Review

Diagnosis and treatment of Burkitt lymphoma in adults:

clinical practice guidelines from ERN-EuroBloodNet
Vincent Ribrag, Dominique Bron, Grzegorz Rymkiewicz, Dieter Hoelzer, Judit Jørgensen, Aythami de Armas-Castellano, Maria Trujillo-Martín,
Pierre Fenaux, Luca Malcovati, Natacha Bolaños, Josep-Maria Ribera, Charles Herbaux, Clémentine Sarkozy, Pier Luigi Zinzani, Jan Walewski,
Martine E D Chamuleau

Lancet Haematol 2025; Burkitt lymphoma is a rare lymphoma entity that represents less than 5% of adult lymphomas. Although prognosis
12: e138–50 has improved with dose-dense therapy, Burkitt lymphoma remains an area of clinical and biological research with
Department of Hematology specificities due to the high incidence of CNS involvement and tumour lysis syndrome in patients with a high tumour
and DITEP, Gustave Roussy,
burden. Few consensus recommendations are available concerning diagnosis, treatment, and prognostic factors in
Villejuif, France (V Ribrag MD);
Pegascy, Villejuif, France adult patients. In this Review, a European Reference Network on Rare Haematological Diseases (ERN-EuroBloodNet)
(V Ribrag); Department of expert panel has reviewed recent advances in the management of Burkitt lymphoma in the first-line setting to develop
Hematology, Jules Bordet updated evidence-based and expert opinion-based recommendations on the management of this disease. The expert
Institute, Brussels, Belgium
(Prof D Bron MD,PhD); Flow
panel consisted of ten clinicians and pathologists involved in the clinical management of Burkitt lymphoma from
Cytometry Laboratory, eight EU member states. Additionally, two haematologists were included to support the systematic review process. A
Department of Cancer balanced representation was ensured between individuals affiliated and not affiliated with ERN-EuroBloodNet.
Pathomorphology Together with providing current indications on diagnosis and risk-adapted first-line therapy, the Review contains
(G Rymkiewicz MD, PhD) and
Department of Lymphoid
specific recommendations for the identification and management of important complications of Burkitt lymphoma
Malignancies such as tumour lysis syndrome and CNS-oriented therapy, and recommendations for prognostic assessment to guide
(Prof J Walewski MD, PhD), treatment. Finally, unresolved questions for Burkitt lymphoma are highlighted, including questions around genetics,
Maria Sklodowska-Curie imaging, and second-line therapies, along with patient perspective.
National Research Institute of
Oncology, ERN-EuroBloodNet
Member, Warsaw, Poland; Introduction balanced representation was ensured between individuals
Onkologikum Frankfurt, Burkitt lymphoma is a rare subtype of B-cell non- affiliated with ERN-EuroBloodNet (n=6 members; DB, JJ,
Frankfurt, Germany Hodgkin lymphoma, and in adults represents less than CH, MEDC, PLZ, and JW) and not affiliated (n=5 non-
(Prof D Hoelzer MD, PhD);
Aarhus University Hospital,
5% of lymphoma cases, with an annual incidence of members; DH, J-MR, VR, CS, CH). A methodology team
Aarhus, Denmark 2–7 cases per 1 000 000 person-years among adults in and patient representative (NB) were also involved
(J Jørgensen MD); Canary Islands Europe.1,2 Burkitt lymphoma in adults has been less (appendix pp 1–2). The work began on Nov 24, 2021, with
Health Research Institute studied than in children, but data suggest important seven expert panel meetings, supported by ERN-
Foundation, Santa Cruz de
Tenerife, Tenerife, Spain
therapeutic improvements made in the past 2 decades. EuroBloodNet, held virtually from Jan 13, 2022 to
(A de Armas-Castellano BS, These improvements have been indicated by clinical April 18, 2023, to reach a consensus on the clinical
M Trujillo-Martín PhD); Network trials or retrospective data, although most of these studies questions to be addressed in the clinical practice
for Research on Chronicity,
included a small number of patients, especially in guideline. Once the list of questions to be answered was
Primary Care, and Health
Promotion, Madrid, Spain prospective studies. selected, they were structured in Patient, Intervention,
(M Trujillo-Martín); Department There is a scarcity of high-level scientific evidence to Comparator, and Outcomes (PICO) format to guide
of Hematology, Hôpital Saint- guide daily practice on diagnostic and therapeutic the evidence review and subsequent formulation of
Louis, Université de Paris, Paris,
procedures accessible to all European haematology recommendations.
France (Prof P Fenaux MD, PhD);
ERN-EuroBloodNet, Paris, centres, prevention and treatment of tumour lysis Four main clinical questions were selected following
France (Prof P Fenaux); syndrome (TLS), treatment of Burkitt lymphoma, and the PICO methodology (designated as PICO 1–4 in these
Department of Hematology prognostic factors in adult patients. Therefore, the guidelines): PICO 1, what are the recommendations for
Oncology, Fondazione IRCCS
European Reference Network on Rare Haematological proper diagnosis of Burkitt lymphoma? PICO 2, what is
Policlinico S Matteo, Pavia,
Italy (Prof L Malcovati MD, PhD); Diseases (ERN-EuroBloodNet) decided to promote a the recommended prevention and treatment of TLS in
Department of Molecular process involving key European experts in this area to patients with Burkitt lymphoma? PICO 3, what is the
Medicine, University of Pavia, develop evidence-based and consensus-based clinical preferred first-line treatment of patients with Burkitt
Pavia, Italy (Prof L Malcovati);
practice guidelines for adults with Burkitt lymphoma. lymphoma? PICO 4, what are key parameters for
Membership and Alliances,
Lymphoma Coalition, individual risk assessment and for guiding therapeutic
Barcelona, Spain (N Bolaños); Methods strategies? The PICO formats for each question are
Department of Haematology, An expert panel of eight clinicians and pathologists (DB, outlined in the appendix (p 5). The questions were
ICO-Hospital Germans Trias i
Pujol, Josep Carreras Leukaemia
DH, JJ, J-MR, VR, PLZ, MEDC, and JW) involved in the considered as separately important.
Research Institute, Barcelona, clinical management of Burkitt lymphoma from eight EU A separate search was done for each of the PICO
Spain (Prof J-M Ribera MD, PhD); member states (Belgium, Denmark, France, Germany, questions in MEDLINE (OVID interface), Embase
Hématologie Clinique, CHU de Italy, the Netherlands, Poland, and Spain), was recruited (Elsevier interface), and the Cochrane Central Register
Montpellier, Montpellier,
France (Prof C Herbaux MD,
within the framework of ERN-EuroBloodNet (appendix of Controlled Trials (Cochrane Library interface;
PhD); Hematology p 1). Additionally, two haematologists were included to appendix p 2). The search date and the definitive
Department, Institut Curie, support the systematic review process (CS and CH). A strategies used in each electronic database for each

