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PubMed1995

Polymerase chain reaction-based detection of minimal residual disease in acute lymphoblastic leukemia predicts relapse after allogeneic BMT.

We studied 20 patients who had received allogeneic bone marrow transplants for acute lymphoblastic leukemia. Using the polymerase chain reaction (PCR), we examined them for the presence of immunoglobulin heavy chain variable-diversity-junctional (IgH V-D-J) gene rearrangements as a marker of minimal residual disease (MRD). Seventeen of the patients were transplanted in relapse or for primary refractory disease, and three were transplanted in "high risk" remission. Thirteen patients had at least one positive PCR assay for MRD in the first 100 days after transplant; two died of nonleukemic causes, while all the remaining 11 relapsed. Seven patients had all negative PCR assays; two died of nonleukemic causes, four remain alive and well, and one patient with consistently negative PCR assays relapsed 47 days after his last negative test. Considering PCR status as a time-dependent covariate, the relative risk of relapse for PCR-positive patients compared to PCR-negative patients is 6.4 (p = 0.0067; 95% CI, 1.6-24.4), and the relative risk of relapse or death is 4.8 (p = 0.0052; 95% CI, 1.6-14.2). The Kaplan-Meier estimate of relapse at 1 year for PCR-positive patients is 100% compared to 33% for PCR-negative patients. The estimate for disease-free survival at 1 year for PCR-positive patients is 0% compared to 44% at 3 years for the PCR-negative group. The PCR assay for MRD appears to be a sensitive and specific test, identifying patients at high risk of relapse following allogeneic BMT who might benefit from further therapeutic interventions.

Adolescent↗

PubMed1997

[High-dose chemotherapy in relapse of medulloblastoma in young children].

Craniospinal irradiation is the gold standard treatment used in non metastatic medulloblastoma as prophylaxis against central nervous system (CNS) metastases. However, given the severe late effects caused by this procedure in children under 3 years of age, most pediatric oncologists are currently treating these patients with conventional chemotherapy in order to postpone or even avoid irradiation. In the French Society of Pediatric Oncology (SFOP) this attitude has been adopted since 1990. Among the patients treated without radiotherapy, 20 relapsed while on conventional chemotherapy and were entered in a study of high-dose chemotherapy (HDC) followed by autologous bone marrow transplantation (ABMT). Their median age at diagnosis was 23 months (range: 5-71 months) and the relapse occurred at a median time of 6.3 months after the initiation of chemotherapy. Complete surgical removal of the local relapse was the first treatment in 4/20 patients who were not evaluable for response. Sixteen of the 20 patients had measurable disease at the primary site (9 patients), or at metastatic sites (3 patients) or both (4 patients). The conditioning regimen consisted of combination busulfan 600 mg/m2 over 4 days and thiotepa 900 mg/m2 over 3 days. After recovery from aplasia, patients with a local relapse received local radiotherapy limited to posterior fossa. Among the 16 patients with measurable disease, 6 complete responses, 6 partial responses, 3 non response, were observed following HDC (response rate 75%). One patient was not evaluable. For the 20 patients, the event free survival (EFS) is 50%. Among the surviving patients, the median follow-up is 39.5 months post BMT (range: 21-92 months). Ten patients who developed a local relapse or local progression are alive with non evidence of disease (NED) without craniospinal irradiation. Among the 7 patients who developed a metastases or progression of metastases, only 1 is alive. Toxicity was high but manageable. One complication-related death occurred 1 month post BMT. With a 75% response rate, this HDC proved to be very efficient in relapsed medulloblastoma. A longer follow-up is necessary to demonstrate whether, after a local relapse, HDC could replace craniospinal irradiation as prophylaxis against CNS metastases.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

[Cytokine-secreting cells in relapsing multiple sclerosis patients treated with high-dose intravenous methylprednisolone].

