BL is a highly aggressive tumor; however, therapy with multiagent chemotherapeutic programs results in excellent long-term remission rates and long-term survival of up to 85 percent of children. Applying the same chemotherapy regimens to adults has shown dramatically improved response rates.45,46,47 Risk stratification allows patients with limited disease to be treated with less-intensive therapy than more advanced cases and still achieve very high responses, although the vast majority of patients present with advanced disease. Patients with extensive disease can achieve 80 percent long-term survival. The regimens employ multiple non–cross-resistant drugs used over a short period. These drugs include high-dose cyclophosphamide, methotrexate, vincristine, prednisone, high-dose methotrexate, high-dose cytarabine, etoposide, and sometimes ifosfamide. CNS prophylaxis therapy, either intrathecal or systemic, is given in almost all patients with BL. Radiation therapy does not play a role in the treatment of BL, and use of radiation therapy for limited-stage diseases is of no additional benefit.48,49
The tumor lysis syndrome is a serious metabolic complication of rapidly growing tumors, of which BL is a classic example. The syndrome is the result of the rapid destruction of tumor cells, highly sensitive to chemotherapy, and can result in hyperuricemia, hyperkalemia, hyperphosphatemia, secondary hypocalcemia, metabolic acidosis, and renal failure. In tumors such as BL the cell death rate (and proliferative rate) may be so substantial in patients with bulky disease that the tumor lysis syndrome may occur before therapy, so-called spontaneous tumor lysis.50 Spontaneous tumor lysis is a highly morbid phenomenon with a poor prognosis for a salutary outcome from therapy and a complication with a high death rate. It occurs in patients with a high body burden of tumor, usually with abdominal disease, a common situation in BL. Its principal manifestation is the combination of hyperuricemia and azotemia. In BL a critical part of therapy is recognizing incipient or overt spontaneous tumor lysis rapidly or preventing chemotherapy-induced tumor lysis. LDH has been used as a surrogate marker for risk of tumor lysis with a serum level twice the upper limit of normal for the laboratory in question being the threshold for urgent concern. The usual prophylactic therapy for this situation is carefully monitored hydration of at least 3 L of saline per day and either allopurinol or rasburicase to decrease serum uric acid concentration and thereby hyperuricosuria. Rasburicase acts more quickly than allopurinol and should be used if risk is considered high or if evidence of spontaneous tumor lysis is present initially.51,52 Continuous venovenous hemofiltration has also been very useful in allowing concomitant full-dose chemotherapy and preventing tumor lysis and renal failure.53,54
The specific regimens that have been developed to treat BL have historically been adapted from pediatric experience; Table 102–2 depicts representative trial results, including adult patients. There are no studies directly comparing these regimens, and comparison among the single-arm studies is difficult because of lack of uniform diagnostic criteria, staging, and the heterogeneous patient populations studied. In general, shorter durations of chemotherapy (i.e., 6 months) are as good as longer (18 months) periods of treatment. Other studies have shown a dramatically improved response with use of four cycles of chemotherapy as opposed to 15 cycles. BL has a high proliferative rate, so subsequent chemotherapy cycles should be started as soon as hematologic recovery occurs. Waiting for a fixed period between cycles may lead to regrowth of resistant tumor cells between cycles.
Table 102–2.Outcome of Burkitt Lymphoma in Larger Studies ||Download (.pdf) Table 102–2. Outcome of Burkitt Lymphoma in Larger Studies
|Citation ||Regimen ||No. of Patients ||2-Year Outcome |
|Hoelzer71 ||Short duration/dose intensive; pediatric NHL based ||35 ||51% (estimated survival) |
|Magrath45 ||CODOX-M/IVAC ||54 ||89% (actual survival) |
|Mead57 ||CODOX-M/IVAC ||58 ||64% (progression-free survival) |
|Rizzieri65 ||Short duration/dose intensive with rituximab ||105 ||74% (3-year event-free survival) |
|Thomas64 ||Hyper-CVAD with rituximab ||31 ||89% (estimated survival) |
|Dunleavy61 ||Dose adjusted R-EPOCH ||29 ||95% (event-free survival) |
|Evens60 ||R-CODOX-M/IVAC ||25 ||80% (progression-free survival) |
Cyclophosphamide, doxorubicin, vincristine, methotrexate, ifosfamide, etoposide, and high-dose cytarabine, with intrathecal cytarabine and methotrexate (CODOX-M/IVAC) is among the most commonly used regimens in the United States for adults with BL, based upon an initial favorable publication from the National Cancer Institute (NCI) indicating extremely high response rates.45 Two subsequent, small, phase II trials have used this regimen with minor modifications, and have successfully enrolled greater numbers of older patients, demonstrating cure rates of approximately 64 percent.55,56 These cure rates are substantially less than the initial report,49 but still better than historical data with standard-dose regimens. A modification of this regimen in patients with aggressive lymphomas and high proliferative rate as measured by Ki-67 fraction has been proposed.57 BL was strictly defined as the following: germinal center phenotype, BCL2-negative, MYC-rearrangement–positive, and absence of the t(14;18) or abnormalities at chromosome 3q27. Overall survival of the subgroup defined as BL was 67 percent in this group of older patients. Treatment-related mortality was 8 percent. Outcomes were similar among all age groups with the exception of patients older than age 65 years who clearly had an inferior prognosis. These results likely reflect the true outcome of this regimen in practice. Several groups have further modified this regimen with the addition of rituximab, demonstrating superior outcomes compared with historical controls.58,59,60 Based upon these findings and extrapolating from studies in other histologies of lymphoma, rituximab should be routinely incorporated in the treatment algorithms of BL.
The NCI has published an experience using a lower-intensity chemotherapy program consisting of infusional etoposide, vincristine and doxorubicin, with bolus rituximab, cyclophosphamide and steroids (dose-adjusted R-EPOCH). Nineteen patients with a median age of 25 years with generally favorable features (only 37 percent had elevated LDH, and only one patient had CNS disease) achieved a 95 percent rate of freedom from disease progression.61 Intrathecal methotrexate was administered to all patients for CNS prophylaxis.
Other regimens used for the therapy of BL include fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) alternating with high-dose methotrexate and cytarabine.62 The outcome of patients at a single institution (M.D. Anderson Cancer Center) with BL treated with this regimen in combination with rituximab resulted in an overall survival of 89 percent with only one death.63,64 The Cancer and Leukemia Group B has developed an intensive short duration regimen consisting of cyclophosphamide, ifosfamide, methotrexate, vincristine, cytarabine, etoposide and glucocorticoids. This regimen was combined with rituximab in a trial enrolling high risk patients with a median age of 43 years, with 74 percent event-free survival at 3 years.65
No advantage of autologous stem cell transplantation in patients with BL has been observed, although incorporating planned autologous transplantation into the initial therapeutic algorithm has been used with reasonable results.66
Historically, patients with HIV have been managed with less-intensive chemotherapy because of the concern of immunosuppression-related morbidity. In the highly active antiretroviral therapy (HAART) era, HIV-positive patients with BL should be treated similarly to nonimmunocompromised patients, and the dose-adjusted R-EPOCH regimen may be an excellent option for these patients. The rate of treatment failure in HIV-positive patients with BL was significantly lower with a highly aggressive protocol when compared with patients who were treated with less-aggressive chemotherapy. In addition, patients tolerated the aggressive protocol reasonably well, particularly when HAART therapy was incorporated into the regimen.67