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 Review

PICO question are provided in the appendix (pp 6–12). diagnosed in non-malarial areas], and immunodeficiency- Hôpital Saint-Cloud, Université
To complement the study search, the reference lists of all associated [eg, associated with HIV] variants) was de Versailles Saint-Quentin,
Versailles, France (C Sarkozy MD,
relevant papers were examined to identify additional replaced by Epstein–Barr virus (EBV) status (positive or PhD); Institute of Hematology
studies meeting selection criteria. With the same negative).3,4 High-quality epidemiological data on EBV- “L e A Seràgnoli”, University of
purpose, articles that referenced the included studies positive versus EBV-negative disease are still absent. The Bologna, Bologna, Italy
were searched in Google Scholar. Additionally, the annual incidence of sporadic and immunodeficiency- (Prof P L Zinzani MD, PhD);
Department of Hematology,
following information resources on rare diseases were associated Burkitt lymphoma is 2–3 cases per million of Cancer Center Amsterdam,
searched: Orphanet, the European Organisation for Rare the population per year.1,5 In European and North Amsterdam UMC, Amsterdam,
Diseases database, the National Organization of Rare American countries, Burkitt lymphoma occurs most Netherlands
Diseases database, RARE-Bestpractices, and the Genetic commonly in younger patients, with a peak incidence at (Prof M E D Chamuleau MD)

and Rare Diseases Information Center. The grey age 30 years in adults.1 HIV-associated Burkitt lymphoma Correspondence to:
Dr Vincent Ribrag, Department
literature database OpenGrey was also searched (URL has similar characteristics to sporadic Burkitt lymphoma of Hematology and DITEP,
addresses provided in the appendix [p 2]). Each platform in terms of clinical stage, CNS involvement, bone marrow Gustave Roussy, 94805 Villejuif,
was accessed and searched for reports and documents of involvement, and histology with a higher predilection for France
any kind related to the population of interest. extranodal sites,1,6 and frequently occurs when CD4 T-cell vincent.ribrag@gustaveroussy.
fr
The study selection process was done independently counts are above 200 cells per μL.6 The risk of developing
See Online for appendix
and in duplicate by two reviewers (VR and MEDC). The Burkitt lymphoma after organ transplantation increases
full study selection criteria for each PICO question are 4–5 years after the procedure and is notably more frequent
provided in the appendix (pp 13–14), and the results of in HIV-infected individuals than in those who are
this process for each question are summarised in HIV-negative.7 The annual incidence of immuno­
PRISMA flowcharts in the appendix (pp 15–18). Data deficiency-associated Burkitt lymphoma in the USA is
extraction and risk of bias assessments for the included six cases per 1000 AIDS cases among adults.6
studies were done by one reviewer (VR) and checked by a
second reviewer (DB, DH, JJ, J-MR, VR, PLZ, MEDC, or PICO 1: Clinical and pathological diagnostic
JW, depending on the PICO question; appendix investigations
pp 3, 19–25). Final recommendations were rated according Burkitt lymphoma is a mature, highly aggressive B-cell
to the GRADE methodology (appendix pp 4, 26–126) non-Hodgkin lymphoma, with rapid tumour growth of
based on randomised controlled trials (RCTs), non- lymphoma lesions and massive apoptosis resulting in TLS
randomised clinical trials, longitudinal observational even before initiation of therapy.8,9 Clinical mani­festations
studies, or original published systematic reviews of Burkitt lymphoma can be severe with rapid onset, and
(systematic reviews included for PICO 3 only), in adults any suspicion of Burkitt lymphoma (eg, lactate
(≥18 years) with Burkitt lymphoma. Cohort and case– dehydrogenase [LDH] above the upper limit of normal
control studies that did an evaluation of the diagnostic [ULN], extranodal and particularly ileocecal involvement,
validity of clinical factors or biomarkers associated with bulky tumour mass [≥7 cm] particularly in the abdomen,
disease course, disease-related toxicity, and response to advanced clinical stage [III or IV], or rapidly progressive
therapy for the disease were also included for all PICO disease) should be considered a medical emergency
questions. All included studies had to be published in (figure).
English in the past 15 years (from 2007). We excluded
case reports and case series, cross-sectional studies, Clinical diagnostic investigations
animal studies, in vitro studies, conference summaries, Clinical tests should be completed as soon as possible in
narrative reviews, editorials, letters to the editor, opinion patients with suspected Burkitt lymphoma, with an aim
pieces, and conference abstracts. Data analyses including to achieve a first preliminary diagnosis of Burkitt
meta-analysis, subgroup analysis, and sensitivity analysis lymphoma preferably within one day of admission,
used in the development of these guidelines are described except for patients with no bulky disease (tumour mass
in the appendix (p 3). <7 cm) and ECOG performance status 0–1 when
We provide recommendation ratings based on quality commencing therapy, and should include collection of a
of evidence per GRADE rating (“A” indicating high tumour sample.
quality, to “D” indicating very low quality) and strength To obtain a tumour sample, preferably a surgical biopsy
of recommendation by the panel (“1” indicating a strong or lymph node excision or thick needle biopsy for
recommendation, and “2” indicating a weak histopathology examination and immunohistochemistry
recommendation). (IHC), including imprint cytology, should be attempted.
An ascites or pleural effusion sample or fine-needle
Epidemiology of Burkitt Lymphoma in adults aspiration biopsy (FNAB) of lymph node tumour cells is
In the 5th edition of the WHO Classification of recommended for cytological evaluation, flow cytometry,
Haematolymphoid Tumours (WHO-HAEM5), the and conventional cytogenetics, or fluorescence in situ
historical subdivision of three different entities of Burkitt hybridisation (FISH) examinations, in order to establish
lymphoma (endemic, sporadic [predominant variant a provisional diagnosis of Burkitt lymphoma. FISH

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 Review

Suspicion of Burkitt lymphoma

• Bulky tumor mass, in particular abdominal, or
• Advanced clinical stage (III or IV), or
• Elevated serum LDH (>ULN), or
• Spontaneous TLS, or
• Rapidly progressive disease

Initiate diagnostic procedure

• Preferably morphological diagnosis (excision or biopsy)
• If morphological diagnosis not possible: cytological diagnostics
with flow cytometry (fluid of bone marrow aspirate or cell
suspension obtained by fine needle aspiration biopsy)
• Fresh or fixed material for cytogenetics or fluorescence in situ
hybridisation

Evaluate risk factors for TLS If one or more TLS risk factors present:
• Circulating Burkitt lymphoma cells start TLS prophylaxis immediately
• Elevated serum LDH (>ULN)
• Bulky disease (≥7 cm)
• Bone marrow infiltration or leukaemic disease
• Advanced clinical stages (III or IV)
• ECOG performance status >1
• Poor renal function (creatinine clearance <80 mL/min)

If progressive disease:
Start prednisolone 0·5 mg/kg day 1, 1 mg/kg day 2,
1 mg/kg until diagnosis

When flow cytometry with cytology or histology matches

Burkitt lymphoma, assess risk categories

Risk assesment for individual prognosis: use BL-IPI Risk assessment to define treatment
• Age >40 years
• ECOG performance status ≥2, Low-risk disease; all of the following: • Three cycles of R-CODOX-M, or
• Elevated serum LDH (>ULN) • WHO performance status 0–1 • Three to six cycles of DA-EPOCH-R (PET-CT-
• CNS involvement • Ann Arbor stage I or II(E) guided), or
• Normal serum LDH • LMB-R group B
• Tumor mass <7 cm

