The Philippine Clinical Practice Guidelines on the Diagnosis, Management, Psychosocial Support and Palliative Care of Burkitt Lymphoma in Children and their Families

Burkitt lymphoma (BL) is the most common type of non-Hodgkin lymphoma in children and
adolescents accounting for 30–50% of all pediatric lymphomas. Despite its fast-growing nature, BL is
one of the most curable forms of non-Hodgkin lymphoma. A child's probability of surviving cancer is
dismal in less developed countries and extreme discomfort is likely in the absence of palliative care.
Considering this situation and the lack of clinical practice guidelines for BL in our country, Southern
Philippines Medical Center organized a Technical Working Group to develop Clinical Practice Guidelines
(CPG) for Burkitt Lymphoma in children and adolescents. The aim was to provide recommendations
regarding clinical assessment, diagnostic and ancillary tests, risk stratification, staging, prognosis, BL
treatment and its side effects, supportive measures, palliative care and the involvement of the health
system in managing pediatric patients afflicted with BL.
The SPMC-CCI BL Guideline Development group followed the guidelines set forth by the
Department of Health based on DOH Administrative Order No. 2021-0020 entitled Revised Guidelines
on National Practice Guideline Development, Adoption and Dissemination and the modified Grading of
Recommendations, Assessment, Development and Evaluation or the GRADE approach. Briefly the
following steps were done which will be elaborated in greater detail in the methodology section: 1)
Formation of the Technical Working Group, 2) Consultation with Care Providers, Patients and Families
and Formulation of Key Questions, 3) Searching, Selection and Assessment of the Evidence, 4)
Consensus Panel Review and Evidence to Decision, and 5) External Review and Updating of
Recommendations.

Clinical Assessment

Recommendation 1: Among children suspected of having Burkitt Lymphoma, look for the following
during physical examination: abdominal masses; lymphadenopathy; head and neck masses; evidence of
bone marrow abnormalities like pallor, ecchymoses, bleeding, or petechiae; CNS involvement findings
such as headache, dizziness, vomiting, paralysis and paresthesia; ascites and pleural effusion. (High
Quality Evidence; Strong Recommendation)

Recommendation 2: Among children suspected of having Burkitt Lymphoma, ask for B symptoms in the
clinical history such as fever, night sweats and weight loss. (High Quality Evidence; Strong
Recommendation)

Recommendation 3: Aside from the common items in the history and physical examination
recommended above, the physician must also be aware of atypical presentations such as thyroid mass,
URTI, dyspnea, dysphagia, and cavernous sinus thrombosis. (High Quality Evidence; Strong
Recommendation)

Diagnostic and Ancillary Tests

Recommendation 4: Among pediatric patients suspected of having Burkitt Lymphoma, do image-guided
core needle biopsy for lymph nodes to establish histopathological diagnosis. (Moderate Quality
Evidence; Strong Recommendation)

Recommendation 5: Among pediatric patients suspected of having Burkitt Lymphoma with equivocal
results from core needle biopsy, repeat image guided core needle biopsy or perform surgical excision
biopsy of lymph nodes. (Moderate Quality Evidence; Strong Recommendation)

Recommendation 6: Morphological features are the cornerstone in the diagnosis of Burkitt Lymphoma.
If available, employ immunophenotypic, cytogenetic, and molecular tests to strongly establish or
validate the diagnosis. (High Quality Evidence; Strong Recommendation)

Recommendation 7: Among pediatric patients diagnosed to have BL, offer CT imaging or PET scan for
pretreatment staging and monitoring. If not available, ultrasound may be used. (High Quality Evidence;
Strong Recommendation)

Staging, Risk Classification, and Prognosis

Recommendation 8: Among pediatric patients diagnosed with Burkitt Lymphoma, we recommend using
the International Pediatric Non-Hodgkin Lymphoma Staging System. (High Quality Evidence; Strong
Recommendation)