Interleukin-2 (IL-2), interleukin-2 receptor (IL-2R), interferon gamma (INF gamma), interleukin-4 (IL-4) secreting peripheral blood cells were enumerated by enzyme-linked immunospot (ELISPOT) assay in 9 relapsing multiple sclerosis (MS) patients treated with high-dose intravenous methylprednisolone (MP), in 7 MS patients with remission,and in 9 controls. IL-2, IL-2R, INF gamma, IL-4 secreting cells were significantly higher before MP therapy in relapsing MS patients as compared with after MP therapy in relapsing MS patients, with MS patients in remission, and with controls. IL-2, INF gamma secreting cells before MP in relapsing MS patients and those in remission significantly increased in response to myelin basic protein (MBP) 4-14, 68-84 and proteolipid protein (PLP). INF gamma secreting cells after MP therapy in relapsing MS patients significantly increased in response to MBP 4-14, 68-84, and PLP. IL-2R secreting cells in MS patients in remission significantly increased in response to MBP 4-14, 68-84, and PLP and were significantly higher after MP therapy in relapsing MS patients and in controls. This fact suggested that there was a systemic T-cell response to myelin antigens in MS patients in remission. The use of ELISPOT to investigate cytokine-secreting cells may play a role in the evaluation of clinical activity during treatment with high-dose intra-venous MP in relapsing MS patients.

Adult↗

PubMed1997

Risk factors for relapse in human immunodeficiency virus type 1 infected adults with pulmonary tuberculosis.

SETTING: A study conducted by the Uganda-Case Western Reserve University Research Collaboration in Kampala, Uganda, a country with high incidence rates of tuberculosis (TB) and human immunodeficiency virus type 1 (HIV-1) infection. OBJECTIVE: To assess clinical, microbiologic and radiographic factors associated with risk for relapse in HIV-infected adults treated for initial episodes of pulmonary TB. DESIGN: Nested case-control study within a randomized prospective clinical trial comparing the safety and efficacy of thiacetazone- and rifampicin-containing regimens for TB treatment in HIV-infected adults. RESULTS: The analysis was based on 119 patients who completed therapy. Median follow-up for all subjects was 22.3 months. Ten patients relapsed a median of 12.7 months after the end of therapy; seven of these were initially treated with the thiacetazone (T)-containing regimen. Each relapse case was matched to four controls by length of follow-up after initial TB treatment. In a univariate analysis risk for relapse was associated with treatment with the T-containing regimen (OR = 4.2, P = 0.08), age > or = 30 yrs (OR = 2.9, P = 0.16), and irregular compliance (OR = 3.6, P = 0.1). Baseline anergy on Mantoux tuberculin skin testing, cavitary disease, radiographic extent of disease and sputum bacillary burden, two month culture negativity, and residual cavitary disease at the end of treatment did not differ between relapses and controls. CONCLUSION: Older HIV-1 infected patients, those with poor treatment compliance, and those being treated with T-containing regimens, may be at increased risk for relapse after TB treatment and require closer post-treatment surveillance. Risk for relapse in HIV-infected adults with pulmonary TB after treatment with a nine month rifampicin-containing regimen was low (3.1 per 100 person-years observation) compared with those treated with a thiacetazone-containing regimen (10.1 per 100 person-years observation).

AIDS-Related Opportunistic Infections↗

PubMed1998

Toxicity and efficacy of defined doses of CD4(+) donor lymphocytes for treatment of relapse after allogeneic bone marrow transplant.

