INTRODUCTION — Burkitt lymphoma (BL) is a highly aggressive B cell neoplasm characterized by the translocation and deregulation of the MYC gene on chromosome 8. Three distinct clinical forms of BL are recognized: endemic, sporadic, and immunodeficiency-associated. Although these differ in their epidemiology, clinical presentation, and genetic features, they are histologically identical and have similar clinical behavior. All three clinical forms are generally treated in a similar fashion.
BL and Burkitt leukemia are classified as different manifestations of the same disease. Diagnostic criteria have evolved to incorporate immunohistochemical, cytogenetic, and molecular diagnostic techniques. As such, many older studies included a heterogeneous patient population that contained many patients that would not be diagnosed with BL by current criteria.
The treatment of BL is presented here. The epidemiology, clinical presentation, and genetic features are discussed separately. (See "Epidemiology, clinical manifestations, pathologic features, and diagnosis of Burkitt lymphoma".)
Oncologic emergencies and treatment-related hematologic toxicities are common in the highly aggressive NHLs. Physicians must always be alert to their potential presence, and be prepared to deal with them urgently and effectively. In particular, patients with BL are at high risk for the development of tumor lysis syndrome (TLS). Prophylactic therapy for and management of TLS is presented in detail separately. (See "Tumor lysis syndrome: Pathogenesis, clinical manifestations, definition, etiology and risk factors" and "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Oncologic emergencies'.)
PRETREATMENT EVALUATION — The pretreatment evaluation both determines the bulk of disease and provides information about the individual's comorbidities that are likely to have an impact on treatment options. In addition to a history and physical examination, it is our practice to perform the following pretreatment studies in patients with BL:
●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), hepatitis B, HIV, and uric acid. (See "Hepatitis B virus reactivation associated with immunosuppressive therapy".)
●Unilateral bone marrow biopsy is recommended for all patients.
●Lumbar puncture is recommended for all patients but may be performed at the start of therapy if intrathecal chemotherapy is a component of the treatment regimen. Cerebrospinal fluid should be sent for both cytology and flow cytometry. (See 'CNS involvement' below.)
●A diagnostic positron emission tomography (PET)/computed tomography (CT) examination should be performed prior to initiation of treatment, if possible. CT scans of the chest, abdomen, and pelvis are an acceptable alternative. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas", section on 'Imaging'.)
●A study of cardiac ejection fraction (eg, echocardiogram or MUGA) should be performed if anthracyclines are used. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
●Men and women of child-bearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures. Given the urgent need for treatment with BL, options for women are limited, but men can often participate in sperm banking. (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)
General approaches to the diagnostic work-up and staging of non-Hodgkin lymphoma are presented separately (table 1). (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma" and "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)
There is a significant risk of tumor lysis syndrome in patients treated for BL. This syndrome is best prevented via appropriate treatment with aggressive intravenous hydration, rasburicase, and correction of any prior electrolyte disturbances and elements of reversible renal failure (table 2). (See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)
INITIAL TREATMENT — The standard of care for BL has yet to be defined and our preferred treatment approach is to enroll patients in well-controlled cooperative research trials. However, for patients who are not candidates for such trials or for those who choose not to participate, we use aggressive combination chemotherapy with central nervous system (CNS) prophylaxis. Dose reduction should be avoided if at all possible and therapy should be initiated quickly. At our institutions, we aim to start therapy within 48 hours of encountering a patient with suspected BL.
As response to chemotherapy is rapid and disease is inevitably diffuse, there is no role for radiation therapy in BL, even in patients with localized disease. In addition, surgery is no longer employed in BL. Most patients with BL can be treated according to the method outlined below. Patients with AIDS-related lymphoma, cardiac disease, central nervous system involvement at presentation, and older adults require special consideration. Treatment of these patient populations is presented below. (See 'Special scenarios' below.)
Choice of chemotherapy — Patients with BL require intensive, frequent multi-agent therapy with adequate CNS prophylaxis. Less intensive regimens (eg, CHOP) used in other subtypes of non-Hodgkin lymphoma are not adequate therapy as they result in frequent relapses [1,2]. In addition, approximately 30 to 50 percent of patients will develop CNS relapse if CNS prophylaxis is not given . With the incorporation of CNS prophylaxis, CNS relapse rates have dropped to approximately 6 to 11 percent [4,5].
