Nivolumab for relapsed or refractory Hodgkin lymphoma: real-life experience.

BACKGROUND: Reed-Sternberg cells of classical Hodgkin's lymphoma (cHL) are characterized by genetic alterations at the 9p24.1 locus, leading to over-expression of programmed death-ligand 1 and 2. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed or refractory cHL, with an acceptable safety profile. PATIENTS AND METHODS: We present a retrospective analysis of 82 patients (median age: 30 years; range: 18-75) with relapsed/refractory HL treated with nivolumab in a named patient program from 24 centers throughout Turkey. The median follow-up was 7 months, and the patients had a median of 5 (2-11) previous lines of therapy. Fifty-seven (70%) and 63 (77%) had been treated by stem-cell transplantation and brentuximab vedotin, respectively. RESULTS: Among 75 patients evaluated after 12 weeks of nivolumab treatment, the objective response rate was 64%, with 16 complete responses (CR; 22%); after 16 weeks, it was 60%, with 16 (26%) patients achieving CR. Twenty patients underwent subsequent transplantation. Among 11 patients receiving allogeneic stem-cell transplantation, 5 had CR at the time of transplantation and are currently alive with ongoing response. At the time of analysis, 41 patients remained on nivolumab treatment. Among the patients who discontinued nivolumab, the main reason was disease progression (n = 19). The safety profile was acceptable, with only four patients requiring cessation of nivolumab due to serious adverse events (autoimmune encephalitis, pulmonary adverse event, and two cases of graft-versus-host disease aggravation). The 6-month overall and progression-free survival rates were 91.2% (95% confidence interval: 0.83-0.96) and 77.3% (0.66-0.85), respectively. Ten patients died during the follow-up; one of these was judged to be treatment-related. CONCLUSIONS: Nivolumab represents a novel option for patients with cHL refractory to brentuximab vedotin, and may serve as a bridge to transplantation; however, it may be associated with increased toxicity.

Brentuximab vedotin for relapsed or refractory Hodgkin lymphoma: experience in Turkey.

Current treatment modalities can cure up to 70-80 % of patients with classical Hodgkin lymphoma. Approximately, 20-30 % of patients require further treatment options. Brentuximab vedotin has been approved for the treatment of relapsed and refractory Hodgkin lymphoma. In the present study, we report the experience with brentuximab vedotin as single agent in 58 patients with relapsed or refractory Hodgkin lymphoma. The objective response rate was 63.5 % with 13 complete responders (26.5 %) among 49 patients evaluated at the early phase of treatment (2-5 cycles). Upon treatment prolongation (≥6 cycles), 37 patients achieved a final objective response rate of 32.4 % with 21.6 % of complete and 10.8 % of partial response. Overall survival at 12 months was 70.6 %, and progression-free survival at 12 months was 32.8 %. Median overall survival could not be reached and median progression-free survival was 7 months. While the median duration of response was 9 months in the whole cohort, it was 11.5 months in the complete responders. Complete response rates in patients treated with >3 chemotherapy regimens before brentuximab vedotin were significantly lower (p = 0.016). Fourteen patients were subsequently transplanted. In conclusion, brentuximab vedotin provided a bridge to transplantation in approximately one quarter of the patients. The declining response rates during the course of treatment suggest that transplantation should be implemented early during brentuximab vedotin treatment.

The significance of autoantibodies in non-Hodgkin's lymphoma.

Lymphoproliferative diseases are the most common disorders associated with autoimmune disturbances. We determined the autoimmune phenotype of 64 non Hodgkin's lymphoma patients' and compared their clinicopathologic properties. Serum direct antiglobulin test [(DAT) n=64], indirect antiglobulin test [(IAT) n=61], platelet autoantibodies [(PAA) n=51], anti nuclear antibodies [n=33], anti-native DNA [n=29], anti phospholipid antibodies [n=40] and, lupus anticoagulant [n=33] were used as autoimmune markers. Twenty five patients (39%) displayed one or more autoimmune marker positivity (+). Three patients with (+) DAT and IAT had autoimmune hemolytic anemia and two patients with PAA had autoimmune thrombocytopenia. Male patients were more susceptible to autoimmunity in low grade lymphomas and the statistical difference was significant (p=0.035). Most of the autoimmune markers (+) patients had low grade and disseminated disease but this was not significant. Remission rates were not found to be different between autoimmune marker (+) and (-) patients. Although statistically not significant. median survival was longer in autoimmune marker (-) patients than in the others (50 versus 39 months). The significance of autoimmunity in NHL in a larger series of patients should be investigated in future studies.

