Overview
An estimated 16,850 children and adolescents aged 19 years or younger will be diagnosed with cancer in the United States in 2020, and 1,730 will die of the disease.1 In those aged 14 or younger, non-Hodgkin lymphoma (NHL) accounts for 5% of cancers, whereas in adolescents aged 15 to 19 years, NHL accounts for 7%.1 The 5‐year relative survival rates for patients with NHL in these age groups are 91% and 88%, respectively.1 Pediatric aggressive mature B-cell lymphomas are the most common NHL types in children, and they include Burkitt lymphoma (BL) and diffuse large B-cell lymphoma (DLBCL).2
Three epidemiologic variants of BL exist: endemic, immunodeficiency-associated, and sporadic.3 The endemic form of BL is associated with Epstein-Barr virus (EBV) infection in approximately 95% of cases and occurs mainly in equatorial Africa, South America, Turkey, and Papua New Guinea, with presentation most commonly in the jaw, orbit, mesentery, and central nervous system (CNS). It is also often associated with malaria infection.4,5 In fact, endemic BL accounts for as many as 70% of childhood cancers in equatorial Africa, where malaria is highly prevalent and intense.6 Immunodeficiency-associated disease occurs primarily in people living with HIV, in whom it may be the initial AIDS-defining condition. Up to 70% of these patients test positive for EBV. Sporadic cases, about 15% of which are EBV+, mainly occur in North America and Europe and commonly present in the abdomen, lymph nodes, bone marrow, or cerebrospinal fluid (CSF). Endemic DLBCL has also been described and may be associated with EBV, hepatitis B virus (HBV), and/or John Cunningham virus infection.7–9 These guidelines do not address endemic or immunodeficiency-associated BL or DLBCL at this time.
This discussion summarizes the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Pediatric Aggressive Mature B-Cell Lymphomas. These guidelines are intended to provide guidance regarding pathology and diagnosis, staging, initial treatment, disease reassessment, surveillance, therapy for relapsed/refractory disease, and supportive care for clinicians who treat sporadic pediatric BL and DLBCL. These guidelines do not include recommendations for the management of patients with primary mediastinal B-cell lymphoma, who should be treated as per the adult NCCN Guidelines for B-Cell Lymphomas (available at NCCN.org). Pediatric BL and DLBCL are highly aggressive but curable, and the treatment is complex. It is preferred that treatment occur at centers with expertise in the management of these diseases.
The Pediatric Aggressive Mature B-Cell Lymphoma Panel considers pediatric to include any patient aged 18 years and younger, and adolescent and young adult (AYA) patients older than age 18 years who are treated in a pediatric oncology setting. Practice patterns vary from center to center in terms of whether AYA patients (defined by the National Cancer Institute as <39 years of age) with mature B-cell lymphoma are treated primarily by pediatric or adult oncologists. These guidelines are intended to apply to all pediatric patients and to AYA patients treated in a pediatric oncology setting who have good organ function. AYA patients treated in an adult oncology setting and those without good organ function should be treated as per the adult NCCN Guidelines for B-Cell Lymphomas (available at NCCN.org).
Medical practitioners should note that unusual patient scenarios (presenting in <5% of patients) are not specifically discussed in these guidelines and that all recommendations are classified as category 2A if not otherwise noted. Although the guidelines are believed to represent the optimal treatment strategy, the panel believes that, when appropriate, patients should preferentially be included in a clinical trial over standard or accepted therapy.
Literature Search Criteria and Guidelines Update Methodology
Before initial development of these NCCN Guidelines, an electronic search of the PubMed database was performed to obtain key literature using the following search terms: pediatric Burkitt lymphoma and pediatric diffuse large lymphoma. The PubMed database was chosen because it remains the most widely used resource for medical literature and indexes only peer-reviewed biomedical literature.10 The search results were narrowed by selecting studies in humans published in English.
The data from key PubMed articles and articles from additional sources deemed as relevant to these guidelines and discussed by the panel have been included in this version of the discussion section (eg, e-publications ahead of print, meeting abstracts). Recommendations for which high-level evidence is lacking are based on the panel’s review of lower-level evidence and expert opinion. The complete details of the development and update of the NCCN Guidelines are available on the NCCN website (NCCN.org).
Initial Presentation
Patients with DLBCL and BL may present with fever, chills, night sweats, unexplained/unintentional weight loss, painless regional or diffuse lymphadenopathy, fatigue, bone pain, and/or irritability. Extranodal involvement on presentation is common.11 Oncologic emergencies may also be the reason for initial presentation, because of the potential for complications of rapid tumor growth (ie, tumor lysis syndrome, superior vena cava syndrome, respiratory compromise, spinal cord compression). In addition, patients with abdominal tumors may have a history of abdominal pain/swelling, poor appetite/early satiety, constipation, and/or nausea/emesis.12 Intrathoracic masses can cause coughing, dyspnea, wheezing, stridor, chest pain, and/or reduced endurance. Tumors in the head and neck may be associated with swollen glands; swelling in the neck, jaw, gingival area, or maxilla; difficulty swallowing; choking; and/or vision changes. Finally, CNS involvement can lead to bladder or bowel dysfunction, lower extremity weakness, and/or headaches.
Pathology and Diagnosis
Excisional or incisional biopsy of the most accessible site is preferred, with fresh biopsy tissue sent to pathology in saline to ensure viable diagnostic tissue. Touch preparation for cytologic examination is recommended, and morphologic and immunohistochemistry review should be performed as clinically indicated.13 Immunophenotyping and cytogenetics are essential to establish a diagnosis of BL or DLBCL. However, definitive diagnosis may not be feasible before beginning treatment. Morphology and flow cytometry are the minimum methodologies from which to yield diagnostic information to begin treatment, especially if the patient is very sick. Malignant fluid cytology and flow cytometry may suffice.
Morphology
BL and DLBCL are morphologically distinct.14,15 Cytologically, BL lymphoid cells are intermediate in size (similar in size to a histiocyte nucleus) and have round nuclei, relatively coarse chromatin with multiple small nucleoli, and scant cytoplasm. Clear cytoplasmic vacuoles may be seen on Wright Giemsa-stained touch preparations. The cells of DLBCL are large with variable nuclear contours, condensed to vesicular chromatin, single or multiple nucleoli, and scant to moderately abundant cytoplasm. Cytoplasmic vacuoles are not typically present.
Tissue sections of BL and DLBCL are also distinctive.14–16 BL is composed of patternless sheets of lymphoid cells that appear to mold to one another (pseudo-cohesion). Scattered histiocytes with apoptotic debris in the cytoplasm (tingible-body macrophages) confer the so-called “starry sky” appearance indicative of high cell turnover. Pediatric BL tends to show little morphologic variation. The architecture of DLBCL also shows sheet-like growth, but the significant nuclear pleomorphism and scant to abundant cytoplasm confer a lighter color at low magnification. “Starry sky” appearance is generally not prominent.
Immunophenotyping
Immunophenotyping to establish a diagnosis of BL or DLBCL is performed by immunohistochemistry and flow cytometry.14,15 As mature B-cell lymphomas, BLs and DLBCLs express surface immunoglobulin and the surface B-cell marker CD20. All BLs and most DLBCLs also express CD10, a germinal center B-cell marker. They are both typically negative for terminal deoxynucleotidyl transferase, a marker of cellular immaturity, and negative for CD3, a T-cell marker. BLs are negative for BCL2 and positive for BCL6. Greater than or equal to 95% of BLs are Ki-67–positive. For DLBCL, expression of Ki-67, BCL2, and BCL6 is variable.