Donor lymphocyte infusions (DLI) can induce remissions in patients who have relapsed after allogeneic bone marrow transplantation (BMT). However, DLI frequently also result in significant acute and/or chronic graft-versus-host disease (GVHD). Several clinical and experimental lines of evidence have suggested that CD8(+) T cells play a critical role in the pathogenesis of GVHD. To develop methods to reduce the incidence of GVHD associated with DLI, we administered defined numbers of CD4(+) donor T cells after ex vivo depletion of CD8(+) lymphocytes to 40 patients with relapsed hematologic malignancies after allogeneic BMT. Cohorts of patients received 0.3, 1.0, or 1.5 x 10(8) CD4(+) cells/kg. Overall, 12 of 38 patients (32%) evaluable for toxicity developed acute or chronic GVHD. However, 6 of 27 patients (22%) receiving 0.3 x 10(8) CD4 cells/kg developed GVHD compared with 6 of 11 patients (55%) who received >/=1.0 x 10(8) CD4 cells/kg (P = .07). Treatment-related mortality was low (3%), with 1 death related to infection in the setting of immunosuppression for GVHD. Disease responses after CD4(+) DLI were documented in 15 of 19 patients (79%) with early-phase chronic myelogenous leukemia (CML) relapse, 5 of 6 patients (83%) with relapsed multiple myeloma, and 1 patient with myelodysplasia. For patients with early-phase CML relapse, the Kaplan-Meier probability of achieving complete cytogenetic remission was 87% and the probability of complete molecular response was 78% at 1 year after DLI. The median time to complete cytogenetic response and molecular response in patients with CML was 13 weeks (range, 9 to 30 weeks) and 34 weeks (range, 10 to 56 weeks), respectively. The median time to response in patients with multiple myeloma was 26 weeks (range, 15 to 62 weeks). All patients in this trial who developed GVHD demonstrated tumor regression, but the presence of GVHD was not required for patients to achieve a response, because 48% of responding patients never developed evidence of GVHD. Two patients with CML who did not respond at dose level 1 subsequently achieved complete cytogenetic remission after a second infusion of CD8-depleted cells at dose level 2. In patients with evidence of mixed hematopoietic chimerism who achieved a complete remission after DLI, cytogenetic analysis of marrow cells also demonstrated conversion to complete donor hematopoiesis in all evaluable patients. These studies suggest that relatively low numbers of CD8-depleted donor lymphocytes are effective in inducing complete remissions in patients with stable-phase CML and multiple myeloma who have relapsed after allogeneic BMT. Because of the relatively low risk of toxicity associated with the infusion of defined numbers of CD4(+) donor cells, further studies can be undertaken in the setting of persistent minimal residual disease to prevent relapse after allogeneic BMT.

Adult↗

PubMed1998

Efficacy of a combination of idarubicin, etoposide and intermediate-dose cytosine arabinoside as salvage therapy in relapsing or resistant unfavorable lymphoma.

BACKGROUND AND OBJECTIVE: Idarubicin, an anthracycline analogue, is active in non-Hodgkin's lymphoma. This study evaluates the efficacy and toxicity of a combination of idarubicin, etoposide and intermediate-dose cytarabine (IVA) in unfavorable lymphoma in relapse or resistant to prior doxorubicin- or novantrone-based regimens. DESIGN AND METHODS: Thirty patients with relapsing or resistant unfavorable lymphoma received a combination of idarubicin 12 mg/m2 i.v. on day 1, etoposide 60 mg/m2 i.v. every 12 hours for 3 days, and Ara-C 1 g/m2 i.v. every 12 hours for 3 days (3-hour infusion). Median age was 39 years (range: 22-60). All patients had been given prior doxorubicin or novantrone; 54% of them had received 2 or more chemotherapy regimens; 67% of total were in clinical relapse (30% in their second relapse), and 23% had resistant disease. RESULTS: The overall response rate to IVA was 60% (18 of 30 patients). Complete remission rate was 20% (6 of 30) in the whole group, 45% (5 of 11) among patients in their first relapse. Remission median duration was 9 months (range: 1-18), with a 3-year relapse-free and overall survival of 20% and 15%, respectively. Severe neutropenia occurred in 13 patients (43%) and severe thrombocytopenia in 11 patients (37%), with a median duration of 9 and 13 days, respectively. No cardiac toxicity developed; sepsis during neutropenia was documented in four instances and two patients (7%) died of therapy-related events (septic shock). INTERPRETATION AND CONCLUSIONS: Idarubicin combined with etoposide and intermediate-dose cytarabine proved to be an active salvage therapy in unfavorable lymphoma given prior doxorubicin or novantrone; the best results were obtained among patients in their first relapse, with low tumor burden.

Adult↗

PubMed1998

Disease-adapted relapse therapy for ovarian cancer: results of a prospective study.