High-risk disease; one of the following • Two cycles of R-CODOX-M/R-IVAC, or

• WHO performance status >1 • LMB-R group C, or
• Ann Arbor stage III or IV • GMALL-B-ALL/NHL 2002, or
• Elevated serum LDH (>ULN) • Six cycles of DA-EPOCH-R (not when CNS is
• Tumor mass ≥7 cm involved)

Figure: Decision tree for Burkitt lymphoma in adult patients

BL-IPI=Burkitt lymphoma international prognostic index. ECOG=Eastern Cooperative Oncology Group. LDH=lactate dehydrogenase. TLS=tumour lysis syndrome.
ULN=upper limit of normal.

results could be obtained after starting treatment if the abnormalities suggestive of bone marrow involvement,
disease is rapidly progressing or the patient’s status is or if a diagnosis of stage IV disease changes the treatment
rapidly deteriorating. A lumbar puncture with cytology regimen.
and flow cytometry before treatment initiation and
without causing delay is recommended to exclude CNS Pathological diagnostic investigations
involvement. In the case of circulating Burkitt lymphoma All patients with a clinical suspicion of Burkitt lymphoma
cells (without neurological symptoms), lumbar puncture should be evaluated with use of the following methods:
should be delayed until peripheral Burkitt lymphoma histopathology or IHC examination of a representative
cells have disappeared during treatment. Trephine bone tissue sample from the tumour; flow cytometry of cell
marrow biopsy or aspiration should be done only in cases suspension obtained by FNAB of tumour cells or cells
of clinical and laboratory indications of a leukaemic form from ascites or pleural effusion or peripheral blood or
of Burkitt lymphoma or in cases of haematological bone marrow tissue suspected of being involved;10–12

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detection of EBV-encoded RNA (EBER-1, EBER-2, and seen. IHC is not a surrogate for the presence of MYC
EBNA-1) in Burkitt lymphoma cells to differentiate rearrangement but might help in identifying cases with
between EBV-positive versus EBV-negative Burkitt high MYC protein expression.8–10,13,16,17 Strong MYC
lymphoma as recommended by WHO-HAEM5;3,8 and expression in more than 80% of cells supports MYC
FISH of cells from an FNAB sample.8,12–14 Recently, a new rearrangement, but the absence of a positive MYC result
pathogenetic classification of Burkitt lymphoma has been despite the presence of MYC rearrangement is often
published.15 The authors of this publication divided explained by an MYC gene mutation. MYC-positive,
Burkitt lymphoma into three categories, namely EBV- LMO2-negative staining was found to be associated with
negative SOX11-positive, EBV-negative SOX11-negative MYC rearrangement in Burkitt lymphoma.16 Nearly 100%
(double negative), and EBV-positive SOX11-negative. of the cells are positive for Ki67 (Ki67 index >95%). Burkitt
Among EBV-negative Burkitt lymphoma, SOX11 lymphoma cells are usually negative for BCL2. However,
expression status was associated with significant genetic weak BCL2 protein expression (weaker than BCL2
differences, suggesting a possible distinct molecular expression on normal T lymphocytes) can be seen in about
pathogenesis. Therefore, it seems advisable to simul­ 20% cases and does not exclude diagnosis. Approximately
taneously evaluate EBV and SOX11 in IHC in newly half of Burkitt lymphoma cases show weak, aberrant
diagnosed Burkitt lymphoma cases. Conventional expression of MUM1 and FOXP1.8,10,16 Overexpression of
cytogenetics including karyotyping is not mandatory but CSE1L and ID3 is also associated with the diagnosis of
recommended and helpful for a differential diagnosis Burkitt lymphoma.10
with other similar lymphomas. Flow cytometry: Burkitt lymphoma cells express the
same antigens that are used in the IHC tests. Flow
Final diagnosis cytometry analysis of CD38 antigen expression
The final diagnosis of Burkitt lymphoma should be (CD38higher) on Burkitt lymphoma cells in relation to
established according to the WHO-HAEM5 criteria.3,8 It CD38 expression on normal T lymphocytes (ie, higher
requires integrated evaluation of clinical, pathomor­ expression on Burkitt lymphoma cells) is a substitute of
phological, flow cytometry, and cytogenetic data. No MYC rearrangement and is the easiest, fastest, and most
single characteristic can be conclusive. reliable way to detect MYC rearrangement in routine
According to the WHO-HAEM5 classification,3,8 lymphoma diagnosis.10–12,17 Cell expression of BCL2, CD44,
essential and desirable criteria for Burkitt lymphoma terminal deoxynucleotidyl transferase (TdT), and usually
diagnosis include the following. CD54 is not detected.10–11 Burkitt lymphoma cells express
Morphology: the morphological spectrum of Burkitt monoclonal surface light chain κ or λ and moderate to
lymphoma on smear and histopathological examination strong levels of membrane IgM or IgD and IgM, and
is relatively broad, most commonly with medium-sized, sometimes IgG (monoclonal heavy immunoglobulin
monomorphic, basophilic cytoplasmic lymphoma cells chain). CD71 expression, representing proliferative
and multiple small nucleoli in classic type Burkitt activity, is detected in 100% of Burkitt lymphoma cells.10
lymphoma. The nuclei are round with finely clumped Conventional cytogenetics: Burkitt lymphoma cells
and dispersed chromatin, with multiple basophilic, usually have a simple karyotype with t(8;14) (q24;q32)
medium-sized, eccentrical nucleoli. The cytoplasm is involving the MYC gene or variants, defined by three or
deeply basophilic and usually contains lipid vacuoles. less clonal aberrations (including the 8q24 breakpoint) as
In the setting of atypical morphology, one should detected by karyotyping. Most of the other aggressive B-cell
ensure that other immunophenotypic and genetic non-Hodgkin lymphomas with MYC rearrangement (with
features fully support a diagnosis of Burkitt blastoid or B-cell lymphoma, unclassifiable morphology)
lymphoma.2,8 usually have a complex karyotype. The most common
Histopathology: this shows a diffuse growth pattern secondary aberrations (occurring in 44% of cases) are copy
and squared-off cytoplasmic borders of retracted number gains involving chromosomes 1q, 7, and 12 and
cytoplasm. The cells display some degree of cohesion, losses involving chromosomal regions 6q, 13q32–34, and
with abundant mitosis and apoptosis. Many macrophages 17p. Gain of 1q seems to be associated with an absence of
with phagocytic activity containing apoptotic debris are other recurrent abnormalities.8,12
seen in the background as a starry sky pattern. However, FISH: for exclusion of BCL2 and BCL6 rearrangements.8,12
some Burkitt lymphoma cases do not have a starry sky Molecular examination: Currently, molecular analysis
pattern. Coagulative necrosis is common. Reactive small based on next-generation sequencing is not required for
lymphocytes are rare.8 the diagnosis of Burkitt lymphoma.8
IHC: Burkitt lymphoma expresses pan B-cell antigens According to WHO-HAEM5,3,8 the essential criteria list
(CD19, CD20, CD79α, CD22, and PAX5), germinal centre- medium-sized, monomorphic lymphoma cells with
associated antigens (CD10, BCL6, CD38, and HGAL), and basophilic cytoplasm and multiple small nucleoli, CD20
frequently shows strong expression of IgM. Burkitt and CD10 positivity, absence or (rarely, ~20% of cases)
lymphoma cells are consistently negative for LMO2 and weak expression of BCL2, a Ki-67 index above 95%,
CD44. Aberrant expression of CD43, LEF1, and TCL1A is usually strong expression of MYC (in >80% of cells), or