Chemotherapy regimens used for adults with BL have been adapted from those used in children [6,7]. There have been no randomized trials and it is virtually impossible to compare regimens because single-arm trials have differed in their diagnostic criteria, staging, and age of subjects included.
There are three main treatment approaches that have been used in adults with BL. While initial studies did not include rituximab therapy, rituximab is now routinely incorporated into the treatment of these patients (beginning with cycle 2). The addition of rituximab to these regimens may improve outcomes. (See 'Incorporation of rituximab' below.)
●Intensive, short-duration combination chemotherapy (eg, R-CODOX-M/IVAC, CALGB 9251, GMALL-B-ALL/NHL2002) (table 3 and table 4) [1,8-24].
●ALL-like therapy with a stepwise induction, consolidation, and maintenance therapy lasting at least two years from diagnosis (eg, CALGB 8811 regimen, R-HyperCVAD) (table 5) .
●Infusional chemotherapy with dose-adjusted EPOCH plus rituximab (table 6) .
Among these treatment approaches, for most adults with BL, we suggest intensive, short-duration combination chemotherapy rather than ALL-like therapy. This is principally because it is quicker and less complicated, and because we have more clinical experience with this treatment approach. Infusional chemotherapy with dose-adjusted EPOCH plus rituximab is an acceptable alternative for patients who may not tolerate more aggressive regimens (eg, older or less fit patients). Details regarding the use of these regimens are presented below.
There is a paucity of data on these approaches in adult populations. An international retrospective analysis of 543 adult patients with BL (including more than 40 percent >40 years old) examined clinical outcomes from prospective, non-randomized clinical trials that utilized intensive, short-duration combination chemotherapy or ALL-like therapy . The modest numbers of patients in most of these studies do not permit direct comparison of outcomes between treatment approaches or age groups.
CODOX-M plus IVAC ("Magrath regimen") — CODOX-M (cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate) with IVAC (ifosfamide, cytarabine, etoposide, and intrathecal methotrexate), also called the Magrath regimen (table 3), has traditionally been the combination chemotherapy regimen most frequently used for the treatment of BL outside of a clinical trial [13,14,21]. Given the toxicity of CODOX-M/IVAC, some experts suggest the use of dose-adjusted EPOCH in older or less fit patients. (See 'Dose-adjusted EPOCH' below.)
One case series and three prospective trials have been reported on the use of CODOX-M/IVAC in patients with newly diagnosed BL [13,14,21,28]. Dosing of CODOX-M/IVAC has varied slightly between studies. All of these trials used a risk-adapted approach. In general, patients were considered low risk if they had non-bulky, early stage disease with a good performance status and a normal LDH. Low risk patients were treated with three cycles of CODOX-M. All other patients were considered high risk and were treated with alternating CODOX-M/IVAC twice (ie, CODOX-M/IVAC/CODOX-M/IVAC) (table 3).
All patients received prophylaxis for tumor lysis syndrome. In addition, CNS prophylaxis was administered with intrathecal cytarabine and methotrexate. Patients with documented CNS involvement received additional intrathecal therapy. Patients could have received one cycle of a CHOP-like regimen prior to enrollment. Toxicity with CODOX-M/IVAC is severe and virtually all patients require a prolonged inpatient hospital stay and blood product support. With this approach, reported two-year overall survival ranges from 67 to 92 percent, although among adults the rate is approximately 75 percent.
The following are the three largest reports of the use of CODOX/IVAC in newly diagnosed BL:
●The initial report of CODOX-M/IVAC from the National Cancer Institute (NCI) was a series of 41 patients (20 adults, 21 children) with newly diagnosed BL including 34 high risk and 7 low risk patients . Low risk patients were those with a single extraabdominal mass or completely resected abdominal disease and a normal LDH. All others were considered high risk. Ninety-three percent completed protocol. There were no toxic deaths but severe (grade 3/4) toxicity included neutropenia (100 percent), thrombocytopenia (96 percent), and mucositis (61 percent). Sepsis occurred in 22 percent of patients. The two-year event-free survival rate was 92 percent.
