Paediatric Aggressive Mature B Cell Non-Hodgkin Lymphoma (Burkitt lymphoma)

- Acknowledgment

We would like to acknowledge the Guidelines Development Group (GDG) of Paediatric Oncology for adapting this Guideline.

• Chair of the Committee:

Prof Alaa El-Haddad (Professor of Paediatric Oncology and Former Dean of the National Cancer Institute - Cairo University, Head of the Paediatric Oncology Department and the Bone Marrow Transplant Unit at the Children’s Cancer Hospital Cairo, Egypt).

 • The Scientific Committee Members:

Prof Iman Sidhom (Professor and Head of Department of Paediatric Oncology - National Cancer Institute - Cairo University).

Prof Emad Ebied (Deputy Director, National Cancer Institute and Professor of Paediatric Oncology - National Cancer Institute - Cairo University).

Prof Mahmoud Hammad (Committee Rapporteur and Professor of Paediatric Oncology - National Cancer Institute - Cairo University - and Director of the Oncology and Nuclear Medicine Centre at Nasser Institute Hospital).

Prof Youssef Madney (Professor of Paediatric Oncology - National Cancer Institute - Cairo University - and Consultant of Paediatric Oncology at Dar Al Salam Cancer Hospital Harmal).

Dr Ahmed Mustafa (Lecturer of Paediatric Oncology - National Cancer Institute - Cairo University - and Assistant Head of the Specialized Medical Centres Secretariat for Oncology Affairs).

Dr Zaki Ahmed Zaki (Consultant and Director, Haematology Unit at Sheikh Zayed Specialized Hospital).

Dr Amal Ahmed Zein (Paediatric Oncology Consultant at Al-Sahel Teaching Hospital- and at Oncology Centre of Nasser Institute Hospital).

Prof Shady Fadel (Assistant Professor, Faculty of Medicine, Alexandria University - Director and Head, Paediatric Oncology Department, Borg El Arab Hospital).

Dr Mahmoud Motaz (Lecturer, South Egypt Oncology Institute, Assiut University, Medical Director and Head of the Paediatric Oncology Department at Shifa Al Orman Oncology Centre).

Dr Ebtehal Mahmoud Ali (Assistant lecturer of Paediatric Oncology at National Cancer Institute – Cairo University).

Dr Mai Mamdouh (Clinical Pharmacist, Paediatric Oncology, Dar El Salam Cancer Hospital Harmal).

- Abbreviations

BM (bone marrow)

CNS (central nervous system)

COG (Children’s Oncology Group)

COP (cyclophosphamide, vincristine, prednisone)

COPAD (cyclophosphamide, vincristine, prednisone, and doxorubicin)

COPADM₃ (cyclophosphamide, vincristine, prednisone, doxorubicin, and 3-gram methotrexate)

COPADM₈ (cyclophosphamide, vincristine, prednisone, doxorubicin, and 8-gram methotrexate)

CR (complete remission)

CRb (complete response biopsy negative)

CRu (complete response unconfirmed)

CSF (cerebrospinal fluid)

CT (computed tomography)

CYM (cytarabine and methotrexate)

CYVE (Cytarabine, Etoposide)

EFS (event-free survival)

FAB (French American-British)

FDG (fluorodeoxyglucose F18)

IHC (immunohistochemistry)

IT (intrathecal)

LDH (lactate dehydrogenase)

LMB (Lymphoma Malignancy B)

LN (lymph node)

MR (minor response)

MRI (magnetic resonance imaging)

NCCN (National Comprehensive Cancer Network)

NHL (non-Hodgkin lymphoma)

NR (no response)

PD (progressive disease)

PET (positron emission tomography)

PR (partial response)

RT (radiation therapy)

SPD (sum of product of greatest perpendicular diameters)

ULN (upper limit of normal)

- Glossary

Sequence 1: Includes prednisolone, cyclophosphamide, doxorubicin, methotrexate, Vincristine. ⁽¹⁾

