Effect of late prophylaxis in hemophilia on joint status: a randomized trial.

Essentials High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. SUMMARY: Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.

Randomized, controlled, parallel-group trial of routine prophylaxis vs. on-demand treatment with sucrose-formulated recombinant factor VIII in adults with severe hemophilia A (SPINART).

BACKGROUND: The benefits of routine prophylaxis vs. on-demand treatment with factor VIII products have not been evaluated in controlled clinical trials in older patients with hemophilia A. OBJECTIVES: To report results from a preplanned analysis of data from the first year of the 3-year SPINART study, which compares routine prophylaxis with on-demand treatment with sucrose-formulated recombinant FVIII (rFVIII-FS). PATIENTS/METHODS: SPINART is an open-label, randomized, controlled, parallel-group, multinational trial. Males aged 12-50 years with severe hemophilia A, ≥ 150 days of exposure to FVIII, no FVIII inhibitors, no prophylaxis for > 12 consecutive months in the past 5 years and 6-24 bleeding episodes in the preceding 6 months were randomized 1 : 1 to rFVIII-FS prophylaxis (25 IU kg(-1) , three times weekly) or on-demand treatment. The primary efficacy endpoint, number of total bleeding episodes in the intent-to-treat population, was analyzed after the last patient had completed 1 year of follow-up. A negative binomial model was used for the primary endpoint analysis; analysis of variance was used for confirmatory analysis of annualized bleeding rates. RESULTS: Eighty-four patients were enrolled and analyzed (n = 42 per group; mean age, 30.6 years; median treatment duration, 1.7 years). The median number of total bleeding episodes and total bleeding episodes per year were significantly lower with prophylaxis than with on-demand treatment (total, 0 vs. 54.5; total per year, 0 vs. 27.9; both P < 0.0001). No treatment-related adverse events occurred, and no patients developed FVIII inhibitors. CONCLUSIONS: Routine prophylaxis with rFVIII-FS leads to a significant reduction in bleeding as compared with on-demand treatment. Adverse events were consistent with the established rFVIII-FS safety profile.

Fluoroquinolone prophylaxis for bacterial infections in neutropenic patients with hematologic malignancies.

INTRODUCTION: The use of fluoroquinolones as prophylaxis for bacterial infections in patients with chemotherapy induced neutropenia is debatable. The present study was conducted to assess the prophylactic efficacy of fluoroquinolones in adult neutropenic patients with hematologic malignancies. MATERIALS AND METHODS: For the period 1994 through 2000 a prospective, randomized trial was conducted at the University Clinic of Hematology (Medical University, Plovdiv). Two groups of patients were included--experimental group, consisting of 36 patients with 41 granulocytopenic episodes and a control group of 34 patients with 41 granulocytopenic episodes. Non parametrical and psi methods were used for statistical analysis. Kaplan-Meier test was employed to determine patients' survival rate. Comparison of survival rates between the two groups was performed using the log-rank test. RESULTS: A statistically significant difference between the two groups was found in the number of infection-free neutropenic episodes (P < 0.001), in infection-related mortality rate (p = 0.001) and mortality rate within 1 month of the onset of infection (p < 0.001). Difference in long term survival rates was not statistically significant (p > 0.05). CONCLUSIONS: Prophylaxis with fluoroquinolones reduced the occurrence of infection in adult neutropenic patients without affecting the long-term survival. Moreover, it is especially beneficial for patients with severe neutropenia and during the active phase of the disease.

[Light chain diseases--pathogenetic forms, diagnostic criteria. A suggestion for classification]. / Bolesti na lekite verigi--patogenetichni formi, kriterii za diagnoza. Predlozhenie za klasifikatsiia.

