Nader Kim El-Mallawany

Characterization and treatment of chronic active Epstein-Barr virus disease: a 28-year experience in the United States

Chronic active EBV disease (CAEBV) is a lymphoproliferative disorder characterized by markedly elevated levels of antibody to EBV or EBV DNA in the blood and EBV RNA or protein in lymphocytes in tissues. We present our experience with CAEBV during the last 28 years, including the first 8 cases treated with hematopoietic stem cell transplantation in the United States. Most cases of CAEBV have been reported from Japan. Unlike CAEBV in Japan, where EBV is nearly always found in T or natural killer (NK) cells in tissues, EBV was usually detected in B cells in tissues from our patients. Most patients presented with lymphadenopathy and splenomegaly; fever, hepatitis, and pancytopenia were common. Most patients died of infection or progressive lymphoproliferation. Unlike cases reported from Japan, our patients often showed a progressive loss of B cells and hypogammaglobulinemia. Although patients with CAEBV from Japan have normal or increased numbers of NK cells, many of our patients had reduced NK-cell numbers. Although immunosuppressive agents, rituximab, autologous cytotoxic T cells, or cytotoxic chemotherapy often resulted in short-term remissions, they were not curative. Hematopoietic stem cell transplantation was often curative for CAEBV, even in patients with active lymphoproliferative disease that was unresponsive to chemotherapy. These studies are registered at http://www.clinicaltrials.gov as NCT00032513 for CAEBV, NCT00062868 and NCT00058812 for EBV-specific T-cell studies, and NCT00578539 for the hematopoietic stem cell transplantation protocol.

Clinical characteristics and outcomes of HIV-infected children diagnosed with Kaposi sarcoma in Malawi and Botswana.

Kaposi sarcoma (KS) is the most common HIV‐associated malignancy in sub‐Saharan Africa. The presentation and outcomes of pediatric KS are not well understood.

Clinical trials to improve childhood cancer care and survival in sub-Saharan Africa

Over 80% of children with cancer live in low and middle-income countries where survival rates are much lower than high-income countries. Challenges to successful treatment of paediatric cancers in these countries include late presentation, malnutrition, failure to complete treatment and less-intense supportive care leading to increased treatment-related mortality and the need to reduce the intensity of treatment. Clinical trials can contribute to improved care and survival by providing objective information on the number of patients treated, accuracy of diagnosis, causes of treatment failure and the efficacy of specific interventions. Clinical trials can also help to build capacity (salary support and training), improve facilities (equipment) and fund treatment or essential associated costs (social support, nutritional support and follow-up care). In this article, we discuss our experience with clinical trials in Malawi and sub-Saharan Africa with emphasis on the treatment of children with Wilms tumour.

Adenovirus infection in paediatric allogeneic stem cell transplantation recipients is a major independent factor for significantly increasing the risk of treatment related mortality

Adenovirus infection is a significant complication in paediatric AlloSCT recipients with a mortality rate for disseminated adenovirus that may exceed 80%. We sought to determine the incidence, risk factors, and associated outcomes of adenovirus infection in 123 consecutive paediatric AlloSCT recipients. Adenovirus was diagnosed by antigen detection or viral culture, and was defined by isolation of virus with presence of correlating clinical symptoms. The probability of developing adenovirus infection was 12·3% (CI95 6·0–18·6). There were no statistically significant differences in probability of adenovirus infection in univariate analysis of risk factors including donor source, use of ATG/Alemtuzumab, ≥Grade II GVHD, among others (age, diagnosis, conditioning regimen). Probability of overall survival for patients that experienced adenovirus infection was 15·4% vs. 50% for those without adenovirus (P = 0·0286). In multivariate analysis, the most important risk factor for an increased risk of death was adenovirus infection [HR 3·15 (CI95 1·6–6·18) P = 0·0009]. In this series of paediatric AlloSCT recipients, the development of adenovirus infection was the leading multivariate predictor of treatment‐related mortality. Enhanced surveillance with adenovirus PCR and identification of the risk factors associated with poor outcomes from adenovirus infection may identify patients that may benefit from pre‐emptive therapeutic interventions including adenovirus‐specific cellular immunotherapies.

