Standard treatment options for Burkitt lymphoma

The treatment of Burkitt lymphoma is the same as treatment for diffuse large B-cell lymphoma, and the following discussion is pertinent to both types of childhood NHL.

Unlike mature B-lineage NHL seen in adult patients, there is no difference in outcome based on histology in pediatric patients (Burkitt lymphoma or diffuse large B-cell lymphoma). Pediatric Burkitt lymphoma and diffuse large B-cell lymphoma are clinically very aggressive, and patients are treated with very intensive regimens.[21-26]

Source links and citations

21
26

Tumor lysis syndrome is often present at diagnosis or after initiation of treatment. This emergent clinical situation should be anticipated and addressed before treatment is started. For more information, see the Tumor lysis syndrome section.

Source links and citations

Tumor lysis syndrome

Current treatment strategies are based on risk stratification, as described in Table 4. Involvement of the bone marrow may lead to confusion about whether the patient has lymphoma or leukemia. Traditionally, patients with more than 25% marrow blasts are classified as having mature B-cell leukemia, and those with fewer than 25% marrow blasts are classified as having lymphoma. It is not clear whether these arbitrary definitions are biologically distinct, but there is no question that patients with leukemic involvement should be treated with protocols designed for Burkitt lymphoma.[21,23,26]

Source links and citations

Table 4. FAB/LMB and BFM Staging Schemas for B-cell NHL
	Stratum	Disease Manifestation
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Münster; CNS= central nervous system; FAB = French-American-British; LDH = lactate dehydrogenase; LMB = Lymphome Malin de Burkitt; NHL = non-Hodgkin lymphoma.
aBased on results of the FAB/LMB-96 study, a serum LDH level more than twice the upper limit of normal has been used to define a group B high-risk group in the international B-cell NHL study ANHL1131 (NCT01516567).[22]
COG-C5961 (FAB/LMB-96);[22,23,27]COG-ANHL1131 (Inter-B-NHL Ritux 2010) [26]	A	Completely resected stage I and abdominal stage II
	Ba	Multiple extra-abdominal sites
	Ba	Nonresected stage I and II, III, IV (marrow <25% blasts, no CNS disease); epidural masses (stage III Murphy staging) are treated as group B unless there is evidence of dural invasion
	C	Mature B-cell ALL (>25% blasts in marrow) and/or CNS disease

BFM Group [28]	R1	Completely resected stage I and abdominal stage II
	R2	Nonresected stage I or II and stage III with LDH <500 IU/L
	R3	Stage III with LDH 500–999 IU/L
	R3	Stage IV, B-ALL (>25% blasts), no CNS disease, and LDH <1,000 IU/L
	R4	Stage III, IV, B-cell ALL with LDH >1,000 IU/L
	R4	Any CNS disease

Source links and citations

The following studies have contributed to the development of current treatment regimens for pediatric patients with Burkitt lymphoma and diffuse large B-cell lymphoma.

Evidence (chemotherapy):

Berlin-Frankfurt-Münster (BFM) studies

Localized disease (R1 and R2 groups): The BFM group has treated risk group R1 patients with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[21,28] R2 patients received a cytoreductive phase followed by five cycles of chemotherapy.[21,28]

Source links and citations

Berlin-Frankfurt-Münster (BFM) studies › Localized disease (R1 and R2 groups): The BFM group has treated risk group R1 patients with two cycles of multiagent chemotherapy (GER-GPOH-NHL-BFM-90 and GER-GPOH-NHL-BFM-95).[21,28] R2 patients received a cytoreductive phase followed by five cycles of chemotherapy.[21,28]

Event-free survival (EFS) rates with best therapy in the NHL-BFM-95 study were higher than 95% for R1 and R2 group patients.[21]

Source links and citations

21

Berlin-Frankfurt-Münster (BFM) studies

Advanced/disseminated disease (R3 and R4 groups): In the NHL-BFM-95 study, the EFS rate was 93% with best therapy.[21]

Source links and citations

21

Berlin-Frankfurt-Münster (BFM) studies › Advanced/disseminated disease (R3 and R4 groups): In the NHL-BFM-95 study, the EFS rate was 93% with best therapy.[21]

Inferior outcome was observed for patients with CNS disease at presentation (3-year EFS rate, 70%).[28]

Source links and citations

28

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies

Localized disease (group A): Patients who received two cycles of multiagent chemotherapy, without intrathecal chemotherapy or rituximab, had excellent outcomes (COG-C5961 [FAB/LMB-96]).[27][Level of evidence B4]

Source links and citations

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies

Advanced disease (group B):

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies › Advanced disease (group B):

The 3-year EFS rate was 90% for stage III patients and 86% for stage IV (CNS-negative and nonleukemic) patients.

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies › Advanced disease (group B):

Patients with a lactate dehydrogenase (LDH) level more than twice the upper limit of normal had an EFS rate of 86% compared with 96% in those with lower LDH levels.

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies

Disseminated disease (group C):

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies › Disseminated disease (group C):

Patients with leukemic disease only, and no CNS disease, had a 3-year EFS rate of 90%, while patients with CNS disease at presentation had a 3-year EFS rate of 70%.

