Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis.

BACKGROUND: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. METHODS: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. RESULTS: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). CONCLUSION: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.

Differences between in vivo and in vitro activation of cancer patient lymphocytes by recombinant interleukin 2: possible role for lymphokine-activated killer cell infusion in the in vivo-induced activation.

In this study 15 consecutive melanoma patients were treated with two courses of bolus recombinant interleukin 2 (rIL2) and rIL2 plus in vitro-generated lymphokine-activated killers (LAK), respectively. The immunological monitoring performed after 4 days of rIL2 or rIL2 plus LAK, indicate that the in vivo peripheral blood lymphocyte (PBL), activation (spontaneous proliferation, tumor cytotoxicity, number of DR+ PBL, obtained after the second cycle of rIL2 plus LAK is significantly higher than after the first cycle of rIL2 alone. During the 5-day interval between the two courses, PBL activation returns to baseline levels and no evidence for increased sensitivity of PBL to rIL2 is present. To further confirm this, two additional patients were studied, in whom rIL2 was administered by continuous i.v. infusion. In these two patients the in vitro versus in vivo PBL activation could be directly and simultaneously compared by using in vitro the same concentration of rIL2 reached and maintained in the patients' sera. The PBL activation induced in vivo by a cycle of rIL2 alone was significantly less (about 10 times) than that obtained in vitro with a comparable rIL2 concentration. Thus, the infusion of in vitro highly activated PBL could explain the increased in vivo lymphocyte activation of the second cycle of rIL2 plus LAK over the first cycle of rIL2 alone.

Intraperitoneal recombinant gamma-interferon in patients with recurrent ascitic ovarian carcinoma: modulation of cytotoxicity and cytokine production in tumor-associated effectors and of major histocompatibility antigen expression on tumor cells.

Seven patients with advanced epithelial carcinoma and ascites, relapsing after two or more regimens of standard chemotherapy, have been treated with recombinant gamma-interferon (rIFN-gamma) i.p., via a permanent catheter. rIFN-gamma (Immuneron; Biogen; 0.5 mg = 10(7) IU in 2 liters of saline) was administered 3 times a week, on alternate weeks, for a total of nine courses. No major toxicities were observed: mild fever, malaise, and a flu-like syndrome occurred in all patients. The modulation of immunological parameters was studied. Cytotoxic activity of immunocompetent cells against tumor cell lines was measured both in the peritoneal compartment and in peripheral blood mononuclear cells. A significant increase of cytotoxicity of tumor-associated macrophages was observed in 5 of 7 patients and in 4 of 7 patients with tumor-associated peritoneal lymphocytes. Circulating effector cells were only occasionally stimulated. Tumor-associated macrophages isolated from the ascitic fluid and stimulated with lipopolysaccharide produced higher amounts of interleukin 1 in 5 of 6 patients tested, while interleukin 6 production by unstimulated tumor-associated macrophages was augmented in 2 of 2 patients after rIFN-gamma treatment. Freshly isolated ovarian carcinoma cells from the ascitic fluid has a variable, although usually low, expression of HLA-DR antigens. rIFN-gamma treatment caused a marked increase in HLA-DR expression in all patients tested. Expression of HLA class I antigens was negative in 2 of 5 patients and was strongly increased in 1 of the 2 after treatment. The observation that rIFN-gamma administered i.p. activates in situ effector cells and augments major histocompatibility antigen expression in tumor cells, with minimal toxicity, encourages further efforts to investigate its therapeutic potential in ovarian carcinoma.

Repetitive weekly cycles of 4-day continuous infusion of recombinant interleukin-2: a phase I study.

A phase I trial was performed with a new interleukin-2 (IL-2) given as a continuous intravenous infusion in patients with solid tumors. The objectives of the study were to examine the feasibility of administering IL-2 in 4-day cycles for 4 consecutive weeks, and to investigate the response pattern of peripheral blood lymphocytes. Tumor necrosis factor (TNF) and IL-2 serum concentrations were also measured. Prior to this study, IL-2 had been tested at increasing dosages during one 4-day cycle, and it appeared that a dose of 1300 mcg/m2/day was tolerated. However, when this treatment schedule was maintained for 4 consecutive weeks, the maximum tolerated dose was 430 mcg/m2/day. In this schedule, a dose-dependent progressive increase in rebound lymphocyte count occurred after each weekly cycle, resulting in a 5-70-fold increase after the 4th cycle. Serum TNF peak concentrations also showed a tendency to increase during each subsequent cycle, while serum IL-2 peak concentrations showed a paradoxical decrease. Clinical toxicity comprised several events, which, possibly, could be ascribed to autoimmune phenomena. Myocardial infarction as a late toxicity of IL-2 is suggested. One complete response (renal carcinoma) and two partial responses (renal and breast carcinoma) were documented, one of these occurring in a patient who previously had shown a transient response on interferon therapy.

