number of infections (P =.02). Age was associated with incidence of major infection in the combination arm (P =.004). CONCLUSION: Combination therapy with fludarabine plus chlorambucil resulted in significantly more infections than treatment with either single agent. Patients receiving single-agent fludarabine had more major infections and herpesvirus infections compared with chlorambucil-treated patients.

Fas ligand expression in the bone marrow in myelodysplastic syndromes correlates with FAB subtype and anemia, and predicts survival.

Increased apoptosis in the bone marrow (BM) may contribute to the cytopenias that occur in myelodysplastic syndromes (MDS). The Fas receptor, Fas ligand (FasL) pathway is a major mechanism of apoptosis. Since hematopoietic progenitors can express the Fas receptor, they may be susceptible to apoptosis induced by FasL-expressing cells. We examined FasL expression in the BM of patients with MDS (n = 50), de novo acute myeloid leukemia (AML; n = 10), AML following prior MDS (n = 6), and normal controls (n = 6). Compared to controls, FasL expression was increased in MDS, and was highest in AML. In MDS, FasL expression was seen in myeloid blasts, erythroblasts, maturing myeloid cells, megakaryocytes and dysplastic cells, whereas in AML, intense expression was seen in the blasts. FasL expression correlated with the FAB subtype groups of MDS, and also correlated directly with the percentage of abnormal metaphases on cytogenetic analysis. The FasL expressed in MDS BM inhibited the growth of clonogenic hematopoietic progenitors. This inhibition could be blocked by a soluble recombinant FasFc protein. In MDS, FasL expression in the initial diagnostic BM was higher in patients who were more anemic, correlated directly with red cell transfusion requirements over the subsequent course of the disease, and was predictive of survival. These studies indicate that FasL expression in MDS is of prognostic significance, and suggest that pharmacological blockade of the Fas-FasL pathway may be of clinical benefit.

The impact of culture isolation of Aspergillus species: a hospital-based survey of aspergillosis.

The term "aspergillosis" comprises several categories of infection: invasive aspergillosis; chronic necrotizing aspergillosis; aspergilloma, or fungus ball; and allergic bronchopulmonary aspergillosis. In 24 medical centers, we examined the impact of a culture positive for Aspergillus species on the diagnosis, risk factors, management, and outcome associated with these diseases. Most Aspergillus culture isolates from nonsterile body sites do not represent disease. However, for high-risk patients, such as allogeneic bone marrow transplant recipients (60%), persons with hematologic cancer (50%), and those with signs of neutropenia (60%) or malnutrition (30%), a positive culture result is associated with invasive disease. When such risk factors as human immunodeficiency virus infection (20%), solid-organ transplantation (20%), corticosteroid use (20%), or an underlying pulmonary disease (10%) are associated with a positive culture result, clinical judgment and better diagnostic tests are necessary. The management of invasive aspergillosis remains suboptimal: only 38% of patients are alive 3 months after diagnosis. Chronic necrotizing aspergillosis, aspergilloma, and allergic bronchopulmonary aspergillosis have variable management strategies and better short-term outcomes.

The spectrum of non-Candida fungal infections following bone marrow transplantation.

We evaluated a consecutive series of patients who underwent bone marrow transplantation (BMT) at a single institution between 1974 and 1989 for the occurrence of a non-Candida fungal infection in the first 180 days after BMT. Of the 1186 patients, 129 (11%) patients developed a total of 138 significant non-Candida fungal infections in this period. Eight patients had multiple distinct infections. The most common isolate was Aspergillus spp. (n = 97), followed by Fusarium (n = 10), and Alternaria (n = 6). The 4 clinical subtypes of infections were minor skin or soft-tissue infections (n = 7), infections of a single organ or site (n = 61), disseminated fungal infection (n = 58), and isolated fungemia (n = 12). The respiratory tract was involved in 95% of single organ or site infections, and 84% of disseminated infections. Outcome was poor, with only 18% of patients surviving. The cause of death was directly related to the non-Candida fungal infection in 66% of patients who died. Mortality rates were significantly higher in patients with either single-organ or site infections (41%) or disseminated infections (83%). The cause-specific mortality rate was greatest following infections with Aspergillus, Chrysosporium, Fusarium, Mucor, or Scopulariopsis, in which there was a high potential for invasive disease and disseminated infection. In contrast, the cause-specific mortality rate was lowest in infections which were either isolated fungemia or were localized and amenable to surgical debridement, most often seen with those infections caused by Acremonium, Alternaria, Penicillium, and Saccharomyces. The spectrum of clinical infections caused by these uncommon non-Candida fungal isolates both in our series and in the literature is reviewed. These unusual opportunistic fungal isolates are now gaining recognition in immunosuppressed patients such as the BMT population, and have a significant impact on patient outcome. Effective therapy of non-Candida fungal infections remains difficult. Early aggressive surgical debridement appears to be important in control of localized invasive infections. Prolonged therapy with amphotericin B is the standard of care, although the role of the newer antifungal agents is not yet well-defined. Ancillary roles may also be provided by granulocyte transfusions and the colony-stimulating factors.