●A prospective multicenter study reported on the use of a risk-adapted CODOX-M/IVAC protocol in 52 patients with newly diagnosed BL . This protocol differed from the NCI protocol by the omission of an injection of vincristine on day 15. The trial included 12 low risk patients and 40 high risk patients. Low risk patients had a normal LDH level, WHO performance status of 0 or 1, Ann Arbor stage I-II, and no tumor mass ≥10cm. All other patients were high risk. Approximately 80 percent of the patients completed protocol. Severe (grade 3/4) toxicities were common including neutropenia (100 percent), thrombocytopenia (66 percent), mucositis (42 percent), and diarrhea (8 percent). Two-year overall survival rates for the low- and high-risk patients were 82 and 70 percent, respectively. Several female patients were able to have successful pregnancies following completion of therapy.
●A prospective, non-randomized trial included 53 patients (median age 37 years) with newly diagnosed BL treated with a risk-adjusted, dose-modified (dm) CODOX-M/IVAC protocol . This trial differed from the previous trial in that the methotrexate dose was decreased to 3 g/m2. This trial included 11 low risk and 42 high risk patients. Low risk patients were those with a normal LDH, WHO performance status 0 to 1, Ann Arbor stage I to II and ≤1 extra-nodal sites. All other patients were high risk. Seventy-six percent of the patients were able to complete the planned therapy. Severe (grade 3/4) toxicities included neutropenia (99 percent), neutropenic fever (80 percent), thrombocytopenia (86 percent), mucositis (47 percent), and neuropathy (8 percent). There was an 8 percent treatment-related death rate. Two-year progression-free and overall survival rates were 64 and 67 percent, respectively.
CALGB 9251 — A six cycle high-intensity treatment regimen, based upon a protocol for the treatment of adult B cell ALL, was developed by the Cancer and Leukemia Group B (study 9251) . Treatment included one seven-day cycle of cyclophosphamide (CYT) and prednisone followed by alternating 21-day cycles including ifosfamide or CYT, high-dose methotrexate (MTX), vincristine, dexamethasone, either doxorubicin or etoposide/cytarabine, and triple intrathecal therapy (MTX, cytarabine, hydrocortisone) with or without CNS irradiation (table 4). Subsequent studies have evaluated this regimen in combination with rituximab and filgrastim support .
A prospective, non-randomized study of CALGB 9251 plus rituximab and filgrastim support (CALGB 10 002) in 105 adults (age 19 to 79 years) with Burkitt lymphoma had the following results :
●Complete remission (CR) was attained in 83 percent, with estimated event-free and overall survival rates at four years of 74 and 78 percent, respectively.
●Common severe (grade 3/4) toxicities included stomatitis/upper gastrointestinal toxicity (69 percent), renal insufficiency (10 percent), neurologic events (25 percent), and pulmonary toxicity (18 percent). There were seven treatment-related deaths, five of which were in patients >60 years.
●Comparison with historical controls from CALGB 9251 suggested an improvement in response rates, event-free survival, and overall survival with the addition of rituximab and filgrastim .
HyperCVAD — Single-arm prospective trials have evaluated the use of regimens containing hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HyperCVAD) with or without rituximab alternating with high-dose methotrexate and cytarabine in patients with newly diagnosed BL [9,22,23]. Such protocols are similar to the intensive treatment regimens used for ALL.
●Twenty-six adults with newly diagnosed BL were prospectively treated with HyperCVAD . CNS prophylaxis included alternating cycles of intrathecal methotrexate and cytarabine. There were five induction deaths. All patients had severe (grade 3/4) hematologic toxicity despite prophylactic growth factor support. Febrile neutropenia occurred in 86 percent. Complete remissions were obtained in 81 percent. The three-year overall survival rate was 49 percent.
●Another prospective, single-arm study evaluated HyperCVAD plus rituximab alternating with high-dose methotrexate and cytarabine in 31 patients with newly diagnosed BL . Planned treatment was completed in 73 percent. Severe, prolonged myelosuppression was universal and febrile neutropenia was common, occurring in 45 percent of patients during the first cycle. Complete responses were seen in 86 percent of patients and the three-year overall survival rate was 89 percent.
