Biljana Mihaljevic

Pharmacokinetics and safety of subcutaneous rituximab in follicular lymphoma (SABRINA): stage 1 analysis of a randomised phase 3 study

BACKGROUND Intravenous rituximab is a mainstay of treatment for follicular lymphoma. A subcutaneous formulation that achieves equivalent rituximab serum concentrations might improve convenience and save health-care resources without sacrificing clinical activity. We aimed to assess pharmacokinetic non-inferiority of 3 week cycles of fixed-dose subcutaneous rituximab versus standard intravenous rituximab. METHODS In our two-stage, randomised, open-label, phase 3 trial, we enrolled patients with previously untreated grade 1-3a, CD20-positive follicular lymphoma at 67 centres in 23 countries. In stage 1, we randomly allocated patients 1:1 with the Pocock and Simon algorithm to intravenous rituximab (375 mg/m(2)) or fixed-dose subcutaneous rituximab (1400 mg), stratified by induction chemotherapy regimen (cyclophosphamide, doxorubicin, vincristine, prednisone or cyclophosphamide, vincristine, prednisone), Follicular Lymphoma International Prognostic Index score, and region. After randomisation, patients received one induction dose of intravenous rituximab in cycle 1 and then allocated treatment for cycles 2-8. Patients with a complete or partial response following induction therapy continued intravenous or subcutaneous rituximab as maintenance every 8 weeks. The primary endpoint was the ratio of observed rituximab serum trough concentrations (Ctrough) between groups at cycle 7 (before cycle 8 dosing) of induction treatment in a per-protocol population. Patients were analysed as treated for safety endpoints. Stage 2 follow-up is ongoing and is fully accrued. This study is registered with ClinicalTrials.gov, number NCT01200758. FINDINGS Between Feb 4, 2010, and Oct 21, 2011, we enrolled 127 patients. Pharmacokinetic data were available for 48 (75%) of 64 patients randomly allocated intravenous rituximab and 54 (86%) of 63 patients randomly allocated subcutaneous rituximab. Geometric mean Ctrough was 83·13 μg/mL in the intravenous group and 134·58 μg/mL in the subcutaneous group (ratio 1·62, 90% CI 1·36-1·94), showing non-inferiority of subcutaneous rituximab. 57 (88%) of 65 patients in the intravenous rituximab safety population had adverse events (30 [46%] grade ≥3), as did 57 (92%) of 62 patients in the subcutaneous rituximab safety population (29 [47%] grade ≥3). The most common grade 3 or worse adverse event in both groups was neutropenia (14 [22%] patients in the intravenous group and 16 [26%] patients in the subcutaneous group). Adverse events related to administration were mostly grade 1-2 and occurred in 21 (32%) patients in the intravenous group and 31 (50%) patients in the subcutaneous group. INTERPRETATION Stage 1 data show that the pharmacokinetic profile of subcutaneous rituximab was non-inferior to intravenous rituximab and was not associated with new safety concerns. Stage 2 will provide data for efficacy and safety of the subcutaneous administration. FUNDING F Hoffmann-La Roche.

The prognostic relevance of tumor associated macrophages in advanced stage classical Hodgkin lymphoma

Although the treatment of Hodgkin lymphoma (HL) has been improved, distinguishing reliable prognostic biomarkers could better stratify patients for more effective treatment. We analyzed the prognostic relevance of CD68+ tumor-associated macrophages (TAMs) by immunohistochemical analysis at diagnosis and standard clinical parameters in 52 ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine)-treated patients with advanced stage classical HL (cHL). Patients with >25% CD68+ TAMs compared to those with ≤25% had worse 5-year overall survival (45% vs. 77%, log-rank p = 0.019) and showed a trend toward shorter 5-year event-free survival (51% vs. 71%, log-rank p = 0.19). Additionally, no significant correlation with selected clinical features was found. Significantly shorter 5-year overall survival was associated with International Prognostic Score (IPS) >2, bulky disease, elevated erythrocyte sedimentation rate (log-rank test, p = 0.003, p = 0.049, p = 0.007, respectively). In multivariate analysis, increased CD68+TAMs, IPS >2, and bulky disease were identified as independent prognostic factors for overall survival (Cox multivariate model, p = 0.006, p = 0.007, p = 0.013, respectively). Tumor-associated macrophages represent a potential prognostic biomarker which could contribute to better risk stratification of patients with cHL.

Clinical and prognostic significance of apoptotic profile in patients with newly diagnosed nodal diffuse large B-cell lymphoma (DLBCL)

Background:  Apoptosis‐related proteins might play an important role in the pathogenesis of lymphoma and sensibility to chemotherapy (CH) in patients with non‐Hodgkin’s lymphoma. We have analyzed the relationship between expression of two proapoptotic (CD95, caspase‐3) and four antiapoptotic proteins (c‐FLIP, bcl‐2, survivin, and XIAP) and clinical outcome of patients with nodal diffuse large B‐cell lymphoma (DLBCL).

