Burkitt Lymphoma In Children Research Articles

Burkitt lymphoma in children and adolescents: a single-center analysis over a 30-year period

Burkitt lymphoma in children and adolescents: a single-center analysis over a 30-year period

A multicenter study on effect of delayed chemotherapy on prognosis of Burkitt lymphoma in children

Objective: To analyze the factors affecting delayed chemotherapy in children with Burkitt lymphoma (BL) and their influence on prognosis. Methods: Retrospective cohort study. Clinical data of 591 children aged ≤18 years with BL from May 2017 to December 2022 in China Net Childhood Lymphoma (CNCL) was collected. The patients were treated according to the protocol CNCL-BL-2017. According to the clinical characteristics, therapeutic regimen was divided into group A, group B and group C .Based on whether the total chemotherapy time was delayed, patients were divided into two groups: the delayed chemotherapy group and the non-delayed chemotherapy group. Based on the total delayed time of chemotherapy, patients in group C were divided into non-delayed chemotherapy group, 1-7 days delayed group and more than 7 days delayed group. Relationships between delayed chemotherapy and gender, age, tumor lysis syndrome before chemotherapy, bone marrow involvement, disease group (B/C group), serum lactate dehydrogenase (LDH) > 4 times than normal, grade Ⅲ-Ⅳ myelosuppression after chemotherapy, minimal residual disease in the interim assessment, and severe infection (including severe pneumonia, sepsis, meningitis, chickenpox, etc.) were analyzed. Logistic analysis was used to identify the relevant factors. Kaplan-Meier method was used to analyze the patients' survival information. Log-Rank was used for comparison between groups. Results: Among 591 patients, 504 were males and 87 were females, the follow-up time was 34.8 (18.6,50.1) months. The 3-year overall survival (OS) rate was (92.5±1.1)%,and the 3-year event-free survival (EFS) rate was (90.5±1.2)%. Seventy-three (12.4%) patients were in delayed chemotherapy group and 518 (87.6%) patients were in non-delayed chemotherapy group. The reasons for chemotherapy delay included 72 cases (98.6%) of severe infection, 65 cases (89.0%) of bone marrow suppression, 35 cases (47.9%) of organ dysfunction, 22 cases (30.1%) of tumor lysis syndrome,etc. There were 7 cases of chemotherapy delay in group B, which were seen in COPADM (vincristine+cyclophosphamide+prednisone+daunorubicin+methotrexate+intrathecal injection,4 cases) and CYM (methotrexate+cytarabine+intrathecal injection,3 cases) stages. There were 66 cases of chemotherapy delay in group C, which were common in COPADM (28 cases) and CYVE 1 (low dose cytarabine+high dose cytarabine+etoposide+methotrexate, 12 cases) stages. Multinomial Logistic regression analysis showed that the age over 10 years old (OR=0.54,95%CI 0.30-0.93), tumor lysis syndrome before chemotherapy (OR=0.48,95%CI 0.27-0.84) and grade Ⅲ-Ⅳ myelosuppression after chemotherapy (OR=0.55,95%CI 0.33-0.91)were independent risk factors for chemotherapy delay.The 3-year OS rate and the 3-year EFS rate of children with Burkitt lymphoma in the delayed chemotherapy group were lower than those in the non-delayed chemotherapy group ((79.4±4.9)% vs. (94.2±1.1)%, (80.2±4.8)% vs. (92.0±1.2)%,both P<0.05). The 3-year OS rate of the group C with chemotherapy delay >7 days (42 cases) was lower than that of the group with chemotherapy delay of 1-7 days (22 cases) and the non-delay group (399 cases) ((76.7±6.9)% vs. (81.8±8.2)% vs. (92.7±1.3)%, P=0.002).The 3-year OS rate of the chemotherapy delay group (9 cases) in the COP (vincristine+cyclophosphamide+prednisone) phase was lower than that of the non-chemotherapy delay group (454 cases) ((66.7±15.7)% vs. (91.3±1.4)%, P=0.005). Similarly, the 3-year OS rate of the chemotherapy delay group (11 cases) in the COPADM1 phase was lower than that of the non-chemotherapy delay group (452 cases) ((63.6±14.5)% vs. (91.5±1.3)%, P=0.001). Conclusions: The delayed chemotherapy was related to the age over 10 years old, tumor lysis syndrome before chemotherapy and grade Ⅲ-Ⅳ myelosuppression after chemotherapy in pediatric BL. There is a significant relationship between delayed chemotherapy and prognosis of BL in children.