Clinical and immunopathological results of a phase II study of perilymphatically injected recombinant interleukin-2 in locally far advanced, nonpretreated head and neck squamous cell carcinoma.

Fifteen patients with locally far advanced, nonpretreated head and neck squamous cell carcinoma were treated with low-dose recombinant interleukin-2, using 10 daily perilymphatic injections. The therapy was well tolerated. No tumor regression was observed. Tumor biopsies were taken before and after treatment. Histopathological studies including evaluation of the mononuclear cell infiltrate and immunohistochemical detection of human leukocyte antigen (HLA) expression on tumor cells were performed. HLA class I was not detectable in 1 of 10 samples, and HLA class II expression was seen in 2 of 10 samples. As compared to pretreatment biopsies, no changes were found after treatment. This is in agreement with the lack of a clinical response.

Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy. Geref International Study Group.

The efficacy and safety of 1 yr of GH-releasing hormone [GHRH-(1-29)] therapy in GH-deficient children were determined. One hundred and ten previously untreated prepubertal GH-deficient children were treated for up to 1 yr in a multicenter, open label study with 30 micrograms/kg GHRH-(1-29)/day, sc, given at bedtime. Eighty-six of the 110 patients were eligible for efficacy analysis. The main outcome measures, monitored every 3-6 months, were linear growth enhancement (height velocity), bone age progression, and safety measures including clinical chemistry. The mean height velocity for the group increased from 4.1 +/- 0.9 cm/yr at baseline to 8.0 +/- 1.5 and 7.2 +/- 1.3 cm/yr after 6 and 12 months of therapy, respectively. At 6 months, 74% of the children were considered to have a good response to GHRH. The ratio of the change in bone age to height age was not significantly different from unity at 12 months (1.04 +/- 0.58; P = 0.63). No adverse changes in general biochemical or hormonal analyses were noted. No change in fasting glucose concentration or excessive generation of insulin-like growth factor I occurred, and overall GHRH was well tolerated. We conclude that GHRH administered as a once daily dose of 30 micrograms/kg GHRH.(1-29), s.c., was effective in increasing height velocity in GH-deficient children.

Pharmacokinetics and pharmacodynamics of recombinant human interferon-beta in healthy male volunteers.

The pharmacokinetics and pharmacodynamics of recombinant human interferon-beta (rHuIFN-beta 1a) were assessed following administration to 12 healthy male volunteers. Each subject received, in a double-blind, balanced, random-order, crossover sequence, single doses of 6 MIU of rHuIFN-beta 1a (Rebif) i.v., i.m., and s.c. or matching placebo on four occasions separated by washout periods of 1 week. Blood samples were collected at preset times for the measurement of serum IFN-beta levels and of intracellular 2'-5'-oligoadenylate synthetase levels. Blood pressure, sitting heart rate, respiratory rate, oral body temperature, and tolerance were monitored regularly. All administrations of rHuIFN-beta 1a were well tolerated, although about half of the subjects had a flu-like syndrome, as expected. After i.v. bolus injection, the pharmacokinetics of rHuIFN-beta 1a were well described by a classic two-compartment model. Mean total clearance of rHuIFN-beta 1a was about 100 L.h-1. The distribution half-life was 5 min, and the terminal half-life was approximately 5 h. After i.m. or s.c. injection, serum IFN-beta profiles were rather flat, and about one sixth of the administered dose was available systemically. Extent and duration of clinical and biologic effects were independent of the route of administration and of the IFN-beta serum levels. Biologic pharmacodynamic effects persisted even when IFN-beta serum levels had returned to baseline and were still significantly elevated 3 days after a single dose. Because of the independence of the extent and duration of clinical and biologic pharmacodynamic effects from the route of administration and from the IFN-beta serum levels, the s.c route of administration is preferred in indications in which primarily an immunomodulatory action is sought. Predominantly antiviral and antiproliferative activity is enhanced by the i.v. route to provide adequate drug levels at the site of pathology, although its application is limited on practical grounds.