More than a third of non-gastric malt lymphomas are disseminated at diagnosis: a single center survey

Mucosa‐associated lymphoid tissue (MALT) lymphomas are extranodal B‐cell tumors that generally follow an indolent course. The gastrointestinal tract is the most common site of MALT lymphoma, comprising 50% of all cases. The tissue lesions are often localized, have high therapeutic response rates with late relapses with a long overall survival (OS). The patients with non‐gastric lesions may follow a different clinical course and many of them present with disseminated disease. This study reports a series of 51 patients with non‐gastric MALT lymphoma. Twenty patients (39.2%) presented with disseminated disease, seven (13.7%) patients had two MALT mucosal sites involved and eight (15.7%) had involvement of three or more mucosal sites. At presentation, 17 (33.3%) patients had the lymph node and 12 (23.5%) the bone marrow involvement. Following various combinations of treatment, complete remission was achieved in 40 (81.6%), and partial remission in three of the 49 treated patients with no difference in response rates between different disease stages. Relapse occurred in 12/43 (27.9%) patients among whom eight (18.6%) recurred in the presenting organ system. Five patients (9.8%) died because of a rapid disease progression after a median follow‐up of 56 months; two patients with primary lung lesions, 1 patient with secondary intestinal disease, and 2 patients suffered transformation to diffuse large B‐cell lymphoma. No significant difference in survival was found between localized and disseminated disease (log rank 0.05, df = 1, P = 0.81). A patient age ≥ 60 yr at diagnosis and presentation with the nodal disease were found to be statistically significant negative prognostic factors (P < 0.05). Median OS was not reached after 145 months of follow‐up, with the estimated OS being 88% at 2 yr, and 78% at 5 yr.

Increased risk of venous thromboembolism in patients with primary mediastinal large B-cell lymphoma

BACKGROUND Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma, arising in the mediastinum. Compression of large mediastinal vessels is common in patients with PMBCL, predisposing these patients to venous thrombosis. The incidence of this complication is still unknown. MATERIALS AND METHODS We conducted a retrospective chart review of 42 consecutive patients diagnosed with PMBCL at a Clinic for hematology, Clinical Center of Serbia between 1999 and 2009 to identify the frequency and risk factors for venous thromboembolic disease (VTE) and its correlation with survival. RESULTS In the subgroup of patients with thrombosis (VTE subgroup) were 15/42 patients (35.7%): 14 patients had deep venous thrombosis and 1 had pulmonary embolism. Ten patients had a thrombosis at the moment of diagnosis PMBCL, while in five thrombosis occurred during the course of the disease. According to hemostasis variables, patients in the VTE subgroup had significantly higher fibrinogen (P=0.02) and D-Dimer (P<0.001). Also, patients in the VTE subgroup had significantly larger diameter of mediastinal tumor mass (P=0.01) and the incidence of syndrome venae cava superior (P=0.009). The median survival rate in the VTE subgroup was 45 months (95% CI; 22 to 68 months) while in the NVTE it was 93 (95% CI; 46 to 140 months), (log rank P=0.058). CONCLUSIONS VTE is a common complication in PMBCL patients and according to our results negatively influences survival. Use of antithrombotic prophylaxis may be considered together with chemotherapy, especially in those with bulky mediastinal tumor mass.

Intravascular large B-cell lymphoma of central nervous system - a report of two cases and literature review.

Intravascular large B-cell lymphoma (IVL) is a rare form of diffuse large B cell lymphoma (DBCL) frequently presenting with skin and/or central nervous system (CNS) involvement. IVL involves CNS in 75 - 85% of patients and neurological symptoms include sensory and motor deficits or neuropathies, meningoradiculitis, paresthesia, hypostenia, aphasia, dysarthria, hemiparesis, seizures, transient visual loss, vertigo and impaired cognitive function. Neuroimaging discloses CNS involvement only in half of patients with neurological symptoms because there are no pathognomonic neuroradiological findings for IVL; ischemic foci are the most common presentation pattern and therefore vasculitis is the most common differential diagnosis. According to all mentioned data, diagnosis of CNS IVL requires a histopathological confirmation. Brain biopsy is absolutely indicated in patients with progressive neurological deterioration with unclear abnormalities in cerebral MR imaging. A general policy is that patients with IVL should be considered to have disseminated disease and should be treated with systemic chemotherapy. In younger patients with unfavorable features the high-dose chemotherapy with autologous stem cell transplantation should be used. Nevertheless, the course of IVL is rapidly progressive and ultimately fatal.

The number of lymphoma-associated macrophages in tumor tissue is an independent prognostic factor in patients with follicular lymphoma.