Recommendation 9: Among pediatric patients diagnosed with Burkitt Lymphoma, the French-American-
British Mature B-Cell Lymphoma (FAB-LMB) or Berlin Frankfurt Munster (BFM) risk stratification can be used. (Moderate Quality Evidence; Strong Recommendation

Recommendation 10: In pediatric patients with Burkitt Lymphoma, identify the following prognostic
factors: extent of the disease (CNS and bone marrow involvement, minimal disseminated disease*), age
of patient at diagnosis, primary site of tumor, LDH level, presence of EBV*, and cytogenetic
abnormalities* (*depending on availability). (Moderate to High Quality Evidence; Strong
Recommendation).

Treatment and Side Effects

Recommendation 11: Among pediatric patients with newly diagnosed Burkitt Lymphoma with CNS
and/or bone marrow involvement Burkitt Lymphoma (Group C patients or R3-R4), offer treatment that includes Rituximab 375 mg/m2 x 4-6 doses added to systemic chemotherapy with FAB LMB Regimen
(High Quality Evidence) or BFM Regimen (Moderate Quality evidence; Strong Recommendation).

Recommendation 12: Among pediatric patients with newly diagnosed Burkitt Lymphoma with
Intermediate Risk (Group B) and Low Risk (Group A) or R1 and R2 risk stratification, offer treatment that
includes systemic chemotherapy with FAB LMB Regimen or BFM Regimen. (Moderate Quality Evidence;
Strong Recommendation)

Recommendation 13: Among pediatric patients with Burkitt Lymphoma undergoing treatment, watch
out for febrile neutropenia, hematologic toxicities (anemia, thrombocytopenia), infection, mucositis,
and tumor lysis syndrome which are the most common side effects. Monitor also for possible gastric
toxicities (diarrhea and constipation), kidney failure, and infusion-related reactions such as
hypersensitivity reactions and hypotension (usually associated with Rituximab) that are less common
side effects. (Moderate Quality Evidence; Strong Recommendation) Side Effects and Management

Recommendation 14: Among children with Burkitt Lymphoma undergoing chemotherapy, watch out for
the most common treatment-related infections such as febrile neutropenia and mucositis. (High Quality
Evidence; Strong Recommendation)

Recommendation 15: Among children with Burkitt Lymphoma who develop febrile neutropenia, offer
empiric antibiotic treatment. (High Quality Evidence; Strong Recommendation)

Recommendation 16: Among pediatric Burkitt Lymphoma patients with oral mucositis, offer
Chlorhexidine mouthwash and anti-fungal treatment. In addition, oral care, antivirals, pain management
using patient-controlled analgesia (PCA)/nurse-controlled analgesia (NCA) opioid administration, and
intravenous Ketamine can be used as supportive management. (High Quality evidence; Strong
recommendation)

Supportive and Palliative Care

Recommendation 17: Among Burkitt Lymphoma patients undergoing chemotherapy, consider
nutritional support from pre-induction through post chemotherapy as supportive management. Use
urate oxidase (Rasburicase) for the prevention and treatment of hyperuricemia in tumor lysis syndrome
(if not available, the alternative treatment is Allopurinol). (High Quality Evidence; Strong
Recommendation) Granulocyte colony- stimulating factor (GCSF) may reduce hospitalization days during
neutropenic episodes. (Moderate Quality Evidence; Strong Recommendation)

Recommendations 18: For Burkitt Lymphoma patients, recommend behavioral intervention like
distraction, paced breathing and positive reinforcement to reduce parental rated pain, parental anxiety
and usage of restraints during chemotherapy and cancer-related procedures. Counselling and skill-based
interventions that aim to improve resilience, quality of life and psychological distress should also be
offered. (Moderate Quality Evidence; Strong Recommendation)

Recommendation 19 - Palliative care may be offered to pediatric patients with Burkitt lymphoma to
improve overall quality of life and well-being. (Low Quality Evidence; Strong Recommendation)

Health System Recommendations

Recommendation 20: Treatment of pediatric Burkitt Lymphoma should be covered by PhilHealth and
other health insurance companies because it is cost effective (High Quality Evidence; Strong
Recommendation). It should also be emphasized that having insurance can increase overall survival rate
(Low Quality Evidence; Strong Recommendation).