Cytogenetics
Fluorescence in situ hybridization for C-MYC rearrangement is also recommended for diagnosis of BL and DLBCL. BLs generally exhibit a simple karyotype, with MYC translocation involving an immunoglobulin gene as their sole abnormality.17–20 The karyotype of DLBCL is variable and may include rearrangements of MYC, BCL6, BCL2, and/or other IgH rearrangements.21–24 Double- and triple-hit lymphomas (ie, those with MYC rearrangement that also have BCL2 and/or BCL6 rearrangements) are rare in the pediatric BL and DLBCL populations, but may be more common in AYA patients.25–29 The recommended treatment of double- and triple-hit lymphomas in the pediatric patient population is the same as for other BLs and DLBCLs in the pediatric age group. Therefore, the treatment recommendations in these guidelines apply to double- and triple-hit lymphomas.
Demonstration of EBV association using EBV-encoded RNA by in situ hybridization may be performed in BL and DLBCL, if indicated by a history or suspicion of immunodeficiency. Historically, EBV expression was predominantly seen in the endemic form of BL. However, EBV-positive DLBCL and BL can be seen in pediatric patients without recognized immunodeficiency.15,30,31 Some evidence suggests that EBV positivity in sporadic BL may be associated with older age at diagnosis and higher incidence of nodal involvement.32
Burkitt-Like Lymphoma
In the absence of a C-MYC rearrangement, the diagnosis of Burkitt-like lymphoma with 11q aberration may be pursued.33,34 Burkitt-like lymphomas have a more complex karyotype than BL and are sometimes seen in the posttransplant setting.35,36 The epidemiology and natural history of this recently recognized entity has yet to be defined, but pediatric cases have been described.37–39 The recommended treatment of Burkitt-like lymphoma is the same as for BL.
Workup
Workup for patients with a diagnosis of BL or DLBCL is delineated in the guidelines. It includes history and physical exam, laboratory analysis, bilateral bone marrow aspirate and biopsy, lumbar puncture, and imaging. FDG-PET/CT or FDG-PET/MRI is recommended if available.40 However, treatment should not be delayed to obtain this scan, and FDG-PET does not exclude the need for full diagnostic quality, high-resolution CT or MRI (also see “Response Assessment,” page 1116). Information regarding bone marrow and CNS involvement and distant spread is important for staging (see “Staging and Risk Group Classification,” next section). CNS positivity is found in approximately 9% and 3% of pediatric patients with BL and DLBCL, respectively.41,42
In addition, a baseline echocardiogram or multigated acquisition scan is recommended, and fertility counseling should be offered with fertility preservation as clinically appropriate.
Staging and Risk Group Classification
Historically, the Murphy/St. Jude Childhood NHL staging classification, published in 1980, was used for staging of pediatric BL and DLBCL.43 A revised system, the international pediatric NHL staging system (IPNHLSS), was published in 2015.44 It addresses some limitations of the original system by including newer histologic entities; recognizing frequent skin, bone, kidney, ovarian, and other organ involvement; and accounting for improved detection of bone marrow and CNS involvement and distant spread. The panel supports use of the revised IPNHLSS, as detailed in the algorithm.
CNS Positivity
Patients with CNS involvement have stage IV disease. The CNS is considered involved if one or more of the following applies:
Any lymphoma cells by cytology in CSF
Any CNS tumor mass by imaging
Cranial nerve palsy (if not explained by extracranial tumor)
Clinical spinal cord compression
Parameningeal extension: cranial and/or spinal
Bone Marrow Positivity
Bone marrow involvement is defined by morphologic evidence of ≥5% lymphoma cells in a bone marrow aspirate.44 Patients with bone marrow involvement have stage IV disease. However, patients with any detectable bone marrow involvement should not be considered for Group A or Pediatric Oncology Group (POG) 9219 therapy.
Risk Groups
The panel’s treatment recommendations for pediatric patients with BL and DLBCL are based on the risk group classification used in the French-American-British/Lymphoma Malignancy B group FAB/LMB96 trial.45
Group A includes patients with completely resected stage I or completely resected abdominal stage II disease.
Group C includes patients with CNS involvement and/or with ≥25% lymphoma cells in the bone marrow.
Group B includes all patients not eligible for Group A or C.
Group B is further divided into low risk and high risk:
To qualify as low-risk Group B, the patient must have incompletely resected stage I or II disease or stage III disease if lactate dehydrogenase (LDH) is ≤2 times the upper limit of normal.
High-risk Group B includes patients with CNS-negative stage IV disease and bone marrow involvement of <25% and includes patients with stage III disease and LDH >2 times the upper limit of normal.
Initial Treatment
Systemic therapy is the mainstay of initial treatment of patients with BL or DLBCL based on many clinical trials, including those discussed subsequently. Several cooperative groups have been instrumental in establishing the standard regimens for these patients, including the Children’s Oncology Group (COG), the POG, the French Society of Pediatric Oncology, the Children's Cancer Group, the United Kingdom Children's Cancer Study Group, and the German Berlin-Frankfurt-Münster (BFM) group.
The intensive, multiagent regimens used as initial therapy are highly effective for most patients. For example, in the FAB/LMB96 study (see next section), only 2.5% of patients had refractory disease and 6.8% experienced disease relapse after complete response (CR) to initial therapy.46
Rituximab, a CD20-directed monoclonal antibody with indications in certain adults with NHL,47 may be included for low-risk Group B patients (see “Group B,” page 1113), and is recommended for patients with high-risk Group B and Group C disease.
Group A
Group A patients should receive the POG9219 regimen or the FAB/LMB96 regimen A if they are not enrolled in a clinical trial, with the exception of Group A patients with any detectable bone marrow disease, who should be treated as Group B.
The POG9219 regimen is based on 2 trials with a total of 340 pediatric patients with stage I or II NHL, resected or not (ie, Group A and low-risk Group B), conducted by the POG between 1983 and 1991.48 In the first trial, patients were randomized to receive induction and consolidation chemotherapy with or without radiation therapy (RT). In the second trial, all patients received induction and consolidation chemotherapy without RT, and those with complete remission after 9 weeks were randomized to continuation of therapy or no continuation. The chemotherapy regimen included vincristine, doxorubicin, cyclophosphamide, and prednisone. The 5-year rates of continuous complete remission were 89%, 86%, and 88%, respectively, for those who received 9 weeks of chemotherapy without RT, 8 months of chemotherapy without RT, and 8 months of chemotherapy with RT. These results indicate that 9 weeks of chemotherapy is sufficient in this group of patients.
The FAB/LMB96 international study included pediatric patients with all stages of NHL.49 All patients with resected stage I or completely resected abdominal stage II disease received 2 courses of COPAD (cyclophosphamide, vincristine, prednisone, and doxorubicin) without intrathecal therapy after surgery (Regimen A). After a median follow-up of 50.5 months, the 4-year event-free survival (EFS; with events defined as treatment failure for any reason) was 98.3% and overall survival (OS) was 99.2%.
Alternatively, an equivalent BFM regimen can be considered. The NHL-BFM95 trial was a randomized noninferiority study that compared methotrexate infused over 4 hours with a 24-hour infusion in patients with stage I or II B-cell NHL in an attempt to reduce toxicity.50 Patients in Group A received 2 cycles of chemotherapy; failure-free survival at 1 year in this group was 95% ± 5% (n=20) versus 100% (n=19) for the 4-hour and 24-hours arms, respectively, meeting the noninferiority endpoint. The incidence of grade 3/4 mucositis was significantly lower in the 4-hour arm in all risk groups.