Sequence 2: Includes cytarabine and etoposide. ⁽¹⁾

Positive FDG-PET/CT: Residual lesion is Deauville score more than 3. ⁽²⁾

Negative FDG-PET/CT: Residual lesion is Deauville score < 3. ⁽²⁾

Risk group definitions ⁽¹⁾

Group A

· Completely resected stage I

or

· Completely resected abdominal stage II

Group B (Low risk)

· Unresected stage I and non-abdominal stage II

or

·  stage III with low LDH (≤2 times [ULN])

Group B (High risk)

· Stage III with high LDH (>2 times ULN),

or

· All non-CNS stage IV with bone marrow involvement (<25% lymphoma cells)

· Achieving more than 20% regression after COP

Group C

· Any CNS involvement and/or Bone marrow involvement (≥25% lymphoma cells)

· Achieving less than 20% regression after COP

International Paediatric NHL Response criteria ⁽³⁾:

CR

·  Disappearance of all disease

·  CT or MRI reveals no residual and no new lesions

·  Residual mass pathologically negative for disease BM and CS free of disease pathologically

CRb

· Residual mass with no pathologic evidence of disease from limited or core biopsy; no new lesions by imaging examination

·  BM and CSF free of disease pathologically

·  No new and/or progressive disease elsewhere

CRu

· Residual mass negative by FDG-PET; no new lesions by imaging examination

· BM and CS free of disease pathologically

·  No new and/or progressive disease elsewhere

PR

· At least 50% decrease in SPD on CT or MRI; FDG-PET may be positive (Deauville score 4 or 5 with reduced lesional uptake compared to baseline)

· May have evidence of disease in BM or CSF if present at diagnosis but should have 50% reduction in percentage of lymphoma cells.

· No new and/or progressive disease

MR

· Decrease in SPD >25%, but <50% on CT or MRI

·  May have evidence of disease in BM or CS if present at diagnosis, but should have 25% to 50% reduction in percentage of lymphoma cells

·  No new and/or progressive disease

NR

· Not meeting CR, PR, MR, or PD criteria

PD

· >25% increase in SPD on CT or MRI; Deauville score 4 or 5 on FDG-PET with increase in lesional uptake from baseline; or new morphologic disease in BM or CSF

- Executive Summary

This guidance provides a data-supported approach to the diagnosis, risk stratification, treatment and follow up of paediatric patients diagnosed with Burkitt lymphoma.

- Introduction

NHL accounts for approximately 8–10% of all paediatric malignancies and comprises a heterogeneous group of lymphoid neoplasms with diverse clinicopathological and biological profiles. Burkitt lymphoma constitutes around 40% of paediatric NHL cases in developed countries. Despite its aggressive behaviour and high-grade pathology, paediatric survival rates for BL have markedly improved due to significant advances in multi-agent chemotherapy regimens and enhanced supportive care protocols. In high-resource settings, the event-free survival (EFS) now ranges from 80-90%, depending on both the stage of the disease at diagnosis and the primary anatomical site of involvement. ⁽⁴⁾⁽⁵⁾

- Scope and purpose

This guideline was developed aiming to enhance the quality of care for paediatric Burkitt lymphoma (NHL) patients by establishing a consistent standard of care nationwide. They focus on aiding in the early diagnosis, treatment, and follow-up of Burkitt lymphoma to achieve better clinical outcomes.

Clinicians who are involved in the care and treatment of patients with Burkitt lymphoma (NHL), including paediatric oncologists, surgeons, radiologists, pathologists, and palliative care specialists.

- Methodology

A comprehensive search for guidelines was undertaken to identify the most

relevant guidelines to consider for adaptation.

◾ inclusion/exclusion criteria followed in the search and retrieval of

guidelines to be adapted:

- Selecting only evidence-based guidelines (guideline must include a

 report on systematic literature searches and explicit links between

 individual recommendations and their supporting evidence).