Recommendation 21: Among pediatric patients suspected of having Burkitt Lymphoma, encourage
carers to improve their perspective of health-seeking behavior by participating in support groups and
thorough health education discussions. (Moderate Quality Evidence; Strong Recommendation)
Recommendation 22: Among pediatric patients suspected of having Burkitt Lymphoma, provide
assistance to affected families, by considering their non-medical needs such as transportation and/or
accommodation, access to financial assistance and psychosocial guidance. (Moderate Quality Evidence;
Strong Recommendation)

Every year, an estimated 400,000 children aged 0–19 years develop cancer globally. (Ward et
al., 2019) The Department of Health in the Philippines reported about 5,133 childhood cancer cases
annually and the most common cases include acute lymphocytic leukemia, acute myelogenous
leukemia, central nervous system (CNS) tumors, lymphoma, retinoblastoma, osteosarcoma, Wilms
tumor, rhabdomyosarcoma, and neuroblastoma. Non-Hodgkin lymphoma (NHL) is the fourth most
common malignant tumor in children. Burkitt lymphoma (BL) is the most common type of non-Hodgkin
lymphoma in children and adolescents (Miles et al., 2012) accounting for 30–50% of all pediatric
lymphomas. (Huang et al., 2015) BL is a fast-growing tumor and is associated with impaired immunity
and is rapidly fatal if left untreated. However, despite its fast-growing nature, BL is one of the most
curable forms of non-Hodgkin lymphoma. More than 90% of children with localized tumors and more
than 85% with widespread disease are cured. Determining the precise histology is critical because
clinical presentations and therapeutic strategies for the various lymphomas are distinct. Accurate and
reliable histopathology diagnosis is crucial for confirmation of BL. There is no single parameter used as
the gold standard for BL diagnosis. (Arber et al., 2000) The challenges of confidently establishing BL
diagnoses is considerable amid severe limitations especially in lower middle-income countries (LMIC)
such as the Philippines.

The Philippine Pediatric Society Disease Registry Program reported 403 cases of Burkitt
Lymphoma from 2016 until October 2021. Seventy-three cases were from Davao Southern Mindanao
Chapter. A total of 15 cases from 2013 to 2021 were diagnosed at the Southern Philippines Medical
Center Children’s Cancer Institute (SPMC-CCI). These numbers can be an underestimation of actual cases
of BL since the cases reported were mainly from tertiary training institutions. In addition, only a
proportion of the children who are registered receive appropriate treatment. From a survey of health
care workers in 10 LMICs, including Bangladesh, Philippines, Tanzania, and Vietnam, only 15–37 percent
of the expected patients were seen by health-care providers [WHO 2021], suggesting insufficient access
to appropriate care. (Ribeiro 2008 ) A child's probability of surviving cancer is dismal in less developed
countries, [Ma X, Liu Y, 2018] and extreme discomfort is likely in the absence of palliative care.
[American Cancer Society] Considering this situation and the lack of clinical practice guidelines for BL in
our country, Southern Philippines Medical Center organized a Technical Working Group to develop
Clinical Practice Guidelines (CPG) for Burkitt Lymphoma in children and adolescents. The aim was to
provide recommendations regarding clinical assessment, diagnostic and ancillary tests, risk stratification,
staging, prognosis, BL treatment and its side effects, supportive measures, palliative care and the
involvement of the health system in managing pediatric patients afflicted with BL. With this guideline,
we hope to improve quality of cancer care to BL patients that may bring better patient outcomes,
improve cost effectiveness, help authorities to decide on the approval of medicines, reagents and
devices, and eventually identify areas of needed research.