Group B
Low-risk Group B patients with stage I or II disease can be treated with the POG9219 regimen as for patients with Group A disease (discussed previously), or with the COG ANHL1131 regimen B with or without rituximab. The latter regimen is the only recommended option for low-risk Group B patients with stage III disease and normal LDH levels (with or without rituximab) and for patients with high-risk Group B disease (with rituximab). Rituximab has not been tested in clinical trials for patients with low-risk Group B. However, in keeping with adult practice and data on efficacy and toxicity in high-risk patients (see following paragraphs), the panel deems the inclusion of rituximab in the treatment of this patient population to be appropriate.
COG ANHL1131 regimen B is based on that used for Group B patients in the FAB/LMB96 trial.51 In that trial, patients with Group B disease received COP reduction, followed by induction with two courses of COPADM with either full-dose or half-dose cyclophosphamide for those with good response, followed by consolidation with two courses of CYM, and then followed by maintenance or no maintenance for those with continued response. Intrathecal therapy was included. The results showed that treatment reductions did not have significant effects on EFS. Therefore, COG ANHL1131, a trial comparing EFS in pediatric patients with high-risk Group B or Group C NHL treated with and without rituximab, used the lower-intensity chemotherapy as its backbone.52
The use of rituximab in high-risk Group B patients is supported by the COG ANHL01P1 trial.53 In this international study of patients <30 years of age with high-risk (stage III/IV) Group B mature B-cell lymphoma, 45 patients received FAB/LMB96 chemotherapy plus rituximab. No serious adverse events were attributed to rituximab, and 3-year EFS was 93% (95% CI, 79%–98%). Likewise, initial results of the COG ANHL1131 trial support the improved efficacy of rituximab in addition to standard LMB therapy in children and adolescents with high-risk BL and DLBCL.54 This trial, which randomized 310 patients with high-risk mature B-cell lymphomas between standard LMB chemotherapy and the same chemotherapy with the addition of rituximab, demonstrated a 1-year EFS of 95% in the rituximab group versus 81.5% in the chemotherapy only group, a statistically significant difference.
The panel recommends COG ANHL1131 regimen B starting with a COP reduction phase with or without rituximab for patients in low-risk Group B and with rituximab for those in high-risk Group B. Those with <20% tumor reduction after COP start induction with R-COPADM1 of COG ANHL1131 regimen C1 CNS-negative with rituximab, even if rituximab was not included initially (see “Group C,” next page). Those with ≥20% tumor reduction after COP reduction proceed to COPADM1 induction of COG ANHL1131 regimen B with or without rituximab, based on initial therapy (ie, if rituximab was included at day 6 of COP reduction, it should be continued throughout therapy). A second response assessment is performed in these initial responders after consolidation 1. Those with CR continue regimen B with or without rituximab based on initial therapy, while those with a less than CR change to COG ANHL1131 regimen C1 CNS-negative with rituximab, starting with R-CYVE1 (see “Group C,” below).
Alternatively, an equivalent BFM regimen can be used. In the NHL-BFM95 trial (see “Group A,” page 1112), patients with nonresected stage I or stage II disease and those with stage III disease and LDH <500 U/L received 5 cycles of therapy, including a cytoreductive prephase.50 Failure-free survival at 1 year for the 4-hour versus the 24-hour infusion was 94% ± 2% versus 96% ± 2% in these patients. The NHL-BFM90 trial included a cytoreductive prephase, followed by 6 courses of chemotherapy with intrathecal therapy for patients with high-risk Group B and Group C disease.55 The 6-year pEFS was 78% ± 3% in this group of patients.
Group C
The recommended treatment regimens for patients in Group C are those being used in COG ANHL1131 (see previous sections) and are dependent on CNS and CSF involvement.52 These regimens are based on those used in the FAB/LMB96 trial, with omission of 2 maintenance cycles.45,51 The COG ANHL1131 Arm C1 CNS-positive regimen is an option for patients with CNS-positive disease, regardless of CSF positivity. Patients with CNS and CSF involvement can alternatively be treated according to the Arm C3 regimen. The relative efficacy of the C3 versus the C1 regimen for CSF-positive patients has not been established. Patients without CNS involvement should receive the Arm C1 CNS-negative regimen.
Rituximab should be included for all patients in Group C. The small COG ANHL01P1 study in pediatric patients with CNS and/or bone marrow-positive BL evaluated FAB/LMB96 chemotherapy with rituximab.56 The 3-year EFS/OS was 90% (95% CI, 76%–96%) in the 40 evaluable patients, and the regimen was well tolerated. In addition, a combined analysis of results from the inclusion of rituximab for patients with CNS involvement in the FAB/LMB96 C1 arm and COG ANHL01P1 showed that EFS and OS were improved with rituximab compared with historic LMB89 results.57 Other studies have also seen high cure rates with the use of rituximab in these patients.58,59 The randomized comparison of chemotherapy with and without rituximab in the COG ANHL1131 has been published only in abstract form to date.52
An equivalent BFM regimen can be used for patients in Group C. In the NHL-BFM90 and NHL-BFM95 trials, Group C patients received a cytoreductive prephase and 6 courses of chemotherapy.50,55
Response Assessment
Response assessment is critical during therapy for patients with pediatric aggressive mature B-cell lymphomas, especially for Group B patients on COG ANHL1131 regimen B, because their treatment depends on the level of response to early rounds of therapy.
Sites of original disease should be reassessed with radiologic studies as indicated (abdominal ultrasound, chest/abdominal/pelvic CT with contrast, and/or MRI of the head, neck, abdomen, and/or pelvis). Bone marrow and CSF studies should also be performed if they were initially involved.
FDG-PET/CT or FDG-PET/MRI may be considered if not obtained as part of diagnostic evaluation. FDG-PET should not replace imaging with contrast-enhanced diagnostic-quality CT or MRI. A patient's therapy should not be escalated based on FDG-PET alone. If a residual lesion is FDG-PET negative (Deauville 1, 2, or 360), biopsy is not necessary because of the high negative predictive value of FDG-PET.61–65 In the absence of clinical concern, FDG-PET does not need to be repeated once it is negative. It is important to note, however, that the positive predictive value of FDG-PET is fairly low.66 False-positive findings may include inflammation, necrotic tumor, reactive lymphadenitis, brown fat, thymic rebound, and secondary malignancy.
The panel recommends use of the International Pediatric NHL Response Criteria, as adapted in these guidelines.67 In the response criteria system, disease is classified as progressive disease, no response, minimal response, partial response, and CR. For patients with less than CR by these criteria at the end of therapy, the residual mass should be biopsied to confirm the presence or absence of residual disease. The majority of residual masses at the end of therapy are necrotic tumor.
Surveillance
As few as 5% of patients treated for BL or DLBCL experience a relapse.68,69 Most of these relapses occur in the first 6 months after treatment, with fewer than 10% of relapses occurring after 15 months.68,69 DLBCL relapses tend to occur later than BL relapses and may be seen up to 3 years after treatment. Treatment of relapsed disease can lead to sustained complete second remissions in some patients.68–73 Therefore, patients with a CR to initial treatment should undergo routine clinical surveillance.