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 Review

demonstration of MYC rearrangement or IGH:MYC A lumbar puncture to exclude CNS involvement is

translocation. mandatory, to be delayed in case of peripheral blasts.
The desirable criteria lists a starry-sky pattern, cohesive A bone marrow assessment is needed only in cases of
growth pattern, BCL6 positivity, TdT negativity, CD38 clinical and laboratory indications of a leukaemic form of
positivity, and exclusion of BCL2 and BCL6 rearrangements Burkitt lymphoma or in cases of haematological
(mainly required in adult Burkitt lymphoma). abnormalities suggestive of bone marrow involvement, or
if a diagnosis of stage IV disease changes the treatment
Differential diagnosis regimen (A1).
Use of the aforementioned methods in routine The diagnosis of Burkitt lymphoma should be
diagnosis enables differential diagnosis of Burkitt established according to WHO-HAEM5 with reporting of
lymphoma from other de novo and transformed B-cell EBV status (A1).
non-Hodgkin lymphomas that also have MYC The diagnosis tests should include complete blood
rearrangement. Indeed, MYC rearrangement, although count, serum LDH, renal and liver function, TLS
characteristic of Burkitt lymphoma, is not specific. parameters (eg, calcium, phosphorus, and uric acid serum
MYC rearrangement in other aggressive B-cell non- concentrations), viral serology (HIV, hepatitis B virus, and
Hodgkin lymphomas results in morphology like Burkitt hepatitis C virus), PCR (EBV), and imaging by CT scan
lymphoma on cytology and histopathology (eg, B-cell (mandatory) and PET-CT (not mandatory but highly
lymphoma [unclassifiable] and blastoid morphology, recommended), and MRI in case of neurological
often with a starry-sky pattern). Differential diagnoses symptoms (A1).
(at the clinical, pathom­ orphological, immuno­ Recommendations on the diagnostic procedure are
phenotypic, and cyto­ genetic levels) include the summarised in the figure.
following entities: diffuse large B-cell lymphoma or
high-grade B-cell lymphoma with MYC and BCL2 PICO 2: Prevention and treatment of TLS
double-hit rearrangements; diffuse large B-cell Patients with Burkitt lymphoma are at high risk of
lymphoma or high-grade B-cell lymphoma with MYC developing TLS spontaneously before therapy, or
and BCL6 double-hit rearrangements; high-grade B-cell immediately after therapy initiation.1,18 TLS is caused by
lymphoma, not otherwise specified (NOS), with MYC massive tumour cell lysis with the release of large amounts
rearrangement; high-grade B-cell lymphoma with 11q of potassium, phosphate, and nucleic acids into systemic
aberration; diffuse large B-cell lymphoma, NOS, with circulation. Catabolism of nucleic acids to uric acid leads to
MYC rearrangement; other diffuse large B-cell hyperuricaemia and a marked increase in uric acid
lymphoma with MYC rearrang­ement; B-lymphoblastic excretion in the renal tubules, and can also induce renal
lymphomas or leukaemias with MYC rearrangement; vasoconstriction, impaired renal autoregulation, decreased
blastoid variant of mantle cell lymphoma with MYC renal blood flow, and inflammation, resulting in acute
rearrangement; and plasmablastic lymphoma and kidney injury. Hyperphosphataemia with calcium
plasma cell neoplasms with MYC rearrangement. phosphate deposition in the renal tubules also causes
In addition, based on morphological features, the acute kidney injury and, in the cardiac conduction system,
differential diagnoses include some rare myeloid can result in arrhythmias. Hyperkalaemia is associated
sarcomas and de novo peripheral T-cell lymphoma. with cardiac dysrhythmias and hypocalcaemia leads to
From the histopathological and immunohistochemical painful muscle spasms. Clinical manifestations of TLS can
perspective, the listed aggressive B-cell non-Hodgkin be multiorgan and can lead to death. The Cairo–Bishop
lymphomas with MYC rearrangement or 11q aberration criteria require two or more of all the components for
are very similar to each other. Differences between diagnosis (table 2).19
Burkitt lymphoma and these aggressive B-cell non- TLS prevention, or treatment if already present, is
Hodgkin lymphoma at the morphological level, particularly important as major drugs used in the
immunophenotypic level in IHC and flow cytometry treatment of Burkitt lymphoma are eliminated by the
studies, and in conventional cytogenetic studies are kidneys.20 Literature and particularly prospective
included in table 1. randomised trials are scarce in the field of TLS and
Burkitt lymphoma. However, because of strong
Panel recommendations for clinical and pathological confidence from experts and proven benefit in patients
diagnostic investigations with Burkitt lymphoma, these peer-reviewed guidelines
A surgical biopsy, multiple core biopsies, or lymph node are highly recommended, and the level of evidence was
excision for histopathology examination including rated B1 (see Panel recommendations for prevention and
imprint cytology should be attempted. However, a treatment of TLS).
preliminary diagnosis can be made rapidly and reliably
based on cytological analysis (bone marrow, serous TLS risk factors and medical indicators
effusion, and FNAB of lymph node) before the final and Risk factors include serum LDH concentration above
complete pathological analysis (A1). normal (>ULN), a tumour mass of 7 cm or greater, bone

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Morphology (cytology and IHC Flow cytometry immunophenotype Conventional cytogenetics