The SPMC-CCI BL Guideline Development group followed the guidelines set forth by the
Department of Health based on DOH Administrative Order No. 2021-0020 entitled Revised Guidelines
on National Practice Guideline Development, Adoption and Dissemination and the modified Grading of

Recommendations, Assessment, Development and Evaluation or the GRADE approach. Briefly the
following steps were done which will be elaborated in greater detail in the methodology section: 1)
Formation of the Technical Working Group, 2) Consultation with Care Providers, Patients and Families
and Formulation of Key Questions, 3) Searching, Selection and Assessment of the Evidence, 4)
Consensus Panel Review and Evidence to Decision, and 5) External Review and Updating of
Recommendations.

4.1 TARGET POPULATION

The clinical practice guideline is intended for newly diagnosed Burkitt's Lymphoma patients less than 19
years old. This will cover all stages of the disease. The clinical practice guideline does not address
relapsed or refractory Burkitt’s Lymphoma. Recommendations on how to treat these conditions will be
discussed in a separate clinical practice guideline. The clinical practice guideline does not address the
other types of lymphoma other than Burkitt’s Lymphoma.

4.2 TARGET USERS

The intended users are medical practitioners involved in the care of patients with Burkitt’s Lymphoma
namely primary care physicians and nurses, pediatric hematologist or oncologist, pathologists, palliative
care and social workers. The goal of this clinical practice guideline is to inform and provide the local
primary health care workers as well as the Specialists on current evidence-based practice on Burkitt’s
Lymphoma diagnosis and holistic management. This will assist them whenever they are faced with the
dilemma of identifying a source of guideline that are relevant to their specific question that is answered
by each recommendation. The primary health care physicians need to have an immediate and accurate
initial evaluation of a presenting symptom and may take some additional evaluation, such as laboratory
testing, imaging, and/or other diagnostic tests. A timely referral to Specialist is also warranted to treat
the patient with BL competently.

5.1 GENERAL OBJECTIVE

The main goal of the clinical practice guideline is to provide evidence-based recommendations
on the early identification, diagnosis, assessment, management and provision of psychosocial support
and quality of life for newly diagnosed Burkitt’s lymphoma aged 19 years and below and their family.

5.2 SPECIFIC OBJECTIVES

•  Provide and identify physical findings that can recognize early Burkitt’s lymphoma.
• Provide the most accurate diagnostic test for the diagnosis of Burkitt’s lymphoma
•  Determine ancillary tests that are helpful in the diagnosis of Burkitt's lymphoma.
• Determine the most effective treatment for Burkitt’s lymphoma including treatment related
  complications and toxicities.
• Provide recommendations on how to provide palliative care for patients diagnosed with Burtkitt
  Lymphoma

5.3 CLINICAL QUESTIONS ADDRESSED BY THE RECOMMENDATIONS

The population covered by this guideline are children at risk or diagnosed to have Burkitt’s
Lymphoma. clinical questions to be addressed with recommendations among newly diagnosed BL
patient below 19 years old were grouped into the following:

1. Among children at risk of developing Burkitt’s Lymphoma,
   • what are the early identification strategies?
   • what should be the clinical assessment for patients with BL?
2. Among children with clinical impression of Burkitt’s lymphoma, what are the diagnostic and
   ancillary tests for patients with BL?
   • what are the effective treatments and their complications?
   • what are the monitoring tests during and post treatment for BL?
   • what are the indicators of poor prognosis in BL?
3. Among children diagnosed to have Burkitt’s Lymphoma,
   • what are the effective treatments and their complications?
   • what are the monitoring tests during and post treatment for BL?
   • what are the indicators of poor prognosis in BL?
4. Among children undergoing treatment for Burkitt’s Lymph
   • what are the supportive managements in patients with BL?
   • should palliative care be integrated for patients with Burkitt Lymphoma?
   • is counselling effective in relieving psychosocial and spiritual distress among patients
     with Burkitt Lymphoma?
   • is national health insurance system and private insurance coverage for the treatment of
     BL cost effective?
   • what are the factors affecting adherence/compliance to therapy of BL patients and how
     do we address them?