Primary therapy of advanced ovarian cancer is standardized, the therapy in relapsed ovarian cancer however is still controversial. In a prospective study the benefit of secondary surgery and/or second-line chemotherapy were evaluated. 139 patients with relapsed ovarian cancer were stratified according to a treatment plan: patients with early relapse (recurrence-free interval 12 months) or primary progression during chemotherapy (n=43) were treated chemotherapeutically with etoposide (p.o. vs. i.v.). Patients with late relapse (recurrence-free interval >12 months, n=96) were referred, if possible, to a secondary debulking operation, followed by a platinum-based chemotherapy. Remission-rate, toxicity and survival time were analyzed. Median survival time in the group was 15 months compared to 30 months in patients with late relapse (p=0.0004). Within the group patients with secondary debulking and chemotherapy (n=59) had a statistically significant survival advantage compared to patients who had only chemotherapy (n=37) (38 vs. 12 months, p<0.0001). The unfavorable group of patients with early relapse should be treated chemotherapeutically, whereas in patients with late relapse a secondary debulking seems to improve prognosis.

Adult↗

PubMed1998

Early detection of relapse by prospective reverse transcriptase-polymerase chain reaction analysis of the PML/RARalpha fusion gene in patients with acute promyelocytic leukemia enrolled in the GIMEMA-AIEOP multicenter "AIDA" trial. GIMEMA-AIEOP Multicenter "AIDA" Trial.

Although the majority of patients with acute promyelocytic leukemia (APL) are potentially cured by treatments combining all-trans retinoic acid (ATRA) and chemotherapy (CHT), a sizable proportion (around 30%) will relapse during follow-up. Retrospective molecular monitoring studies using reverse transcriptase-polymerase chain reaction (RT-PCR) for the specific PML/RARalpha fusion gene, have shown that a positive test usually precedes the occurrence of hematologic relapse. Prospective RT-PCR analyses were performed since 1993 at diagnosis and at preestablished time intervals during follow-up in bone marrow (BM) samples of 163 patients with PML/RARalpha+ APL enrolled in the multicenter Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA) trial AIDA (All-trans retinoic acid plus Idarubicin). Treatment consisted of ATRA and idarubicin for induction followed by three polychemotherapy courses as consolidation. The sensitivity level of the RT-PCR assay for PML/RARalpha, as assessed by serial dilution experiments, was 10(-4). All patients were in hematologic remission and tested PCR- at the end of consolidation. Of 21 who converted to PCR-positive thereafter, 20 underwent hematologic relapse at a median time of 3 months (range, 1 to 14) from the first PCR+ result. Seventeen of these 21 (81%) PCR+ conversions were recorded within the first 6 months postconsolidation. Of 142 who tested persistently PCR- in >/=2 tests after consolidation, 8 had hematologic relapse and 134 remained in complete remission (CR) after a median follow-up of 18 months (range, 6 to 38) postconsolidation. Using a time-dependent Cox model, the relative risk of hematologic relapse of patients who converted to PCR+ was 31.8 (confidence limits 95%, 12.9 to 78.3). Our results indicate that conversion to PCR positivity for PML/RARalpha during remission is highly predictive of subsequent hematologic relapse and highlight the prognostic value of stringent molecular monitoring during the early postconsolidation phase in APL. As a result of the present study, salvage treatment in patients enrolled in the GIMEMA trial AIDA is now anticipated at the time of molecular relapse, defined as the conversion to PCR positivity in two successive BM samplings during follow-up.

Adolescent↗

PubMed1998

Favorable prognosis after late relapse of Hodgkin's disease.