Dose-adjusted EPOCH — Dose-adjusted infusional etoposide, vincristine, and doxorubicin, with oral prednisone and bolus dose-escalated cyclophosphamide chemotherapy (daEPOCH) has been evaluated in single-arm prospective trials. The greatest experience has been in patients with AIDS-related BL. In this approach, vincristine, doxorubicin and etoposide are administered as a 96-hour continuous infusion, followed by bolus administration of cyclophosphamide. Dosages are adjusted based on nadir neutrophil counts in the preceding treatment cycle. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Dose-adjusted EPOCH plus rituximab'.)
In a single arm prospective trial, 17 patients (median age 25 years) with sporadic BL were treated with daEPOCH plus rituximab for six to eight cycles (two cycles past complete response) . Most cycles were administered in the outpatient setting. All patients also received G-CSF support and central nervous system prophylaxis with intrathecal chemotherapy. Neutropenic fever occurred in 22 percent of cycles. Sensory (17 percent) and motor (7 percent) neurologic toxicity was observed. After a median follow-up of 86 months, the estimated rates of freedom from progression (95 percent; 95% CI 75-99 percent) and overall survival (100 percent; 95% CI 82-100 percent) at seven years were high.
The apparent superiority of this infusional regimen over similar anthracycline-based bolus regimens (eg, R-CHOP) suggests that the duration of exposure to anthracyclines above a certain threshold level may be more important than the peak dose. Larger studies are needed to better evaluate this regimen for this population prior to its routine incorporation into the treatment of patients with sporadic BL. It may be an acceptable alternative for patients who may not tolerate more aggressive regimens (eg, older or less fit patients). Dose-adjusted EPOCH does not penetrate the CNS, but the regimen does include intrathecal methotrexate.
Incorporation of rituximab — For most patients with BL, we recommend the addition of rituximab to combination chemotherapy. Although practice varies, we generally wait until the second cycle of chemotherapy to add rituximab in order to minimize tumor lysis. Several uncontrolled, prospective trials and one randomized trial suggest that the addition of rituximab improves event-free survival (EFS) and overall survival (OS) without increasing toxicity; two-year overall survival rates were 77 to 100 percent [9,24,29-33].
In a multicenter, open-label trial, 260 adults with previously untreated HIV-negative BL were randomly assigned to receive dose-dense chemotherapy with or without rituximab . After a median follow-up of 38 months, the addition of rituximab improved EFS (75 versus 62 percent at three years; hazard ratio 0.59; 95% CI 0.38-0.94) and OS (83 versus 70 percent at three years; hazard ratio 0.51; 95% CI 0.30-0.86). Adverse events were similar in the two groups.
Further support comes from nonrandomized trials that have demonstrated high survival rates and low toxicity with the addition of rituximab to standard chemotherapy. One of the largest was a prospective, multicenter trial from Germany, in which 363 patients (age 16 to 85 years) were treated with short-duration intensive combination chemotherapy that incorporated eight doses of rituximab . A complete remission was achieved in 88 percent, and the estimated overall survival and progression-free survival at five years were 80 and 71 percent, respectively. Overall survival rates declined with increasing age being 90, 84, and 62 percent for patients age 15 to 25 years, 26 to 55 years, and >55 years, respectively.
Our approach to treatment — For most patients with BL, we suggest intensive, short-duration combination chemotherapy with central nervous system (CNS) prophylaxis. Our preferred regimen is R-CODOX-M/IVAC (table 3). For older or less fit patients who may not tolerate more aggressive regimens, we suggest infusional chemotherapy with dose-adjusted EPOCH plus rituximab (table 6).
All intensive, short-duration combination chemotherapy regimens for BL are toxic, primarily to the hematopoietic system and mucosal surfaces, and most patients will have a prolonged hospital stay requiring antibiotic therapy and blood product support. Since the different regimens have not been directly compared, the physician's experience with administration is important when choosing among these regimens.
There are several variations on the R-CODOX-M/IVAC protocol and any of these published variants are reasonable options [13-15,21]. All of these regimens include intrathecal therapy given for CNS prophylaxis.
Patients are treated according to a risk-adapted approach using the following stratification system:
●Patients with non-bulky, early stage disease, a good performance status, and a normal LDH have low-risk disease. These patients are treated with three cycles of CODOX-M plus rituximab.