A history and physical exam is recommended more frequently in the first 3 years, and then annually. A CBC with differential is recommended monthly until counts are normal, and then at each exam visit. Routine surveillance imaging is not recommended. FDG-PET/CT or FDG-PET/MRI and chest/abdominal/pelvic CT with contrast should only be considered if there is a clinical suspicion of relapse.74 Ultrasound of abdominal tumors is indicated 3 months after therapy if there is clinical concern.
In addition, patients should be monitored for late effects of treatment as per the COG Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers (available at www.survivorshipguidelines.org). In particular, attention should be paid to cardiac, gonadal, and neurocognitive function; bone health; and the risk for secondary leukemia.
Subsequent Therapy for Relapsed or Refractory Disease
Treatment of patients with relapsed or refractory disease is systemic therapy, with clinical trial participation preferred. Systemic therapy options for most patients are R-CYVE (if not previously received as part of initial therapy) or R-ICE. Consolidation therapy is recommended based on response (see later sections).
It is rare for patients who had Group A disease at initial diagnosis to relapse, and there are little data and no proven standard of care for these patients. For patients with a low risk of relapse (defined as patients with initial Group A disease or patients with low stage [stage I or II] Group B treated according to POG9219), chemotherapy regimens such as COG ANHL 1131 (arm C1 regimen) or 2 cycles of R-CYVE without consolidative transplant are options that can be considered.
CYVE and ICE were used in the relapse/refractory setting in the LMB89, LBM96, and LBM2001 studies with 29.9% 5-year survival rate for patients with relapses.68 After 1996, 16 relapsed/refractory patients received rituximab with CYVE or ICE. Six patients were in complete remission after relapse/refractory treatment, but there was no difference in survival rates between those that did and did not receive rituximab.68,69 A multicenter case series in the United Kingdom, however, demonstrated an association between rituximab and survival in the relapse/refractory setting.75 In a small COG study, patients with relapsed/refractory NHL received rituximab with ICE (ie, R-ICE).76 Toxicities were manageable. The CR/PR rate was 60% in 20 evaluable patients, with 30% able to complete consolidation therapy. In addition, a Japanese study reported a 73% response rate from 223 patients treated with R-ICE in this setting.77
Consolidation Therapy
Most patients with relapsed/refractory disease with a CR to systemic therapy should receive an autologous or allogeneic hematopoietic stem cell transplant (HSCT). The exception is for patients with Group A or stage I/II Group B disease at diagnosis (see “Subsequent Therapy for Relapsed or Refractory Disease,” page 1117). In the multicenter case series in the United Kingdom mentioned previously, 9 of 16 patients who received HSCT survived >6 years; no patient who did not receive transplant survived.75 In another case series, OS was better for patients who received transplant compared with patients who did not (P<.01).71 Other studies have also shown comparable survival rates for patients who undergo HSCT in this setting.70,73,78,79
No data support autologous versus allogeneic HSCT; therefore, the decision regarding type of transplant should be based on physician preference.78,80 For an allogeneic transplant, the best available donor should be used: generally, a human leukocyte antigen–matched related donor is the best option, followed by a human leukocyte antigen–matched unrelated donor, then cord blood or a haploidentical donor.81,82
Patients with a partial response to initial therapy for relapsed/refractory disease can also receive an autologous or allogeneic HSCT. For patients with partial response or less than a partial response, a clinical trial of second-line systemic therapy with incorporation of investigational agents can be considered, as can regimens and agents used for adults with relapsed/refractory DLBCL. Best supportive care is another option.
Supportive Care
Supportive care issues that are important in pediatric patients with cancer during treatment include management of pain, chemotherapy-induced nausea and vomiting, fatigue, anxiety and depression, fever and neutropenia, neurologic complications, dermatitis, and mucositis.83–86 The COG and others have evidence-based guidelines addressing some of these supportive care issues, as well as guidelines on antifungal prophylaxis, fertility preservation, and platelet transfusion.87–92 In addition, parents and other caregivers of children with cancer frequently experience distress, depression, and even symptoms of posttraumatic stress disorder due to the stress of watching a child suffering and endangered and the increased financial burden due to medical costs and disruptions in employment.84,93–95
Specific to the treatment regimens recommended for pediatric patients with BL or DLBCL, there is a high risk of serious infections associated with profound neutropenia and severe mucosal toxicity.96 Rituximab is associated with hepatitis B reactivation, and hepatitis B virus polymerase chain reaction monitoring and antiviral prophylaxis is recommended for HBsAg-positive patients.97 The “Principles of Supportive Care” in the algorithm (see supplemental online content at JNCCN.org) list other recommendations for infection prophylaxis and treatment of these patients.
Organ dysfunction and tumor mass effects can affect pediatric patients with BL and DLBCL, causing significant morbidity. Spinal cord compression, kidney injury and obstructive uropathy, intussusception, bowel obstruction, chest masses with risk of superior vena cava syndrome, and hepatopathy have been described.98,99 Chemotherapy should be started as soon as possible to preserve organ function and reduce complications for these patients.
Tumor Lysis Syndrome
One of the most critical supportive care needs of pediatric patients with BL and DLBCL is the prevention and management of tumor lysis syndrome (TLS). TLS results from spontaneous or therapy-induced rapid tumor necrosis and release of tumor cell contents into the blood stream.100,101 It can be asymptomatic or can cause major metabolic derangements leading to seizures, cardiac arrhythmias, acute renal failure, neuromuscular abnormalities, hypotension, and death. Risk factors include bulky disease at presentation, elevated LDH, oliguria, preexisting renal impairment, dehydration, and evidence of TLS before start of therapy.
Prophylaxis with allopurinol or rasburicase before start of systemic therapy is indicated for certain patients as described in the “Principles of Supportive Care” in the algorithm (see supplemental online content at JNCCN.org).102 Management of hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia associated with TLS is also described in that section of the algorithm.100,101,103,104
References
- 1.↑
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin 2020;70:7–30. https://www.ncbi.nlm.nih.gov/pubmed/31912902
- 2.↑
Sandlund JT, Martin MG. Non-Hodgkin lymphoma across the pediatric and adolescent and young adult age spectrum. Hematology (Am Soc Hematol Educ Program) 2016;2016:589–597. https://www.ncbi.nlm.nih.gov/pubmed/27913533
- 3.↑
Casulo C, Friedberg JW. Burkitt lymphoma- a rare but challenging lymphoma. Best Pract Res Clin Haematol 2018;31:279–284. https://www.ncbi.nlm.nih.gov/pubmed/30213397
- 4.↑
Moormann AM, Snider CJ, Chelimo K. The company malaria keeps: how co-infection with Epstein-Barr virus leads to endemic Burkitt lymphoma. Curr Opin Infect Dis 2011;24:435–441. https://www.ncbi.nlm.nih.gov/pubmed/21885920
- 5.↑
Gouveia MH, Bergen AW, Borda V, et al.. Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the “endemic Burkitt Lymphoma belt”. PLoS Genet 2019;15:e1008027. https://www.ncbi.nlm.nih.gov/pubmed/30849090
- 6.↑
Parkin DM, Sitas F, Chirenje M, et al.. Part I: Cancer in Indigenous Africans--burden, distribution, and trends. Lancet Oncol 2008;9:683–692. https://www.ncbi.nlm.nih.gov/pubmed/18598933
- 7.↑
Ren W, Ye X, Su H, et al.. Genetic landscape of hepatitis B virus-associated diffuse large B-cell lymphoma. Blood 2018;131:2670–2681. https://www.ncbi.nlm.nih.gov/pubmed/29545328
- 8.↑
Högfeldt T, Jaing C, Loughlin KM, et al.. Differential expression of viral agents in lymphoma tissues of patients with ABC diffuse large B-cell lymphoma from high and low endemic infectious disease regions. Oncol Lett 2016;12:2782–2788. https://www.ncbi.nlm.nih.gov/pubmed/27698858
- 9.↑
Nomura Y, Lavu EK, Muta K, et al.. Histological characteristics of 21 Papua New Guinean children with high-grade B-cell lymphoma, which is frequently associated with EBV infection. Pathol Int 2008;58:695–700. https://www.ncbi.nlm.nih.gov/pubmed/18844934
- 10.↑
U.S. National Library of Medicine-Key MEDLINE® Indicators. Available at: http://www.nlm.nih.gov/bsd/bsd_key.html. Accessed November 14, 2019.