The clinical significance of the BJ-protein is quite variable: from an asymptomatic course of the light chain proteinuria for a long period of time to specific tissue deposits with serious organ damages and dysfunction. On the basis of literature data a classification of the light chain diseases is proposed: 1. Essential (bening) BJ-proteinuria; 2. Smoldering BJ-myeloma; 3. Light chain disease--BJ myeloma; 4. Light (and heavy) chain deposition disease: LC granular thick deposits mostly k type on electron microscopy, belonging to the constant region of the polypeptide chain and actively reacting with antiserums, not possessing tincturial properties; 5. LC cast nephropathy--LC coprecipitates in the tubular system; 6. LC crystaline deposition disease--specific crystaloid structures (in the Fanconi syndrome and experimental nephropathies); 7. AL-amyloidosis: LC precursor mostly lambda type from the variable region with specific fibrilar structure and typical tincturial properties. The suggested classification would resolve the diagnostic difficulties and determine the correct therapeutic management.

Third malignancy after treatment of Hodgkin's disease.

We present a case of 36-year-old man who was treated for IIB supradiaphragmatic lymphocyte-predominant Hodgkin's disease in 1972 (at the age of 11). The patient remained relapse-free after combined radiotherapy (irradiation of the right supraclavicular field) and chemotherapy (six MOPP cycles) and a 3-year supporting chemotherapy (Velbe). In 1993 he underwent spinal cord surgery for a right-sided "hour glass" schwannoma at C4-5 level. In 1996 a large formation histologically verified as "chondrosarcoma" occurred in the right supraclavicular and axillary regions. The pathogenesis of the second and third malignancies may be attributed to the histologic pattern of HD with long-term survival and increased cumulative risk, non-alternating MOPP courses and continued supporting therapy and radiotherapy given to the involved fields.

Antifungal prophylaxis with low doses fluconazole in patients with hematological malignancies.

INTRODUCTION: The incidence of mycotic infections in immunocompromised patients has reached a 20-fold rise for the last two decades. AIM: The goal of the study was to evaluate fluconazole efficacy as antifungal prophylaxis in patients with hematological malignancies. MATERIAL AND METHODS: Sixty nine patients with hematological malignancies and neutrophil count less than 1.0 x 10(9)/L received fluconazole orally at a dose of 150 mg every other day. Fluconazole was discontinued when a neutrophil count above 1.5 x 10(9)/L was maintained. Duration of neutropenic periods, afebrile cycles, and incidence of mycotic infections were assessed. The same variables were observed in a control group of 41 patients who did not receive antifungal prophylactic therapy. RESULTS: Both groups were similar in the mean duration of neutropenic period but the afebrile cycles in the patients receiving antifungal prophylaxis were longer by 5 days compared to these in the patients without prophylaxis. The mycotic infections had lower incidence in the patients on antifungal prophylaxis and the difference was statistically significant (p < 0.01). The superficial mycotic infections composed the majority of the clinically and/or microbiologically verified infections. These were presented by oropharyngeal infection (61%), esophageal (22%), and single cases of skin, genital or rectal infections. Candida albicans was isolated in 85% of the cases. The adverse reactions of fluconazole therapy were mild, transient, and easily manageable. No signs of liver and renal dysfunction were observed. CONCLUSION: Lower dose of fluconazole, 150 mg every other day p.o., has the same antifungal effect as a dose of 200 mg/day p.o. in neutropenic patients with hematological malignancies which lowers the cost of treatment.

Mucocutaneous infections in hematological malignancies.

INTRODUCTION: Mucocutaneous infections of diverse etiology are frequent complications in patients with hematological malignancies. OBJECTIVE: To study the incidence, predisposing factors, microbiology, and primary clinical manifestations of these complications in oncohematological patients. MATERIAL AND METHODS: The study included 862 patients (394 females and 468 males) with hematological malignancies, treated in the Clinic of Hematology of the Higher Medical Institute, Plovdiv from 1990 to 1998. The patients were divided into three groups according to the primary disorder: lymphoproliferative disorders (541 patients), myeloproliferative disorders (296 patients), and bone marrow insufficiency (25 patients). RESULTS AND DISCUSSION: The mucocutaneous infections studied included most often abscesses and pyodermias. The predominant isolate was Staphylococcus aureus. Viral infections were caused mainly by herpes simplex virus type I and, less frequently, varicella zoster virus with intercostal localization. Candida species was isolated predominantly in oropharyngeal and esophageal mycoses. CONCLUSION: Prolonged cytostatic-induced neutropenia and suppressed cellular immune response are the principal factors for the infectious complications in hematological malignancies. The early clinical diagnosis and prompt etiological treatment of the mucocutaneous infections are crucial for the prophylaxis of the systemic infectious complications.