histology)
Burkitt lymphoma Cohesive monomorphic, medium- Positive for CD10, BCL6, CD38, and MYC; Burkitt lymphoma cells express CD45weaker, CD20, IGH:MYC translocations; absence of
sized cells with multiple small Ki-67 index >95%; most cases negative CD19, CD22, CD79α, CD79β, FMC7, CD10, CD43, BCL2 rearrangement and BCL6
nucleoli and basophilic cytoplasm for BCL2, LMO2, TdT, CD44, and cyclin BCL6, CD81higher, CD38higher, CD52, CD305, CD71, rearrangement; simple
(Burkitt lymphoma morphology) D1; some cases are EBER-positive; HLA-DR, surface light chain κ or λ, and (≤3 aberrations) karyotype
EBER-negative Burkitt lymphoma membrane IgM or IgD and IgM and sometimes
tumours are SOX11-positive in some IgG heavy chain; cells are negative for CD5,
cases CD11c, CD23, CD25, CD44, CD54, CD56, CD62L,
CD200, BCL2, and TdT; the MFI of CD20
expression is higher than that of CD19 and
CD22 (MFI CD20>CD19>CD22); CD71 is
detected in 100% of cells
Diffuse large B-cell Variable: intermediate between Similar to Burkitt lymphoma but most Similar to Burkitt lymphoma but most cases BCL2 (and BCL6) translocation in
lymphoma or high- Burkitt lymphoma and diffuse large cases express BCL2 strongly; some cases express BCL2higher and have low expression of addition to MYC rearrangement;
grade B-cell lymphoma B-cell lymphoma (B-cell show variable TdT expression; rare cases CD20, CD19, and CD22 (MFI close to simple (≤5 aberrations)
with MYC and BCL2 lymphoma, unclassifiable are EBER-positive CD19>CD20>CD22); some cases show variable karyotype in high-grade B-cell
double-hit morphology), diffuse large B-cell TdT expression lymphoma cases, complex
rearrangements lymphoma, blastoid, or sometimes karyotype in diffuse large B-cell
Burkitt lymphoma morphology lymphoma cases
Diffuse large B-cell Variable: intermediate between Similar to Burkitt lymphoma; rare cases Similar to Burkitt lymphoma but in most cases BCL6 translocation in addition to
lymphoma or high- B-cell lymphoma, unclassifiable are EBER-positive low expression of CD20 or CD19 (MFI MYC rearrangement; close to
grade B-cell lymphoma morphology, diffuse large B-cell CD19>CD20>CD22); usually reduced CD43 and simple (≤5 aberrations) karyotype
with MYC and BCL6 lymphoma, blastoid, or sometimes increased CD44 expression in high-grade B-cell lymphoma
double-hit Burkitt lymphoma morphology cases, complex karyotype in diffuse
rearrangements large B-cell lymphoma cases
High-grade B-cell Burkitt lymphoma or B-cell Similar to Burkitt lymphoma; higher Similar to Burkitt lymphoma; discrete IG:MYC translocations and non-
lymphoma, not lymphoma, unclassifiable frequency of TP53 and MYC mutations differences in the expression of various antigens IG:MYC translocations; absence of
otherwise specified, morphology; cohesive growth is than in Burkitt lymphoma, often in relation to Burkitt lymphoma are observed, BCL2 rearrangement and BCL6
with MYC usually reduced; in some cases, associated with increased p53 expression for example, cases with low CD10 expression rearrangement; complex
rearrangement variation in nuclear size is observed and absence of MYC protein, are more common than with Burkitt lymphoma karyotype; TP53 and MYC
respectively; rare cases are EBER-positive mutations
High-grade B-cell Burkitt lymphoma, B-cell Similar to Burkitt lymphoma: positive for Similar to Burkitt lymphoma, but with CD45bright; Gain in 11q23.3 and the terminal
lymphoma with 11q lymphoma, unclassifiable CD20, CD10, and BCL6, negative for discrete differences in antigen expression deletion at 11q24.1-qter; complex
aberration morphology, or blastoid BCL2, CD44, and MUM1, and positive or compared with Burkitt lymphoma; usually low karyotype; absence of MYC
morphology; some cases with negative for CD43 and LMO2 with expression of CD38; approximately 50% of cases translocations by definition but
coarse apoptotic debris within variable MYC expression; some cases are express CD56 some cases have simultaneous
starry sky macrophages; rarely CD56 positive; all cases are EBER 11 q aberration and MYC
diffuse large B-cell lymphoma negative rearrangement
morphology (see below)
Diffuse large B-cell Larger cells than Burkitt lymphoma Similar to Burkitt lymphoma due to Similar to Burkitt lymphoma, but with CD45bright, IG:MYC translocations and
lymphoma, not with more prominent nucleoli germinal centre B-cell IHC: positive for discrete differences in antigen expression non-IG:MYC translocations; always
otherwise specified, (diffuse large B-cell lymphoma CD20, CD10, and BCL6, negative for compared with Burkitt lymphoma complex karyotype
with MYC morphology) with apoptotic debris BCL2, and positive or negative for
rearrangement and starry sky macrophages MUM1, CD44, CD43, and LMO2; some
cases express BCL2; rare cases are
EBER-positive
B-lymphoblastic Fine nuclear chromatin; less Uniform TdT expression in most cases; CD20dim and CD34 expression; sometimes other IG:MYC translocations and non
lymphomas or conspicuous nucleoli than Burkitt CD34 expression in a subset; all cases are early lymphoid-myeloid antigens expression; IG:MYC translocations; extremely
leukaemias with MYC lymphoma (blast cells morphology) EBER-negative more cases without light chain (κ or λ) and rare cases of lymphomas among
rearrangement without membrane Ig heavy chain than in B-lymphoblastic lymphoma or
Burkitt lymphoma; only cytoplasmic IgM leukaemia or B-cell acute
expression acceptable lymphoblastic leukaemia
Blastoid variant of Blastoid morphology Positive for cyclin D1, CD5, CD43, SOX11, Completely different immunophenotype Non-IG:MYC translocations; CCND1
mantle cell lymphoma CD44, BCL2, TdT, and MYC; Ki-67 index compared with Burkitt lymphoma translocation in addition to MYC
with MYC >95%; all cases are EBER-negative rearrangement; complex
rearrangement karyotype; extremely rare cases of
lymphomas among mantle cell
lymphoma
EBER=Epstein–Barr virus-encoded RNA. IHC=immunohistochemistry. MFI=median fluorescence intensity. TdT=terminal deoxynucleotidyl transferase. CD81higher and CD38higher denotes higher expression of CD81
and CD38 antigens on Burkitt lymphoma cells than on the surface of T lymphocytes and normal B lymphocytes. CD45weaker denotes weaker CD45 expression on Burkitt lymphoma cells than on T lymphocytes.
BCL2higher denotes higher expression in lymphoma cells (eg, double-hit lymphoma with MYC and BCL2 gene rearrangement) than in T lymphocytes and normal B lymphocytes, which have a weaker level of BCL2
expression. CD45bright denotes a single peak (homogeneous) expression pattern similar to CD45 expression on T lymphocytes. CD20dim denotes more heterogeneous and weaker expression (often in double-hit
lymphoma) than on normal B lymphocytes. In Burkitt lymphoma, CD20 expression is higher than the expression of CD20 on normal B lymphocytes and on double-hit lymphoma cells and bright type.

Table 1: Differential diagnosis of Burkitt lymphoma from other aggressive B-cell non-Hodgkin lymphomas, usually with MYC rearrangements

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care unit should be notified when treatment of a patient