The infectious complications of chronic lymphocytic leukemia.

Infectious complications continue to have a major impact on the clinical course of patients with chronic lymphocytic leukemia despite advances in therapeutic approaches to this disease and supportive care. Although the pathogenesis of infection in these patients is multifactorial, systemic hypogammaglobulinemia is the major immune defect accounting for the increased risk of infection. Despite common knowledge of systemic immune defects in this population, information regarding mucosal immune function is minimal. In patients treated with conventional alkylating agents, infections commonly occur at mucosal sites, especially the respiratory tract, and organisms such as Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenzae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa are frequent isolates. The use of purine analogues as fludarabine has resulted in a change in this spectrum of infection, with the appearance of opportunistic infections caused by Pneumocystis, Listeria, Mycobacterium tuberculosis, Nocardia, Candida, Aspergillus, and herpesviruses. Further knowledge of the impact of chemotherapy on immune function, and of the immune defects in these patients, both inherent to the primary disease process and therapy-related, will aid in the formulation of better prophylactic and therapeutic interventions to reduce the risk of infection and improve the ultimate outcome of patients with chronic lymphocytic leukemia.

High-dose therapy and transplantation in non-Hodgkin's lymphoma.

High-dose therapy and transplantation have been explored as a therapeutic option for patients with non-Hodgkin's lymphomas (NHLs) for the past two decades, in an effort to improve the long-term outcome of this spectrum of disorders. Although a plethora of pilot and phase II studies in the various subtypes of NHL have been reported, there is a problematic lack of randomized phase III trials that would aid in answering important questions regarding the role of transplantation in these disease processes. The results of transplantation trials for these patients are also confounded by the relatively short follow-up intervals in low-grade NHL and small patient numbers in studies of transplantation for less common NHL subtypes, such as lymphoblastic, Burkitt's, and mantle cell lymphomas. The emerging late toxicities of transplantation are of increasing concern and underscore the need for more studies that address questions of relative therapeutic benefits. Fortunately, the limitations of these existing studies are recognized, and new transplantation trials presently underway or in development are beginning to address these concerns. As clinical transplantation moves into a more mature phase, these phase III studies should provide more definitive answers as to the specific role of transplantation in specific subtypes of NHL.

Non-Candida fungal infections after bone marrow transplantation: risk factors and outcome.

PURPOSE: To determine the incidence, risk factors, and outcome of non-Candida fungal infections in a bone marrow transplant population. PATIENTS AND METHODS: A consecutive series of 1,186 patients who underwent bone marrow transplant at the University of Minnesota Hospital between 1974 and 1989 were analyzed for the occurrence of a post-transplant non-Candida fungal infection. The risk factors were analyzed with regard to clinical characteristics such as age, sex, primary disease process, type of transplant, recipient cytomegalovirus serostatus, time to engraftment, and the presence of graft-versus-host disease. RESULTS: In this population, 123 of 1,186 patients (10%) developed a non-Candida fungal infection within 180 days of transplant. The majority of infections (85%) occurred in allogeneic recipients, and 58% of infections were prior to white blood cell engraftment. The most common isolates were Aspergillus species (70%), Fusarium species (8%), and Alternaria species (5%). Although 47% of infections involved a single organ or site, 44% were disseminated and 9% were isolated fungemias. Only 17% of patients survived. Sixty-eight percent of deaths were related to the fungal infection. In univariate analysis, allogeneic transplant, positive recipient cytomegalovirus serostatus, delayed engraftment, and recipient age of greater than or equal to 18 years were identified as risk factors for non-Candida fungal infection. All of these factors except for recipient age were independently significant in multivariate analysis. In allogeneic recipients, positive cytomegalovirus serostatus, delayed engraftment, and age of greater than or equal to 18 years were each significantly associated with a greater risk of fungal infection; none of these factors were independently significant in the autologous recipients. CONCLUSION: Fungal infections remain a major cause of morbidity and mortality in patients undergoing bone marrow transplant. More effective antifungal prophylaxis and therapy, earlier diagnosis, and transplant regimens incurring a brief period of neutropenia may substantially reduce the incidence and clinical impact of these infections.

Clinical characteristics of post-transplant lymphoproliferative disorders.