The clinical course of patients with follicular lymphoma is variable from a slowly progressive disease to a progressive disease with a survival time of approximately 1 year. Many prognostic models have been suggested to identify high-risk patients. Recent gene profiling analysis showed that the clinical behavior of follicular lymphoma is determined by the properties of the nonmalignant tumor microenvironment. We investigated the role of lymphoma-associated macrophages (LAMs) in tumor tissue in patients with newly diagnosed follicular lymphoma. The LAM was determined immunohistochemically in lymph node tissue sections by anti-CD68 PG-M1 and analyzed through high-power field (HPF) magnification intrafollicularly (IF) and extrafollicularly. In our study, the patients who had an IF LAM count equal to or more than 10/HPF had significantly shorter overall survival (P=0.018) and 3 years of progression-free survival (P=0.034) compared with patients with <10 LAM/HPF. Multivariate analysis indicated that IF LAM/HPF ≥10 and Eastern Cooperative Oncology Group performance status >1 are independent prognostic factors for a poor outcome.

Unusual presentation of gastric plasmablastic lymphoma in HIV-negative patient

Plasmablastic lymphoma (PBL) has initially been described as a rapidly progressive and almost invariably fatal diffuse large-cell lymphoma with plasmablastic features, exclusively involving the jaw and oral mucosa in HIV-positive patients. Although its clinical features may help in differential diagnosis, an extra-oral localization in a patient without HIV makes it more difficult to suspect clinically. We describe a very rare case of gastric PBL primarily involving stomach in a middle age man without an HIV infection. A biopsy was performed and its findings revealed a diffuse, monomorphous proliferation of the tumor cells with features of immunoblasts, MUM-1, EMA, and lambda light chains positive. Serology was negative for the human immunodeficiency virus (HIV), HBsAg, and hepatitis C virus infection. The patient started treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy, but unfortunately died before the second cycle was given. To our knowledge, this is the second case of gastric PBL presented in HIV-negative patients. The findings in this case suggest that PBL should be included in the differential diagnosis of gastrointestinal tumors.

Increased angiogenesis-associated poor outcome in acute lymphoblastic leukemia: a single center study.

Angiogenesis in solid tumors is important for tumor growth, invasion, and metastasis. However, angiogenesis plays also an important role in hematological malignancies. We have analyzed the expression of vascular endothelial growth factor (VEGF) in the leukemic blast cells and microvessel density (MVD) in the bone marrow biopsy samples of the patients with acute lymphoblastic leukemia (ALL). Bone marrow MVD of the patients with ALL was significantly higher compared with normal controls and complete remission (P<0.001), but slightly lower than in patients with relapsed ALL (P>0.05). The bone marrow blast VEGF expression was significantly higher in newly diagnosed ALL patients, with predominant strong VEGF expression as compared with complete remission patients (who had negative or weak VEGF expression) (P<0.05), whereas initial values were slightly lower than in relapsed patients. There was a strong positive correlation between VEGF expression and MVD at presentation of ALL. Stronger expression of VEGF on blast cells indicates shorter overall survival in ALL. Furthermore, initial values of MVD had positive correlation with overall survival and leukemia-free survival (P=0.024 and P=0.017, respectively). Our data suggest that increased angiogenesis (confirmed by immunohistochemical expression of VEGF in leukemic blasts), and MVD may play an important role in the pathophysiology of ALL with prognostic implications. Thus, targeting VEGF pathway may bring the new approach for ALL treatment—using antiangiogenic drugs and tyrosine kinase inhibitors in combination with standard chemotherapy regimens.

Prognostic effect of comorbidity indices in elderly patients with multiple myeloma.

BACKGROUND Consideration of comorbidity, disability, and frailty represents a significant part of the treatment of elderly multiple myeloma (MM) patients. The aim of study was to analyze the effect of the Charlson Comorbidity Index (CCI) and scale of Instrumental Activities of Daily Living (IADL) on the course of disease. PATIENTS AND METHODS The study included 110 newly diagnosed MM patients older than 65 years of age. According to the CCI most patients had at least 1 comorbidity (CCI score of 1) and most of them (51 of 110 patients; 46.4%) had an age-adjusted CCI (aaCCI) score of 5 to 6. Most of our patients were capable of performing routine daily activities (IADL ≥ 6). Patients were treated with thalidomide- and bortezomib- based combinations, or with conventional chemotherapy. RESULTS International Staging System (ISS) score 3 correlated with high scores of CCI or aaCCI (R = 0.314, P < .003; R = .317, P < .002, respectively), and lower IADL (R = 0.259, P < .007). The probability of adverse events was 70% greater for CCI score ≥ 2 (odds ratio [OR], 1.72); 28% for aaCCI ≥ 5 (OR, 1.28) and 22% higher for IADL < 3 (OR, 2.25). The patients with a CCI score of 0 to 1 had significantly longer overall survival (OS; log rank, 6.538; P < .011). The patients with aaCCI ≥ 5 had significantly shorter OS (log rank, 4.209; P < .040), and the patients with IADL > 3 had significantly longer OS (log rank, 6.62; P < .001). In the proposed model, aaCCI ≥ 5 and IADL > 3 scores had a major effect on the OS (χ(2), 8.46; P = .037). CONCLUSION CCI, aaCCI, and IADL scale are clinical parameters of prognostic significance. A proposed model for a personalized treatment approach is based on variables such as scores for aaCCI ≥ 5 and IADL > 3.