Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.

PURPOSE: This phase II pilot study determined the efficacy and safety of alemtuzumab (Campath-1H; Burroughs Wellcome, United Kingdom) in patients with chronic lymphocytic leukemia (CLL), all of whom had previously received fludarabine and other chemotherapy regimens. PATIENTS AND METHODS: Twenty-four patients were treated with intravenous alemtuzumab at six centers in the United States. The target dose of 30 mg over 2 hours, three times weekly, was administered for up to 16 weeks. Responses were evaluated by an independent panel of experts using 1996 National Cancer Institute-sponsored Working Group criteria. Safety assessments included analysis of lymphocyte subpopulations. Antimicrobial prophylaxis was not mandatory. RESULTS: Eight patients (33%) achieved a major response (all partial remissions), with a median time to response of 3.9 months (range, 1.6 to 5.3 months). The median duration of response was 15.4 months (range, 4.6 to >or= 38.0 months), the median time to disease progression was 19.6 months (range, 7.7 to >or= 42.0 months), and the median survival time was 35.8 months (range, 8.8 to >or= 47.1 months). Acute infusion-related events, mainly grades 1 and 2, were most common and most severe in the first week. Ten patients (eight nonresponders and two responders) experienced major infections on-study. Pneumocystis carinii pneumonia was reported in two patients on-study; neither had received prophylaxis. Median CD4+ and CD8+ counts decreased and then began to increase by the end of the study, with further recovery by 1-month follow-up. One of 53 samples obtained from 10 patients had a low titer of alemtuzumab antibodies. CONCLUSION: Alemtuzumab has significant activity in poor-prognosis, fludarabine-treated CLL patients. However, because of a relatively high incidence of opportunistic infections accompanying profound lymphopenia, future protocols should include mandatory prophylaxis.

Phenotypic transformation of CD52(pos) to CD52(neg) leukemic T cells as a mechanism for resistance to CAMPATH-1H.

Immunotherapy utilizing CAMPATH-1H for patients with chemotherapy-refractory chronic lymphocytic leukemia has yielded encouraging results with many reports of complete remission. Here we report the outcome of two patients with CD4-positive T cell prolymphocytic leukemia treated with CAMPATH-1H. Both patients responded rapidly to treatment and subsequently developed CD4 lymphopenia. One patient remained in complete remission after 14 weeks of treatment. Serial peripheral blood flow cytometry revealed that the CD52 antigen was present throughout treatment. The other patient who was initially CD52-positive, became CD52-negative after 6 weeks of treatment, and developed progressive symptoms of T cell prolymphocytic leukemia. Immunotherapy was stopped, chemotherapy proved futile, and the patient died. This change in phenotype from CD52-positive to -negative during CAMPATH-1H therapy points out a need to develop strategies for maintaining antigenic expression during monoclonal antibody therapy.

Infections in hypothermic patients.

Of 59 adults admitted to Bellevue Hospital, New York, between 1968 and 1979 because of hypothermia due to exposure, 24 (41%) had 32 serious infections. Nine infections were not diagnosed at the time of admission. Infected patients warmed to higher peak temperatures were more likely to be comatose and had lower lymphocyte counts. At admission, physicians gave antibiotics to only one of nine patients with occult infection but to ten of 35 uninfected patients, thus failing to identify which patients required prompt antibiotic therapy. Delay in therapy contributed to the death of two patients. Since infection is frequently masked in hypothermic patients, careful repeated evaluations should be carried out to identify early infections. Although the proper use of antibiotics in patients with hypothermia is unresolved, we believe that prompt empiric antibiotic therapy is appropriate.

Rickettsialpox: report of an outbreak and a contemporary review.