Bernard-Soulier syndrome: a flow cytometric analysis of membrane GP-Ib expression.

A case of Bernard-Soulier syndrome in a five-year-old female is presented. The diagnosis was confirmed by flow cytometric analysis of glycoprotein Ib (CD 42b) in addition to the patient's classic laboratory findings such as prolonged bleeding time, mild thrombocytopenia, large platelets and failure of platelet aggregation with ristocetin. Her parents and sibling had normal coagulation tests and CD 42b levels. It is emphasized that flow cytometric analysis is useful in the confirmation of congenital platelet function defects.

Successful Surgical Management of Typhlitis in a Patient with Acute Myeloblastic Leukemia.

Typhlitis (neutropenic enterocolitis) is a potentially life-threatening complication associated with neutropenia and combination chemotherapy. The incidence of this disease is increasing in both patients with hematologic malignancies and solid tumors with the advent of more aggressive chemotherapy. Here, we describe a patient with acute myeloblastic leukemia in whom typhlitis developed during induction chemotherapy and managed successfully with both medical and surgical intervention during neutropenic period. Our experience reinforces prior reports that intense medical treatment, close observation and emergent surgical intervention has been shown to be life saving.

Increased Serum Soluble CD23 and Soluble IL-2R Levels in Haematologic Malignancies.

Serum soluble CD23 (sCD23) and soluble IL-2 receptor (sIL-2R) levels increase not only in disorders with immune system activation, but also in hematological malignancies. They have been used as markers of disease progression and/or the response to therapy in lymphoproliferative disorders (LPD). In this study, we investigated the serum sCD23 and sIL-2R levels of 21 patients with different hematological malignancies [10 LPD, 6 multiple myeloma (MM), and 5 myelodysplastic syndrome (MDS)] before treatment, and compared them with 19 age- and sex- matched healthy subjects. Median sIL-2R levels were found to be significantly elevated in both the overall patient group and each of the subgroups. Median sCD23 levels were significantly higher in the overall patient group and in patients with LPD and MM. A positive correlation was found between sIL-2R and sCD23 levels in LPD. Our preliminary findings suggest that elevated serum levels of these soluble factors are not only markers of LPD but might be also used for other hematologic malignancies, except for MDS. Further studies should be designed to find out if it might be the result of an overactive immune system or not.

A long-term survival pattern for breast cancer treated in a single institution.

AIM: This paper presents a 14-year retrospective study evaluating the survival rates and prognostic factors of breast carcinoma patients treated in private treatment center in the west coast of Turkey. MATERIALS AND METHODS: The survival rates of breast cancer patients (n = 1746) who have been treated from 1995 until 2008 were analyzed. The clinical data include age, menopausal stage, oestrogen (ER) and progesterone (PR) receptor status, and C-erbB-2 status as well as histopathological evaluation. AJCC (2002) was used for clinical tumor staging. Survival rates were computed using standard Kaplan-Meier methods, and the difference in survival curves was analyzed with the log-rank test. RESULTS: The 14-year overall survival, disease-free survival, local failure-free survival, and distant failure-free survival rates were 77%, 95%, 77%, and 94%, respectively. Early-stage patients had higher overall survival rates compared to advanced-stage patients (stage IIIb and IIIc, AJCC 2002), and early-stage patients had higher survival rates than advanced-stage patients for disease-free survival, local failure-free survival, and distant failure-free survival. The risk for cancer development increases significantly for advanced-stage patients with positive ER and PR receptor as well as C-erbB-2 receptor. CONCLUSIONS: The incidence of breast cancer in Turkey is smaller compared to other European countries. Low advanced-stage patient numbers compared to high early-stage patient numbers; and very high median survival times could possibly be the result of the improvement of detection and treatment of breast cancer over the years.

