Is the Use of Low-Intensity Therapy Effective in Adults with Burkitt’s Lymphoma?

Tanya Huang, Mercer University College of Pharmacy

Burkitt’s lymphoma (BL) is a type of non-Hodgkin lymphoma that is most prevalent in equatorial Africa. [1] There are three epidemiological subtypes of BL: endemic (African), sporadic (non-endemic), and immunodeficiency-related. [2] Chemotherapy treatments for BL are usually intensive short-cycle regimens due to the highly proliferative nature of the disease. However, they are associated with severe side effects in patients with immunodeficiencies, such as human immunodeficiency virus (HIV).

Previous attempts to use a significantly reduced intensity for BL in adults have not been successful. However, researchers have hypothesized that BL may be sensitive to genotoxic stress, leading to the prediction that prolonged exposure, not increased dose, as the therapeutic strategy for maximizing tumor cell death. Based on the concept, a study was conducted to compare efficacy of two different low-intensity regimens composed of etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) for sporadic or immunodeficiency-associated BL patients. [3] A summary is provided below.

 

Low-Intensity Therapy in Adults with Burkitt’s Lymphoma
Design Uncontrolled, prospective study; N= 30
Objective To determine if a low-intensity chemotherapy regimen is as effective in treating Burkitt’s lymphoma than the current treatments
Study Groups
  • Standard dose-adjusted combination in HIV-negative patients (DA-EPOCH-R);n= 19
  • Lower-dose short-course combination with a double dose of rituximab in HIV-positive patients (SC-EPOCH-RR);n= 11
Methods Inclusion criteria:

  • Systemic chemotherapy naive
  • Adequate organ function apart from organ function affected by disease
  • Females- negative pregnancy test required

The dose adjusted- etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) group received two cycles after complete remission, for a total of six to eight cycles. The DA-EPOCH-R group was pharmacodynamically dose-adjusted based on neutrophil nadir. The short-course etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, double-dosed rituximab (SC-EPOCH-RR) group received one cycle after complete remission, for a total of three to six cycles. The HIV positive patients in the SC-EPOCH-RR group did not receive antiretroviral therapy during chemotherapy. Follow-up was performed for five years in both studies. Both treatment groups received fluids and 300 mg of allopurinol prior to the first cycle and were monitored for tumor lysis syndrome (TLS).

Duration November 2000- December 2009
Primary Outcome Measure Rate of complete response, time to progression, and treatment toxicity
Baseline Characteristics
Characteristic All Patients (N = 30) DA-EPOCH-R (n = 19) SC-EPOCH-RR (n = 11) p Value
Male sex — no. (%) 22 (73) 13 (68) 9 (82) 0.67
Age — yr 0.03
 Median 33 25 44
 Range 15–88 15–88 24–60
Age ≥40 yr — no. (%) 12 (40) 5 (26) 7 (64) 0.06
Ann Arbor stage III or IV — no. (%) 20 (67) 11 (58) 9 (82) 0.25
ECOG performance-status score ≥2 — no. (%)† 9 (30) 3 (16) 6 (55) 0.04
Serum lactate dehydrogenase >ULN — no. (%) 16 (53) 7 (37) 9 (82) 0.03
Extranodal site — no. (%)‡ 19 (63) 10 (53) 9 (82) 0.14
Bowel 15 (50) 9 (47) 6 (55) 1.00
Bone marrow or blood 4 (13) 3 (16) 1 (9) 1.00
Central nervous system 1 (3) 1 (5) 0 1.00
LMB risk group — no. (%)
 A 5 (17) 5 (26) 0 0.16
 B 22 (73) 12 (63) 10 (91)
 C 3 (10) 2 (10) 1 (9)
Burkitt’s lymphoma variant — no. (%) <0.001
Sporadic 17 (57) 17 (89) 0
Immunodeficiency-associated¶ 13 (43) 2 (11) 11 (100)
Secondary 11 (37) 0 11 (100)
Primary 2 (7) 2 (11) 0
Molecular marker — no./total no. (%)
MYC rearrangement 22/22 (100) 14/14 (100) 8/8 (100) 1.00
BCL6 protein expression 24/24 (100) 15/15 (100) 9/9 (100) 1.00
BCL2 protein expression 0/26 0/16 0/10 1.00
EBER in situ hybridization 6/21 (29) 4/14 (29) 2/7 (29) 1.00

*DA-EPOCH-R denotes dose-adjusted infusional therapy with etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone, and rituximab; EBER Epstein–Barr virus–encoded RNA; SC-EPOCH-RR short-course infusional therapy with etoposide, doxorubicin, and vincristine with cyclophosphamide, prednisone, and a double dose of rituximab; and ULN upper limit of the normal range.

†Eastern Cooperative Oncology Group (ECOG) performance-status scores range from 0 to 5, with 0 indicating no symptoms and full activity and higher scores indicating increasing levels of disability.

‡Patients may have had more than one extranodal site. In the SC-EPOCH-RR group, three patients had a site not listed in the table (liver, kidney, or other site).