Plasma metabolites in childhood Burkitt lymphoma cases and cancer-free controls in Uganda

IntroductionBurkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma associated with Plasmodium falciparum and Epstein-Barr virus, both of which affect metabolic pathways. The metabolomic patterns of BL is unknown.Materials and methodsWe measured 627 metabolites in pre-chemotherapy treatment plasma samples from 25 male children (6–11 years) with BL and 25 cancer-free area- and age-frequency-matched male controls from the Epidemiology of Burkitt Lymphoma in East African Children and Minors study in Uganda using liquid chromatography-tandem mass spectrometry. Unconditional, age-adjusted logistic regression analysis was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) for the BL association with 1-standard deviation increase in the log-metabolite concentration, adjusting for multiple comparisons using false discovery rate (FDR) thresholds and Bonferroni correction.ResultsCompared to controls, levels for 42 metabolite concentrations differed in BL cases (FDR < 0.001), including triacylglyceride (18:0_38:6), alpha-aminobutyric acid (AABA), ceramide (d18:1/20:0), phosphatidylcholine ae C40:6 and phosphatidylcholine C38:6 as the top signals associated with BL (ORs = 6.9 to 14.7, P < 2.4✕10− 4). Two metabolites (triacylglyceride (18:0_38:6) and AABA) selected using stepwise logistic regression discriminated BL cases from controls with an area under the curve of 0.97 (95% CI: 0.94, 1.00).ConclusionOur findings warrant further examination of plasma metabolites as potential biomarkers for BL risk/diagnosis.

Therapeutic Effects of Rituximab on Burkitt Lymphoma in Children and Adolescents

Therapeutic Effects of Rituximab on Burkitt Lymphoma in Children and Adolescents

Human leukocyte antigen-DQA1*04:01 and rs2040406 variants are associated with elevated risk of childhood Burkitt lymphoma

Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10−6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10−8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10−6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.

Sickle cell allele HBB-rs334(T) is associated with decreased risk of childhood Burkitt lymphoma in East Africa.

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma that significantly contributes to childhood cancer burden in sub-Saharan Africa. Plasmodium falciparum, which causes malaria, is geographically associated with BL, but the evidence remains insufficient for causal inference. Inference could be strengthened by demonstrating that mendelian genes known to protect against malaria-such as the sickle cell trait variant, HBB-rs334(T)-also protect against BL. We investigated this hypothesis among 800 BL cases and 3845 controls in four East African countries using genome-scan data to detect polymorphisms in 22 genes known to affect malaria risk. We fit generalized linear mixed models to estimate odds ratios (OR) and 95% confidence intervals (95% CI), controlling for age, sex, country, and ancestry. The ORs of the loci with BL and P. falciparum infection among controls were correlated (Spearman's ρ = 0.37, p = .039). HBB-rs334(T) was associated with lower P. falciparum infection risk among controls (OR = 0.752, 95% CI 0.628-0.9; p = .00189) and BL risk (OR = 0.687, 95% CI 0.533-0.885; p = .0037). ABO-rs8176703(T) was associated with decreased risk of BL (OR = 0.591, 95% CI 0.379-0.992; p = .00271), but not of P. falciparum infection. Our results increase support for the etiological correlation between P. falciparum and BL risk.