Phase I study of subcutaneously-administered bacterially-synthesised recombinant human granulocyte-macrophage colony-stimulating factor.

A phase I study was initiated to test the effect of bacterially-synthesised recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF). 15 patients with advanced cancers were entered into the study and 14 were evaluable. Patients were administered a single subcutaneous injection (3.0-300 micrograms/m2) of rhGM-CSF. Starting at a concentration of 100 micrograms/m2, an approximate 2-fold increase in leucocyte count was noted 24 h after the injection. By 48 h the counts had returned to baseline. The 300 micrograms/m2 concentration also induced an approximate 2-fold increase. The leucocytosis was associated with a predominant increase in circulating neutrophils and bands. An increase in monocytes was also noted, but peak levels were recorded 48-72 h after the injection. At both the 100 micrograms/m2 and the 300 micrograms/m2 doses, significant levels of circulating rhGM-CSF were detected. The levels measured in the plasma of patients receiving 300 micrograms/m2 were over 10-fold greater than those measured at 100 micrograms/m2. There was no detectable antibody formation against the rhGM-CSF in any of the study patients. The drug was exceptionally well-tolerated. This study shows that rhGM-CSF can be safely administered by subcutaneous administration and a single injection is capable of inducing a leucocytosis with increased circulating neutrophils, bands, and monocytes when doses are used which result in significant levels of circulating rhGM-CSF.

Immunity to tetanus and diphtheria in various age groups of the Polish population.

The concentration of tetanus and diphtheria antitoxins was determined in 279 sera of 18 to 81-year-old women and 509 sera of 22 to 46-year-old men. Tetanus antitoxin content was determined also in 246 samples of fluid from human placentas and 428 lots of commercial human normal immunoglobulins. Immunity to tetanus was clearly age-dependent: in younger age groups the percentage of immunized persons amounted to 90%-100%, in middle-age groups to about 80%, and at age above 60 to about 25%. The findings are in agreement with age-dependent incidence of tetanus, which has become now in Poland a disease primarily of older people. Two groups of the population are now protected against diphtheria: a younger group under 20, and an older one above 40. Immunity in younger age groups was induced by artificial immunization, and among older persons by natural immunization through contact with diphtheria bacilli during severe diphtheria epidemics in the past. Between these groups, gaps exist including 20-30 years of age, who are sensitive to diphtheria.

Botulinum antitoxins and antibacterial IgM and IgG antibodies in sera of persons immunized with botulinum polytoxoid combined with cholera vaccine. I. Response to botulinum toxoid.

Two groups of subjects were immunized with combined vaccine containing aluminum hydroxide-adsorbed botulinum toxoids, types A, B, and E, and 4 mld of formaldehyde-inactivated V. cholerae Inaba and Ogawa organisms. The first group included laboratory workers who were previously immunized against cholera and had professional contact with botulinum toxins and viable V. cholerae organisms. The second group included young men who were never vaccinated against botulism or cholera. The three-dose immunization schedule with combined vaccine resulted in clear-cut antitoxin response; after the third dose, the A, B, and E antitoxin level ranged from 0-2 to 10 IU/ml. Immunity against botulinum toxins lasted at least one year. Distribution of the antitoxins among IgM and IgG globulin classes resembled that in the case of response to other toxoids; 21 days after the third immunization antitoxin activity was found in IgG globulins.

Botulinum antitoxins and antibacterial IgM and IgG antibodies in sera of persons immunized with botulinum polytoxoid combined with cholera vaccine. II. Response to cholera vaccine.

The response of humans to cholera vaccine was very heterogeneous. The proportion of IgG vibriocidal antibodies was high in persons having previous natural or artificial contact with V. cholerae antigens. Predominance of IgM antibody response was seen in persons vaccinated for the first time. This type of response was sometimes evoked by unspecific stimuli such as botulinum polytoxoid without cholera vaccine. Antibodies passively protecting mice were found both in IgM and IgG globulins but the activity of these antibodies was higher in IgG than in IgM globulins.