6.1 TECHNICAL WORKING GROUP

This guideline development for BL in children was funded by the Department of Health (DOH). A
Steering Committee was formed from the Children’s Cancer Institute (CCI) of the SPMC Department of
Pediatrics assisted by the SPMC Training Office. The committee led the formation of the Technical
Working Group to develop the guideline. The team was composed of a multi-specialty group that
included pediatric oncologists, pediatric hematologists, clinical pathologists, palliative care specialists,
family physicians, nurses, medical technologists and other allied health professionals. The team also
hired an external consultant who is an experienced clinical epidemiologist and guideline developer. The
consultant guided the development process from start to finalization. The consultant also provided the
team orientation and training on guideline development including question formulation, literature
search, selecting, appraising and abstracting the evidence and the tools to be used such as GRADEPro
and AGREE. The GRADEPro was the tool used for summarizing and assessing the quality of the evidence,
while the AGREE was the standard used in writing the final guideline.

Conflicts of interest were also gathered by requiring the TWG and consensus panel members to
complete a conflict-of-interest form. Partial or full-time employment with a pharmaceutical or medical
device company at the time of guideline development was considered a direct conflict of interest and
was therefore ineligible for review of evidence, development of recommendation and consensus voting.
The members of the TWG were not employed by companies with interest in pharmaceuticals, medical
devices and diagnostics.

6.2 CONSENSUS PANEL

A Consensus Panel (CP) was convened to review the BL TWG recommendations. This consist of a
pediatric hematologist, oncologist, pathologist, hospital administrator and charity foundation officer to
represent community and family perspective. A draft document of the BL TWG recommendations and
supporting evidence was sent to all CP members to review in preparation for the online meetings. The
CP members were provided with a preliminary grading sheet that was populated prior to meeting and
results reviewed after TWG presentation and scientific literature evidence to recommendations. The CP
voted Weak, Moderate and Strong depending on the number of votes per recommendation.

In a manner similar to the TWG, conflicts of interest were also gathered from the consensus panel
using the same conflict-of-interest form. The members of the consensus panel were not employed by
companies with interest in pharmaceuticals, medical devices and diagnostics. They all declared to have
no direct conflict of interest.

6.3 CONSULTATION WITH CARE PROVIDERS, PATIENTS AND FAMILIES

The Technical Working Group consulted the target users of the guideline in a meeting. The
meeting discussed relevant decisions to be made by the health care provider for BL patients.
Consultations were also done with patients and families of children with BL. They are asked for relevant
information and health care services that they need. The results of these consultations were
summarized in the Appendix. From these consultations, the TWG was able to formulate the key
questions to be answered by the guidelines as shown in Box 1. These initial questions were further
refined as the search strategy, retrieval and appraisal of the evidence were being conducted.

7.1 CLINICAL ASSESSMENT

Recommendation 1: Among children suspected of having Burkitt Lymphoma, look for the following
during physical examination: abdominal masses; lymphadenopathy; head and neck masses; evidence
of bone marrow abnormalities like pallor, ecchymoses, bleeding, or petechiae; CNS involvement
findings such as headache, dizziness, vomiting, paralysis and paresthesia; ascites and pleural effusion.
(High Quality Evidence; Strong Recommendation)

Recommendation 2: Among children suspected of having Burkitt Lymphoma, ask for B symptoms in
the clinical history such as fever, night sweats and weight loss. (High Quality Evidence; Strong
Recommendation)

Recommendation 3: Aside from the common items in the history and physical examination
recommended above, the physician must also be aware of atypical presentations such as thyroid
mass, URTI, dyspnea, dysphagia, and cavernous sinus thrombosis. (High Quality Evidence; Strong
Recommendation)