BACKGROUND: Most relapses of Hodgkin's disease (HD) occur within the first 2 years after diagnosis, but they may develop after a longer observation period. The aim of this study was to define the incidence, clinical course, and prognostic factors for late relapse (LR) of Hodgkin's disease. For this purpose, the authors defined LR as relapse that occurred in patients who achieved a complete remission that lasted a minimum of 24 months. METHODS: During the years 1974-1994, 375 patients with newly diagnosed HD were treated at out institution. Of these patients, 223 remained free of disease for at least 2 years. In addition, 26 patients had been in complete remission for a minimum of 24 months after salvage treatment. Thus, 249 patients were identified as being at risk of LR, and they were the study subjects. The median age was 29 years. Fifty-nine percent of the patients had early stage disease (Stage I/II), and 48% underwent staging laparotomy. Ninety patients presented B symptoms at diagnosis, and 87 had bulky disease. Treatment consisted of radiotherapy for 68 patients, chemotherapy for 68, and combined modality therapy for 113. RESULTS: With a median follow-up of 125 months (range, 22-287 months), the authors observed LR in 25 patients (10%). The estimated relapse rate at 15 years was 13.4%. Relapse occurred after a median disease free interval of 45 months (range, 25-113 months), and it involved sites of previous disease in 70% of the patients. Age > 30 years and treatment with radiotherapy alone were the only significant independent predictors for an increased risk of LR. At a median of 79 months (range, 6-168 months) after therapy for LR, 20 patients were still alive and free of disease (1 of them after rescue treatment for second relapse), and 5 had died (3 of HD, 2 of second tumor). The estimated overall survival (OS) after LR was 82% at 8 years. OS was not significantly different for LR patients than for those who did not relapse. CONCLUSIONS: The actual incidence of LR emphasizes the need for continuous follow-up of patients treated for HD. LR, if properly managed with conventional therapy, does not compromise survival.

Adult↗

PubMed1998

Polysomnographic and subjective sleep predictors of alcoholic relapse.

Previous studies indicate that subjectively reported and objectively measured sleep abnormalities at baseline can increase the risk of relapse in treated alcoholics. However, previous studies did not include both subjective and objective sleep measures in the same group of patients. We utilized polysomnography and the Sleep Disorders Questionnaire to determine if baseline polysomnography increased the ability to predict relapse beyond the prediction with subjective measures alone, after controlling for nonsleep variables that were associated with relapse. We followed 74 patients with a DSM-III-R diagnosis of alcohol dependence, of whom 36 relapsed to at least some drinking during an average follow-up interval of 5 months. Univariate analyses revealed that relapsed patients did not differ from abstinent patients at baseline in demographics or psychiatric co-morbidity, but they had more prior treatment episodes for alcoholism, more difficulty falling asleep, more complaints of abnormal sleep, and, on polysomnography, longer sleep latencies, shorter rapid eye movement sleep latencies, and less stage 4 sleep percentage than abstinent patients. With a series of logistic regression analyses, which controlled for age and gender, we demonstrated that sleep measures improved the prediction model compared with nonsleep variables alone, and that polysomnography-measured sleep latency was the most significant predictor variable. We conclude that subjective and objective measures of baseline sleep are predictors of relapse in treated alcoholic patients. These data also suggest that neurophysiological dysfunction contributes strongly to the etiology of relapse. Finally, sleep disturbance warrants clinical attention as a target of alcoholism treatment.

Adult↗

PubMed1998

Incidence of TEL/AML1 fusion in children with relapsed acute lymphoblastic leukemia.

The TEL/AML1 fusion associated with t(12;21)(p13;q22) is the most common gene rearrangement in childhood leukemia, occurring in approximately 25% of pediatric acute lymphoblastic leukemia (ALL), and is associated with a favorable prognosis. For example, a cohort of pediatric patients with ALL retrospectively analyzed for the TEL/AML1 fusion treated on Dana-Farber Cancer Institute (DFCI) ALL Consortium protocols between 1980 to 1991 demonstrated a 100% relapse-free survival in TEL/AML1-positive patients with a median of 8.3 years of follow-up. However, two recent studies analyzing pediatric patients with relapsed ALL have reported the same incidence of the TEL/AML1 rearrangement as in patients with newly diagnosed ALL, suggesting that TEL/AML1 positivity is not a favorable prognostic indicator. To clarify this apparent discrepancy, 48 pediatric patients treated on Dana-Farber Cancer Institute (DFCI) protocols with ALL at first or second relapse were tested for TEL/AML1 using reverse transcriptase-polymerase chain reaction (RT-PCR). The TEL/AML1 fusion was identified in only 1 of 32 analyzable relapsed ALL patients, in concordance with our previous reports of improved disease-free survival in TEL/AML1-positive patients. The low frequency of TEL/AML1-positive patients at relapse is significantly different than that reported in other studies. Although there are several potential explanations for the observed differences in TEL/AML1-positive patients at relapse, it is plausible that relapse-free survival in TEL/AML1-positive patients may be changed with different therapeutic approaches. Taken together, these results support the need for prospective analysis of prognosis in TEL/AML1-positive patients.