- 11.↑
Chung EM, Pavio M. Pediatric extranodal lymphoma. Radiol Clin North Am 2016;54:727–746. https://www.ncbi.nlm.nih.gov/pubmed/27265605
- 12.↑
Miron I, Miron L, Lupu VV, et al.. Silent presentation of multiple metastasis Burkitt lymphoma in a child: a case report and review of the literature. Medicine (Baltimore) 2017;96:e7518. https://www.ncbi.nlm.nih.gov/pubmed/28700504
- 13.↑
Iyer VK. Pediatric lymphoma diagnosis: role of FNAC, biopsy, immunohistochemistry and molecular diagnostics. Indian J Pediatr 2013;80:756–763. https://www.ncbi.nlm.nih.gov/pubmed/23925793
- 14.↑
Swerdlow SH, Campo E, Harris NL, et al.., eds. Burkitt Lymphoma. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Vol. 2. Lyon, France: IARC; 2017 .
- 15.↑
Swerdlow SH, Campo E, Harris NL, et al.., eds. Diffuse Large B-Cell Lymphoma, NOS. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, Vol. 2. Lyon, France: IARC; 2017 .
- 16.↑
Huang H, Liu ZL, Zeng H, et al.. Clinicopathological study of sporadic Burkitt lymphoma in children. Chin Med J (Engl) 2015;128:510–514. https://www.ncbi.nlm.nih.gov/pubmed/25673455
- 17.↑
Boerma EG, Siebert R, Kluin PM, et al.. Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge. Leukemia 2009;23:225–234. https://www.ncbi.nlm.nih.gov/pubmed/18923440
- 18.↑
Maria Murga Penas E, Schilling G, Behrmann P, et al.. Comprehensive cytogenetic and molecular cytogenetic analysis of 44 Burkitt lymphoma cell lines: secondary chromosomal changes characterization, karyotypic evolution, and comparison with primary samples. Genes Chromosomes Cancer 2014;53:497–515. https://www.ncbi.nlm.nih.gov/pubmed/24590883
- 19.↑
Scholtysik R, Kreuz M, Klapper W, et al.. Detection of genomic aberrations in molecularly defined Burkitt’s lymphoma by array-based, high resolution, single nucleotide polymorphism analysis. Haematologica 2010;95:2047–2055. https://www.ncbi.nlm.nih.gov/pubmed/20823134
- 20.↑
Toujani S, Dessen P, Ithzar N, et al.. High resolution genome-wide analysis of chromosomal alterations in Burkitt’s lymphoma. PLoS One 2009;4:e7089. https://www.ncbi.nlm.nih.gov/pubmed/19759907
- 21.↑
Akyurek N, Uner A, Benekli M, et al.. Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Cancer 2012;118:4173–4183. https://www.ncbi.nlm.nih.gov/pubmed/22213394
- 22.↑
Barrans S, Crouch S, Smith A, et al.. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol 2010;28:3360–3365. https://www.ncbi.nlm.nih.gov/pubmed/20498406
- 23.↑
Clipson A, Barrans S, Zeng N, et al.. The prognosis of MYC translocation positive diffuse large B-cell lymphoma depends on the second hit. J Pathol Clin Res 2015;1:125–133. https://www.ncbi.nlm.nih.gov/pubmed/27347428
- 24.↑
Szczepanowski M, Lange J, Kohler CW, et al.. Cell-of-origin classification by gene expression and MYC-rearrangements in diffuse large B-cell lymphoma of children and adolescents. Br J Haematol 2017;179:116–119. https://www.ncbi.nlm.nih.gov/pubmed/28643426
- 25.↑
Johnson NA, Savage KJ, Ludkovski O, et al.. Lymphomas with concurrent BCL2 and MYC translocations: the critical factors associated with survival. Blood 2009;114:2273–2279. https://www.ncbi.nlm.nih.gov/pubmed/19597184
- 26.↑
Lu B, Zhou C, Yang W, et al.. Morphological, immunophenotypic and molecular characterization of mature aggressive B-cell lymphomas in Chinese pediatric patients. Leuk Lymphoma 2011;52:2356–2364. https://www.ncbi.nlm.nih.gov/pubmed/21740296
- 27.↑
Perry AM, Crockett D, Dave BJ, et al.. B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma: study of 39 cases. Br J Haematol 2013;162:40–49. https://www.ncbi.nlm.nih.gov/pubmed/23600716
- 28.↑
Snuderl M, Kolman OK, Chen YB, et al.. B-cell lymphomas with concurrent IGH-BCL2 and MYC rearrangements are aggressive neoplasms with clinical and pathologic features distinct from Burkitt lymphoma and diffuse large B-cell lymphoma. Am J Surg Pathol 2010;34:327–340. https://www.ncbi.nlm.nih.gov/pubmed/20118770
- 29.↑
Tomita N, Tokunaka M, Nakamura N, et al.. Clinicopathological features of lymphoma/leukemia patients carrying both BCL2 and MYC translocations. Haematologica 2009;94:935–943. https://www.ncbi.nlm.nih.gov/pubmed/19535347
- 30.↑
Nicolae A, Pittaluga S, Abdullah S, et al.. EBV-positive large B-cell lymphomas in young patients: a nodal lymphoma with evidence for a tolerogenic immune environment. Blood 2015;126:863–872. https://www.ncbi.nlm.nih.gov/pubmed/25999451
- 31.↑
Vaillant V, Reiter A, Zimmermann M, et al.. Seroepidemiological analysis and literature review of the prevalence of Epstein-Barr virus and herpesvirus infections in pediatric cases with non-Hodgkin lymphoma in Central Europe. Pediatr Blood Cancer 2019;66:e27752. https://www.ncbi.nlm.nih.gov/pubmed/30977593
- 32.↑
Satou A, Asano N, Nakazawa A, et al.. Epstein-Barr virus (EBV)-positive sporadic burkitt lymphoma: an age-related lymphoproliferative disorder? Am J Surg Pathol 2015;39:227–235. https://www.ncbi.nlm.nih.gov/pubmed/25321330
- 33.↑
Aukema SM, Theil L, Rohde M, et al.. Sequential karyotyping in Burkitt lymphoma reveals a linear clonal evolution with increase in karyotype complexity and a high frequency of recurrent secondary aberrations. Br J Haematol 2015;170:814–825. https://www.ncbi.nlm.nih.gov/pubmed/26104998
- 34.↑
Pienkowska-Grela B, Rymkiewicz G, Grygalewicz B, et al.. Partial trisomy 11, dup(11)(q23q13), as a defect characterizing lymphomas with Burkitt pathomorphology without MYC gene rearrangement. Med Oncol 2011;28:1589–1595. https://www.ncbi.nlm.nih.gov/pubmed/20661666