- Selecting only national and/or international guidelines.

- Specific range of dates for publication (using Guidelines published or

 updated 2015 and later).

- Selecting peer reviewed publications only.

- Selecting guidelines written in English language.

- Excluding guidelines written by a single author not on behalf of an

 organization in order to be valid and comprehensive, a guideline

 ideally requires multidisciplinary input.

- Excluding guidelines published without references as the panel needs

 to know whether a thorough literature review was conducted and

 whether current evidence was used in the preparation of the

 recommendations.

◾ All retrieved Guidelines were screened and appraised using AGREE II

instrument (www.agreetrust.org) by at least two members. the panel decided

a cut-off points or rank the guidelines (any guideline scoring above 50% on

the rigour dimension was retained)

The NCCN guidelines are the main source used while formulating the national guidelines for Burkitt lymphoma (NHL).

◾ Evidence assessment

According to WHO handbook for Guidelines we used the GRADE (Grading

of Recommendations, Assessment, Development and Evaluation) approach

to assess the quality of a body of evidence, develop and report

recommendations. GRADE methods are used by WHO because these

represent internationally agreed standards for making transparent

recommendations. Detailed information on GRADE is available through the

on the following sites:

. GRADE working group: http://www.gradeworkingroup.org

 . GRADE online training modules: http://cebgrade.mcmaster.ca/

 . GRADE profile software: http://ims.cochrane.org/revman/gradepro

◾ Table 1: Quality of evidence in GRADE

The strength of the recommendation

The strength of a recommendation communicates the importance of adherence to the recommendation:

➡️Strong recommendations

With strong recommendations, the guideline communicates the message that

the desirable effects of adherence to the recommendation outweigh the

undesirable effects. This means that in most situations the recommendation

can be adopted as policy.

➡️Conditional recommendations

These are made when there is greater uncertainty about the four factors

above or if local adaptation must account for a greater variety in values and

preferences, or when resource use makes the intervention suitable for some,

but not for other locations. This means that there is a need for substantial

debate and involvement of stakeholders before this recommendation can be

adopted as policy.

 When not to make recommendations.

When there is lack of evidence on the effectiveness of an intervention, it may

be appropriate not to make a recommendation.

- Recommendations

1-Work up for newly diagnosed NHL

Pathology specimen is recommended with the proper IHC.

strong recommendation, high quality level of evidence (ICC report) ⁽⁶⁾

We recommend whole body FDG- PET CT if available otherwise contrast enhanced CT neck, chest, abdomen and pelvis is recommended.

strong recommendation, high quality level of evidence (COG report, retrospective analysis, retrospective analysis,) ^{(7)(8)(9)(10)}

Bilateral bone marrow aspiration and biopsy is recommended as well as CSF examination.

strong recommendation, high quality level of evidence (prospective trial, retrospective review) ^(11)(12)

2-Treatment of clinical group A

Two 21-day cycles COPAD are recommended

strong recommendation, high quality level of evidence (prospective trials, multinational cooperative trial) ^(13)(14)(15)

Response assessment is recommended to include imaging of the primary site.

strong recommendation, high quality level of evidence (COG report, retrospective analysis) ⁽⁷⁾⁽⁹⁾

3-Treatment of clinical group B

Multiagent chemotherapy is recommended starting with pre phase COP Followed by response assessment post COP. Then administer 2 induction courses COPADM₃ and two consolidation courses CYM.

strong recommendation, high quality level of evidence (prospective trial, prospective randomised trial) ^(11)(14)

Contrast enhanced CT neck, chest, abdomen and pelvis is recommended for response assessment after COP and FDG- PET/CT is recommended for assessment after CYM I.

strong recommendation, high quality level of evidence (prospective trial, prospective randomised trial) ^(10)(12)

Response assessment after CYM I:

· If in CR, then continuation of CYM II is recommended.