Adolescent↗

PubMed2001

Orbital mucosa-associated lymphoid tissue (MALT)-type lymphoma in a patient with relapsing polychondritis.

Relapsing polychondritis is characterized by recurrent inflammation of the cartilaginous tissues of the ears, nose, peripheral joints, and the tracheobronchial tree. The eye is also a frequent target organ in relapsing polychondritis, and proptosis is a well-recognized manifestation of eye involvement. Similar to other rheumatologic diseases, an association of relapsing polychondritis with malignancy has been reported. We describe a patient with relapsing polychondritis who presented with exophthalmos. When treatment directed toward control of her underlying disease was only partially effective, further investigation revealed that she had an orbital mucosa-associated lymphoid tissue (MALT)-type B cell lymphoma. We hypothesize that the lymphoma resulted from malignant transformation of the relapsing polychondritis-induced inflammatory pseudotumor and emphasize that neoplastic disease should be considered in the differential diagnosis in patients with relapsing polychondritis presenting with exophthalmos.

Adult↗

PubMed1996

A new Borrelia species isolated from patients with relapsing fever in Spain.

BACKGROUND: Lyme disease and tick-borne relapsing fever are worldwide systemic borrelioses caused by several Borrelia species transmitted by hard ticks (family Ixodidae) and soft ticks (family Argasidae), respectively. A previous seroepidemiological study of Lyme borreliosis showed several serologically reactive patients with clinically atypical presentations, and this discovery led to the hypothesis that some of the cases of Lyme borreliosis had been caused by another borrelia organism. METHODS: Blood from patients in southern Spain who had suspected Lyme disease or relapsing-fever borreliosis was cultured before treatment began. Isolates of Borrelia spp were inoculated into several strains of mice of different ages. The 16S rRNA and flagellin in genes of Borrelia spp were sequenced by PCR and assessed by phylogenetic analyses. FINDINGS: We isolated a species of Borrelia from three patients with relapsing fever and from Ornithodorus spp ticks in southern Spain. This organism (refractory to in-vitro cultivation) caused a relapsing spirochaetaemia with multiple organ involvement in laboratory mice that recreated the human disease. Phylogenetic analysis showed that this organism is a previously unrecognised species. INTERPRETATION: We have discovered a new borrelia pathogen that is closely related to the other tick-borne agents of relapsing fever in Europe and Africa, and which causes a relapsing systemic disease with serological similarities to Lyme borreliosis.

Animals↗

PubMed2000

Interferon beta-1b treatment in patients with relapsing--remitting multiple sclerosis under a standardized protocol in Spain.

OBJECTIVE: A protocol system is being used in Spain for the prescription of innovative drugs including interferon beta-1b (IFNbeta-1b). Petitions for dispensing and reimbursement are based on the inclusion and exclusion criteria of pivotal trials, and are reviewed individually for approval by specialist committees. To estimate the performance of IFNbeta-1b in the clinical setting, data collected by the INSALUD and regional health services of Andalusia and Catalonia, together responsible for the healthcare of nearly 30 million individuals, were compiled in a common database for analysis. METHODS: Data comprise demographic and disease characteristics at the time of petition and at follow-up 3 months after treatment initiation and every 6 months thereafter. Efficacy was estimated by mean number of relapses per year, proportion of relapse-free patients, and disease progression as measured by the Expanded Disability Status Scale (EDSS). Safety parameters included adverse events and laboratory analyses. RESULTS: Between September 1995 and database cutoff in mid-1998, petitions of 1419 patients were approved for IFNbeta-1b treatment. Patients were homogenous across the three databases and in the subgroups of patients completing 1 year (n = 940) and 2 years (n = 302) of treatment. There was a marked decrease in the mean number of relapses in the first 12 months of IFNbeta-1b treatment for the 938 patients documented for 12 months, with a mean of 0.4 (+/- 0.7 SD) relapses per patient and year, and a 2-year mean of 0.9 (+/- 1.20 SD) in the 302 patients documented for 24 months. Of the 938 patients followed for > or = 12 months, 505 (53.8%) were documented as being relapse-free during 12 months of treatment, and 146 (48.3%) of the 302 patients followed for > or = 24 months, were relapse-free during 24 months of treatment. There were no differences in mean or median EDSS scores between baseline and months 12 and 24. Skin disorders were the most frequent adverse events, reported in over one-third of all patients; there were 159 injection site events, most frequently erythema (115 events). Systemic AEs pointing towards flu-like symptoms were reported in 288 of 1419 patients (20.3%). Leukopenia was the most frequently reported laboratory event. Elevations in liver transaminases were noted for 12 patients (0.8%) with SGOT increase and 7 (0.5%) with SGPT increase. CONCLUSION: The protocol system has helped make IFN treatment available to 8-10% of the estimated 15,000-18,000 MS patients in the regions studied. In terms of efficacy, IFNbeta-1b performed in line with the pivotal study results. The safety profile of IFNbeta-1b was consistent with the published findings and the drug labelling, and no new side effects or increased incidence of known side effects was observed.