Primary hepatic Burkitt lymphoma in a child and review of literature

BackgroundPrimary hepatic Burkitt lymphoma (PHBL) in children is an extremely rare hepatic malignancy with a dismal prognosis, unless it is detected and treated promptly.Case summaryAn 11-year-old child with abdominal pain was admitted to our hospital. No notable abnormalities were found during his physical examination or laboratory workup, but the abdominal computed tomography and magnetic resonance imaging both indicated a malignant hepatic mass measuring 9.2 × 7.1 × 7.5 cm in size. His postoperative pathology revealed an unexpected primary hepatic Burkitt lymphoma following a laparoscopic liver lobectomy. He then received rituximab and intense multi-agent chemotherapy as treatment. Despite post-chemotherapy bone marrow suppression, the patient eventually made a full recovery and had a good overall state.ConclusionIn this study, we describe a rare case of pediatric primary hepatic Burkitt lymphoma and review the literature on clinical features, diagnosis, and treatment for primary hepatic Burkitt lymphoma in children. We stress that this diagnosis should be taken into account in the absence of other single hepatic lesions or primary tumors of hematological disorders, particularly when there is a normal AFP level.

IFNL4 Genotypes and Risk of Childhood Burkitt Lymphoma in East Africa.

Interferon lambda 4 (IFN-λ4) is a novel type-III interferon that can be expressed only by carriers of the genetic variant rs368234815-dG within the first exon of the IFNL4 gene. Genetic inability to produce IFN-λ4 (in carriers of the rs368234815-TT/TT genotype) has been associated with improved clearance of hepatitis C virus (HCV) infection. The IFN-λ4-expressing rs368234815-dG allele (IFNL4-dG) is most common (up to 78%) in West sub-Saharan Africa (SSA), compared to 35% of Europeans and 5% of individuals from East Asia. The negative selection of IFNL4-dG outside Africa suggests that its retention in African populations could provide survival benefits, most likely in children. To explore this hypothesis, we conducted a comprehensive association analysis between IFNL4 genotypes and the risk of childhood Burkitt lymphoma (BL), a lethal infection-associated cancer most common in SSA. We used genetic, epidemiologic, and clinical data for 4,038 children from the Epidemiology of Burkitt Lymphoma in East African Children and Minors (EMBLEM) and the Malawi Infections and Childhood Cancer case-control studies. Generalized linear mixed models fit with the logit link controlling for age, sex, country, P. falciparum infection status, population stratification, and relatedness found no significant association between BL risk and 3 coding genetic variants within IFNL4 (rs368234815, rs117648444, and rs142981501) and their combinations. Because BL occurs in children 6-9 years of age who survived early childhood infections, our results suggest that additional studies should explore the associations of IFNL4-dG allele in younger children. This comprehensive study represents an important baseline in defining the health effects of IFN-λ4 in African populations.

Clinical Research in Western Africa: Efficacy and Safety of a Phase II Study of R-CHOP in First-Line DLBCL in Senegal

