Non-Hodgkin Lymphoma in Children with Primary Immunodeficiencies: Clinical Manifestations, Diagnosis, and Management, Belarusian Experience

Introduction. Non-Hodgkin lymphoma (NHL) is the most frequent malignancy associated with primary immune deficiency disease (PID). We aimed to present the clinical characteristics and outcomes of Belarusian children with PID who developed NHL. Procedure. We reviewed 16 patients with PID and NHL. Eight patients had combined PID: 5—Nijmegen breakage syndrome, 1—Bloom syndrome, 1—Wiskott-Aldrich syndrome, and 1—Х-linked lymphoproliferative syndrome. Results. In 75% cases PID was diagnosed simultaneously or after the NHL was confirmed. PID-associated NHL accounted for 5.7% of all NHL and was characterized by younger median age (6.3 versus 10.0 years, P<0.05) and by prevalence of large-cell types (68.8% versus 24.5%, P<0.001). Children with combined PID had median age of 1.3 years; 5 of them developed EBV-associated diffuse large B-cell lymphoma with lung involvement. Five of 6 patients with chromosomal breakage syndrome developed T-NHL. Six patients died of infections; two died after tumor progression; one child had early relapse; two died of second NHL and one of secondary hemophagocytic syndrome. Overall, 4 children are alive and disease-free after a follow-up from 1.4 to 5.7 years. Conclusions. PID needs to be diagnosed early. Individualized chemotherapy, comprehensive supportive treatment, and hematopoietic stem cell transplantation may improve survival of children with PID and NHL.

FoxP3-Positive T-Regulatory Cells in Lymph Nodes with Mycosis Fungoides and Sézary Syndrome

Mycosis fungoides and Sézary syndrome are indolent cutaneous T-cell lymphomas, with skin-associated peripheral lymph nodes being the most frequent extracutaneous site of involvement. Acquisition of functional properties of regulatory T-cells by malignant T-cells in advanced disease may contribute to immunosuppression. Whereas previous studies examining FoxP3 protein expression in mycosis fungoides and Sézary syndrome have focused on skin specimens, little data are available on lymph nodes from patients with these conditions. In this study we examined FoxP3+ regulatory T-cells in lymph nodes from 26 patients with mycosis fungoides and Sézary syndrome and correlated the findings with clinical data, molecular assays for T-cell clonality, and flow cytometry. Except for one case of Sézary syndrome in which malignant T-cells expressed FoxP3 protein, a significantly lower number of FoxP3-expressing cells occurred in lymph nodes that were clearly involved with lymphoma as compared to uninvolved nodes. Cox proportional hazards model showed that lymph node rating and histological evidence of transformation, but not number of FoxP3+ cells, were factors significantly associated with adverse prognosis. We speculate that modulation of FoxP3+ cells in lymph nodes involved with lymphoma might play a role in disease progression. Attainment of a regulatory T-cell phenotype by a subset of lymphoma cells might signal a poor prognosis.

Rituximab Induced Interstitial Lung Disease in Patients with Non-Hodgkin’s Lymphoma: A Clinical Study of Six Cases and Review of the Literature

Background. Rituximab-induced lung disease (R-ILD) is a rare entity that should be considered in patients treated with rituximab who present with dyspnea, fever, and cough but no clear evidence of infection. Aim. The aim of this prospective longitudinal study is to describe the clinical presentation, management, and response to rechallenge in patients diagnosed with rituximab induced ILD over a period of one year. Results. Out of sixteen patients with CD20 positive non-Hodgkin’s lymphoma who received rituximab along with standard chemotherapy, six patients developed features suggestive of R-ILD. Four (66.6%) of these patients had diffuse large B cell lymphoma. The median time of presentation of R-ILD was after the 3rd cycle of chemotherapy. Three patients (50%) presented with acute onset of high fever, dyspnea, and dry cough while the remaining three presented with insidious onset of dyspnea and dry cough. An infectious etiology for the respiratory illness was ruled out in all patients with an exhaustive work-up. Four patients (66.6%) responded to corticosteroid treatment and supplemental oxygen. One patient required mechanical ventilation and succumbed to ILD while another required prolonged supplemental oxygen. Two (33.3%) of patients were successfully rechallenged with rituximab under cover of corticosteroids. Conclusions. Rituximab induced lung disease is a rare but potentially fatal pulmonary toxicity which requires a high index of suspicion for early diagnosis and treatment.