Transferrin receptor in proliferation of T lymphocytes in infants with iron deficiency.

The aim of this study was to contribute to clarify the mechanism of cellular immune insufficiency occurring during iron deficiency. We studied the expression of the transferrin receptor (TfR) which is called as CD71, on the surface of T lymphocytes in infants with iron deficiency (with and without anemia). A total of 33 infants, aged between 7 and 26 months were included in this study. These subjects were divided into three groups: (i) latent iron deficiency (LID) (group 1), (ii) iron deficiency anemia (IDA) (group 2), and (iii) healthy infants (group 3). Both CD3 levels and CD71 expression of T lymphocytes were analysed by flow cytometry before and after phytohaemagglutinin (PHA) stimulation. The percentage of CD3(+) lymphocytes in infants with IDA was lower than that in controls after PHA stimulation (mean +/- SD, 48.6 +/-10.5% vs. 70.7 +/-7.8%, P < 0.001). The TfR expression of T lymphocytes (CD3 + CD71%) increased in all three groups after PHA stimulation (P < 0.001). No significant difference was seen among the three groups with respect to CD3 + CD71%. Although there was a reduction in the proliferative capacity of T lymphocytes in infants with IDA, their ability to express transferrin receptor on T-lymphocyte cell surface was normal.

Novel cytogenetic findings revealed by conventional cytogenetic and FISH analyses in leukaemia patients.

AIM: To describe novel cytogenetic findings in four leukaemia patients. METHODS: Conventional cytogenetic (CC) and fluorescence in situ hybridization (FISH) analyses were performed on bone marrow samples of four leukaemia patients. RESULTS: In this study, t(3;10)(q11;q25) and t(2;22)(p21;q11.2) were detected as novel translocations. t(8;16;21)(q22.1;q13;q22) and t(1;6;9;22)(p36.1;p21.3;q34;q11) were found as variant translocations, and these variant translocations were confirmed by Interphase-FISH and Multi-colour-FISH. CONCLUSION: Newly identified cytogenetic findings can lead us to characterize cytogenetic evolution of the haematological malignancies. Further investigations are certainly warranted to resolve the prognostic impact of these new cytogenetic abnormalities.

Automated plateletpheresis does not cause an increase in platelet activation in volunteer donors.

Activation of platelets during collection and storage has been implicated as a major cause of the platelet storage lesion. In this study, we investigated the effect of an automated plateletpheresis procedure on the in vivo platelet activation in 20 volunteer donors. Peripheral blood samples were collected immediately before and after plateletpheresis on the Haemonetics V50 Blood Cell Separator. Activation of platelets was determined by quantitating the amount of platelet P-selectin (CD62) expression using a whole blood method on flow cytometry. Adenosine diphosphate (ADP), collagen, and ristocetin induced platelet aggregations were also measured on a whole blood impedance aggregometer. Plateletpheresis caused a significant decrease in the CD62-positive platelet percentage and aggregation responses to 3 agonists. We concluded that the plateletpheresis procedure did not cause an increase in platelet activation in donors. Further studies are required to elucidate whether activated platelets are collected during the procedure or removed from the circulation of the donor and replaced by resting platelets, activated platelets bind to leukocytes or endothelial cells, and the plateletpheresis procedure is a powerful stimulus for platelet activation.

Single automated donor plateletpheresis increases the plasma level of proinflammatory cytokine tumor necrosis factor-alpha which does not associate with endothelial release markers von Willebrand factor and fibronectin.