§Lymphomes malins B (LMB) risk groups are defined as follows: group A includes patients with low-risk disease (resected stage I or abdominal stage II cancer), group B includes those with intermediate-risk disease (patients not in group A or C), and group C includes those with high-risk disease (central nervous system involvement, at least 25% blasts in bone marrow, or both characteristics).

¶Patients with the immunodeficiency-associated variant may have had HIV infection, the autoimmune lymphoproliferative syndrome, or a deficiency of dedicator of cytokinesis 8.

Results
  • Fever and neutropenia
    • DA-EPOCH-R: 22%
    • SC-EPOCH-RR: 10%
  • Median cumulative doses of administered doxorubicin- etoposide and cyclophosphamide were 47% and 57% lower in the SC-EPOCH-RR group, respectively, than the DA-EPOCH-R group.
  • Median follow-up times
    • DA-EPOCH-R: 86 months
    • SC-EPOCH-RR: 73 months
  • Rates of freedom from progression of disease
    • DA-EPOCH-R: 95% (95% CI, 75-99)
    • SC-EPOCH-RR: 100% (95% CI, 72-100)
  • Overall survival:
    • DA-EPOCH-R: 100% (95% CI, 82- 100)
    • SC-EPOCH-RR: 90% (95% CI, 60-98)
Event All Cycles (N = 155) DA-EPOCH-R Cycles (n = 116) SC-EPOCH-RR Cycles (n = 39) p Value
Tumor lysis syndrome — no. of cycles (%) 1 (1) 0 1 (3) NA
Absolute neutropenia — no. of cycles (%)
Nadir <500 cells/mm3 72 (46) 60 (52) 12 (31) 0.03
Nadir <100 cells/mm3 26 (17) 20 (17) 6 (15) 1.00
Thrombocytopenia — no. of cycles (%)
Nadir <50,000 platelets/mm3 12 (8) 7 (6) 5 (13) 0.18
Nadir <25,000 platelets/mm3 3 (2) 2 (2) 1 (3) 1.00
Fever and neutropenia necessitating hospital admission
Any patient — no. of cycles (%) 30 (19) 26 (22) 4 (10) 0.11
Patients ≥40 yr of age — no. of cycles/total no. (%) 4/54 (7) 2/30 (7) 2/24 (8) 1.00
Gastrointestinal event — no. of cycles (%)
Mucositis 8 (5) 7 (6) 1 (9) 0.68
Constipation 2 (1) 0 2 (5) 0.06
Ileus 2 (1) 2 (2) 0 1.00
Neurologic event — no. of patients/total no. (%)‡
Sensory impairment 5/30 (17) 4/19 (21) 1/11 (9) 0.63
Motor impairment 2/30 (7) 2/19 (11) 0/11 0.52

*NA denotes not applicable.

All the gastrointestinal events were grade 3.

All the sensory-impairment events were grade 3, and all the motor-impairment events were grade 2.

Adverse Events
  • Absolute neutropenia nadir < 500 cells/mm3
    • DA-EPOCH-R: 60 (52%)
    • SC-EPOCH-RR: 12 (31%)
  • Absolute neutropenia nadir < 100 cells/mm3
    • DA-EPOCH-R: 20 (17%)
    • SC-EPOCH-RR: 6 (15%)
  • Thrombocytopenia nadir < 50,000 platelets/mm3
    • DA-EPOCH-R: 7 (6%)
    • SC-EPOCH-RR: 5 (13%)
  • Fever/Neutropenia requiring hospital admission
    • DA-EPOCH-R: 26 (22%)
    • SC-EPOCH-RR: 4 (10%)
  • Tumor Lysis Syndrome
    • DA-EPOCH-R: 0
    • SC-EPOCH-RR: 1 (3%)
Study Author Conclusions Low-intensity EPOCH-R based treatment was highly effective in treating adults with Burkitt’s lymphoma in this uncontrolled prospective study.

Some major limitations of this study include the small sample size of patients as well as the small number of participants with central nervous system involvement. This study also has wide confidence intervals, which suggests a possibility of seeing wide variability in outcomes. The study also included immunodeficiency-associated Burkitt’s lymphoma, which is associated with worse outcomes compared to other types of Burkitt’s lymphoma.

The current standard of care chemotherapy treatment for BL is suggested to be suboptimal due to the serious adverse effects. This study shows a possible alternative low-intensity regimen that appears to be effective in treating BL while reducing treatment toxicity. However, further studies with larger sample size may be needed.

References

[1] Magrath I. Epidemiology: clues to the pathogenesis of Burkitt lymphoma. Br J Haematol. 2012;156(6):744-56.

[2] Dozzo M, Carobolante F, Donisi PM, et al. Burkitt lymphoma in adolescents and young adults: management challenges. Adolesc Health Med Ther. 2017;8:11-29.

[3] Dunleavy K, Pittaluga S, Shovlin M, et al. Low-intensity therapy in adults with Burkitt’s lymphoma. N Engl J Med. 2013;369(20):1915-25.

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