Evidence to Recommendation on Clinical Assessment

seen by the medical community with symptoms affecting one or more anatomic sites. PubMed was
utilized in searching related articles, studies and journals. MeSH terms used are: "Burkitt lymphoma",
"signs and symptoms" and "children". A total of 28 studies reviewed, eight of which were selected.
All eight studies included with a total of 657 patients are of high-quality evidence. One high
quality study noted that B symptoms were noted in 35% (Huang et al., 2015). In terms of physical
examination findings, six high quality studies included abdominal tumors as one of the most common
clinical presentations (52% mean percentage) (Ertem et al., 1996; Mbulaiteye et al., 2009; Huang et al.,
2015; Cavdar et al., 1994; Zheng et al., 2019). Lymphadenopathies (38%) were cited in five high quality
studies (Mbulaiteye et al., 2009; Huang et al., 2015; Cavdar et al., 1994; Anavi et al., 1990). Head and
neck masses were mentioned in four studies (33%) (Ertem et al., 1996; Mbulaiteye et al., 2009; Cavdar
et al., 1994; Zheng et al., 2019). The less common clinical presentations of BL were bone marrow
abnormalities (16%), ascites (13% and CNS involvement (13%) and pleural effusion (11%) (Ertem et al.,
1996; Mbulaiteye et al., 2009; Cavdar et al., 1994; Anavi et al., 1990; Zheng et al., 2019). The rest of
the less common presentations of BL were liver involvement (6%), mediastinal (6%) and kidney
presentations (6%); ovarian mass, skin nodule (3.7%); and least are testis involvement and breast mass
(2.5%) (Ertem et al., 1996; Cavdar et al., 1994)

Table 5. Medicines and Side Effects

Drugs	Side Effects
Rituximab	Fever, chills, fatigue, hypotension and other infusion related symptoms, anaphylactoid events, tumor lysis syndrome, infections, febrile neutropenia or neutropenia
Vincristine	Local necrosis if extravasation occurs, jaw pain, paresis, constipation, neurotoxicity, alopecia, paralytic ileus, hyponatremia, SIADH
Vindesine	Paresthesia, autonomic neuropathy, cranial nerve toxicity, peripheral neuropathy, ileus, acute pneumonitis
Cyclophosphamide	Myelosuppression, nausea, vomiting, alopecia, hemorrhagic cystitis, sterility, hepatotoxicity, hypersensitivity, sterility, hyperpigmentation, secondary malignancies
Ifosfamide	Myelosuppression, nausea, vomiting, alopecia, cranial nerve toxicity, encephalopathy, hypersensitivity, hemorrhagic cystitis, renal toxicity
Doxorubicin	Local necrosis if extravasation occurs, cardiotoxicity, bone marrow suppression, mucosal ulceration, nausea, vomiting, alopecia, red or orange discoloration of urine
Etoposide	Gastric irritation, glycosuria, hyperglycemia, nausea, osteoporosis, irritability, headache, dizziness, increased appetite, sleeping problems, acne, weight gain (mainly in the face and abdomen), fluid and salt retention, hypertension, hypokalemia, increased white blood count but decreased numbers of infection-fighting cells, decreased muscle
Cytarabine	Hepatotoxicity, neurotoxicity, mucositis, liver dysfunction, bone marrow depression, renal failure, mucosal membrane inflammation, ulceration and bleeding, diarrhea, hyperpigmentation Intrathecal administration: Headache, stiff neck, lethargy, nausea, vomiting, confusion, seizures
Methotrexate	Bone marrow suppression, nausea, vomiting, oral ulceration, fever and arthralgia, diarrhea, mucosal membrane inflammation, ulceration, bleeding, alopecia, anemia, flu-like syndrome, encephalopathy, hypersensitivity, cerebellar syndrome Intrathecal administration: Headache, stiff neck, lethargy, nausea, and vomiting