Recombinant human interferon-beta in the treatment of condylomata acuminata.

The number of clinic consultations for condylomata acuminata (genital warts) has increased substantially during the last 30 years. Most infections produce benign lesions but a few types may be associated with cervical and penile cancers. Interferons (IFN) have shown antiviral properties to these infections and IFN-beta in particular has demonstrated a specific cytopathic effect in humans. A total of 124 patients with condylomata acuminata, the majority of whom had failed previous therapy, were treated intralesionally with either recombinant human interferon-beta la (r-hIFN-beta-1a) or placebo. Up to 6 lesions were treated in each patient, and injections were made 3 times per week for a total of 9 injections. The patients were then followed up for 3 months. Efficacy assessments at all time points (day 19, week 6 and month 3) showed a clear advantage for the r-hIFN-beta-1a interferon-beta treatment. Patients receiving r-hIFN-beta-1a showed a greater proportion of treatment success in terms of the complete or partial reduction (at least 50%) of the total area of the treated lesions. The treatment was also well tolerated. Headache, flu-like symptoms and asthenia were more common in patients receiving r-hIFN-beta-1a, but these adverse events were generally mild in severity and rarely led to patient withdrawal. It was concluded that r-hIFN-beta-1a has good efficacy in condylomata acuminata, and therefore presents a useful therapeutic alternative in this hard-to-treat condition.

Surveillance of foodborne botulism in Poland: 1960-1998.

Human foodborne botulism, in contrast to the other two forms of botulism (wound and infant botulism), is an intoxication that results when preformed botulinum toxin is ingested. Sporadic cases and family and general outbreaks occur when food products are

Why do adults contract diphtheria?

When diphtheria was a common disease, it most commonly affected children. Typically, at least 40% of diphtheria cases were children under 5 years of age, and some 70% of cases were children under 15 years of age. This classical pattern of diphtheria cases

Changes in age specific immunity to diphtheria in Poland in the past 40 years.

In recent years people in Poland have acquired diphtheria from eastern neighbours. It was considered important therefore to study the age specific immunity against diphtheria and to compare it with the results of seroepidemiological studies conducted in t

A phase II study of the administration of recombinant interleukin 2 (rIL-2) plus lymphokine activated killer (LAK) cells in stage IV melanoma patients.

From January 1987 to February 1988, 15 stage IV melanoma patients were treated with two courses of bolus injection of rIL-2 plus LAK cell infusions at the National Cancer Institute of Milan. The original treatment regimen included a first course of rIL-2 administration (400 micrograms/m2 bolus injection 3 times a day [TID] for 4 days) and a second course of rIL-2 administration (800 micrograms/m2 bolus injection TID for 7 days) separated by 4 consecutive daily leukaphereses. Autologous lymphokine activated killer (LAK) cells were reinfused into each patient on three occasions during the second period of rIL-2 administration. Due to the appearance of grade III-IV neurological, hepatic and cardiopulmonary toxicity, 7 patients discontinued dosing before the end of treatment, one patient desired to be withdrawn and one patient died from rapidly progressive disease, although complications of rIL-2 administration may have contributed to her death. Only 6 patients completed the schedule without evidence of major intolerance, even though the planned dose during the second course of rIL-2 was reduced to 400 micrograms/m2. The complete duration of treatment ranged from 11 to 19 days. The total dose of rIL-2 injected ranged from 12.6 to 30.4 mg. The number of infused LAK cells ranged from 15.5 x 10(9) to 60 x 10(9)/patient. Two of the 14 evaluable patients showed a minor anti-tumor response. In 5 patients new metastases in other sites were documented from 2 to 5 months after completion of dosing. No apparent association was found between progression of the disease (or the appearance of new metastases) and the total dose of rIL-2 injected, the number of LAK cells administered or the number of days of treatment. By December 1988, all patients had died of their disease in a period ranging from 3 to 14 months from the last injection of rIL-2. The lack of significant clinical responses in this study and the high toxicity of this treatment lead us to conclude that at least as far as melanoma patients are concerned, adoptive immunotherapy with rIL-2 plus LAK cells (as described here) is not a justifiable treatment option unless new evidence presents itself.

A phase I study of recombinant interleukin 2 in melanoma patients. Toxicity and clinical effects.