Kappa and lambda light chain proteins--clinical and prognostic significance in patients with multiple myeloma.

In 76 patients with multiple myeloma an independent or combined light chain production at a ratio of kappa (kappa) to lambda (lambda) chains of 43:33 was proved. Two groups of patients were formed depending on the type of the light chain production. They were compared by a number of biological, clinical and biochemical parameters, which demonstrate the frequency and pathogenetic participation of the two light chains in the main syndromes of the disease. The therapeutic response and prognostic value were also estimated. Bence Jones (lambda) chains prevail in men, in the III clinical stage of the disease, in patients with tubular proteinuria and in syndromes indicating an advanced stage of evolution of the main process, in non-reversible azotaemia, hypercalcaemia and hypoalbuminemia. The survival rate in thus group of patients is an average of 7 months shorter in comparison with the BJ (kappa) group (the difference is non-significant). The median survival of patients with BJ (kappa) is 30 months and 21 months for BJ (lambda).

Acute renal failure in patients with multiple myeloma.

Nitrogen retention of various intensity was found in 61 patients with multiple myeloma. In seven (11%) of them the disturbances of the depurative renal function manifested as acute renal failure (ARF). The syndrome was characterised in etiologic, pathogenetic, clinical, therapeutic and prognostic aspects. ARF in the study developed on the background of a light chain proteinuria in patients with hypercalcemia, dehydration, radiocontrast studies, blood loss, surgical interventions, and severe infections. Following conservative treatment, the renal function normalized in one patient, a gradual transition to chronic renal failure was observed in five patients, and lethal outcome in one patient. The average survival rate after ARF was 8 months (1-13 months).

Nephrogenic diabetes insipidus--prodromal phase of multiple myeloma.

We report on a 65-year-old female patient with an A-kappa multiple myeloma diagnosed on the grounds of bone pain, anemia and extremely elevated erythrocyte sedimentation rate (ESR). Eight years prior to admission to the Clinic of Haematology the patient started to excrete a considerable amount of urine (4-6 liters per 24 hrs) with low specific gravity and to experience hardly controllable thirst. The disorder was specified in a specialised endocrinologic clinic as diabetes inspidus with ambiguous aetiology. The administered treatment with adiuretin had a small effect. A course of cyclophosphamide and glucocorticosteroids was started after myeloma was diagnosed--this had a considerable effect on the polyuria and polydipsia; the specific gravity of the urine increased. This effect, as well as the proven light chain proteinuria in the patient, leads to the interpretation of the early complaints of the patient as onset of the underlying disease in the form of nephrogenic diabetes insipidus--a rare light chain tubular syndrome.

Clinical problems of infectious complications in patients with multiple myeloma.

Infectious complications in 126 patients with multiple myeloma were studied throughout the entire course of the disease. Various infectious complications were found in 71 patients (56.3%). They had predominantly pulmonary (42%) and renal (37%) localisation. Most commonly, they were manifested in the acute stages of the myelomatosis: the onset of the disease, during and after the induction therapy, the relapses and in the terminal stage. Using various biologic, clinical, immunologic, biochemical, therapeutic and prognostic criteria all patients presenting with infectious complications were compared with the rest of the patients. Statistically significant risk factors for an infectious process were shown to be old age, the disease in its third clinical stage, light chain myelomas, secretion of lamda light chains, leucopenia, azotaemia, polyclonal suppression of immunoglobulins and inadequate therapeutic response. The infection complications do not have significant impact on the survival of myeloma patients.