- 35.↑
Wagener R, Seufert J, Raimondi F, et al.. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 2019;133:962–966. https://www.ncbi.nlm.nih.gov/pubmed/30567752
- 36.↑
Yanik EL, Shiels MS, Smith JM, et al.. Contribution of solid organ transplant recipients to the pediatric non-hodgkin lymphoma burden in the United States. Cancer 2017;123:4663–4671. https://www.ncbi.nlm.nih.gov/pubmed/28759103
- 37.↑
Lones MA, Sanger WG, Le Beau MM, et al.. Chromosome abnormalities may correlate with prognosis in Burkitt/Burkitt-like lymphomas of children and adolescents: a report from Children’s Cancer Group Study CCG-E08. J Pediatr Hematol Oncol 2004;26:169–178. https://www.ncbi.nlm.nih.gov/pubmed/15125609
- 38.↑
Hutchison RE, Finch C, Kepner J, et al.. Burkitt lymphoma is immunophenotypically different from Burkitt-like lymphoma in young persons. Ann Oncol 2000;11(Suppl 1):S35–38. https://www.ncbi.nlm.nih.gov/pubmed/10707776
- 39.↑
Cairo MS, Sposto R, Perkins SL, et al.. Burkitt’s and Burkitt-like lymphoma in children and adolescents: a review of the Children’s Cancer Group experience. Br J Haematol 2003;120:660–670. https://www.ncbi.nlm.nih.gov/pubmed/12588354
- 40.↑
Riad R, Omar W, Kotb M, et al.. Role of PET/CT in malignant pediatric lymphoma. Eur J Nucl Med Mol Imaging 2010;37:319–329. https://www.ncbi.nlm.nih.gov/pubmed/19756591
- 41.↑
Salzburg J, Burkhardt B, Zimmermann M, et al.. Prevalence, clinical pattern, and outcome of CNS involvement in childhood and adolescent non-Hodgkin’s lymphoma differ by non-Hodgkin’s lymphoma subtype: a Berlin-Frankfurt-Munster Group Report. J Clin Oncol 2007;25:3915–3922. https://www.ncbi.nlm.nih.gov/pubmed/17761975
- 42.↑
Cairo MS, Sposto R, Gerrard M, et al.. Advanced stage, increased lactate dehydrogenase, and primary site, but not adolescent age (≥ 15 years), are associated with an increased risk of treatment failure in children and adolescents with mature B-cell non-Hodgkin’s lymphoma: results of the FAB LMB 96 study. J Clin Oncol 2012;30:387–393. https://www.ncbi.nlm.nih.gov/pubmed/22215753
- 43.↑
Murphy SB. Classification, staging and end results of treatment of childhood non-Hodgkin’s lymphomas: dissimilarities from lymphomas in adults. Semin Oncol 1980;7:332–339. https://www.ncbi.nlm.nih.gov/pubmed/7414342
- 44.↑
Rosolen A, Perkins SL, Pinkerton CR, et al.. Revised international pediatric non-Hodgkin lymphoma staging system. J Clin Oncol 2015;33:2112–2118. https://www.ncbi.nlm.nih.gov/pubmed/25940716
- 45.↑
Cairo MS, Gerrard M, Sposto R, et al.. Results of a randomized international study of high-risk central nervous system B non-Hodgkin lymphoma and B acute lymphoblastic leukemia in children and adolescents. Blood 2007;109:2736–2743. https://www.ncbi.nlm.nih.gov/pubmed/17138821
- 46.↑
Cairo M, Auperin A, Perkins SL, et al.. Overall survival of children and adolescents with mature B cell non-Hodgkin lymphoma who had refractory or relapsed disease during or after treatment with FAB/LMB 96: A report from the FAB/LMB 96 study group. Br J Haematol 2018;182:859–869. https://www.ncbi.nlm.nih.gov/pubmed/29984828
- 47.↑
Genentech, Inc. RITUXAN® (rituximab) injection, for intravenous use. 2019. Accessed November 14, 2019. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/103705s5457lbl.pdf
- 48.↑
Link MP, Shuster JJ, Donaldson SS, et al.. Treatment of children and young adults with early-stage non-Hodgkin’s lymphoma. N Engl J Med 1997;337:1259–1266. https://www.ncbi.nlm.nih.gov/pubmed/9345074
- 49.↑
Gerrard M, Cairo MS, Weston C, et al.. Excellent survival following two courses of COPAD chemotherapy in children and adolescents with resected localized B-cell non-Hodgkin’s lymphoma: results of the FAB/LMB 96 international study. Br J Haematol 2008;141:840–847. https://www.ncbi.nlm.nih.gov/pubmed/18371107
- 50.↑
Woessmann W, Seidemann K, Mann G, et al.. The impact of the methotrexate administration schedule and dose in the treatment of children and adolescents with B-cell neoplasms: a report of the BFM Group Study NHL-BFM95. Blood 2005;105:948–958. https://www.ncbi.nlm.nih.gov/pubmed/15486066
- 51.↑
Patte C, Auperin A, Gerrard M, et al.. Results of the randomized international FAB/LMB96 trial for intermediate risk B-cell non-Hodgkin lymphoma in children and adolescents: it is possible to reduce treatment for the early responding patients. Blood 2007;109:2773–2780. https://www.ncbi.nlm.nih.gov/pubmed/17132719
- 52.↑
Intergroup randomized trial for children or adolescents with B-cell non Hodgkin lymphoma or B-acute leukemia: Rituximab evaluation in high risk patients. Gustave Roussy, Cancer Campus, Grand Paris; Children's Oncology Group; 2017. Accessed May 24, 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT01516580
- 53.↑
Goldman S, Smith L, Anderson JR, et al.. Rituximab and FAB/LMB 96 chemotherapy in children with Stage III/IV B-cell non-Hodgkin lymphoma: a Children’s Oncology Group report. Leukemia 2013;27:1174–1177. https://www.ncbi.nlm.nih.gov/pubmed/22940833
- 54.↑
Minard-Colin V, Auperin A, Pillon M, et al.. Results of the randomized Intergroup trial Inter-B-NHL Ritux 2010 for children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and mature acute leukemia (B-AL): Evaluation of rituximab (R) efficacy in addition to standard LMB chemotherapy (CT) regimen [abstract]. J Clin Oncol 2016;34.15_suppl:10507. Available at: https://ascopubs.org/doi/abs/10.1200/JCO.2016.34.15_suppl.10507.