Background: Diffuse large B cell lymphoma (DLBCL) is the most frequent adult Non Hodgkin Lymphoma (NHL) subtype. DLBCL gold standard treatment associates CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) and Rituximab for a total of 6 to 8 cycles leading to an ORR of 83% (including 75% of CR and uCR, (Coiffier B, et al). Little is known about NHL in Africa, except for the high incidence of Burkitt lymphoma in children. DLBCL in adults have also been related to a close association with various infectious agents (Naresh K, et al). Yet, difficulties including low access to health care, use of cytopuncture instead of nodal biopsy, non-respect of dose intensity, cost of drugs including CD20 monoclonal antibodies and absence of supportive care (including G-CSF) lead to poor prognosis for patients with DLBCL (overall response rate (ORR) <30%) (S Diop et al). The Senegal Government has built a national anti-cancer program, focusing on prevention and improvement of diagnosis and treatment. Our hypothesis was that the insurance of prompt and accurate diagnosis, as well as the availability of standard treatment, would improve ORR in Senegalese patients diagnosed with DLBC. Recently, a phase1/2 in Malawi showed that R-CHOP could be feasible and safe in HIV+ DLBCL patients (Kimani S, et al). Methods: This prospective single arm non-randomized phase 2 clinical trial was performed at Dakar University Hospital. Eligible patients were adults (18-70 years old) with newly DLBCL, an ECOG-PS of 0-2, absence of HIV, HCV or HBV active infection and absence of CNS involvement. Our hypothesis was to obtain an ORR of 70% including 60% of CR or Cru (Cheson criteria 1999). Eligible patients received IV Rituximab 375 mg/m², cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1.4 mg/m² at Day 1 and oral prednisone 60 mg/m² (Day 1 to Day 5) every 21 days for 6 cycles. G-CSF was given at 5 µg/kg for 4 days (D8 to D11). The primary study endpoint was ORR at the end of treatment; secondary study endpoints were CR and CRu after 6 cycles of R CHOP, treatment toxicity, PFS, respect of treatment intensity. Whole CT scan as well as surgical nodal biopsy were mandatory. DLBCL diagnosis was confirmed by retrospective central pathology review as well as review of biopsies via an international telepathology platform using the software i-Path. Findings: Between July 2018 and May 2022, 69 patients admitted with a clinical presentation suggestive of lymphoma were investigated with at least one biopsy, DLBCL diagnosis was confirmed for 30 of them, thus enrolled in the study. Their median age was 43 years old (range 18-64), 14 (46.6%) were women, 17 (56.6%) had stage III-IV DLBCL. The International prognostic index was 2 or higher in 23 (77%). Patients completed a median of 6 therapeutic cycles. Grade 3 or 4 hematological toxic effects were rare (one anemia, one neutropenia) but blood counts were not performed between treatment courses. One patient was hospitalized for gastroenteritis. The ORR at the end of treatment was 69 % for the whole population including 57% of CR or uCR. Of 7 (23%) deaths, 6 were due to lymphoma progression and one to unknown cause. With a median follow-up of 19.9 months, OS and PFS at 24 months were 79.9% and 73.8%, respectively (Image 1). Interpretation: Clinical Research is feasible in Western Africa. R CHOP therapy is safe and efficacious in HIV negative patients in Senegal, leading to similar responses as observed in high-income countries. These results should encourage health authorities to increase access to health care in order to improve the treatment of cancer. This clinical trial was supported by the French National Institute (INCA). Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Research in Africa: Collaborative Project between Senegal and France to Improve the Diagnosis and Therapeutic Management of Adult Lymphoma Patients

Background: Little is known about Non-Hodgkin Lymphoma (NHL) in Africa except for the high incidence of Burkitt lymphoma in children and the high association with HIV in Eastern Africa but not Western Africa. Difficulties including low access to health care, use of cytopuncture instead of nodal biopsy, cost of drugs and absence of supportive care lead to poor prognosis for NHL patients (pts) (overall response rate (ORR) <30%) (Diop et al., Bull Soc Patho Exo 2004). Meaningful lymphoma research cannot be conducted without accurate diagnosis (Naresh et al., Br J Hematol 2011). The Senegal Government has built a national anti-cancer program, focusing on prevention and improvement of diagnosis and treatment. A prospective single arm non-randomized phase 2 clinical trial was thus designed for adult pts with newly diagnosed diffuse large B-cell lymphoma (DLBCL) at Dakar (Senegal) University Hospital (DUH), in collaboration with Nancy (France) University Hospital (NUH). Methods: Histological results of suspected lymphoma in pts likely to be included in this trial are reported here. Only non-HIV adult patients were enrolled. A first histological study was performed in the pathology department of DUH. This included biopsies that were submitted to apposition before embedding. Hematoxylin and eosin staining was performed as well as immunohistochemistry (IHC). The panel used allowed to examine the expression of the following antigens: CD20, CD79a, CD3, CD5, CD23, cyclin D1, CD30, Bcl2, CD10 and Ki67. Biopsies were reviewed via an international telepathology platform using the i-Path software and retrospectively, in NUH Pathology department, by sending paraffin-embedded blocks on site. Findings: Between July 2018 and May 2022, 70 pts admitted with a clinical presentation suggestive of NHL were evaluated with a surgical biopsy, 31 of whom being confirmed with a diagnosis of DLBCL or equivalent as T-cell/histiocyte-rich large B cell LBCL, and thus eligible for the therapeutic trial. Median age of the 70 pts was 42 years old (18-70) and 32% were female. Other hematological diagnoses were Hodgkin lymphoma, small B-cell lymphoma, T-cell lymphoma, unclassed lymphoma and histiocytosis. There was no Burkitt lymphoma. Non-hematological diagnoses were achieved for 14 pts: lipoma, tuberculosis, reactive adenitis or metastasis of solid neoplasia. In nearly half of all cases, diagnosis was obtained without IHC, notably due to non-hematological diagnoses. In nearly half of all cases, the diagnosis was obtained without IHC. When IHC was used, CD20 and CD3 were mainly used to establish the diagnosis. The median time to obtain pathology results was 31 days. Thirty-one cases were diagnosed with the help of I-Path. Currently, 17 biopsies have been reviewed at NUH with diagnosis concordance in 71% of cases. The 5 inconsistent diagnoses were 2 NHL ultimately classified as adenocarcinoma, 1 reactive adenitis being in fact DLBCL and 2 T-cell/histiocyte-rich LBCL diagnosed as respectively DLBCL and small B-cell lymphoma. Interpretation: This is a large cohort of consecutive surgical biopsies performed in Senegal for lymphoma suspicion, showing the distribution of lymphoma in Western Africa and more interestingly, demonstrating that an accurate diagnosis is possible locally. The current hindrances in lymphoma diagnosis include basing treatment decisions on fine needle aspiration cytology in a large proportion of cases, poor quality histology or complete lack of IHC in cases where biopsies are performed, limited number of hematopathologists and lack of discussion between hematopathologists. In this study, systematic surgical biopsy, homogenous IHC staining procedures, electronic interaction between hematopathologists and retrospective review of biopsies have contributed to a huge improvement of the quality of diagnosis.