Adjuvants, Immunologic↗

PubMed2000

Variable small protein (Vsp)-dependent and Vsp-independent pathways for glycosaminoglycan recognition by relapsing fever spirochaetes.

Tick-borne relapsing fever, caused by pathogenic Borrelia such as B. hermsii and B. turicatae, features recurrent episodes of bacteraemia, each of which is caused by a population of spirochaetes that expresses a different variable major protein. Relapsing fever is also associated with the infection of a variety of tissues, such as the central nervous system. In this study, we show that glycosaminoglycans (GAGs) mediate the attachment of relapsing fever spirochaetes to mammalian cells. B. hermsii strain DAH bound to immobilized heparin, and heparin and dermatan sulphate blocked bacterial binding to host cells. Bacterial binding was diminished by inhibition of host cell GAG synthesis or sulphation, or by the enzymatic removal of GAGs. GAGs mediated the attachment of relapsing fever spirochaetes to potentially relevant target cells, such as endothelial and glial cells. B. hermsii was able to attach to GAGs independently of variable major proteins, because strains expressing the variable major proteins Vsp33, Vlp7 or no variable major protein at all each recognized GAGs. Nevertheless, we found that a variable major protein of B. turicatae directly promoted GAG binding by this relapsing fever spirochaete. B. turicatae strain Oz1 serotype B, which expresses the variable major protein VspB, bound to GAGs more efficiently than did B. turicatae Oz1 serotype A, which expresses VspA. Recombinant VspB, but not VspA, bound to heparin and dermatan sulphate. Previous studies have shown that strain Oz1 serotype B grows to higher concentrations in the blood than does Oz1 serotype A. Thus, relapsing fever spirochaetes have the potential to express Vsp-dependent and Vsp-independent GAG-binding activities and, for one pair of highly related B. turicatae strains, differences in GAG binding correlate with differences in tissue tropism.

Animals↗

PubMed2003

A controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein alpha4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an alpha4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. METHODS: In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing-remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinical outcomes included relapses and self-reported well-being. RESULTS: There were marked reductions in the mean number of new lesions in both natalizumab groups: 9.6 per patient in the placebo group, as compared with 0.7 in the group given 3 mg of natalizumab per kilogram (P<0.001) and 1.1 in the group given 6 mg of natalizumab per kilogram (P<0.001). Twenty-seven patients in the placebo group had relapses, as compared with 13 in the group given 3 mg of natalizumab per kilogram (P=0.02) and 14 in the group given 6 mg of natalizumab per kilogram (P=0.02). The placebo group reported a slight worsening in well-being (a mean decrease of 1.38 mm on a 100-mm visual-analogue scale), whereas the natalizumab groups reported an improvement (mean increase of 9.49 mm in the group given 3 mg of natalizumab per kilogram and 6.21 mm in the group given 6 mg of natalizumab per kilogram). CONCLUSIONS: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.

Adult↗

PubMed2006

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).

Adolescent↗

PubMed2006

A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis.

BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).

Adolescent↗