- 55.↑
Reiter A, Schrappe M, Tiemann M, et al.. Improved treatment results in childhood B-cell neoplasms with tailored intensification of therapy: a report of the Berlin-Frankfurt-Münster Group Trial NHL-BFM 90. Blood 1999;94:3294–3306. https://www.ncbi.nlm.nih.gov/pubmed/10552938
- 56.↑
Goldman S, Smith L, Galardy P, et al.. Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children’s Oncology Group Report. Br J Haematol 2014;167:394–401. https://www.ncbi.nlm.nih.gov/pubmed/25066629
- 57.↑
Frazer JK, Li KJ, Galardy PJ, et al.. Excellent outcomes in children and adolescents with CNS+ Burkitt lymphoma or other mature B-NHL using only intrathecal and systemic chemoimmunotherapy: results from FAB/LMB96 and COG ANHL01P1. Br J Haematol 2019;185:374–377. https://www.ncbi.nlm.nih.gov/pubmed/30117142
- 58.↑
Meinhardt A, Burkhardt B, Zimmermann M, et al.. Phase II window study on rituximab in newly diagnosed pediatric mature B-cell non-Hodgkin’s lymphoma and Burkitt leukemia. J Clin Oncol 2010;28:3115–3121. https://www.ncbi.nlm.nih.gov/pubmed/20516455
- 59.↑
Samochatova EV, Maschan AA, Shelikhova LN, et al.. Therapy of advanced-stage mature B-cell lymphoma and leukemia in children and adolescents with rituximab and reduced intensity induction chemotherapy (B-NHL 2004M protocol): the results of a multicenter study. J Pediatr Hematol Oncol 2014;36:395–401. https://www.ncbi.nlm.nih.gov/pubmed/23823112
- 60.↑
Meignan M, Gallamini A, Meignan M, et al.. Report on the first international workshop on interim-PET-scan in lymphoma. Leuk Lymphoma 2009;50:1257–1260. https://www.ncbi.nlm.nih.gov/pubmed/19544140
- 61.↑
Bailly C, Eugène T, Couec ML, et al.. Prognostic value and clinical impact of (18)FDG-PET in the management of children with Burkitt lymphoma after induction chemotherapy. Front Med (Lausanne) 2014;1:54. https://www.ncbi.nlm.nih.gov/pubmed/25593926
- 62.↑
Abdel Rahman H, Sedky M, Hamoda A, et al.. Role of FDG-PET scan in the management of pediatric mature B cell non-Hodgkin’s lymphoma. CCHE experience. J Egypt Natl Canc Inst 2016;28:95–99. https://www.ncbi.nlm.nih.gov/pubmed/27133974
- 63.↑
Bhojwani D, McCarville MB, Choi JK, et al.. The role of FDG-PET/CT in the evaluation of residual disease in paediatric non-Hodgkin lymphoma. Br J Haematol 2015;168:845–853. https://www.ncbi.nlm.nih.gov/pubmed/25382494
- 64.↑
Furth C, Erdrich AS, Steffen IG, et al.. Interim PET response criteria in paediatric non-Hodgkin’s lymphoma. Results from a retrospective multicenter reading. Nucl Med (Stuttg) 2013;52:148–156. https://www.ncbi.nlm.nih.gov/pubmed/23928982
- 65.↑
Karantanis D, Durski JM, Lowe VJ, et al.. 18F-FDG PET and PET/CT in Burkitt’s lymphoma. Eur J Radiol 2010;75:e68–e73. https://www.ncbi.nlm.nih.gov/pubmed/19716248
- 66.↑
Riad R, Omar W, Sidhom I, et al.. False-positive F-18 FDG uptake in PET/CT studies in pediatric patients with abdominal Burkitt’s lymphoma. Nucl Med Commun 2010;31:232–238. https://www.ncbi.nlm.nih.gov/pubmed/20032800
- 67.↑
Sandlund JT, Guillerman RP, Perkins SL, et al.. International pediatric non-Hodgkin lymphoma response criteria. J Clin Oncol 2015;33:2106–2111. https://www.ncbi.nlm.nih.gov/pubmed/25940725
- 68.↑
Jourdain A, Auperin A, Minard-Colin V, et al.. Outcome of and prognostic factors for relapse in children and adolescents with mature B-cell lymphoma and leukemia treated in three consecutive prospective “Lymphomes Malins B” protocols. A Société Française des Cancers de l’Enfant study. Haematologica 2015;100:810–817. https://www.ncbi.nlm.nih.gov/pubmed/25724577
- 69.↑
Rigaud C, Auperin A, Jourdain A, et al.. Outcome of relapse in children and adolescents with B-cell non-Hodgkin lymphoma and mature acute leukemia: A report from the French LMB study. Pediatr Blood Cancer 2019;66:e27873. https://www.ncbi.nlm.nih.gov/pubmed/31207026
- 70.↑
Fujita N, Mori T, Mitsui T, et al.. The role of hematopoietic stem cell transplantation with relapsed or primary refractory childhood B-cell non-Hodgkin lymphoma and mature B-cell leukemia: a retrospective analysis of enrolled cases in Japan. Pediatr Blood Cancer 2008;51:188–192. https://www.ncbi.nlm.nih.gov/pubmed/18428432
- 71.↑
Kim H, Park ES, Lee SH, et al.. Clinical outcome of relapsed or refractory burkitt lymphoma and mature B-cell lymphoblastic leukemia in children and adolescents. Cancer Res Treat 2014;46:358–365. https://www.ncbi.nlm.nih.gov/pubmed/25043820
- 72.↑
Hartmann O, Pein F, Beaujean F, et al.. High-dose polychemotherapy with autologous bone marrow transplantation in children with relapsed lymphomas. J Clin Oncol 1984;2:979–985. https://www.ncbi.nlm.nih.gov/pubmed/6381657
- 73.↑
Naik S, Martinez CA, Omer B, et al.. Allogeneic hematopoietic stem cell transplant for relapsed and refractory non-Hodgkin lymphoma in pediatric patients. Blood Adv 2019;3:2689–2695. https://www.ncbi.nlm.nih.gov/pubmed/31511228
- 74.↑
Eissa HM, Allen CE, Kamdar K, et al.. Pediatric Burkitt’s lymphoma and diffuse B-cell lymphoma: are surveillance scans required? Pediatr Hematol Oncol 2014;31:253–257. https://www.ncbi.nlm.nih.gov/pubmed/24087880
- 75.↑
Anoop P, Sankpal S, Stiller C, et al.. Outcome of childhood relapsed or refractory mature B-cell non-Hodgkin lymphoma and acute lymphoblastic leukemia. Leuk Lymphoma 2012;53:1882–1888. https://www.ncbi.nlm.nih.gov/pubmed/22448922
- 76.↑
Griffin TC, Weitzman S, Weinstein H, et al.. A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2009;52:177–181. https://www.ncbi.nlm.nih.gov/pubmed/18816698
- 77.↑
Osumi T, Mori T, Fujita N, et al.. Relapsed/refractory pediatric B-cell non-Hodgkin lymphoma treated with rituximab combination therapy: a report from the Japanese Pediatric Leukemia/Lymphoma Study Group. Pediatr Blood Cancer 2016;63:1794–1799. https://www.ncbi.nlm.nih.gov/pubmed/27314926
- 78.↑
Giulino-Roth L, Ricafort R, Kernan NA, et al.. Ten-year follow-up of pediatric patients with non-Hodgkin lymphoma treated with allogeneic or autologous stem cell transplantation. Pediatr Blood Cancer 2013;60:2018–2024. https://www.ncbi.nlm.nih.gov/pubmed/24038967
- 79.↑
Andion M, Molina B, Gonzalez-Vicent M, et al.. High-dose busulfan and cyclophosphamide as a conditioning regimen for autologous peripheral blood stem cell transplantation in childhood non-Hodgkin lymphoma patients: a long-term follow-up study. J Pediatr Hematol Oncol 2011;33:e89–e91. https://www.ncbi.nlm.nih.gov/pubmed/21358341
- 80.↑
Gross TG, Hale GA, He W, et al.. Hematopoietic stem cell transplantation for refractory or recurrent non-Hodgkin lymphoma in children and adolescents. Biol Blood Marrow Transplant 2010;16:223–230. https://www.ncbi.nlm.nih.gov/pubmed/19800015
- 81.↑