ABCL-203 Outcome Predictors of Childhood Burkitt's Lymphoma: A Developing Country Experience

The outcome of childhood Burkitt's lymphoma (BL) has improved remarkably over the past decade because of the development of risk-adapted multi-agent chemotherapeutic regimens. This study aimed to assess the outcome predictors of BL in children and adolescents. A retrospective study included all patients ≤18 years old diagnosed with BL and treated according to the modified LMB 96 protocol at National Cancer Institute, Cairo University from January 2012 to December 2016. A total of 170 patients were diagnosed with BL, with a median age of 5 years old. The abdomen was the most common primary site (90.0%). Bone marrow involvement was encountered in 12 patients (7%) and 10 (6%) had central nervous system (CNS) disease at presentation. From the whole study cohort, 7 patients (4.1%) were treated in group A, 130 (76.5%) in group B, and 27 (15.9%) patients in group C. The 5-year overall survival (OS) and event-free survival (EFS) were 82.9% and 82.8% respectively for the whole group. OS and EFS were 100%, 87.2%, and 57.7% for groups A, B, and C respectively (P<0.001). BM and/or CNS involvement were associated with significantly worse outcomes (50% for BM+ve vs 84.2% for BM-ve, P= 0.026) and (40% for CNS+ve vs 85.8% for CNS-ve, P<0.001). Early initiation of the induction cycle in a period ≤10 days of CVP start was associated with better outcomes 87.3% vs 68.6% for delayed group >10 days (P=0.020). The outcome of BL was significantly affected by disease group, BM and/or CNS involvement, and early initiation of induction therapy.

Management of Hepatic Burkitt Lymphoma in Children

Hepatic Burkitt lymphoma is extremely rare in childhood and can be overlooked in differential diagnosis of liver masses. Patient: A8-year-old girl presented with a 1 month history of abdominal pain and weight loss and jaundice. Results: Physical examination revealed hepatomegaly and no palpable lymph node. Laboratory finding showed mild anemia (hemoglobin, 10,8 g/dL), elevated transaminase (ALT, 305 IU/L; ASAT,755 IU/L), elevated bilitubin (Bilirubin total, 179mg/L, Bilirubin direct, 143mg/l). Abdominal ultrasound shouwed a multiple hepatic lesions. Liver biopsy examination confirmed Burkitt's lymphoma. No metastasis was detected in the thoracic cavity, bone marrow, and spinal fluid. The patient was treated with the combination regimen of cyclophosphamide, doxorubicin, vincristine, prednisone and high dose methotrexate. Cytosine arabinoside and methotrexate were added for CNS prophylaxis by intrathecal installation. Serial follow-up ultrasound showed a marked decrease in the size of hepatic lesions but residual hilar lymph nodes at 2cm and the control showed stable size of lymph node after 28 months of chemotherapy. Conclusion: The clinical feature of primary hepaticlymphoma varies from no symptom to fulminant hepatic failure. There are no specific imaging criteria for diagnosing primary hepatic Burkitt’s lymphoma. Thus, histology by biopsy is necessary for diagnosis.