Rickettsialpox is a mild illness characterized by the appearance of a primary eschar at the site of a mite bite followed by fever, headache, and a papulovesicular rash. It can be confused with a variety of illnesses including several other rickettsial diseases and chickenpox. R. akari, the etiologic agent, is a rickettsia belonging to the spotted fever group (SFG) of rickettsial illnesses. In spite of significant serologic cross-reactivity with other SFG agents, there is no convincing evidence of cross-immunity to these agents after recovery from rickettsialpox. Tetracyclinie is the drug of choice in the treatment of this disease.

Hemorrhagic cystitis due to herpes simplex virus as a marker of disseminated herpes infection.

Herpetic cystitis has rarely been reported. Herein are described two immunocompromised female patients with genital or buttock herpetic lesions in whom hemorrhagic cystitis due to herpes simplex virus type 2 developed in the setting of disseminated herpetic infection. Both patients had indwelling Foley catheters. Urinary tract instrumentation may cause local or widespread dissemination of genital herpes in immunocompromised patients.

Legionnaires' disease. A cause of severe abscess-forming pneumonia.

In two previously well nonsmokers fatal pneumonia developed with extensive abscess formation. Legionnaires' bacillus was the only pathogen isolated. These cases indicate that Legionnaires' bacillus is capable of causing extensive necrosis of the lung.

Chronology of a hospital-wide measles outbreak: lessons learned and shared from an extraordinary week in late March 1989.

In March 1989, Mount Sinai Hospital, a community hospital in Hartford, Connecticut, faced a potential hospital-wide outbreak of measles when eight cases of measles occurred among medical personnel during several days. This article describes the chronology of events, from the initial discovery of the outbreak to the evolution of the hospital-wide containment program designed to protect patients and staff members. Measles IgG immune status was determined for 1249 employees during a 9-day period. Measles vaccine and immune serum globulin were administered to patients and employees. We offer advice from our experience for infection control practitioners who may face outbreak situations in their institutions.

Pharmacokinetics and safety of single oral doses of VX-366 (isobutyramide) in healthy volunteers.

VX-366 (isobutyramide) is an orally available branched chain amide that may offer an alternative to current treatments for beta-hemoglobinopathy. A phase I, double-blind, randomized, placebo-controlled study was conducted to investigate four single oral doses of VX-366 (1, 7, 14 or 28 grams or approximately 14, 100, 200 or 400 mg/kg) administered to four male volunteers each, with two other subjects in each group receiving a matching placebo. The total number of volunteers enrolled in this study was 24, with a mean age of 27 +/- 6.4 years. VX-366 was well tolerated at all dose levels studied, and peak plasma concentrations (Cmax) of 18.88 +/- 1.02 micrograms/mL (0.2 mmol/L), 171.13 +/- 32.13 micrograms/mL (2 mmol/L), 331.58 +/- 35.48 micrograms/mL (3.8 mmol/L), and 538.83 +/- 54.19 micrograms/mL (6 mmol/L) were achieved after the four respective doses. The half-life (t1/2) of VX-366 was more than 7 hours, and there was evidence of nonlinear pharmacokinetics. It is likely that nonrenal (metabolic) clearance plays a predominant role in elimination. Based on these data, VX-366 given as a single daily dose of 100 to 150 mg/kg should be well tolerated and can be expected to result in peak plasma levels in excess of 170 micrograms/mL (2 mmol/L) and in trough plasma levels in excess of 40 micrograms/mL (0.5 mmol/L). These plasma levels exceed the concentrations previously shown to stimulate gamma globin synthesis both in vitro and in baboons.

Severe necrotizing soft-tissue infections: report of 22 cases.