Outcomes for paediatric Burkitt lymphoma treated with anthracycline-based therapy in Malawi

Burkitt lymphoma (BL) is the most common paediatric cancer in sub‐Saharan Africa (SSA). Anthracyline‐based treatment is standard in resource‐rich settings, but has not been described in SSA. Children ≤18 years of age with newly diagnosed BL were prospectively enrolled from June 2013 to May 2015 in Malawi. Staging and supportive care were standardized, as was treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for six cycles. Among 73 children with BL, median age was 9·2 years (interquartile range 7·7–11·8), 48 (66%) were male and two were positive for human immunodeficiency virus. Twelve (16%) had stage I/II disease, 36 (49%) stage III and 25 (34%) stage IV. Grade 3/4 neutropenia occurred in 17 (25%), and grade 3/4 anaemia in 29 (42%) of 69 evaluable children. Eighteen‐month overall survival was 29% (95% confidence interval [CI] 18–41%) overall. Mortality was associated with age >9 years [hazard ratio [HR] 2·13, 95% CI 1·15–3·94], female gender (HR 2·12, 95% CI 1·12–4·03), stage (HR 1·52 per unit, 95% CI 1·07–2·17), lactate dehydrogenase (HR 1·03 per 100 iu/l, 95% CI 1·01–1·05), albumin (HR 0·96 per g/l, 95% CI 0·93–0·99) and performance status (HR 0·78 per 10‐point increase, 95% CI 0·69–0·89). CHOP did not improve outcomes in paediatric BL compared to less intensive regimens in Malawi.

Pediatric T-and NK-cell lymphomas: New biologic insights and treatment strategies

T- and natural killer (NK)-cell lymphomas are challenging childhood neoplasms. These cancers have varying presentations, vast molecular heterogeneity, and several are quite unusual in the West, creating diagnostic challenges. Over 20 distinct T- and NK-cell neoplasms are recognized by the 2008 World Health Organization classification, demonstrating the diversity and potential complexity of these cases. In pediatric populations, selection of optimal therapy poses an additional quandary, as most of these malignancies have not been studied in large randomized clinical trials. Despite their rarity, exciting molecular discoveries are yielding insights into these clinicopathologic entities, improving the accuracy of our diagnoses of these cancers, and expanding our ability to effectively treat them, including the use of new targeted therapies. Here, we summarize this fascinating group of lymphomas, with particular attention to the three most common subtypes: T-lymphoblastic lymphoma, anaplastic large cell lymphoma, and peripheral T-cell lymphoma-not otherwise specified. We highlight recent findings regarding their molecular etiologies, new biologic markers, and cutting-edge therapeutic strategies applied to this intriguing class of neoplasms.

Hodgkin lymphoma, HIV, and Epstein–Barr virus in Malawi: Longitudinal results from the Kamuzu Central Hospital Lymphoma study

Contemporary descriptions of classical Hodgkin lymphoma (cHL) are lacking from sub‐Saharan Africa where human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV) are prevalent.

Adolescent and young adult non-Hodgkin lymphoma

Non‐Hodgkin lymphoma (NHL) is a heterogeneous group of lymphoid malignancies accounting for a significant portion of cancers occurring in children, adolescents and young adults with an increasing incidence with age. The adolescent and young adult (AYA) population presents a specific set of characteristics and challenges. The most common diseases occurring in adolescents and young adults include Burkitt lymphoma, lymphoblastic lymphoma, diffuse large B‐cell lymphoma, anaplastic large cell lymphoma and primary mediastinal B‐cell lymphoma. There is also a higher incidence of primary central nervous system lymphoma in AYA patients. Cure rates largely depend on risk‐stratification, and are generally superior to outcomes in comparison to older adult data but less than in younger children. Here, we review the unique clinical and biological characteristics of NHL occurring in the AYA population with a focus on how to achieve similar curative outcomes in AYA that have been established in younger cohorts.

Plasma Epstein-Barr virus DNA for pediatric Burkitt lymphoma diagnosis, prognosis, and response assessment in Malawi.