FISH-Guided Evaluation of Hyperdiploidy and Other Cytogenetic Abnormalities in Childhood Burkitt Lymphoma

Background: Burkitt lymphoma (BL) is the most common lymphoma in childhood. Apart from MYC rearrangement, considered the hallmark of the disease, BL often presents with additional chromosome aberrations, the biological and clinical significance of which is not fully understood. Materials and methods: The study included 72 children (55 boys, 17 girls), aged 2-16 years (median 9), with BL diagnosed on the basis of histopathology and a demonstrable MYC rearrangement. Touch imprints from the diagnostic biopsy samples were investigated with i-FISH for MYC, BCL2, BCL6, IGH, IGK and IGL rearrangements genes and copy number aberrations involving 1q21/1p32, 7cen/7q31, 9cen/9p21, 13q14/13q34 and 17cen/17p13. Deviations from the diploid status were further investigated for aneusomies of the carrier chromosome with the use of appropriate chromosome enumeration probes. Results: MYC gene was demonstrated in all cases with MYC/IGH fusion in 83.3% (60/72). 47 cases (65.3%) were found with least one additional aberration, most commonly with 1q gain (29.2%), 7q gain (19.4%), 13q deletion (19.4%), hemizygous 9p loss (8.3%) and hyperdiploidy (8.3%). Advanced clinical stage (IV), 7q gain (but not trisomy 7) and -9/9p- were significantly associated with shorter overall survival. There was no instance of relapse or death among the hyperdiploid cases. Conclusions: This extensive FISH investigation on imprints of affected tissue provides clinically meaningful information on the genetic profile of BL and may prove valuable in the management of patients with no karyotype available. In particular, the demonstration of hyperdiploidy through the use of chromosome enumeration probes could offer the means for the delineation of clonal evolution pathways and the recognition of a subgroup of children with excellent prognosis who could be cured with low-intensity chemotherapy regimens. DisclosuresKattamis: VIFOR: Consultancy; CRISPR/Vertex: Consultancy, Honoraria; Agios Pharmaceuticals: Consultancy; IONIS: Consultancy; BMS/Celgene: Consultancy, Honoraria, Research Funding; Chiesi: Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy.

Fish evaluation of additional cytogenetic aberrations and hyperdiploidy in childhood Burkitt lymphoma

Beyond MYC rearrangement, Burkitt lymphoma (BL) often presents with additional aberrations. Biopsy touch imprints from 72 children with BL were tested with interphase fluorescence in-situ hybridization (i-FISH) for MYC, BCL2, BCL6, IGH, IGK and IGL rearrangements and copy-number aberrations involving 1q21/1p32, 7cen/7q31, 9cen/9p21, 13q14/13q34 and 17cen/17p13. Diploid status deviations were investigated with chromosome enumeration probes. MYC rearrangement was demonstrated in all cases. Additional aberrations included +1q (21/72:29.2%), +7q (14/72:19.4%), 13q- (14/72:19.4%), 9p-(6/72:8.3%) and hyperdiploidy (6/72:8.3%). Advanced clinical stage IV, +7q and 9p- were associated with shorter overall survival, with stage IV and +7q retaining prognostic significance on multivariate analysis. No relapse or death was reported among the hyperdiploid cases. This i-FISH investigation provides information on the genetic profile of BL and may prove valuable for patients with no karyotype analysis. Demonstration of hyperdiploidy could evolve research on clonal evolution pathways and probably identify a subgroup of children with favorable prognosis.

48-Year-Old Woman With Dyspnea and Chest Pain

48-Year-Old Woman With Dyspnea and Chest Pain

Identification of clinical molecular targets for childhood Burkitt lymphoma.

