The use of anthracyclines in the treatment of endemic Burkitt lymphoma

Molyneux, Elizabeth; Schwalbe, Ed C.; Chagaluka, George; Banda, Kondwani Joseph; Israëls, Trijn; Depani, Sarita; Mittermayer-Vassallo, Kirstin; Windebank, Kevin; Mvula, Jessie; Njirammadzi, Jenala; O’Brien, Stephen G.; Carey, Peter; Bailey, Simon

doi:10.1111/bjh.14440

Cited by 18 publications

(21 citation statements)

References 20 publications

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“…Despite the success of the BL Project in addressing treatment gaps, survival of children with BL remained far below that of children in more affluent countries. A recent report from Malawi showed promising 72% 12‐month OS results in 42 children with stage III/IV disease with the use of two doses of doxorubicin . Other analyses conducted within the Sub‐Saharan African (SSA) region reported OS as 45% in Kenya and 33% to 63% in Malawi depending on tumor site location .…”

Section: Discussionmentioning

confidence: 99%

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda

McGoldrick

Mutyaba

Adams

et al. 2019

Pediatric Blood & Cancer

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Purpose “Endemic” Burkitt lymphoma (BL) is a common childhood cancer in Africa. Social and treatment factors may contribute to poor survival. With the aim of improving BL outcomes in Uganda, we undertook a comprehensive project (BL Project) that provided diagnostic support, access to standard chemotherapy, nutritional evaluations, and case management. We evaluated survival of children with BL in the context of the project. Patients and methods Patients followed by the BL Project who consented to research were enrolled in this study. Children with a pathology diagnosis consistent with BL were eligible. Data were collected prospectively. First‐line chemotherapy generally consisted of six cycles of cyclophosphamide, vincristine, low‐dose methotrexate (COM). We used Kaplan–Meier and Cox regression analyses to evaluate factors associated with overall survival (OS). Results Between July 2012 and June 2017, 341 patients with suspected BL presented to the BL Project. One hundred eighty patients with a pathology‐based diagnosis were included in this study. The median age was seven years (interquartile range, 5–9), 74% lived ≥100 km from the Uganda Cancer Institute, 61% had late‐stage disease, 84% had ECOG performance status < 3, 63% reported B‐symptoms, and 22% showed neurologic symptoms. Fewer than 10% abandoned therapy. The four‐year OS rate was 44% (95% CI, 36%–53%). In a multivariate model, ECOG status was significantly associated with mortality. Conclusion The BL Project reduced effects of lacking supportive care and oncology resources, and allowed patients from Uganda to receive curative intent therapy with minimal loss to follow‐up. Nonetheless, OS remains unacceptably low. Improved therapeutic approaches to endemic BL are urgently needed in Africa.

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Section: Discussionmentioning

confidence: 99%

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda

McGoldrick

Mutyaba

Adams

et al. 2019

Pediatric Blood & Cancer

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“…In Malawi the one-year overall survival for the combined stages 3 and 4 was 66% compared to previous outcomes of 28-43% for this group of patients. (Molyneux et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Haematological cancers in African children: progress and challenges

et al. 2017

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SummaryCancer is increasingly important in low and middle-income settings where infectious diseases are declining. Childhood cancers treated in well-resourced centres have excellent outcomes with more than 80% survival. This success is not reflected in low-income settings where challenges involve every step on the care pathway. Access to diagnosis, delayed presentation, advanced disease, co-morbidities and underlying malnutrition make treatment difficult. Treatments are costly for impoverished families. Yet, the common haematological malignancies (Burkitt lymphoma, Hodgkin lymphoma, non Hodgkin lymphoma) are relatively easy to diagnose and, when managed with simple chemotherapy protocols, give limited but good results. As funding becomes available for cancer research we must ensure that the care and cure of these children is top of the agenda. There is already evidence of improved outcomes in middle-income countries. For others there is a long journey ahead.

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“…For both sporadic and endemic BL, diagnoses were confirmed by pathology review according to World Health Organization criteria using immunocytochemistry (including CD20, CD3, CD10, BCL2, BCL6, and Ki67), in situ hybridization for Epstein-Barr virusencoded small RNA and fluorescence in situ hybridization for MYC translocations. 25 Sporadic BL patients were treated according to French-American-British/Lymphome Mains de Burkitt-based protocols, [26][27][28] and endemic BL patients were treated with lowintensity therapy based on a published 28-day regimen 29,30 ( Table 1).…”

Section: Patient Samples and Cell Linesmentioning

confidence: 99%

“…*Endemic BL patients were treated with low-intensity 28-d regimen, 29,30 receiving cyclophosphamide (cyclo), vincristine (vcr), prednisolone (pred), and doxorubicin (dox). Eighteen endemic BL patients received a reduced protocol (4 had cyclo only, 6 cyclo1vcr, and 8 cyclo1vcr1pred).…”

Section: Patient Samples and Cell Linesmentioning

confidence: 99%

Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

et al. 2019

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FOXO1 has an oncogenic role in adult germinal center–derived lymphomas, in which mutations, predominately within the AKT recognition motif, cause nuclear retention of FOXO1, resulting in increased cell proliferation. To determine the prevalence and distribution of FOXO1 mutations in pediatric Burkitt lymphoma (BL), we sequenced a large number of sporadic and endemic BL patient samples. We report a high frequency of FOXO1 mutations in both sporadic and endemic BL at diagnosis, occurring in 23/78 (29%) and 48/89 (54%) samples, respectively, as well as 8/16 (50%) cases at relapse. Mutations of T24 were the most common in sporadic BL but were rare in endemic cases, in which mutations of residue S22, also within the AKT recognition motif, were the most frequent. FOXO1 mutations were almost always present in the major tumor cell clone but were not associated with outcome. Analysis of other recurrent mutations reported in BL revealed that FOXO1 mutations were associated with mutations of DDX3X and ARID1A, but not MYC, TCF3/ID3, or members of the phosphatidylinositol 3-kinase signaling pathway. We further show common nuclear retention of the FOXO1 protein, irrespective of mutation status, suggesting alternative unknown mechanisms for maintaining FOXO1 transcriptional activity in BL. CRISPR/Cas9 knockout of FOXO1 in an endemic cell line produced a significant decrease in cell proliferation, supporting an oncogenic role for FOXO1 in endemic BL. Thus, FOXO1 is frequently mutated in both sporadic and endemic BL and may offer a potential therapeutic target for pediatric BL patients worldwide.

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The use of anthracyclines in the treatment of endemic Burkitt lymphoma

Cited by 18 publications

References 20 publications

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda

Survival of children with endemic Burkitt lymphoma in a prospective clinical care project in Uganda

Haematological cancers in African children: progress and challenges

Sporadic and endemic Burkitt lymphoma have frequent FOXO1 mutations but distinct hotspots in the AKT recognition motif

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