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Thrombotic Thrombocytopenic Purpura: Etiopathogenesis, Diagnostics and Basic Principles of Treatment

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a clinical syndrome that manifests with thrombocytopenia, microangiopathic haemolytic anaemia and symptoms and signs of kidney and brain damage, but it rarely involves other organs. The main pathophysiological cause of TTP is diminished metalloproteinase ADAMTS13 activity; the main function of ADAMTS13 is to degrade large multimers of the von Willebrand factor. Diminished activity of ADAMTS13 is caused either by a genetic mutation in the gene that codes ADAMTS13 (congenital TTP) or by antibodies that block ADAMTS13 enzyme activity or accelerate the degradation of ADAMTS13 (acquired TTP). Clinically, TTP presents most frequently with signs and symptoms of brain and kidney damage with concomitant haemorrhagic syndrome. TTP is suspected when a patient presents with a low platelet count, microangiopathic haemolytic anaemia (negative Coombs tests, low haptoglobine concentration, increased serum concentration of indirect bilirubin and lactate dehydrogenase, increased number of schysocytes in peripheral blood) and the typical clinical presentation. A definitive diagnose can be made only by measuring the ADAMTS13 activity. The differential diagnosis in such cases includes both typical and atypical haemolytic uremic syndrome, disseminated intravascular coagulation, HELLP syndrome in pregnant women and other thrombotic microangiopathies. The first line therapy for TTP is plasma exchange. In patients with acquired TTP, in addition to plasma exchange, immunosuppressive medications are used (corticosteroids and rituximab). In patients with hereditary TTP, the administration of fresh frozen plasma is sometimes required.

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Research advances in reactivation of hepatitis virus after chemotherapy for non-Hodgkin’s lymphoma-combined hepatitis B virus infection

Abstract

Infection rate of hepatitis B virus (HBV) in our country remains high. Many patients showed combined HBV infection; the most common blood system disease is non-Hodgkin’s lymphoma (NHL)-combined HBV infection. Drugs used in treating lymphoma may induce different degrees of HBV reactivation. Such condition may lead to hepatic failure or death. Currently, scholars pay increasing attention to reactivation of HBV by rituximab and/or chemotherapy for NHL-combined HBV patients. This study summarizes research advances in this topic, with a view of providing background information for further research.

Open access
Maintenance Therapy with Rituximab in Adult Patients with Immune Thrombocytopenia

Abstract

Immune thrombocytopenia (ITP) is an autoimmune disease of unknown etiology, characterized by isolated thrombocytopenia and the absence of any underlying cause for thrombocytopenia. Corticosteroids are the standard first line treatment for patients with symptomatic disease, inducing platelet count recovery in 70-80% of patients; but in many cases, steroid tapering or withdrawal is followed by a decrease of platelet count and the need for additional treatment. Splenectomy is still the standard salvage therapy in cases refractory to corticosteroid therapy. In the past decade monoclonal anti-CD20 antibodies (Rituximab) are being increasingly used in patients with refractory ITP and other autoimmune diseases. Recent studies show that Rituximab is useful in the treatment of patients with chronic and refractory ITP. We report two cases with chronic ITP treated with standard dose of Rituximab in four weekly doses and than continue to receive maintenance therapy with Rituximab for 2 years.

Open access
Stosowanie leków biopodobnych w hematoonkologii – stanowisko Polskiego Towarzystwa Hematologów i Transfuzjologów

Streszczenie

Leki biopodobne odgrywają coraz większą rolę w terapii wielu chorób wraz z wygaśnięciem ochrony patentowej dla kolejnych leków biologicznych. Celem niniejszego opracowania jest przybliżenie terminologii i zasad wprowadzania na rynek leków biopodobnych, zagadnień dotyczących ich etykietowania, ekstrapolacji, wymienialności i automatycznej substytucji. Opracowanie to przedstawia stanowisko Polskiego Towarzystwa Hematologów i Transfuzjologów dotyczące leków biopodobnych, oparte na wytycznych EMA (European Medicine Agency) i stanowisku ESMO (European Society of Medical Oncology).