Definition of biological TLS Definition of clinical TLS
with Burkitt lymphoma at risk of TLS is started, in order
Uric acid >476 μmol/L or 25% increase Creatinine: >1·5 ULN (age to start renal dialysis immediately in case of renal failure
from baseline >12 years)
or uncontrolled hyperkalaemia. Biological TLS para­
Potassium >6 mmol/L or 25% increase Cardiac arrythmia or
from baseline sudden death meters (uric acid, potassium, phosphorus, calcium,
Phosphorous >1·45 mmol/L or 25% Seizure chloride, bicarbonate, creatinine, urea, and serum LDH)
increase from baseline should be monitored every 6 h until phosphataemia
Calcium <1·75 mmol/L or 25% Not applicable normalisation.
decrease from baseline
TLS=tumour lysis syndrome. ULN=upper limit of normal. Panel recommendations for prevention and treatment
of TLS
Table 2: Cairo–Bishop definitions of TLS19
TLS prevention or treatment (if already present) should
be performed in all adult patients, and prevention
marrow infiltration or leukaemic disease, circulating performed immediately in all patients with one or more
Burkitt lymphoma cells, advanced clinical stage (III or TLS risk factors (B1; figure).
IV), Eastern Cooperative Oncology Group (ECOG) Rasburicase should be administered to all adult patients.
performance status greater than 1, and poor renal In populations at risk of G6PD deficiency, starting
function (creatinine clearance <80 mL/min; figure). treatment with allopurinol and screening immediately for
With regard to laboratory and clinical indicators, G6PD deficiency is generally recommended (B1).
electrolytes (sodium potassium, uric acid, phosphorus, The intensive care unit should be notified immediately
calcium, and chloride), renal function, and serum LDH in cases of spontaneous TLS and when treatment for
should be monitored carefully every 6–8 h as soon as Burkitt lymphoma is initiated in adults (B1).
Burkitt lymphoma is suspected and if one or more TLS
risk factors are present. PICO 3: First-line treatment of Burkitt
lymphoma
Prevention and treatment of TLS In devising recommendations for first-line treatment, we
Prevention measures should start immediately if at least considered two RCTs, seven non-randomised clinical trials
one of the TLS risk factors is present.20 Hydration (phase 2), and no longitudinal observational studies
(2–3 L/m² every 24 h intravenously, without potassium) is conducted and published in the past 15 years (from 2007),
crucial to prevent or revert side effects of TLS. Alkalinisation which are listed in table 3 (different regimens summarised
is no more adapted (risk of nephrocalcinosis due to in the appendix [p 127]). During expert panel meetings, it
phosphorus precipitation in the tubules) in the urate was decided that retrospective studies of more than
oxidase area. For the prevention of hyperuricaemia, 100 patients would also be included for a confirmatory
two drugs are available. Rasburicase (recombinant urate purpose (n=7; appendix pp 128–29).
oxidase: 7·5 mg fixed dose or 0·2 mg/kg per day, Outcome data in terms of overall survival, progression-
intravenously), is the drug of choice to reduce the free survival, and complete response rates (when
concentration of serum uric acid. Hypersensitivity available; not shown) were collected and assessed (table 3;
reactions with rasburicase (including anaphylaxis) have appendix pp 128–29). In Burkitt lymphoma, due to the
been reported. Drug interactions with rasburicase have not absence of active second-line therapy,40,41 complete
been reported. High-dose rasburicase might be required in response rates, progression-free survival, and overall
resistant cases.21,22 A single administration of rasburicase survival are generally quite similar between drug
(7·5 mg fixed dose or 0·2 mg/kg per day) can be effective regimens.
to maintain an undetectable concentration of uric acid.20–25 Patients should be treated with the monoclonal
Re-administration of rasburicase at a 7·5 mg fixed dose or anti-CD20 antibody rituximab combined with chemo­
0·2 mg/kg per day can be done to reduce formation of new therapy. This recommendation is based on one randomised
uric acid.20,23,24 In populations at risk of G6PD deficiency for trial showing improved overall survival for the LMB
whom the use of rasburicase is contraindicated, mainly regimen with rituximab (LMB-R) compared with the LMB
patients of sub-Saharan African origin, allopurinol regimen without rituximab (3-year overall survival 83% vs
(300–600 mg/day orally [less effective than rasburicase]) 70%),26 and on the results of two prospective studies
can be initially started and the patient screened without anti-CD20 antibody in which overall survival was
immediately for G6PD deficiency if results are available in less than 80% at 2–3 years.9,37
less than 24 h. Patients should be treated with an anthracycline-
To slowly reduce the tumour load, moderate prephase based regimen. This recommendation is based on
chemotherapy should be administered. It generally one study without anthracyclines in which an overall
should combine low-dose cyclophosphamide survival of 57% at 3 years was observed.36 This low
(300 mg/m²) and steroids for 5–7 days and should be overall survival was confirmed in a retrospective study
associated with TLS prevention. The hospital intensive (33% at 2 years).42

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Regimen* Number of Median age, Ann Arbor Patients CNS Rituximab, Progression-free Overall survival, %
patients years stage I–II, % with HIV, % involvement, % patients survival, %
patients patients % patients
Ribrag et al (2016)26 LMB 129 47 27% 0% 25% 0% 64% (at 3 years) 70% (at 3 years)
Ribrag et al (2016)26 LMB-R 128 47 24% 0% 25% 100% 74% (at 3 years) 83% (at 3 years)
Mead et al (2008)9 Modified CODOX-M/IVAC 53 37 25% 0% 11% 0% 64% (at 2 years) 67% (at 2 years)
Corazzelli et al RD-CODOX-M/IVAC 15 52 30% 0% 13% 100% 92% (at 4 years) 93% (at 4 years)
(2012)27
Evens et al (2013)28 CODOX-M/IVAC 25 44 NA 16% 12% 100% 80% (at 2 years) 84% (at 2 years)
Noy et al (2015)29 Modified R-CODOX-M/IVAC 34 42 20% 100% 0% 100% 69% (at 2 years) 69% (at 2 years)
Intermesoli (2013)30 GMALL-B-ALL/NHL 2002 105 47 26% 15% 7% 100% 75% (disease-free 67% (at 3 years)
survival at 3 years)
Ribera et al (2013)31 GMALL-B-ALL/NHL 2002 118 44 22% 32% 12% 100% 80% (disease-free 73% (at 4 years)
survival at 4 years)
Hoelzer et al (2014)32 GMALL-B-ALL/NHL 2002 363 42 29% NA 10% 100% 71% (at 5 years) 80% (at 5 years)
Rizzieri et al (2014)33 CALGB 10002 105 43 51% 0% 14% 100% 78% (at 2 years) 83% (at 2 years)
Dunleavy et al DA-EPOCH-R 19 25 42% 0% 5% 100% 95% (at 86 months) 100% (at 86 months)
(2013)34
Dunleavy et al SC-EPOCH-RR 11 44 18% 100% 0% 100% 100% (at 73 months) 90% (at 73 months)
(2013)34
Roschewski et al DA-EPOCH-R 113 49 30% 25% 10% 100% 84% (disease-free 87% (at 4 years)
(2020)35 survival at 4 years)
Kasamon et al High-dose CPD/MTX 21 53 29% 0% 14% 100% 52% (at 3 years) 57% (at 3 years)
(2013)36
Kujawski et al High-dose CHOP/MTX 10 51 10% 0% 0% 0% 64% (at 3 years) 72% (at 3 years)
(2007)37
Chamuleau et al R-CODOX-M/R-IVAC 46 50 12% 12% 0% 100% 76% (at 2 years) 76% (at 2 years)
(2023)38
Chamuleau et al DA-EPOCH-R 43 56 7% 10% 0% 100% 70% (at 2 years) 75% (at 2 years)
(2023)38
Ribera et al (2024)39 BURKIMAB14 107 51 29% 24% 19% 100% 87% (at 4 years) 82% (at 4 years)
*Different regimens summarised in the appendix (p 127).