Twenty-two cases of severe necrotizing soft-tissue infections (SNSTIs), seen by the infectious disease service from 1983 to 1988 in a community teaching hospital, are described and compared with previously reported series. Clinical findings were distinguishable from cellulitis at the time of surgery in only 45% of the patients who had either necrosis, crepitus, vesicle or bullae, and/or an abnormal air pattern on x-ray studies. Patients with "cellulitis" were not less sick than patients with "necrosis" findings (ie, presence of shock, leukocytosis with left shift, fever, or anion gap). Despite the fact that all but one of the patients were seen by the infectious disease service preoperatively, and 55% underwent surgical intervention within 48 hours of admission, patient mortality (18%) was not better than some reported in earlier series. However, the epidemiology of SNSTI was different: in our series there were more diabetic patients (64%) and fewer postsurgical infections (14%). Among the diabetic patients, SNSTI developed more frequently at a site not related to peripheral vasculopathy or neuropathy. Abdominal wall involvement was 10 times more likely be diagnosed as cellulitis (5/8 vs 2/14 with involvement elsewhere, P < 0.02).

Population pharmacokinetics-pharmacodynamics of alemtuzumab (Campath) in patients with chronic lymphocytic leukaemia and its link to treatment response.

AIMS: To characterize alemtuzumab pharmacokinetics and its exposure-response relationship with white blood cell (WBC) count in patients with B-cell chronic lymphocytic leukaemia (CLL). METHODS: Nonlinear mixed effects models were used to characterize plasma concentration-time data and WBC count-time data from 67 patients. Logistic regression was used to relate summary measures of drug exposure to tumour response. RESULTS: Alemtuzumab pharmacokinetics were best characterized by a two-compartment model with nonlinear elimination where V(max) (microg h(-1)) was [1020 x (WBC count/10 x 10(9) l(-1))(0.194)], K(m) was 338 microg l(-1), V(1) was 11.3 l, Q was 1.05 l h(-1) and V(2) was 41.5 l. Intersubject variability (ISV) in V(max), K(m), V(1) and V(2) was 32%, 145%, 84% and 179%, respectively. The reduction in WBC over time was modelled by a stimulatory loss indirect response model with values of 18.2 for E(max), 306 microg l(-1) for EC(50), 1.56 x 10(9) cells l(-1) h(-1) for K(in) and 0.029 per h for K(out). The probability of achieving a complete or partial response was >/=50% when the maximal trough concentration exceeded 13.2 microg ml(-1) or when AUC(0-tau) exceeded 484 microg h(-1) ml(-1). CONCLUSIONS: Alemtuzumab displayed time- and concentration-dependent pharmacokinetics with large interpatient variability, both in pharmacokinetics and pharmacodynamics, which was probably reflective of differences in tumour burden among patients. A direct relationship between maximal trough concentrations and clinical outcomes was observed, with increasing alemtuzumab exposure resulting in a greater probability of positive tumour response.

Actinobacillus actinomycetemcomitans prosthetic valve endocarditis.

Actinobacillus actinomycetemcomitans, a fastidious gram-negative bacillus, has been reported as the cause of prosthetic valve endocarditis in 11 patients. Two additional patients are reported and the literature is reviewed. All cases occurred greater than 1 year after implantation of the prosthesis. Six of the 13 patients had had recent dental work or had poor dentition. Three patients had received endocarditis prophylaxis. Ten of 13 were cured with antibiotics alone. Only one patient suffered from congestive heart failure, and only one had documented evidence of major systemic emboli during antimicrobial therapy. Valve replacement was necessary in only two during antimicrobial therapy. A actinomycetemcomitans should be considered as a possible etiologic agent in late prosthetic valve endocarditis, particularly when blood cultures are initially negative. A regimen of a beta-lactam antibiotic in combination with an aminoglycoside is recommended for 4-6 weeks. The excellent in vitro activity of the third-generation cephalosporins and rifampin promise new therapeutic options.

A multi-hospital hepatitis B vaccine program: prevalence of antibody and acceptance of vaccination among high-risk hospital employees.