Open access
Cerebral toxoplasmosis in a diffuse large B cell lymphoma patient

Background

Toxoplasmosis is an opportunistic protozoal infection that has, until now, probably been an underestimated cause of encephalitis in patients with hematological malignancies, independent of stem cell or bone marrow transplant. T and B cell depleting regimens are probably an important risk factor for reactivation of a latent toxoplasma infection in these patients.

Case report

We describe a 62-year-old HIV-negative right-handed Caucasian female with systemic diffuse large B cell lymphoma who presented with sudden onset of high fever, headache, altered mental status, ataxia and findings of pancytopenia, a few days after receiving her final, 8th cycle of rituximab, cyclophosphamide, vincristine, doxorubicin, prednisolone (R-CHOP) chemotherapy regimen. A progression of lymphoma to the central nervous system was suspected. MRI of the head revealed multiple on T2 and fluid attenuated inversion recovery (FLAIR) hyperintense parenchymal lesions with mild surrounding edema, located in both cerebral and cerebellar hemispheres that demonstrated moderate gadolinium enhancement. The polymerase chain reaction on cerebrospinal fluid (CSF PCR) was positive for Toxoplasma gondii. The patient was diagnosed with toxoplasmic encephalitis and successfully treated with sulfadiazine, pyrimethamine and folic acid. Due to the need for maintenance therapy with rituximab for lymphoma remission, the patient now continues with secondary prophylaxis of toxoplasmosis.

Conclusions

With this case report, we wish to emphasize the need to consider cerebral toxoplasmosis in patients with hematological malignancies on immunosuppressive therapy when presenting with new neurologic deficits. In such patients, there are numerous differential diagnoses for cerebral toxoplasmosis, and the CNS lymphoma is the most difficult among all to distinguish it from. If left untreated, cerebral toxoplasmosis has a high mortality rate; therefore early recognition and treatment are of essential importance.

Open access
Original article. Correlation of FcγRIIIa polymorphisms and responses to rituximab in Thai population

Abstract

Background: Rituximab is a chimeric IgG1 monoclonal antibody against CD20, approved for the treatment of B-cell non-Hodgkin’s lymphoma (NHL). Antibody dependent cellular cytotoxicity (ADCC) has been suggested to be an important mechanism of rituximab via binding to the Fc gamma IIIa receptor (FcγRIIIa) on natural killer (NK) cells. FcγRIIIa has two expressed alleles that differ at amino acid position 158 in the extracellular domain, valine (V158) and phenylalanine (F158). These allelic variants have been demonstrated to differ in IgG1 binding and ADCC. V/V homozygotes and V/F heterozygotes bind to IgG with higher affinity than F/F homozygotes.

Objectives: We identified the frequencies of FcγRIIIa polymorphism and investigate the correlation between FcγRIIIa polymorphism and rituximab responses, both in vitro and in vivo in Thai population.

Methods: The RFLP-Nested PCR and allele specific amplification was used to identify the FcγRIIIa polymorphism in the study. The correlation between FcγRIIIa polymorphism and rituximab responses, both in vitro and in vivo, was also studied.

Results: The distributions of FcγRIIIa-158 polymorphism in these subjects are V/V 40.26%, V/F 16.88%, and F/F 42.86%. Higher rituximab-induced Ramos cell cytotoxicity (mean 33.16%, 36.87%) was observed in the subjects with VV and VF genotypes, respectively. However, the lower cytotoxicity (mean 20.07%) was determined in subjects with FF genotype. As for the in vivo study, the NHL patients with V/V or V/F genotypes had a primary response as complete response; whereas, the NHL patients with F/F genotype had partial response.

Conclusion: FcγRIIIa polymorphism and the primary response in NHL patients tend to correlate. The higher number of patients is necessary for further study. These results provide useful information to understand beneficial response of rituximab as well as other IgG1 therapeutic antibody in Thai patients.