Burkitt lymphoma (BL) is a malignant tumor in children. Although BL is generally curable, early relapse and refractoriness may occur. Some molecular indicators have been recently suggested for BL diagnosis, but large heterogeneity still exists. This study aimed at providing clinical molecular targets and methods that may help improve diagnosis and treatment of childhood BL. Only children patients were included in the study, and targeted gene sequencing was conducted to identify tumor specific mutations. The mRNA and protein level expression of potential target genes were measured by real-time PCR and immunohistochemistry. The relationship between BL specific gene mutation and differential expression with clinical features was analyzed. The results showed that i) detailed analysis of c-MYC/BCL2/BCL6 gene loci alteration and gene expression would help in accurate diagnosis and treatment determination of childhood BL; ii) loss-of-function mutations in SOCS1 or CIITA gene might be used as malignant markers for BL diagnosis and prognosis; iii) specific mutations of CD79A, MYD88, KLF2, DNMT3A and NFKBIE genes often concurrently existed in BL and showed association with benign clinical outcomes; iv) the high expression of MYC, TCF3 and loss-of-function ID3 genes in tumor may be potential therapeutic targets and could be used for treatment monitoring; and v) four MYC-translocation negative cases were re-defined as high-grade B-cell lymphoma-not otherwise specified (HGBL-NOS) but showed similar clinical outcomes and molecular features to other BL cases in the study, suggesting more studies needed to explore the molecular mechanisms and clinical significance of this provisional tumor entity.

ABCL-136: Early Deaths in Childhood Burkitt's Lymphoma: A Major Challenge in Developing Countries

Context: The outcome of childhood Burkitt's lymphoma (BL) has improved steadily over the past decades through the use of intensive sequential multi-agent chemotherapy regimens with increased concern about increasing toxicity-related mortality. Objective: This study objective was to assess incidence and risk factors of early mortality in BL. Design/Setting: A retrospective study included all patients 18 years old or younger diagnosed with BL and treated according to the modified LMB 96 protocol at National Cancer Institute, Cairo University from January 2012 to December 2016. Patients or other participants: A total of 170 patients were diagnosed with BL, with a median age of 5 years old. Abdominal presentation was the most common primary site (90.0%). Sixty-two (36.5%) patients were diagnosed as early as less than or equal to 2 weeks and 108 (63.5%) patients were diagnosed beyond 2 weeks from onset of symptoms. A total of 82 (48.2%) patients presented by disease-related emergencies, 49 patients (59.7%) of them with acute renal impairment due to TLS, and 33 (40.2%) had intestinal obstruction and/or complications. Main outcome measures: Total and early deaths (during reduction and 1st induction phase of therapy) were measured and the underlying causes of early mortalities were also reported. Results: Throughout the whole treatment duration, 39 (23%) total deaths were reported and 50% of them (n=19) died before 2nd induction (early mortality). Eleven patients (57.8%) of them died in the first week, 6/11 patients died before completing the 1st CVP. The main causes of early mortalities were sepsis in 58% and acute renal failure due to TLS in 42% of cases. The 5-year overall survival (OS) and event-free survival (EFS) were 82.9% and 82.8%, respectively for the whole group. Conclusions: Early deaths and treatment-related toxic mortalities remain the major challenge affecting outcome in our patients. Early diagnosis and enhanced supportive care measures are essential to improve the outcome for those group of patients.

ABCL-056: Outcome Predictors of Burkitt's Lymphoma in Children and Adolescents in Egypt: A Single-Center Study