Hypercalcaemia and azotaemia in multiple myeloma--clinical and biochemical parallels.

109 patients with multiple myeloma were studied. In 35 (32%) of them calcium level was elevated above 2.65 mmol/l and increased significantly with the clinical stage of the disease. A various degree of nitrogen retention, which was not statistically significantly dependent on the clinical stage, was found in 65 (56%) patients. There was a moderate positive correlation (r = +0.46) between the renal failure and Bence Jones proteinuria. In 27 patients, 77% of the hypercalcaemic and 44% of the azotaemic patients, both the calcium level and azotaemia were increased. In the patients with reversible and partially reversible azotaemia the occurrence of hypercalcaemia as well as the absolute values of serum calcium and creatinine showed parallel dynamics after treatment. The progression of calcaemia with the increase of nitrogen retention is a characteristic feature of renal failure in multiple myeloma. Hypercalcaemia and azotaemia are mutually interacting pathogenetic factors and the correction of increased calcium level is a must in modern therapeutic strategies.

Clinical aspects of biclonal myelomas.

In this study, a cohort of 109 patients with multiple myeloma were followed prospectively. Eight patients (7%) were found to have biclonal M component, an occurrence rate considerably higher than that reported in literature. Biclonal myelomas were compared with the other monoclonal variants of myeloma by a number of biologic, clinical, immunological, biochemical, roentgenological, therapeutical and prognostic parameters. Among the biclonal myeloma patients there was strong male predominance, higher frequency of patients in advanced stage of the disease, combined production of predominantly kappa light chains, hypoalbuminemia and thrombocytopenia. Their response to therapy did not differ from that of the patients with monoclonal myeloma variants. The median survival of patients with biclonal myelomas was 25 months, ranking third by shortened survival after patients with light chain and D-type myelomas.

[Renal onset of multiple myeloma]. / Bubrechno nachalo na multipleniia mielom.

67 patients with multiple myeloma with different duration and stage were studied. In 12 patients (17.91%) the onset of the disease was manifested by renal symptoms which were mistaken for primary renal disease. This group of patients was compared with the patients with usual onset of the disease by clinical, paraclinical and immunologic parameters. 75% of the patients with renal onset were in the III stage of the disease when the correct diagnosis was made. A tendency toward normal proteinuria (80.6 +/- 12.04 g/l), stable azotemia (creatinine 497.83 +/- 313.96 mmol/l), significant and non-selective proteinuria, positive correlation with light-chain secretion (r = +0.77) and lack of therapeutic response in 41.66% of the patients were found. Suggestions about the frequency, characteristics, diagnostic problems, therapeutic responses and the unfavourable prognosis of multiple myeloma with renal onset are put forward.

[Malignant, rapidly progressing nephritis in Schönlein-Henoch disease]. / Zlokachestven, burzo progresirasht nefrit pri bolestta na Schönlein-Henoch.

A case of malignant quickly progressing Henoch-nephritis is described, with a lethal end one and a half month after the initial manifestations. The disease develops with a clinical picture typical for systemic vasculitis, with joint-pain, skin-rash and grave abdominal syndrome, being the reason for unnecessary surgical intervention. The renal changes originate even at the very beginning of the disease and are clinically characterized, besides the exceptionally quick evolution, by the picture of acute renal insufficiency with progressing azotemia, severe electrolyte disturbances and anemic syndrome and pathomorphologically by the picture of severe diffuse intra- and extracapillary proliferative glomerulitis. The treatment with antihistamine preparations, heparin and corticosteroids failed to give an effect.

[Nephropathy in a patient with IgD-myeloma]. / Nefropatiia pri bolen s IgD-mielom.

A myeloma nephropathy in the rarely found paraproteinemia, class IgD is described for the first time in our country, manifested clinically from the very onset of the disease and advancing with a series of peculiarities, causing differential-diagnostic difficulties. The cytostatic treatment applied was with a good effect.