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies › Disseminated disease (group C):

Patients with combined marrow and CNS disease at diagnosis had an EFS rate of only 61%.

French Society of Pediatric Oncology Lymphome Malin de Burkitt (LMB) and French-American British (FAB) studies › Disseminated disease (group C):

This study identified the response to prophase reduction as the most significant prognostic factor. Patients with poorly responding disease (i.e., <20% resolution of disease) had an EFS rate of 30%.

Both the BFM and FAB/LMB studies demonstrated that omission of craniospinal irradiation, even in patients presenting with CNS disease, does not affect outcome (COG-C5961 [FAB/LMB-96] and NHL-BFM-90 [GER-GPOH-NHL-BFM-90]).[21-23,28]

Source links and citations

Evidence (rituximab):

In a phase II study performed by the BFM group, single-agent rituximab showed activity in pediatric patients with Burkitt lymphoma.[29][Level of evidence B4]

Source links and citations

A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL.[30-32]; [24][Level of evidence C1]

Source links and citations

A Children's Oncology Group (COG) pilot study (COG-ANHL01P1) added rituximab to baseline chemotherapy with FAB/LMB-96 therapy in patients with stage III and stage IV B-cell NHL.[30-32]; [24][Level of evidence C1]

Compared with chemotherapy-only protocols, toxicity was similar with the addition of rituximab, despite a trend toward higher peak levels of rituximab in younger patients.

An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.

Source links and citations

26

An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.

For patients in the rituximab arm, the EFS rate was 94% for this high-risk group of patients (stage III with elevated LDH and stage IV), compared with 82% for patients who received standard therapy (hazard ratio, 0.32; 95% confidence interval [CI], 0.15–0.66; one-sided P = .00096).

An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.

Refractory disease or relapse/progression was observed in 15% of patients who received standard therapy, compared with 3% of patients who received rituximab.

An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.

Toxic mortality occurred in 2% of patients in each arm.

An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.

For patients who received rituximab, there was no difference in outcome based on age, histology (diffuse large B-cell lymphoma vs. Burkitt lymphoma), stage, and response to low-dose cyclophosphamide, vincristine, and prednisone (COP regimen).

An international randomized phase III trial (COG-ANHL1131) evaluated the benefit of adding rituximab to standard therapy for Group B patients with high levels of LDH and Group C patients. The study was closed early because of the superior outcomes observed for the patients who received rituximab.[26] This study led to the European Medicines Agency and U.S. Food and Drug Administration approval of rituximab for the treatment of pediatric patients with B-cell lymphoma.

A prespecified, secondary aim of the study was to evaluate the immune effects of rituximab therapy in pediatric patients after the completion of intensive therapy.[33] Patients in the rituximab group were significantly more likely to have low IgG, IgA, and IgM serum concentrations 1 month after the end of therapy than patients in the chemotherapy-only group. Low IgG levels persisted for 1 year after the start of therapy for patients who received rituximab. No fatal infections were observed in the follow-up period. However, a small number of patients who had all received rituximab had severe infections.

Source links and citations

33

Standard treatment options for Burkitt lymphoma and diffuse large B-cell lymphoma are described in Table 5.

Source links and citations

Table 5

Table 5. Standard Treatment Options for Burkitt Lymphoma and Diffuse Large B-cell Lymphoma
Trial	Stratum	Disease Manifestations	Treatment
ALL = acute lymphoblastic leukemia; BFM = Berlin-Frankfurt-Münster; CNS = central nervous system; COG = Children's Oncology Group; FAB = French-American-British; LDH = lactate dehydrogenase; LMB = Lymphome Malin de Burkitt; NHL = non-Hodgkin lymphoma; POG = Pediatric Oncology Group.
COG-C5961 (FAB/LMB-96) [22,27] COG-ANHL01 [31,32]; [24][Level of evidence C1] COG-ANHL1131 (Inter-B-NHL Ritux 2010) [26]	A	Completely resected stage I and abdominal stage II	Two cycles of chemotherapy [27]
	B	Multiple extra-abdominal sites	Prephase + four cycles of chemotherapy (reduced-intensity arm) [22,34]
		Nonresected stage I and II, III (normal LDH)
		Stage III (elevated LDH), marrow <25% blasts, no stage IV CNS disease	Prephase + four cycles of chemotherapy (reduced-intensity arm) + six doses of rituximab [26]
	C	Mature B-cell ALL (>25% blasts in marrow) and/or stage IV CNS disease	Prephase + six cycles of chemotherapy (full-intensity arm) and only two maintenance cycles + six doses of rituximab [26]

GER-GPOH-NHL-BFM-95 [21]	R1	Completely resected stage I and abdominal stage II	Two cycles of chemotherapy
GER-GPOH-NHL-BFM-95 [21]	R2	Nonresected stage I/II and stage III with LDH <500 IU/L	Prephase + four cycles of chemotherapy (4-hour methotrexate infusion)

Source links and citations

Standard treatment options for Burkitt lymphoma

Studies cited in this source section

Publication references