●All other patients have high-risk disease and are treated with four cycles of chemotherapy consisting of alternating CODOX-M and IVAC, both with rituximab.
There is a significant risk of tumor lysis syndrome in patients treated for BL. This syndrome is best prevented via appropriate treatment with aggressive intravenous hydration, rasburicase, and correction of any prior electrolyte disturbances and elements of reversible renal failure (table 2). We wait until the second cycle of chemotherapy before incorporating rituximab into the treatment program. (See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)
SPECIAL SCENARIOS — The general treatment principles for BL apply to most disease presentations and patient populations. However, patients with HIV infection, those with cardiac disease, and older adults require special consideration. In addition, central nervous system involvement at the time of diagnosis requires additional therapy directed at this site.
AIDS-related lymphoma — Among patients with HIV, the diagnosis of NHL is an AIDS-defining malignancy. A significant number of the lymphomas encountered in HIV-infected (HIV+) patients are clinically aggressive (eg, diffuse large B cell lymphoma) or highly aggressive (eg, BL or immunoblastic lymphoma). Treatment of such patients is complicated by their immunocompromised state and also requires specific treatment for their HIV. As such, specific management issues concerning patients with AIDS-related lymphoma are presented separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Burkitt lymphoma/leukemia'.)
Patients with cardiac disease — Although anthracycline-based therapy, such as CODOX-M/IVAC, is recommended for patients with BL, patients with underlying cardiac disease may not be able to tolerate the use of an anthracycline since this agent is toxic to cardiac cells. Doxorubicin or other anthracyclines should not be administered to patients with a baseline ejection fraction below 30 percent. Patients with an ejection fraction greater than 30 percent may require monitoring and guidelines for this are available (table 7). The use of pegylated liposomal doxorubicin may permit substantially higher cumulative doses with efficacy equivalent to the free anthracyclines but a lower incidence of heart failure. The use of anthracyclines in patients with cardiac disease is discussed in detail separately. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)
When an anthracycline is not an option, non-anthracycline-containing combination chemotherapy programs must be used. When choosing among such regimens, one must keep in mind not only the potential cardiac toxicity but also the intravenous fluid requirements of a regimen.
Older adults — Clinicians often have concerns over the ability of older adults (ie, over age 60 years) to tolerate intensive chemotherapy and radiation therapy. The management of lymphoma in older adults can be complicated by an increased number of comorbidities. A comprehensive geriatric assessment may be useful in assessing comorbidity and functional status in the elderly patient, thus permitting the formulation of an appropriate, individualized treatment plan . Special considerations for the use of chemotherapy in the elderly population are discussed separately. (See "Comprehensive geriatric assessment for patients with cancer" and "Systemic chemotherapy for cancer in older adults".)
Older adults have not been included in most trials investigating the therapy of BL. A prospective trial of HyperCVAD with or without rituximab included 25 patients over the age of 60 years . Those who are able to tolerate this regimen may have a similar survival benefit from intensive chemotherapy as younger adults. However, trials of HyperCVAD in other histologies have shown that most older adults are unable to tolerate this regimen .
Studies are needed to evaluate other treatment strategies for older adults who are not fit enough for these intensive regimens. Until such trials are available, treatment options include:
●EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, and prednisone) with or without rituximab . This has not been directly studied in this patient population but is less toxic than conventional therapy and offers promising preliminary results in younger individuals. (See 'Dose-adjusted EPOCH' above and 'Incorporation of rituximab' above.)
●Standard CHOP chemotherapy with rituximab and intrathecal methotrexate with palliative intent . Two-year progression-free survival is likely less than 30 percent with this approach.
CNS involvement — Patients with BL are at high risk for developing CNS involvement and so CNS prophylaxis is a standard component of first line therapy. If prophylaxis is not given, approximately 30 to 50 percent of patients will develop CNS relapse, usually with a median interval from diagnosis to relapse of 5 to 12 months . With the incorporation of CNS prophylaxis, rates drop to approximately 6 to 11 percent [4,5].
However, a percentage of patients will have CNS involvement on presentation or later on in their disease course, despite prophylaxis. Most treatment protocols administer additional intrathecal chemotherapy for those who have CNS involvement at presentation [13,14,21,28].