In July 1982, five Hartford hospitals embarked on a joint hospital-sponsored program to immunize high-risk employees against hepatitis B virus (HBV). The program included a questionnaire to characterize relative risk, serology for anti-HBs, vaccination and a follow-up survey of vaccine non-recipients. Of 2,065 employees who were considered to be at high-risk for infection with HBV, 1,894 (91.7%) responded to the screening questionnaire and 1,279 (67.5%) were tested for anti-HBs serology. The prevalence of antibody varied from hospital to hospital; the highest prevalence (10.9%) was observed at one of the urban university-affiliated community hospitals and the lowest prevalence (4.1%) was reported from the smaller, rural hospital. The prevalence of antibody also varied greatly within the high-risk groups; the highest prevalence of antibody was seen among surgical house officers (15%). The rate of acceptance of vaccine among hospitals ranged from 57.5% to 23.7%. Reasons for vaccine non-acceptance included fear of as yet unknown side effects, perceived low risk of hepatitis acquisition and possible effects on present or future pregnancies. Our experience illustrates some of the epidemiologic and practical aspects that must be addressed in administering a hospital-based HBV vaccine program. Among the five hospitals, we saw marked inter- and intra-hospital variations in the prevalence of anti-HBs among high-risk employees. More significantly, we observed unexpectedly low rates of vaccine acceptance among high-risk personnel.

Crystallocryoglobulinemia resulting from human monoclonal antibodies to albumin.

Two patients had a previously unrecognized form of crystallocryoglobulinemia. Their clinical presentations were similar, consisting of necrotizing vasculitis and purpura involving the legs. Analysis of each cryoglobulin complex showed that two components, albumin and a monoclonal IgG-lambda, were present, and both components were needed in a fixed ratio for precipitation. In addition, cryoprecipitation occurred in serum, but not plasma, due to citrate inhibition of complex formation. Our findings suggest that the monoclonal IgGs have the properties of antibodies directed specifically against a calcium-dependent antigenic site on human albumin, and that the resultant IgG-lambda-albumin immune complexes crystallized in the cold.

Anti-adhesion molecule therapy as an interventional strategy for autoimmune inflammation.

Functional inactivation of leukocyte adhesion molecules has been used to intervene in the development of tissue injury in experimental models of postperfusion infarction as well as autoimmune inflammation. We investigated the use of humanized monoclonal antibodies (mAb) against CD18 in the treatment of five patients with vasculitic tissue injury sufficient to threaten infarction or gangrene. The treatment was monitored in three ways: (i) whole-body gamma camera scintiscanning of autologous indium-labeled PMN, (ii) an index of the therapeutic inhibition of adhesion derived from comparison pre, during, and post mAb treatment of the ability of patients' PMN to be aggregated after activation by fMLP, and (iii) flow cytometric analysis of PMN CD18 expression. Four of five patients given anti-CD18 at 20 mg/day for up to 3 weeks showed prompt clinical improvement, with healing of the ulceration and restoration of limb function within 4 weeks, which was sustained. The fifth patient, who was not doing well clinically, decided to withdraw from all active treatment: at autopsy there was no evidence of the underlying vasculitis evident pretreatment. Our findings suggest that anti-adhesion molecule treatment might be an effective immediate treatment in severe vasculitis especially when tissue viability is threatened by progressive infarction and/or development of gangrene.

An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction.

Eleven cases of community-acquired Pneumocystis carinii pneumonia occurred between 1979 and 1981 and prompted clinical and immunologic evaluation of the patients. Young men who were drug abusers (seven patients), homosexuals (six), or both (two) presented with pneumonia. Immunologic testing revealed that absolute lymphocyte counts, T-cell counts, and lymphocyte proliferation were depressed, and that humoral immunity was intact. Of the 11 patients, one was found to have Kaposi's sarcoma, and another had angioimmunoblastic lymphadenopathy. Eight patients died. In the remaining three, no diagnosis of an immunosuppressive disease was established, despite persistence of immune defects. These cases of pneumocystosis suggest the importance of cell-mediated immune function in the defense against P. carinii. The occurrence of this infection among drug abusers and homosexuals indicates that these groups may be at high risk for this infection.