Background: The outcome of childhood Burkitt's lymphoma (BL) has improved steadily over the past decades through the use of intensive sequential multi-agent chemotherapy regimens. Objective: This study's objective was to assess the outcome predictors of BL in children and adolescents. Methods: A retrospective study included all patients, 18 years old or younger, diagnosed with BL and treated according to the modified LMB 96 protocol at National Cancer Institute, Cairo University from January 2012 to December 2016 and their follow-up till December 2018. Results: A total of 170 patients were diagnosed with BL, with a median age of 5 years. Abdomen was the most common primary site (90.0%). Bone marrow involvement was encountered in 7 patients (4%), and 10 (6%) had central nervous system (CNS) disease at presentation. From the whole study cohort, 7 patients (4.1%) were treated as group A, 130 (76.5%) as group B, and 27 (15.9%) patients as group C. The 5-year overall survival (OS) and event-free survival (EFS) were 82.9% and 82.8%, respectively, for the whole group. OS and EFS were 100%, 87.2%, and 57.7% for group A, B and C, respectively (P 10 days (P=0.020). A total of 39 deaths were reported, about 50% of them were defined as early deaths before 2nd induction, and 11 patients died due to disease progression. Conclusions: Outcome of BL was significantly affected by disease group, BM and/or CNS involvement, and early initiation of induction therapy. Early deaths and treatment-related toxic mortalities remain the major challenge affecting outcome in our patients.

Five decades of low intensity and low survival: adapting intensified regimens to cure pediatric Burkitt lymphoma in Africa

AbstractLong-term cure of childhood Burkitt lymphoma (BL) in sub-Saharan Africa after treatment with single-agent cyclophosphamide has been documented for more than half of a century. Contemporary cure rates for the highest-risk patients with BL in high-income countries exceed 90% using intensive multiagent chemotherapy. By contrast, the majority of African children with BL still die. Data spanning 5 decades in Africa have repeatedly shown that the children most likely to achieve cure with limited cyclophosphamide regimens are those with lower-stage disease isolated to the jaw. Attempts to intensify the cyclophosphamide monotherapy backbone with the addition of vincristine, low-dose methotrexate, prednisone, doxorubicin, and/or low-dose cytarabine have not yielded significant improvement. High-dose methotrexate is a critical component in the treatment of childhood BL worldwide. Although initial efforts in Africa to incorporate high-dose methotrexate resulted in high treatment-related mortality, more recent collaborative experiences from North and West Africa, as well as Central America, demonstrate that it can be administered safely and effectively, despite limitations in supportive care resources. Recognizing the unacceptable disparity in curative outcomes for BL between the United States/Europe and equatorial Africa, there is a critical need to safely adapt contemporary treatment regimens to optimize curative outcomes amid the resource limitations in regions where BL is endemic. Here, we critically review reports of BL treatment outcomes from low- and middle-income countries, in addition to data from high-income countries that predated modern intensified regimens, to identify potential strategies to improve the therapeutic approach for children suffering from BL in sub-Saharan Africa.

Novel replisome-associated proteins at cellular replication forks in EBV-transformed B lymphocytes

Epstein-Barr virus (EBV) is an oncogenic herpesvirus and WHO class 1 carcinogen that resides in B lymphocytes of nearly all humans. While silent in most, EBV can cause endemic Burkitt lymphoma in children and post-transplant lymphoproliferative disorders/lymphomas in immunocompromised hosts. The pathogenesis of such lymphomas is multifactorial but to a large extent depends on EBV’s ability to aggressively drive cellular DNA replication and B cell proliferation despite cell-intrinsic barriers to replication. One such barrier is oncogenic replication stress which hinders the progression of DNA replication forks. To understand how EBV successfully overcomes replication stress, we examined cellular replication forks in EBV-transformed B cells using iPOND (isolation of Proteins on Nascent DNA)-mass spectrometry and identified several cellular proteins that had not previously been linked to DNA replication. Of eight candidate replisome-associated proteins that we validated at forks in EBV-transformed cells and Burkitt lymphoma-derived cells, three zinc finger proteins (ZFPs) were upregulated early in B cells newly-infected with EBV in culture as well as expressed at high levels in EBV-infected B blasts in the blood of immunocompromised transplant recipients. Expressed highly in S- and G2-phase cells, knockdown of each ZFP resulted in stalling of proliferating cells in the S-phase, cleavage of caspase 3, and cell death. These proteins, newly-identified at replication forks of EBV-transformed and Burkitt lymphoma cells therefore contribute to cell survival and cell cycle progression, and represent novel targets for intervention of EBV-lymphomas while simultaneously offering a window into how the replication machinery may be similarly modified in other cancers.