The effect of plateletpheresis on endothelium, which has strong effects on blood coagulation, fibrinolysis and platelet function, is not known. Activation of leukocytes and subsequent generation of proinflammatory cytokines during the extracorporeal circulation may activate the endothelium. To test this hypothesis we measured plasma levels of tumor necrosis factor (TNF)-alpha as a prototype of the proinflammatory cytokines, and von Willebrand factor (vWF) and fibronectin as endothelial release/damage markers before and after a single plateletpheresis procedure on an intermittent-flow machine Haemonetics MCS 3p in 17 healthy donors. We found a significant increase in median plasma level of TNF-alpha following plateletpheresis (3.5 vs 26.5 pg/ml, P=0.02). Such increases in vWF and fibronectin were not observed. The increase in plasma TNF-alpha indicates that a single plateletpheresis procedure causes leukocyte activation which does not seemingly impair endothelial cell function. The relation of plateletpheresis-induced proinflammatory cytokine release to some adverse effects observed in both donors and recipients, and the effect of repeated plateletpheresis on endothelium deserve further studies.

Myelodysplastic syndrome in a patient with Werner's syndrome.

Werner's syndrome is a relatively rare autosomal recessive disorder characterized by several features generally associated with aging. This syndrome is classified in the group of chromosome instability syndromes and there is an increased incidence of neoplasia. Hematologic malignancies associated with this syndrome are, however, unusual. Herein we report a case of Werner's syndrome with myelodysplastic syndrome, a clonal preleukemic disorder of hemopoietic stem cells. Such an association, to the best of our knowledge, has not been reported in the English literature so far.

Sheehan's syndrome associated with pancytopenia due to marrow aplasia; full recovery with hormone replacement therapy.

We describe a 52-year-old woman with pancytopenia associated with Sheehan's syndrome, whose presenting feature was severe malaise and syncope after a psychological stress. Hormonal replacement therapy alone (with L-thyroxine and prednisolone) produced clinical and full haematological recovery. This is a very rare case of Sheehan's syndrome because the diagnosis was delayed for 27 years after delivery, and it was associated with pancytopenia.

Hepatitis C virus association with non-Hodgkin's lymphoma.

Infectious etiology has been confirmed only in a few lymphoproliferative disorders such as human T-cell lymphotropic virus in adult T-cell leukemia lymphoma, Epstein-Barr virus in African-type Burkitt's lymphoma and Hodgkin's disease, and Helicobacter pylori infection in primary gastric B-cell lymphoma. In recent years, Ferri and colleagues have found hepatitis C virus (HCV) association with non-Hodgkin's lymphoma (NHL) in Italy. The aim of our study was to determine the HCV association in NHL patients in Antalya. Forty-eight patients (22 women and 26 men, with a median age of 52 years) with NHL were included in the study. The control group consisted of 28 patients with various hematological disorders (11 women and 17 men with a median age of 50 years). Anti-HCV antibodies were investigated in 48 patients, and HCV RNA was assessed in 35 of them. Anti-HCV antibodies were found to be negative in the NHL group, but HCV RNA was positive in the serum of three patients (8.6%), who were diagnosed with diffuse small cell lymphoma (19%). Anti-HCV antibodies and HCV RNA were negative in the control group. Since HCV association with NHL has previously been reported in Italy, it is likely that both genetic and environmental factors in the Mediterranean sea-region may be involved in the oncogenesis in HCV RNA-positive patients. Multicenter studies with large patient groups will disclose the true association of HCV with NHL in Turkey.

Tuberculosis-associated haemophagocytic syndrome: a report of two cases and a review of the literature.

The haemophagocytic syndrome (HS) is an uncommon reactive proliferation of mature histiocytes, and is more frequently but not exclusively associated with infections in individuals with pre-existing immunologic abnormalities. As far as we know, only 13 cases of tuberculosis-associated HS have previously been reported. We present here two cases of disseminated tuberculosis-associated HS. Both of the cases recovered with antituberculosis therapy. High-dose methylprednisolone and intravenous immunoglobulin were added in one case because of the extremely severe clinical presentation. This therapy seemed to contribute to the favourable outcome of the patient. The similarities in HLA phenotypes of this patient and others reported in the literature may provide evidence for an underlying immune dysregulation in some cases of infection-associated HS.