Tiercy JM. How to select the best available related or unrelated donor of hematopoietic stem cells? Haematologica 2016;101:680–687. https://www.ncbi.nlm.nih.gov/pubmed/27252513
- 82.↑
Lee CJ, Savani BN, Mohty M, et al.. Haploidentical hematopoietic cell transplantation for adult acute myeloid leukemia: a position statement from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Haematologica 2017;102:1810–1822. https://www.ncbi.nlm.nih.gov/pubmed/28883081
- 83.↑
Levine DR, Mandrell BN, Sykes A, et al.. Patients’ and parents’ needs, attitudes, and perceptions about early palliative care integration in pediatric oncology. JAMA Oncol 2017;3:1214–1220. https://www.ncbi.nlm.nih.gov/pubmed/28278329
- 84.↑
Olagunju AT, Sarimiye FO, Olagunju TO, et al.. Child’s symptom burden and depressive symptoms among caregivers of children with cancers: an argument for early integration of pediatric palliative care. Ann Palliat Med 2016;5:157–165. https://www.ncbi.nlm.nih.gov/pubmed/27199271
- 85.↑
Sung L, Zaoutis T, Ullrich NJ, et al.. Children’s Oncology Group’s 2013 blueprint for research: cancer control and supportive care. Pediatr Blood Cancer 2013;60:1027–1030. https://www.ncbi.nlm.nih.gov/pubmed/23255159
- 86.↑
Anghelescu DL, Faughnan LG, Jeha S, et al.. Neuropathic pain during treatment for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer 2011;57:1147–1153. https://www.ncbi.nlm.nih.gov/pubmed/21319291
- 87.↑
Lehrnbecher T, Robinson P, Fisher B, et al.. Guideline for the management of fever and neutropenia in children with cancer and hematopoietic stem-cell transplantation recipients: 2017 update. J Clin Oncol 2017;35:2082–2094. https://www.ncbi.nlm.nih.gov/pubmed/28459614
- 88.↑
Patel P, Robinson PD, Thackray J, et al.. Guideline for the prevention of acute chemotherapy-induced nausea and vomiting in pediatric cancer patients: A focused update [published online April 28, 2017]. Pediatr Blood Cancer doi: 10.1002/pbc.26542 https://www.ncbi.nlm.nih.gov/pubmed/28453189
- 89.↑
Sung L, Robinson P, Treister N, et al.. Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Support Palliat Care 2017;7:7–16. https://www.ncbi.nlm.nih.gov/pubmed/25818385
- 90.↑
Robinson PD, Oberoi S, Tomlinson D, et al.. Management of fatigue in children and adolescents with cancer and in paediatric recipients of haemopoietic stem-cell transplants: a clinical practice guideline. Lancet Child Adolesc Health 2018;2:371–378. https://www.ncbi.nlm.nih.gov/pubmed/30169270
- 91.↑
Diorio C, Robinson PD, Ammann RA, et al.. Guideline for the management of clostridium difficile infection in children and adolescents with cancer and pediatric hematopoietic stem-cell transplantation recipients. J Clin Oncol 2018;36:3162–3171. https://www.ncbi.nlm.nih.gov/pubmed/30216124
- 92.↑
Flank J, Robinson PD, Holdsworth M, et al.. Guideline for the treatment of breakthrough and the prevention of refractory chemotherapy-induced nausea and vomiting in children with cancer. Pediatr Blood Cancer 2016;63:1144–1151. https://www.ncbi.nlm.nih.gov/pubmed/26960036
- 93.↑
Kearney JA, Salley CG, Muriel AC. Standards of psychosocial care for parents of children with cancer. Pediatr Blood Cancer 2015; 62(S5, Suppl 5)S632–S683. https://www.ncbi.nlm.nih.gov/pubmed/26700921
- 94.↑
Choi EK, Yoon SJ, Kim JH, et al.. Depression and distress in caregivers of children with brain tumors undergoing treatment: psychosocial factors as moderators. Psychooncology 2016;25:544–550. https://www.ncbi.nlm.nih.gov/pubmed/26426911
- 95.↑
Warner EL, Kirchhoff AC, Nam GE, et al.. Financial burden of pediatric cancer for patients and their families. J Oncol Pract 2015;11:12–18. https://www.ncbi.nlm.nih.gov/pubmed/25316026
- 96.↑
Mikulska M, Lanini S, Gudiol C, et al.. ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52). Clin Microbiol Infect 2018;24(Suppl 2):S71–S82. https://www.ncbi.nlm.nih.gov/pubmed/29447988
- 97.↑
Barmettler S, Ong MS, Farmer JR, et al.. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open 2018;1:e184169. https://www.ncbi.nlm.nih.gov/pubmed/30646343
- 98.↑
Derinkuyu BE, Boyunağa Ö, Öztunalı Ç, et al.. Imaging features of Burkitt lymphoma in pediatric patients. Diagn Interv Radiol 2016;22:95–100. https://www.ncbi.nlm.nih.gov/pubmed/26611257
- 99.↑
Fallon SC, Redell MS, El-Bietar J, et al.. Intestinal perforation after treatment of Burkitt’s lymphoma: case report and review of the literature. J Pediatr Surg 2013;48:436–440. https://www.ncbi.nlm.nih.gov/pubmed/23414881
- 100.↑
Pession A, Masetti R, Gaidano G, et al.. Risk evaluation, prophylaxis, and treatment of tumor lysis syndrome: consensus of an Italian expert panel. Adv Ther 2011;28:684–697. https://www.ncbi.nlm.nih.gov/pubmed/21779956
- 101.↑
Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med 2011;364:1844–1854. https://www.ncbi.nlm.nih.gov/pubmed/21561350
- 102.↑
Galardy PJ, Hochberg J, Perkins SL, et al.. Rasburicase in the prevention of laboratory/clinical tumour lysis syndrome in children with advanced mature B-NHL: a Children’s Oncology Group Report. Br J Haematol 2013;163:365–372. https://www.ncbi.nlm.nih.gov/pubmed/24032600
- 103.↑
Coiffier B, Altman A, Pui CH, et al.. Guidelines for the management of pediatric and adult tumor lysis syndrome: an evidence-based review. J Clin Oncol 2008;26:2767–2778. https://www.ncbi.nlm.nih.gov/pubmed/18509186
- 104.↑
Cairo MS, Coiffier B, Reiter A, et al.. Recommendations for the evaluation of risk and prophylaxis of tumour lysis syndrome (TLS) in adults and children with malignant diseases: an expert TLS panel consensus. Br J Haematol 2010;149:578–586. https://www.ncbi.nlm.nih.gov/pubmed/20331465
NCCN CATEGORIES OF EVIDENCE AND CONSENSUS
Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise noted.
Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult theNCCN Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their application or use in any way.
The complete NCCN Guidelines for Head and Neck Cancers are not printed in this issue of JNCCN but can be accessed online at NCCN.org.
© National Comprehensive Cancer Network, Inc. 2020. All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.
Disclosures for the NCCN Pediatric Aggressive Mature B-Cell Lymphomas Panel
At the beginning of each NCCN Guidelines Panel meeting, panelmembers reviewall potential conflicts of interest.NCCN, in keeping with its commitment to public transparency, publishes these disclosures for panel members, staff, and NCCN itself.
Individual disclosures for the NCCN Pediatric Aggressive Mature B-Cell Lymphomas Panel members can be found on page 1123. (The most recent version of these guidelines and accompanying disclosures are available at NCCN.org.)
The complete and most recent version of these guidelines is available free of charge at NCCN.org.