Table 3: Prospective studies in Burkitt lymphoma

Treatment according to disease risk and need for supportive care than R-CODOX-M/R-
High-risk Burkitt lymphoma is defined by one of: ECOG IVAC.38 Admin­ istration of all high-intensity and
performance status above 1, Ann Arbor stage III or IV, intermediate-intensity regimens requires a central-
elevated serum LDH (>ULN), or tumour mass of 7 cm venous catheter.
or greater.35,43 Intensive treatment schedules such as Low-risk Burkitt lymphoma is defined by a ECOG
R-CODOX-M/R-IVAC, LMB-R group C, GMALL-B-ALL/ performance status of 0–1, Ann Arbor stage I or II(E),
NHL 2002, and intermediate-intensity DA-EPOCH-R normal serum LDH, and tumour mass below 7 cm.35,43
with intrathecal CNS prophylaxis have been reported to Patients with low-risk disease may be treated with less
have higher overall survival rates than lower dose intensive regimens than patients with high-risk disease
regimens (ie, R-CHOP-like regimens) in prospective (for example, three cycles of R-CODOX-M,9 interim
studies (table 2).26,32,34,35,38 Similar overall survival rates PET-guided or CT-guided DA-EPOCH-R for three to
with these intensive regimens were confirmed in six cycles,35 or LMB-R group B26).
retrospective studies.42,44,45 The choice between these
regimens (R-CODOX-M/R-IVAC, LMB-R group C, CNS prophylaxis and treatment of patients with
GMALL-B-ALL/NHL 2002, and DA-EPOCH-R) can be baseline CNS involvement
made based on local preference, practice (hospitalisation The outcome for patients with CNS relapse of Burkitt
vs outpatient based), experi­ence, and CNS involvement lymphoma is poor (median overall survival 2·8 months),
(see next section). A randomised study comparing providing the rationale to incorporate CNS prophylaxis
R-CODOX-M/R-IVAC with DA-EPOCH-R for patients in all regimens for patients with high-risk disease.46
with Burkitt lymphoma without CNS involvement was Baseline CNS involvement (both leptomeningeal
stopped prematurely but suggested that both regimens cerebrospinal fluid [CSF] positivity by flow cytometry and
might provide similar overall survival benefit, although parenchymal involvement on MRI) in Burkitt lymphoma
DA-EPOCH-R was associated with fewer toxic effects is associated with inferior prognosis to cases without

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CNS involvement, independently of the first-line treat­ were older than 40 years, supporting the use of
ment regimen selected.46 DA-EPOCH-R in older patients.34 Starting with low dose
Patients with parenchymal CNS involvement at levels (ie, dose levels –2 or –1, instead of dose level 1,
baseline were not included in the pivotal DA-EPOCH-R which is the standard starting dose level) could be
studies.34,35 For patients with proven parenchymal CNS considered.
involvement, DA-EPOCH-R is not recommended
due to absence of CNS-penetrating drugs in this Panel recommendations for first-line treatment
regimen. Fit adult patients with high-risk disease should be
Patients with leptomeningeal CSF involvement (n=11) treated with immune-chemotherapy regimens including
were included in one of the DA-EPOCH-R studies and anthracyclines. High-intensity regimens including
received a more intensive intrathecal scheme than R-CODOX-M/R-IVAC, LMB-R group C, and GMALL-B-
patients without CSF involvement who received CNS ALL/NHL 2002, and intermediate-intensity regimen
prophylaxis, with induction, consolidation, and main­ DA-EPOCH-R with intrathecal CNS prophylaxis are
tenance intrathecal therapy.35 Six patients relapsed or associated with higher overall survival than low-intensity
died. A retrospective study of 120 patients with baseline regimens (ie, R-CHOP-like regimens). The choice
CNS involvement (CSF and parenchymal) reported a between the high-intensity and intermediate-intensity
higher incidence of CNS relapses after the DA-EPOCH-R regimens can be made based on local practice, preference,
regimen (reaching 35% at 3 years) than with other and experience (B1).
regimens.46 Omitting CNS prophylaxis in patients with Rituximab should be combined with chemotherapy in
low-risk disease might be feasible, as was shown in a the treatment of all adults with Burkitt lymphoma (A1).
multicentre study of DA-EPOCH-R,35 but numbers were For adult patients with baseline CNS involvement,
small (n=15) and the panel would not routinely advise DA-EPOCH-R is not recommended due to absence of
to omit prophylaxis. CNS-penetrating drugs in this regimen and the paucity
of experience with the intensified intrathecal regimen
Patients with HIV (B1). CNS prophylaxis should not be omitted (C1).
In people with HIV, highly active antiretroviral Adult patients with low-risk disease should be treated
treatment (HAART) is recommended in all patients with three cycles of R-CODOX-M, three to six cycles of
with Burkitt lymphoma treated with an intensive DA-EPOCH-R (PET-guided or PET-CT-guided), or LMB-R
regimen that includes rituximab (tables 1–3). Specific group B. The choice between these regimens can be
attention should be given to the infectious risk in made based on local preference and experience (B1).
patients with very low CD4 lymphocyte counts Patients with HIV shoud be treated similarly as patients
(<200 cells per μL). Prophylaxis of opportunistic without HIV, but treatment should be combined with
infections should be routinely given according to HAART and prophylaxis for opportunistic infections
national guidelines. G-CSF can be added to mitigate should be considered (C1).
neutropenia. In case of previous hepatitis B virus Recommendations in older or frail patients (especially
exposure, prophylaxis against virus reactivation could patients with chronic renal disease) are based on limited
be proposed given that rituximab is a standard part of data. Treatment-related mortality with the intermediate-
treatment for Burkitt lymphoma. intensity DA-EPOCH-R regimen is low, even in older
patients, supporting the use of this regimen (initially
Older and frail patients with low proposed starting levels) for older patients (B2).
In older or frail patients (particularly patients with Treatment recommendations are summarised in the
chronic renal disease), the effectiveness of intensive figure.
treatments for Burkitt lymphoma should be balanced
with the risk of treatment-related mortality. In PICO 4: Prognostic factors in Burkitt lymphoma
retrospective studies, the reported treatment-related Prognostic or predictive factors reported in the literature
mortality was 13% to 17% in patients aged 60 years or were assessed by the panel group. Some of the factors
older, with the most common cause of toxicity-related are already used for risk stratification in clinical trials
death being sepsis in the first cycle of therapy.42,44,45 (factors used as predictive factors). A simple and robust
Treatment-related mortality was higher in patients aged prognostic factor index is difficult to elaborate in Burkitt
60 years or older treated with hyper-CVAD versus lymphoma because there is no consensus on a
CODOX-M/IVAC or DA-EPOCH-R.45 In the multicentre prospectively validated international prognostic score for
study of DA-EPOCH-R, treatment-related mortality was Burkitt lymphoma, contrary to diffuse large B cell
5% and was mainly seen in patients older than 50 years lymphoma.
with an ECOG performance status above 2.35 In the
single-centre prospective study of DA-EPOCH-R, Prognostic factors identified in prospective studies
patients (aged 15–88 years) were treated without Two prospective trials that included more than
treatment-related mortality, and 29 (26%) of 113 patients 200 patients (table 4) confirmed that age and bone

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Number of HIV status Prognostic factors identified Patient Predictive factors used for
patients stratification stratification
Hoelzer et al (2014)32 363 Negative Age, IPI, gender, serum LDH >ULN, Yes Age
bone marrow involvement
Kasamon et al (2013)36 21 Negative No Yes ECOG performance status
Ribrag et al (2016)26 260 Negative Albumin, haemoglobin Yes CNS involvement, bone marrow
involvement, age, early treatment
response
Rizzieri et al (2014)33 105 Negative IPI No NA
Roschewski et al 113 Positive and CNS or bone marrow involvement, or Yes Clinical stage, ECOG performance
(2020)35 negative patients both status, serum LDH >ULN, bulky disease
(≥7cm)
Phillips et al (2020)47 38 Positive and No Yes IPI
negative patients
Galicier et al (2007)48 63 Positive CD4 lymphocyte count, IPI, ECOG Yes CNS involvement, bone marrow
performance status involvement
Ribera et al (2013)31 115 Positive ECOG performance status, bone Yes Clinical stage, age
marrow involvement
ECOG=Eastern Cooperative Oncology Group. IPI=International Prognostic Index. LDH=lactate dehydrogenase. NA=not applicable. ULN=upper limit of normal.

