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1244 Part IX: Lymphocytes and Plasma Cells Chapter 81: Hematologic Manifestations of Acquired Immunodeficiency Syndrome 1245

was 750 mg/m (even in those patients with a low CD4 count) and was Epidemiology, and End Results (SEER) Registry–based study, there was
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dose adjusted, depending on the neutrophil nadir, in subsequent cycles an increase in the number of cases of Burkitt lymphoma in the United
of EPOCH. Patients were treated to complete response plus one addi- States in the late 1980s that is maintained to the present time (see Fig.
tional cycle. The majority (79 percent) of patients received three cycles 81-1), particularly in men, and is thought to be attributable to the HIV
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of short-course EPOCH with dose-dense rituximab, and ART was sus- epidemic. The pathogenesis of HIV-associated Burkitt lymphoma
pended during chemotherapy because of concern about alteration in the is similar to that of Burkitt lymphoma in HIV– people, and involves
pharmacokinetics or pharmacodynamics of the chemotherapy agents or translocation of the Myc gene on chromosome 8 with one of the immu-
overlapping toxicity. CD4 counts dropped a median of 64 cells/μL, and noglobulin genes on chromosomes, 2, 14, or 22, resulting in overex-
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recovered to baseline by 6 to 12 months. Consistent with other studies, pression of Myc. HIV-associated Burkitt lymphoma is an aggressive
patients with initial CD4 counts of 100 cells/μL or greater had a much malignancy, and it is important to act decisively in these often very ill
better 5-year overall survival (90 percent) than did the patients with a patients. More than 80 percent of patients with HIV-associated Burkitt
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CD4 count of less than 100 cells/μL (20 percent). Cyclophosphamide, lymphoma present with stage IV disease and extranodal sites are often
doxorubicin, vincristine, prednisone (CHOP) has also been stud- involved. Marrow, liver, gastrointestinal tract, kidney, and CNS involve-
ied in HIV+ patients with diffuse large B-cell lymphoma. In an AMC ment are common, with cranial nerve palsies a common feature of CNS
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phase III multiinstitution clinical trial (AMC 010), patients with HIV- involvement. The serum lactate dehydrogenase (LDH) is elevated in
associated NHL (diffuse large B-cell lymphoma in 80 percent, Burkitt more than 80 percent of patients, often to high levels (greater than five-
lymphoma in 9 percent) were randomized to six cycles of CHOP (n = fold normal). A number of chemotherapy regimens have been studied in
50) versus rituximab plus CHOP (R-CHOP) (n = 99), with all patients on HIV+ patients with Burkitt lymphoma. As in the HIV– setting, CHOP
ART. The R-CHOP group also received three monthly doses of ritux- is not adequate treatment for Burkitt lymphoma, 140,142 and should not
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imab following completion of chemotherapy. Of note, the median CD4 be used. Recent data show excellent outcomes with a variant of the R-
count at enrollment was 133 cells/μL and 24 percent of the patients had EPOCH regimen. In this single-institution, small prospective clin-
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advanced HIV with CD4 counts less than 50 cells/μL, so this was a fairly ical trial, a total of 30 patients with Burkitt lymphoma were treated,
immunocompromised group of patients. Overall survival was iden- including 11 who were HIV+ with a median CD4 count of 322 cells/μL.