Toxicity and clinical effects of a new brand of recombinant interleukin 2 (rIL2, BioleukinTM, Biogen, Geneva) were evaluated by a phase I study in 12 patients with stage III melanoma. Escalating doses from 100 micrograms/m2 to 800 micrograms/m2 were administered thrice a day with bolus injections given via a peripheral venous catheter for up to a maximum of 7 days. All patients showed malaise, fever and chills and mild gastrointestinal side effects. A modest electrolyte imbalance (hypocalcemia and hypokalemia) was detected in all 12 patients. Renal toxicity as judged by serum creatinine was not observed, and hepatic toxicity was moderate with the possible exception of one patient who had an unclear previous history of liver dysfunction. Mild, transient leukopenia was found in several patients, whereas thrombocytopenia developed in 4 patients; no anemia was observed. Cutaneous rash was seen in half of the patients treated. Fluid retention was minimal, with a weight gain associated to treatment that never exceeded 10% of pretreatment body weight. Electrocardiographic alterations developed in 2 patients in the form of ventricular and supraventricular extrasystoles. In 2 patients given the highest dose of rIL2, a significant reduction in transfer lung factor for carbon monoxide was seen, indicating alterations in pulmonary functions. Other dose-related toxicities were thrombocytopenia and malaise. All side effects disappeared 2-3 days after the end of rIL2 administration. No major responses were seen in association with the 4-8 days of treatment given in this study.

[Can we control pertussis better? I. Changes in the epidemiology of pertussis]. / Czy mozemy lepiej zapobiegac krztuscowi? I. Zmiany w epidemiologii krztusca.

In many industrialized countries pertussis has been successfully controlled due to introduction of immunization programmes. However, decline trends in pertussis incidence, observed since more than 20 years, has been recently halted in individual countries, including Poland. In some industrialized countries, even absolute increase of pertussis incidence is recorded. Important changes in age distribution of pertussis patients are noted; from one side, there is an increase of pertussis incidence in infants, and a slow but continuous shift towards older age. There is an increasing body of evidence that adults may be the main reservoir of pertussis organisms and play an important role in the transmission of pertussis infection to younger children. Studies on the role of adults in transmission of pertussis infection to younger children should be undertaken in Poland. Early beginning and early completion of series of primary immunizations with DTP vaccine in infants and maintainance of a high immunization coverage with all doses of DTP vaccine specified in the immunization calendar are needed to successful control of pertussis. There is an urgent need to improve the diagnosis of pertussis in Poland, and especially the bacteriological confirmation of the diagnosis.

[Can we control pertussis better? II. Old and new vaccines against pertussis]. / Czy mozemy lepiej zapobiegac krztuscowi? II. Stare i nowe szczepionki przeciw krztuscowi.

Although in many countries pertussis had been successfully controlled by the routine mass immunization in infants and children, the disease continues to cause extensive morbidity and mortality throughout the world. Whole-cell pertussis vaccine plays an important role in the control of pertussis in the world and the vaccine proved to be very successful during nearly 50 years of its use. However, the whole-cell pertussis vaccine causes an increased rate of local and general adverse events although many of these events described as caused by vaccination are occurring co-incidentally, not being related to vaccination. Results of recent clinical and field trials in the USA, Sweden, Italy, Germany and Senegal showed that acellular pertussis vaccines are effective in preventing pertussis in children and safe in infants. However, a crucial issue in more general use of acellular pertussis vaccine is its availability and its price. It may be prove too expensive for many countries, including Poland. The cost can be expected to decrease in the future, when the production capacity and the number of doses used increase. The introduction of acellular pertussis vaccine in the immunization programme in Poland will need several organizational, technological and scientific actions.

[The 50th anniversary of the World Health Organization]. / 50 lat swiatowej Organizacji Zdrowia.

In the 1998, the World Health Organization celebrates its 50th anniversary. The creation of the WHO in 1948 has terminated long-lasting efforts in the development of the international organization which can promote, support and coordinate improvement in the international health. In the paper, the history of the WHO, its present structure and functions, budget, main areas of activity, achievements and problems are discussed. The WHO's contribution in the improvements in the world's public health and especially in the control of infectious diseases is essential. However, to meet new challenges of the coming XXI century, and to catalyse, encourage and support needed reforms, the WHO itself has to reorganize its structure and to discuss its strategical concepts.