As an example, patients treated with the CODOX-M/IVAC regimen who have CNS involvement at presentation are treated with more intensified intrathecal therapy for cycles 1 and 2. Intrathecal cytarabine 70 mg (or 15 mg if given via an Ommaya reservoir) is given days 1,3, and 5 of CODOX-M (cycle 1) and on days 7 and 9 of IVAC (cycle 2) supplemented by intrathecal methotrexate 12.5 mg (2 mg if given via an Ommaya reservoir) on days 15 and 17 of CODOX-M (cycle 1) and day 5 of IVAC (cycle 2). For cycles 3 and 4 the intrathecal drug dosing reverts back to the prophylactic doses with intrathecal cytarabine 70 mg given days 1 and 3 of CODOX-M (cycle 3) and intrathecal methotrexate 12 mg given on day 15 of CODOX-M (cycle 3) and day 5 of IVAC (cycle 4).
A more detailed discussion on the diagnosis and treatment of secondary involvement of the central nervous system by non-Hodgkin lymphoma is presented separately. (See "Secondary central nervous system lymphoma: Clinical features and diagnosis" and "Secondary central nervous system lymphoma: Treatment and prognosis".)
PATIENT FOLLOW-UP — After completion of the initially planned treatment, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse.
Response evaluation — One month following the completion of planned therapy (or sooner if the outcome is unfavorable), the response to treatment should be documented by history, physical examination, and laboratory studies (complete blood count, lactate dehydrogenase, and biochemical profile). The post-treatment imaging study of choice is the CT scan.
Using information gathered from the history, physical, and CT scan, disease response is determined (table 8). Patients who fail to obtain a complete response are treated as refractory disease. This is discussed below. (See 'Treatment of recurrent or refractory disease' below.)
Surveillance for relapse — Following the completion of therapy, restaging, and documentation of complete remission, patients are seen at periodic intervals to monitor for treatment complications and assess for possible relapse. We suggest follow-up visits that include a history and physical examination, complete blood count, serum chemistries, and LDH (lactate dehydrogenase) every 3 to 4 months during the first year, every six months during the second year, and then annually. The frequency and extent of these visits depends upon the comfort of both the patient and physician, and there have been no prospective, randomized trials comparing various schedules of follow-up.
The role of imaging in routine surveillance is uncertain, and we often follow patients clinically, and reserve imaging for patients with symptoms suggestive of relapse. Other experts perform routine surveillance imaging (eg, CT scans every six months for the first two years).
Our approach is informed by the following general understandings:
●The majority of relapses occur during the first year after completion of treatment.
●Relapses are usually symptomatic and are rarely identified solely on the basis of routine imaging.
●When planning the post-treatment surveillance strategy, care should be taken to limit the number of CT scans, particularly in younger individuals, given concerns about radiation exposure and the risk for second malignancies [37-39]. (See "Radiation-related risks of imaging".)
Relapsed disease may be suggested by changes on imaging studies, but must be confirmed by biopsy. As such, a biopsy should always be obtained to document relapsed disease before proceeding to salvage therapy.
Survivorship issues — Survivors of Burkitt lymphoma must be monitored periodically for long-term complications related to the disease and its treatment. An overview of the care of the long-term survivor, focusing on issues that require attention at approximately five years from the completion of therapy onwards, is presented separately. (See "Overview of care for adult survivors of non-Hodgkin lymphoma".)
TREATMENT OF RECURRENT OR REFRACTORY DISEASE — There is a paucity of data to guide the treatment of patients with recurrent or refractory BL. Whenever possible, patients should be encouraged to participate in clinical trials. Outside of a clinical trial, patients with refractory disease and those who relapse after an initial response to appropriate initial therapy have an extremely poor prognosis and should be considered for best supportive care. An important exception concerns the patient who did not receive appropriate initial therapy. It is our experience that patients initially treated with lower intensity regimens (eg, R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) may respond to a dose-intensive regimen (eg, CODOX-M plus IVAC). (See 'Clinical trials' below.)
Prognostic factors — Outcomes for patients with BL have been associated with both clinical and laboratory features [40,41]. Examples include:
●Clinical – Advanced age, impaired performance status (PS), advanced-stage, bulky disease, >1 extranodal site, central nervous system (CNS) or bone marrow involvement.