Impact of BMI and Gender on Outcomes in DLBCL Patients Treated with R-CHOP: A Pooled Study from the LYSA

In diffuse large B-cell lymphoma (DLBCL), the age-adjusted International Prognostic Index (aaIPI) score is currently used to predict patient outcomes and to choose the best therapeutic treatment. Body mass index (BMI) and gender are occasionally sited as prognostic factors; however, their value has never been studied in a large series of patients included in prospective clinical trials in the rituximab era. To assess the impact of BMI and gender on OS and PFS independently of the aaIPI score, we pooled 985 patients that were prospectively included in GELA studies and uniformly treated with R-CHOP. Univariate analysis indicated that high aaIPI and male gender were associated with a worse PFS, whereas high (>25) or low (<18.5) BMI scores were not. High aaIPI score was the only factor predictive for OS. In a multivariate analysis, including aaIPI score, gender, BMI, and interaction between BMI and gender, aaIPI remained the strongest predictive factor, and BMI < 18.5 was significantly associated with a worse OS but not PFS. In conclusion, in the rituximab era, the aaIPI score remains the major predictor of outcome in DLBCL patients; however, male gender and low BMI seem to impact outcome.

Primary Non-Hodgkin’s Lymphoma of Stomach: To Report 54 Patients and Analysis of Major Reported Series

Introduction. This study aimed to report the characteristics, prognostic factors, and treatment outcomes of 54 patients with primary gastric lymphoma. Materials and Methods. This retrospective study was carried out by reviewing the medical records of 54 adult patients diagnosed at a tertiary academic hospital. All the patients were treated with curative intent. Forty-four patients (81.5%) underwent gastrectomy followed by adjuvant chemotherapy and/or radiotherapy, whereas 10 ones (18.5%) were treated with chemotherapy alone or with radiotherapy. Results. The study was conducted on 25 males and 29 females with the median age of 50 years. Diffuse large B-cell lymphoma (DLCL) (67%) and Mucosa Associated Lymphoid Tissue (MALT) lymphoma (26%) were the most common histologic types. Besides, 36 (59%), 16 (30%), 5 (9%), and 1 (2%) patients were in stages I, II, III, and IV, respectively. The 5-year disease-free survival and overall survival were 64.7% and 67%, respectively. In univariate analysis for overall survival, International Prognostic Index (IPI) (), the WHO performance status (), Ann Arbor stage (), age (), and LDH serum level () were the prognostic factors. Conclusion. Gastric lymphoma tends to present in early stage of the disease and has a favorable outcome.

Therapy-Related Late Adverse Events in Hodgkin’s Lymphoma

Hodgkin's lymphoma (HL) is one of the most curable hematologic diseases with an overall response rate over 80%. However, despite this therapeutic efficacy, HL survivors show a higher morbidity and mortality than other people of the same age because of long-term therapy-related events. In the last decades, many efforts have been made to reduce these effects through the reduction of chemotherapy dose, the use of less toxic chemotherapeutic agents, and the introduction of new radiation techniques. In this paper, we will describe the main long-term effects related to chemotherapy and radiotherapy for HL, the efforts to reduce toxicity made in the last years, and the clinical aspects which have to be taken into consideration in the followup of these patients.

Is There Any Relationship between Human Herpesvirus-8 and Multiple Myeloma?