PURPOSE: To study the histopathologic findings, clinical course, and therapeutic outcome of patients who developed a lymphoproliferative disorder after undergoing solid organ transplantation. PATIENTS AND METHODS: A series of 26 patients who developed a lymphoproliferative disorder after solid organ transplant during a 27-year period were studied. RESULTS: The 26 patients ranged in age from 6 to 68 years (median 42 years). The lymphoproliferative disorder was diagnosed from 1 to 211 months (median 80 months) after transplantation. The type of transplant was kidney (n = 21), heart or heart-lung (n = 4), or liver (n = 1). Most patients received azathioprine and prednisone, in addition to antilymphocyte globulin or cyclosporine, for post-transplant immunosuppression. Eight patients had lymphoma that could be classified according to the International Working Formulation (IWF-F, IWF-G, IWF-H). Sixteen patients had polymorphic lymphoma, and 2 patients were classified as having polymorphic lymphoid hyperplasia. Patients were staged by the Ann Arbor staging system. Nine patients had stage I disease, 4 stage II, 6 stage III, and 7 stage IV. Central nervous system, lung, or marrow involvement was present in 27%, 23%, and 14% of patients, respectively. In the 17 patients studied, immunophenotype was monoclonal B-cell (n = 12), malignant T-cell (n = 2), or polyclonal B-cell (n = 3). The initial therapeutic approach was generally a reduction in immunosuppression, but, thereafter, the approach to therapy varied. In patients with localized disease, surgical excision and/or involved field radiotherapy were utilized as applicable. For patients with more extensive disease, other approaches such as high-dose acyclovir, combination chemotherapy, or alpha interferon were utilized. Overall, 15 of 26 patients (58%) responded to systemic therapy or were rendered disease-free either by surgery or radiation, including 8 (31%) with a complete remission (CR). Only 3 of 9 patients responded to chemotherapy, whereas 4 of 13 patients responded to acyclovir (including 3 patients who experienced CR). Remission duration ranged from 8 to 122 months (median 32+ months). Twenty-one of 26 patients (81%) have died. Survival ranged from less than 1 to 122 months (median 14 months). CONCLUSION: The outcome of patients with post-solid organ transplant lymphoproliferative disorders is poor, and the optimal approach to therapy is not clear. Newer therapeutic approaches are thus needed to improve the outcome of these patients.

Diagnosis and outcome of 100 consecutive patients with extreme granulocytic leukocytosis.

PURPOSE: To determine the clinical features, causes, and prognostic significance of extreme leukocytosis in adults. PATIENTS AND METHODS: Medical records of 100 consecutive patients who presented at the Minneapolis Veterans Affairs Medical Center between March 1993 and January 1994 with more than 25,000 leukocytes/microL blood and with more than 50% granulocytes were reviewed. Demographic, clinical, and outcome information was recorded, and a cause of extreme leukocytosis was sought in each case. RESULTS: Extreme leukocytosis was attributed to infection in 48 cases, advanced malignancy in 13 cases, hemorrhage in 9 cases, glucocorticoids in 8 cases, and other causes in 22 cases. Four patients had previously diagnosed conditions resulting in chronic leukocytosis. Higher leukocyte counts were associated with malignancy (chi2 for trend=12.5, P <0.002). Fever was more common in patients with infection (weighted rate ratio=3.7, 95% Confidence interval [CI]=2.2 to 6.2). Mortality was high overall (31%), and was greater in patients with noninfectious diagnoses compared with infected patients, an association which persisted after stratification by leukocyte count (weighted rate ratio=2.5, 95% CI=1.2 to 4.9). CONCLUSION: Clinicians should be aware that extreme leukocytosis with a predominance of granulocytes is associated with infection in only 48% of cases. The presence of fever increases the likelihood that infection is the cause. Mortality is high, particularly in patients without infection.

Long-term blood product transfusion support for patients with myelodysplastic syndromes (MDS): cost analysis and complications.

Patients with myelodysplastic syndromes (MDS) frequently become dependent on blood transfusions. We analyzed the total transfusion support required, and its complications and cost, following the diagnosis of MDS (total period = 79.7 patient-years) in 50 patients followed at the Minneapolis VA Medical Center. From diagnosis of MDS to transformation to AML or death (the MDS phase), 41 patients (82%) required transfusions. The median numbers of transfused blood products per patient per year of follow-up in the MDS phase were: packed red blood cells (pRBC), 11.1 (range, 0-91.3) units, random donor platelets (RDP), 6.8 (range, 0-581) units, and single donor apheresis platelet packs (SDP): 0 (range, 0-40) collections. In the AML phase (time from diagnosis of secondary AML to death or last follow-up), median transfusion requirements per patient (n = 5) were 24 (range, 8-88) units pRBC, 94 (range, 24-480) units RDP and 3 (range, 0-19) collections of SDP. Overall, 80% of patients required either special processing or selection of blood products, had reactions to blood products or required premedications (specified/complicated transfusions); 94% of all pRBC and 97% of all platelet transfusions were specified/complicated. The median cost of transfusions per patient was $4048 (range, $0-73210) during the MDS phase and $13210 (range, $5288-59010) during the AML phase. During the MDS phase, the median cost was $4877 (range, $0-67050) per patient-year of follow-up; the major proportion of this cost was for pRBC transfusions. Long-term support with frequent transfusions for MDS usually requires specially selected or processed blood products, and is associated with a high incidence of transfusion reactions. This study provides baseline data on the costs of transfusion support for MDS, and can be used for comparing resource utilization and costs of long-term transfusion support (supportive care) with growth factor therapy or disease-modifying modalities such as allogeneic transplantation.