●Laboratory – Elevated serum lactate dehydrogenase (LDH), decreased hemoglobin (Hb), decreased serum albumin.
●Molecular – The prognostic importance of molecular events associated with BL lymphomagenesis has not been methodically studied. Examples of frequent findings include MYC rearrangement; mutations of TCF3, or its negative regulator ID3; alterations of TP53, CCND3, and CDKN2A; and tonic B cell receptor signaling . (See "Pathobiology of Burkitt lymphoma".)
BL-IPI (BL-international prognostic index) — The Burkitt lymphoma international prognostic index (BL-IPI) can be used to assess prognosis in adults with sporadic or immunodeficiency-related BL and to facilitate comparisons between clinical studies . At present, we do not use the BL-IPI to stratify treatment for BL.
The BL-IPI was generated from a retrospective review of 633 adults (including 22 percent HIV-positive patients) that identified age ≥40 years, impaired PS, elevated serum LDH, and CNS involvement as being independently associated with adverse outcomes; these risk factors were validated using data from an independent, international cohort of 457 patients. The BL-IPI assigns one point for each of the following features :
●Age ≥40 years
●Eastern Cooperative Oncology Group (ECOG) PS (table 9) ≥2
●Serum LDH >3X upper limit of normal (ULN)
The sum of points identifies three categories of patients with distinct outcomes:
●Low risk (0 risk factors; 18 percent of patients): 96 percent three-year overall survival (OS); 92 percent three-year progression-free survival (PFS)
●Intermediate risk (1 risk factor; 36 percent of patients): 76 percent three-year OS; 72 percent three-year PFS
●High risk (≥2 risk factors; 46 percent of patients): 59 percent three-year OS; 53 percent three-year PFS
We suggest not using the international prognostic index (IPI) for non-Hodgkin lymphoma, which is used for other B cell non-Hodgkin lymphomas (table 10); that model lacks discrimination for BL because only 10 to 15 percent of patients with BL are classified as having low-risk disease [13,14,21,28,33,34,44].
Further discussion of the prognosis of patients with AIDS-related BL is presented separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma", section on 'Prognosis'.)
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Burkitt lymphoma".)
SUMMARY AND RECOMMENDATIONS
●Burkitt lymphoma (BL) is a highly aggressive B cell neoplasm characterized by the translocation and deregulation of the c-Myc gene on chromosome 8. (See 'Introduction' above.)
●The pretreatment evaluation both determines the bulk of disease and provides information about the individual's comorbidities that are likely to have impact on treatment options. In addition to a history and physical examination, it is our practice to perform laboratory studies, unilateral bone marrow biopsy, lumbar puncture, cardiac function evaluation, and positron emission tomography (PET)/computed tomography (CT) imaging, when possible (CT scans are an acceptable alternative if PET/CT is not possible). Fertility counseling should be offered to patients in child-bearing years. (See 'Pretreatment evaluation' above.)
●The standard of care has yet to be defined and our preferred treatment is enrollment in a clinical trial. However, for patients who are not candidates for such trials or for those who choose not to participate, we suggest intensive, short-duration combination chemotherapy with central nervous system (CNS) prophylaxis (Grade 2B).
Our preferred regimen is R-CODOX-M/IVAC (table 3). (See 'Initial treatment' above.)
CODOX-M/IVAC is highly toxic, primarily to the hematopoietic system, and most patients will have a prolonged hospital stay. Therapy should be initiated promptly and dose reduction should be avoided, if possible. (See 'Our approach to treatment' above.)
For older or less fit patients who may not tolerate more aggressive regimens, we suggest infusional chemotherapy with dose-adjusted EPOCH plus rituximab (table 6) (Grade 2C). (See 'Dose-adjusted EPOCH' above.)
●We recommend the addition of rituximab to combination chemotherapy (Grade 1B). Although practice varies, we generally wait until the second cycle of chemotherapy to add rituximab in order to minimize tumor lysis. (See 'Incorporation of rituximab' above.)
●There is a significant risk of tumor lysis syndrome in patients treated for BL. This syndrome is best prevented via appropriate treatment with aggressive intravenous hydration, rasburicase, and correction of any prior electrolyte disturbances and elements of reversible renal failure (table 2). (See "Tumor lysis syndrome: Prevention and treatment", section on 'Clinical impact of tumor lysis syndrome'.)