· If not in CR, biopsy is recommended. If biopsy is not feasible then continue as group B if PET/CT is negative. Upgrade to group C if biopsy is viable or PET/CT is positive.

strong recommendation, high quality level of evidence (prospective trial, prospective randomised trial) ^(11)(14)

Rituximab addition to chemotherapy is recommended in all high-risk group B

strong recommendation, high quality level of evidence (international prospective randomised trial) ⁽¹⁵⁾

4-Treatment of clinical group C

Multiagent chemotherapy should be initiated with pre phase R-COP, followed by 2 induction courses (R-COPADM₈), 2 consolidation courses (R-CYVE) and 2 maintenance courses (Sequences 1 and 2).

strong recommendation, high quality level of evidence (prospective trial, randomised trial) ^(12)(16)

Rituximab addition to chemotherapy is recommended for all group C patients

strong recommendation, high quality level of evidence (COG report) ⁽¹⁷⁾

For Group C CNS disease: We recommend a total of 3 intrathecals in pre phase COP and high dose methotrexate after CYVE I

strong recommendation, high quality level of evidence (Randomised trial, international randomised trial) ^(16)(18)

5-End of treatment evaluation

End of treatment evaluation should be done and if in CR then follow up is recommended

If not in CR, repeat biopsy from suspicious lesions, and if relapse is confirmed, start relapse protocol.

strong recommendation, high quality level of evidence (COG report, prospective randomised trial) ^(7)(12)

6-Treatment of relapse or refractory disease

Combination chemotherapy is recommended with regimen:

(R-ICE) Rituximab, ifosfamide, carboplatin, etoposide and intrathecal chemotherapy

strong recommendation, high quality level of evidence (COG report, retrospective analysis of multicentre trial) ^(19)(20)

7- Surveillance (follow up after end of treatment)

Routine scans are not recommended unless clinically suspicious. Monthly clinical examination is recommended for the first 3 years then annually.

Conditional recommendation, moderate quality level of evidence (retrospective analysis) ⁽²¹⁾

Clinical indicators for monitoring:

· Contrast enhanced CT neck, chest, abdomen and pelvis initially.

· Confirmed Pathology.

· CSF analysis initially.

· Bone marrow aspiration and biopsy.

· Evaluation by imaging of primary site after COP in groups B and C.

· Evaluation after CYM I by imaging of primary site.

Update of this guideline

This guideline will be updated whenever there is new evidence.

- Annexes

Staging of NHL according to international paediatric NHL staging system ⁽²²⁾

Stage I:

·  A single tumour not in the mediastinum and abdomen.

Stage II:

·  A single extra nodal tumour with regional LN involvement

·  Two or more nodal areas on the same side of the diaphragm

·  A primary gastrointestinal tract tumour (usually in the ileocecal area, with or without involvement of associated mesenteric nodes, that is completely resectable (if ascites or extension of the tumour to adjacent organs, it should be regarded as stage III)

Stage III:

· Two or more extra nodal tumours (including bone or skin)

·  Two or more nodal areas above and below the diaphragm

·  Any intrathoracic tumour (mediastinal, hilar, pulmonary, pleural, or thymic)

· Intra-abdominal and retroperitoneal disease, including liver, spleen, ovary, and/or kidney localizations, regardless of degree of resection.

· Any paraspinal or epidural tumour, whether or not other sites are involved.

· Single bone lesion with concomitant involvement of extra-nodal and/or non-regional nodal sites.

Stage IV:

· Any of the above findings with initial involvement of the CNS, bone marrow, or both.

Stage IV, due to CNS disease is considered if one or more of the following applies

· Any lymphoma cells by cytology in CSF.

· Any CNS tumour mass by imaging.

· Cranial nerve palsy (if not explained by extracranial tumour).

· Clinical spinal cord compression.

· Parameningeal extension: cranial and/or spinal

Stage IV disease, due to bone marrow involvement

 Defined by morphologic evidence of any lymphoma cells in a bone marrow aspirate.

- References

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