Open access
Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma

Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma

Background. The introduction of rituximab into the treatment of patients with non-Hodgkin's lymphomas has improved the overall response rate, as well as the response duration and the overall survival of patients with B-cell lymphomas. But only a few studies have addressed the question whether the better response (complete response) and the early introduction of rituximab into the treatment translate into the better survival. The aim of this retrospective study was to assess the potential relationship between either the quality of the response or the line of the rituximab treatment and the overall survival (OS) as well as the disease-free survival (DFS) of patients with B-cell lymphomas.

Patients and methods. In the study, we analysed treatment outcomes in patients with different histological types of B-cell lymphomas who were treated at the Institute of Oncology between 2003 and 2007 with rituximab and chemotherapy. We included only patients who had the level of CD20 expression assessed prior to the introduction of the treatment with quantitative flow-cytometric measurements. The OS and DFS were evaluated by Kaplan-Meier survival curves.

Results. One hundred and fourteen patients were enrolled in the study. Patients who achieved a complete response after the rituximab containing treatment had a significantly longer OS than those reaching a partial response (hazard ratio [HR], 0.34; 95% CI, 0.05 to 0.91, P = 0.0375) and than patients with stable (hazard ratio [HR], 0.11; 95% CI, 0.0002 to 0.033, P < 0.0001) or progressive disease (hazard ratio [HR], 0.09; 95% CI, 0.003 to 0.03, P < 0.0001). Patients who achieved a complete response (CR; n = 70; 61.4%) had also a significantly longer DFS (hazard ratio [HR], 0.26; 95% CI, 0.021 to 0.538, P = 0.0068) than those reaching only a partial response (PR; n = 17; 14.9%). Patients treated with rituximab as the first-line treatment (n = 50; 43.9%) had a significantly longer OS than those treated with rituximab for the first (hazard ratio [HR], 0.27; 95% CI, 0.106 to 0.645, P = 0.0036) or second relapse (hazard ratio [HR], 0.22; 95% CI, 0.078 to 0.5, P = 0.0006). Also the DFS of patients treated with rituximab as the first-line treatment (n = 46; 52.9%) was significantly longer (hazard ratio [HR], 0.32; 95% CI, 0.088 to 0.9, P = 0.0325) than in patients treated with rituximab for their first relapse (n = 25; 28.7%).

Conclusions. These data indicate that a better response to rituximab therapy presumably translates into an improved OS and DFS for patients with B-cell lymphomas. The early introduction of rituximab into the treatment (i.e. first-line treatment) might improve OS. Therefore, the response adapted first-line therapy with rituximab should be considered when the treatment decision is taken in B-cell lymphoma patients.

Open access
Clinical And Morphological Improvement Of Lupus Nephritis Treated With Rituximab

Abstract

Aim: TO assess the effects of rituximab (RTM) therapy on clinical and morphologic activity of lupus nephritis (LN).

Material and methods: The study included 45 patients with confirmed diagnosis of systemic lupus erythematosus (SLE), unaffected by previously received standard therapy with glucocorticoids (GCs) and cytostatics. The disease activity was assessed using Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI 2K); to assess the LN activity we used the SLICC RA/RE index. Forty-five patients with LN were given puncture renal biopsy prior to prescribing RTM; 16 patients had repeated renal biopsy 1 year and more after beginning the anti-B-cell therapy. LN was graded histologically in accordance with the WHO classification (2003) with indices of activity (AI) and chronicity (CI).

Results: The predominant number of patients had class III - IV of LN. The repeated renal biopsies demonstrated that LN had undergone a transition into a more favourable morphologic class, which was associated, in most of these cases, with a positive therapeutic effect. The follow-up dynamics showed a statistically significant reduction of AI (p=0.006), and no statistically significant changes in the CI (p = 0.14).

Conclusion: The long-term follow-up in the study has showed that repeated courses of anti-B-cell therapy with RTM have a positive effect both on SLE activity and generally on the renal process. The reduction of the morphologic class of LN as assessed in the repeated renal biopsies is a convincing proof for this. Eleven out of 16 patients experienced transition of the morphologic class into a more favourable type, which in most cases was combined with lower AI (p = 0.006). We found no evidence of increase in the CI (p = 0.14).

Open access