●Patients with HIV, cardiac disease, older adults, and those with CNS involvement at diagnosis require special attention. (See 'Special scenarios' above.)
●After completion of the initially planned treatment, patients should be evaluated to determine the disease response to treatment and should be followed longitudinally for relapse and long-term complications of the disease and its therapy. (See 'Patient follow-up' above.)
●Whenever possible, patients with relapsed or refractory BL should be encouraged to participate in clinical trials. Outside of a clinical trial, patients with refractory disease and those who relapse after an initial response to appropriate initial therapy have an extremely poor prognosis. (See 'Treatment of recurrent or refractory disease' above and 'Clinical trials' above.)
2 : Treatment of Burkitt's/Burkitt-like lymphoma in adolescents and adults: a 20-year experience from the Norwegian Radium Hospital with the use of three successive regimens.
5 : Combined modality therapy for adults with small noncleaved cell lymphoma (Burkitt's and non-Burkitt's types).
6 : 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.
7 : 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.
8 : Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia.
9 : Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia.
10 : Small noncleaved cell lymphoma and leukemia in adults. A retrospective study of 65 adults treated with the LMB pediatric protocols.
11 : Burkitt's and Burkitt-like lymphoma in children and adolescents: a review of the Children's Cancer Group experience.
12 : Burkitt's lymphoma in adults with and without human immunodeficiency virus infection: a single-institution clinicopathologic study of 75 patients.
13 : Adults and children with small non-cleaved-cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen.
14 : An international evaluation of CODOX-M and CODOX-M alternating with IVAC in adult Burkitt's lymphoma: results of United Kingdom Lymphoma Group LY06 study.
15 : Intensive chemotherapy with cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for human immunodeficiency virus-associated Burkitt lymphoma.
16 : Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251.
17 : High response rate and manageable toxicity with an intensive, short-term chemotherapy programme for Burkitt's lymphoma in adults.
19 : A 5-drug regimen maximizing the dose of cyclophosphamide is effective therapy for adult Burkitt or Burkitt-like lymphomas.
20 : Intensive chemotherapy with and without cranial radiation for Burkitt leukemia and lymphoma: final results of Cancer and Leukemia Group B Study 9251.
21 : A prospective clinicopathologic study of dose-modified CODOX-M/IVAC in patients with sporadic Burkitt lymphoma defined using cytogenetic and immunophenotypic criteria (MRC/NCRI LY10 trial).
22 : Hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone and highly active antiretroviral therapy for patients with acquired immunodeficiency syndrome-related Burkitt lymphoma/leukemia.
24 : Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial.
27 : Outcomes of patients with Burkitt lymphoma older than age 40 treated with intensive chemotherapeutic regimens.
28 : Modified magrath regimens for adults with Burkitt and Burkitt-like lymphomas: preserved efficacy with decreased toxicity.
29 : Improved efficacy using rituximab and brief duration, high intensity chemotherapy with filgrastim support for Burkitt or aggressive lymphomas: cancer and Leukemia Group B study 10 002.
30 : High-dose chemotherapy and immunotherapy in adult Burkitt lymphoma: comparison of results in human immunodeficiency virus-infected and noninfected patients.
31 : RD-CODOX-M/IVAC with rituximab and intrathecal liposomal cytarabine in adult Burkitt lymphoma and 'unclassifiable' highly aggressive B-cell lymphoma.
32 : Dose-intensive chemotherapy including rituximab in Burkitt's leukemia or lymphoma regardless of human immunodeficiency virus infection status: final results of a phase 2 study (Burkimab).
33 : A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma.
34 : Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial
36 : High rate of durable remissions after treatment of newly diagnosed aggressive mantle-cell lymphoma with rituximab plus hyper-CVAD alternating with rituximab plus high-dose methotrexate and cytarabine.
38 : Recurrent CT, cumulative radiation exposure, and associated radiation-induced cancer risks from CT of adults.
40 : Population-based prognostic factors for survival in patients with Burkitt lymphoma: an analysis from the Surveillance, Epidemiology, and End Results database.
41 : Population based study of prognostic factors and treatment in adult Burkitt lymphoma: a Swedish Lymphoma Registry study.
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