Point‐of‐care tools are needed in sub‐Saharan Africa (SSA) to improve pediatric Burkitt lymphoma (BL) diagnosis and treatment. We evaluated plasma Epstein–Barr virus (pEBV) DNA as a pediatric BL biomarker in Malawi. Prospectively enrolled children with BL were compared to classical Hodgkin lymphoma (cHL) and nonlymphoma diagnoses. Pediatric BL patients received standardized chemotherapy and supportive care. pEBV DNA was measured at baseline, mid‐treatment, and treatment completion. Of 121 assessed children, pEBV DNA was detected in 76/88 (86%) with BL, 16/17 (94%) with cHL, and 2/16 (12%) with nonlymphoma, with proportions higher in BL versus nonlymphoma (p < 0.001) and similar in BL versus cHL (p = 0.69). If detected, median pEBV DNA was 6.1 log10copies/mL for BL, 4.8 log10copies/mL for cHL, and 3.4 log10copies/mL for nonlymphoma, with higher levels in BL versus cHL (p = 0.029), and a trend toward higher levels in BL versus nonlymphoma (p = 0.062). pEBV DNA declined during treatment in the cohort overall and increased in several children before clinical relapse. Twelve‐month overall survival was 40% in the cohort overall, and for children with baseline pEBV detected, survival was worse if baseline pEBV DNA was ≥6 log10copies/mL versus <6 log10copies/mL (p = 0.0002), and also if pEBV DNA was persistently detectable at mid‐treatment versus undetectable (p = 0.041). Among children with baseline pEBV DNA detected, viremia was the only significant risk factor for death by 12 months in multivariate analyses (adjusted hazard ratio 1.35 per log10copies/mL, 95% CI 1.04–1.75, p = 0.023). Quantitative pEBV DNA has potential utility for diagnosis, prognosis, and response assessment for pediatric BL in SSA.

Clinical Factors Associated with Long-Term Complete Remission versus Poor Response to Chemotherapy in HIV-Infected Children and Adolescents with Kaposi Sarcoma Receiving Bleomycin and Vincristine: A Retrospective Observational Study.

Kaposi sarcoma (KS) is the most common HIV-associated malignancy in children and adolescents in Africa. Pediatric KS is distinct from adult disease. We evaluated the clinical characteristics associated with long-term outcomes. We performed a retrospective observational analysis of 70 HIV-infected children and adolescents with KS less than 18 years of age diagnosed between 8/2010 and 6/2013 in Lilongwe, Malawi. Local first-line treatment included bleomycin and vincristine plus nevirapine-based highly active anti-retroviral therapy (HAART). Median age was 8.6 years (range 1.7–17.9); there were 35 females (50%). Most common sites of presentation were: lymph node (74%), skin (59%), subcutaneous nodules (33%), oral (27%), woody edema (24%), and visceral (16%). Eighteen (26%) presented with lymphadenopathy only. Severe CD4 suppression occurred in 28%. At time of KS diagnosis, 49% were already on HAART. Overall, 28% presented with a platelet count < 100 x 109/L and 37% with hemoglobin < 8 g/dL. The 2-year event-free (EFS) and overall survival (OS) were 46% and 58% respectively (median follow-up 29 months, range 15–50). Multivariable analysis of risk of death and failure to achieve EFS demonstrated that visceral disease (odds ratios [OR] 19.08 and 11.61, 95% CI 2.22–163.90 and 1.60–83.95 respectively) and presenting with more than 20 skin/oral lesions (OR 9.57 and 22.90, 95% CI 1.01–90.99 and 1.00–524.13 respectively) were independent risk factors for both. Woody edema was associated with failure to achieve EFS (OR 7.80, 95% CI 1.84–33.08) but not death. Univariable analysis revealed that lymph node involvement was favorable for EFS (OR 0.28, 95% CI 0.08–0.99), while T1 TIS staging criteria, presence of cytopenias, and severe immune suppression were not associated with increased mortality. Long-term complete remission is achievable in pediatric KS, however outcomes vary according to clinical presentation. Based on clinical heterogeneity, treatment according to risk-stratification is necessary to improve overall outcomes.