Background. Human herpesvirus-8 (HHV-8) is associated with some human diseases including Kaposi’s sarcoma and also some B-cell lymphoproliferative disorders. Few studies have highlighted the potential role of HHV-8 in the development of multiple myeloma (MM) which is known as a malignant proliferation of plasma cells derived from a single clone. Aims. The aim of this study was to find a relationship between HHV-8 and MM using polymerase chain reaction (PCR) method. Materials and Methods. This study was conducted on 30 formalin-fixed, paraffin-embedded (FFPE) bone marrow biopsies of multiple myeloma and 30 normal FFPE bone marrow biopsies. After the sample preparation, Deoxyribonucleic acid (DNA) was extracted by nonheating procedure. PCR for HHV-8 virus was carried out with commercial kit and the PCR products were visualized by gel electrophoresis. Finally, the statistical analysis was performed. Results. HHV-8 virus was not detected by PCR from FFPE blocks of multiple myeloma samples, while only one of the controls showed DNA band of the corrected molecular weights. Fisher’s exact test showed that no statistical differences were found between the two groups (P=0.999). Conclusion. Our report adds to the body of evidence that there is no association between HHV- 8 and MM against a major role of HHV-8 infection in the pathogenesis of clonal plasma cell proliferation.

Polo-Like Kinase 1: A Novel Target for the Treatment of Therapy-Resistant Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a B-cell non-Hodgkin lymphoma (NHL) which is one of the most aggressive lymphomas. Despite recent improvements in therapies, the development of therapy-resistance is still a major problem; therefore, in order to understand the molecular basis of therapy-resistance, stable therapy-resistant MCL cell lines have been established by us. Based on the gene expression profiles of these cell lines, Polo-like kinase 1 (PLK1) was chosen as a therapeutic target. In this paper, we demonstrate a significant antilymphoma effect of targeting PLK1 in therapy-resistant MCL cells and primary MCL cells from refractory patients. PLK1 knockdown with the antisense oligonucleotide (ASO)/or small molecule inhibitor BI2536 showed significantly decreased proliferation and increased apoptosis in therapy-resistant MCL cell lines and MCL primary cells. Additionally, the direct protein-protein interaction partners of PLK1 were mapped using ingenuity pathway and confirmed the level of association of these partners with PLK1 based on their expression changes following PLK1 knockdown using real-time PCR. Results suggest that PLK1 is a viable target for the treatment of therapy-resistant MCL.

The Development and Validation of a Measure of Health-Related Quality of Life for Non-Hodgkin’s Lymphoma: The Functional Assessment of Cancer Therapy—Lymphoma (FACT-Lym)

Background. The individual concerns of non-Hodgkin’s lymphoma (NHL) patients require identification and assessment during clinical research proposing to measure patients’ outcomes. The FACT-Lym was developed as part of the FACIT measurement system to address health-related quality-of-life (HRQL) issues for NHL patients. Patients and Methods. Items for the FACT lymphoma subscale (LymS) were generated from healthcare provider interviews, published literature, and content validity patient interviews. The FACT-Lym was validated on a sample of 84 NHL patients, with additional measures at baseline (T1), 3–7 days (T2), and 8–12 weeks (T3). Results. Item correlations, expert relevance ratings, and patient input on content shortened the initial 22-item LymS to 15 items. The validation sample included 56% female, 76.2% white, 60% indolent disease, and 85% receiving treatment. Internal consistency coefficients for the 15-item LymS (.79, .85, and .84 T1–T3) and test-retest stability (.84) indicated good reliability. Correlations between LymS and SF-36 physical (r=.62) and mental (r=.48) summary scores reflect concurrent validity. Responsiveness to ECOG performance status and treatment status exceeded established FACT subscale scores. The FACT-LymS differentiated patients’ retrospective ratings of change in each of the three groups (better; unchanged; worse), P<0.001. Conclusions. These results support the validity of the FACT-Lym and suggest it will be a useful targeted endpoint in NHL clinical research.

Clinical Features and Prognosis of CD20 Negative Aggressive B-Cell Non-Hodgkins Lymphoma

Cluster designation (CD) 20 antigen is expressed on most B-cell lymphomas and serves as a therapeutic target for rituximab. A small minority of aggressive B-cell lymphomas, predominantly plasmablastic variants, do not express CD 20. We systematically reviewed all cases of aggressive B-cell lymphomas diagnosed at our institution over a period of 13 years. Of the 232 cases, 7 did not express CD 20. Five of these were plasmablastic lymphomas while two were unclassifiable B-cell lymphomas. While most of the plasmablastic lymphomas responded to chemotherapy, patients with unclassifiable lymphomas were primarily refractory or relapsed soon after chemotherapy.