Table 4: Prognostic factors identified in prospective studies

marrow involvement were prognostic.26,32 In one study, TCF3 alterations (including mutations in some but not
haemoglobin concentration and serum albumin were all cases) were associated with poor progression-free
also identified as prognostic factors,32 and in the other, survival and overall survival, respectively. Loss of the 11q,
gender, IPI, and serum LDH concentration above 13q, 15q and 17p chromosomal regions was also
normal value (>ULN) were identified.26 The effect of associated with poor outcome.51
CNS infiltration is more difficult to define, as patients
were treated with a specific CNS-oriented chemotherapy Panel recommendations on prognostic factors
regimen in three of four representative trials.26,31,32,35 To guide treatment, use the prognostic factors that have
Other propsective studies with small sample sizes been validated in prospective trials (age, ECOG
identified ECOG performance status as prognostic31,48 or performance status, serum LDH, bone marrow or CNS
used it for stratification35,36 (table 4). involvement, IPI, serum albumin, and haemoglobin;
A1).
Prognostic factors identified in retrospective studies The BL-IPI simple scoring system includes prognostic
Retrospective registry studies (appendix p 130) parameters identified to date, and should be
confirmed the prognostic value of the prognostic further validated prospectively, but can be used to
factors identified in prospective studies (table 4; indicate the individual prognosis of adult patients (B1;
including one study in which two independent figure).
datasets were used43). The study described a simple Genetics and PET assessment data should be explored
scoring index (Burkitt lymphoma IPI [BL-IPI])43 for (B1). PET imaging and genetic abnormalities might
which most of the parameters were validated in one or become major prognostic prameters but confirmatory
more of the prospective trials. This score was studies are needed (C1).
externally used in one prospective trial.31
Recent retrospective patient cohorts assessed different Conclusion and future directions
prognostic factors (appendix p 131). The variables identified Classification of Burkitt lymphoma is evolving, and the
in several studies, and similar to prospective studies, were last WHO lymphoma classification in 2022 (WHO-
age, ECOG performance status, LDH serum concentration HAEM5) is the new backbone for accurate diagnosis. In
above normal value (>ULN), and CNS or bone marrow considering relevant evidence on diagnosis, the expert
involvement. panel considered that it was essential to obtain a
preliminary morphological diagnosis, within one day of
Non-clinical prognostic parameters admission for urgent treatment onset.
PET imaging has also been studied as a prognostic tool, TLS should be actively prevented or treated as soon as a
but with a paucity of data to date, particularly on the diagnosis of Burkitt lymphoma is suspected. No recent
usefulness of interim PET scans, and on the best time studies on TLS in Burkitt lymphoma cohorts have been
to perform them after treatment onset.49,50 published, but management of TLS can be based on
Genomic abnormalities were analysed in one study older publications and on the panel consensus. This
including 40 patients with Burkitt lymphoma. TP53 and early management is especially important due to the risk

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of acute renal failure and its potential effect on treatment For now, to guide treatment, we propose to use the
delivery. definitions for high and low risk disease as used in
There is a paucity of robust comparative prospective prospective studies and to use the BL-IPI for assessing
studies of therapeutic regimens. Thus, among regimens individual prognosis.
that have shown high efficacy, the standard regimen Contributors
used in the centre where the patient is hospitalised is a VR, DB, GR, PF, CH, CS, JW, and MC contributed to
reasonable option, in part to reduce the risk of excess conceptualisation, methodology, data curation, analysis, supervision,
validation, visualisation, writing the original manuscript draft, and
toxicity because of staff experience of the regimen. manuscript review and editing. NB contributed to conceptualisation,
However, rituximab should be used in those regimens, methodology, data curation, and manuscript review and editing.
and the panel proposes that DA-EPOCH-R is not AdA-C and MT-M provided editorial support. All authors reviewed and
recommended in patients with proven CNS involvement approved the paper.
at baseline (due to the absence of CNS-penetrating Declarations of interest
drugs included in this regimen). Our guidelines do not DH reports consultancy for DKMS, BMS, and a German Breast Group
Independent Data and Safety Monitoring Committee. JJ reports
cover the paediatric population and should be reserved consultancy for AbbVie, Celgene, BMS, Gilead, Novartis, Roche, Sobby,
to adult patients. For adolescent and young adult Incyte, and Orion. J-MR reports consultancy for Pfizer, Amgen, Shire,
lymphoma, the centre’s standard regimen could be Ariad, and Incyte, and research funding from Amgen. PLZ reports
adapted with consensus between the paediatric teams consultancy for MSD, EUSA Pharma, and Novartis, and speakers
bureaus and advisory board membership for Celltrion, Gilead,
in the centre. Janssen-Cilag, BMS, Servier, MSD, AstraZeneca, Takeda, Roche, EUSA
Prognostic factors identified in Burkitt lymphoma Pharma, Kyowa Kirin, Novartis, ADC Therapeutics, Incyte, and
differed across the prospective studies. One hypothesis BeiGene. JW reports consultancy for Roche, AbbVie, Gilead, Novartis,
for this observation is that some of these factors (bone Takeda, and MSD, and research funding from AstraZeneca, Epizyme,
Incyte, Janssen-Cilag, Karyopharm Therapeutics, Loxo@Lilly,
marrow involvement, CNS involvement, and age) are Nanovector, Morphosys, MSD Oncology, Regeneron, Seattle Genetics,
used for treatment adaptation. These factors are Takeda, TG Therapeutics, BMS, Gilead, GSK, Vanda Pharmaceuticals,
commonly used as predictive factors in such studies and Novartis. MC reports consultancy for AbbVie, Genmab, Novartis,
and research funding from BMS, Genmab, Gilead, and AbbVie.
and their effect might be minimised in this context.
VR reports consulting for AbbVie, advisory boards for Ipsen, BeiGene,
Age, IPI, and CNS or bone marrow involvement were AstraZeneca, and Lilly, research contracts with Astex Pharmaceuticals
identified as predictive factors in at least one prospective and GSK, and is an employee at Pegascy. DB reports consulting for
study each, and the BL-IPI was generated in a large Janssen and AstraZeneca, advisory board membership for AbbVie, and
speakers bureau for AbbVie, BeiGene, and Janssen. CS reports
registry study and should be further prospectively
speakers bureau for Incyte, BeiGene, Roche, AstraZeneca, and MSD,
validated. The role of PET-CT and next-generation and advisory board membership for AbbVie, Roche, MSD, BeiGene,
sequencing remain to be investigated in large and Janssen. AdA-C and MT-M are funded by ERN-EuroBloodNet.
prospective cohorts. All other authors declare no competing interests.
Second-line therapies were not investigated in this Acknowledgments
work. Recent reports on second-line therapy showed This publication was done within the framework of ERN-
EuroBloodNet (project ID number 101157011). ERN-EuroBloodNet is
that they had low activity after patients were treated funded by the EU within the framework of the Fourth EU Health
with modern dose-dense chemotherapy in the first-line Programme.
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