tical with CHOP or R-CHOP, unlike HIV-negative patients in whom The short-course EPOCH-RR used in this clinical trial included two
the addition of rituximab significantly improves outcome. In the AMC doses of rituximab per cycle of EPOCH, and a total of three or four
010 clinical trial, there were significantly more deaths from infection cycles of EPOCH (to complete response plus one additional cycle),
in the R-CHOP arm in comparison to the CHOP arm, which offset the and included prophylactic intrathecal methotrexate. With a median
trend toward better control of lymphoma with R-CHOP. The majority follow up of 6 years, the overall survival of the HIV+ patients was 90
of these infectious deaths occurred in patients with a CD4 count of less percent. The major toxicity was neutropenia in 31 percent of cycles
than 50 cells/μL, suggesting that rituximab should be used cautiously in of EPOCH-RR, and hospital admission for febrile neutropenia was
immunologically vulnerable patients. As in studies of EPOCH, patients required in 10 percent of cycles. This study showed that low-intensity
with a CD4 count greater than 100 cells/μL had a better overall survival therapy administered primarily in the outpatient setting can be effec-
than those with a lower CD4 count. Other reports suggest that R-CHOP tive for HIV-associated Burkitt lymphoma. Other studies of R-EP-
treatment in HIV+ patients with diffuse large B-cell lymphoma is safe OCH that included a subset of patients with HIV-associated Burkitt
and effective, 121,130 including in those with a low CD4 count. In a phase lymphoma also report excellent outcomes with R-EPOCH. Other
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II study of modified R-CHOP in 40 patients with diffuse large B-cell regimens reported in patients with HIV-associated Burkitt lymphoma
lymphoma, pegylated liposomal doxorubicin was substituted for dox- include cyclophosphamide, vincristine, doxorubicin, and dexametha-
orubicin and the complete response rate was 48 percent, lower than sone (HyperCVAD) alternating with high-dose methotrexate plus cyta-
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what is reported with rituximab plus EPOCH (R-EPOCH) or R-CHOP. rabine. In this study, patients were very immunocompromised with
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At the time of this writing, there are no phase III data comparing R-E- a median CD4 count of 77 cells/μL; nevertheless, complete remission
POCH to R-CHOP in HIV+ patients. Pooled analysis of two sequential was achieved in more than 90 percent of patients, with 48 percent of
AMC clinical trials, AMC 010 (99 patients on the R-CHOP arm) and patients alive at 2 years. Severe myelosuppression was universal, but
AMC 034 (51 patients on the concurrent R-EPOCH arm) showed that infectious complications were similar to HIV– patients. In this small
the 2-year overall survival was approximately 50 percent with R-CHOP study, those on ART had a better outcome than those not on ART.
and approximately 65 percent with R-EPOCH (p <0.01), suggesting Cyclophosphamide, vincristine, doxorubicin, methotrexate/ifosfa-
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superiority of R-EPOCH. Similarly, a pooled analysis of 1546 patients mide, mesna, etoposide, cytarabine (CODOX-M/IVAC) has also been
enrolled in 19 prospective clinical trials, concluded that EPOCH was employed to treat HIV-associated Burkitt lymphoma, 145–147 with 3-year
associated with a better overall survival than CHOP in patients with overall survival of approximately 50 percent. A retrospective review
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HIV-associated diffuse large B-cell lymphoma (hazard ratio 0.33, p = compared eight HIV+ patients who received CODOX-M/IVAC to 24
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0.03). However these observations require validation in prospective HIV– patients with Burkitt lymphoma : Patients had similar rates of
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randomized studies. For patients with relapsed or refractory HIV- myelosuppression, infection, and complete response regardless of HIV
associated diffuse large B-cell lymphoma, salvage regimens such as status. The LMB86 protocol (including high-dose methotrexate plus
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gemcitabine/dexamethasone/cisplatin or etoposide, methylpredniso- cytarabine) was used to treat HIV-related Burkitt lymphoma in a
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lone, high-dose cytarabine, cisplatin (ESHAP) can provide response prospective single center study of 63 patients on ART. The complete
rates of approximately 50 percent. response rate was 70 percent and the estimated disease-free survival at 2
years was 67 percent. This regimen was characterized by severe marrow
HUMAN IMMUNODEFICIENCY toxicity, and more than 10 percent of patients died of regimen-related
VIRUS–ASSOCIATED BURKITT LYMPHOMA toxicity. Poor prognostic factors included a CD4 count of less than 200
cells/μL and an Eastern Cooperative Oncology Group (ECOG) perfor-
HIV-associated Burkitt lymphoma is approximately one-third as mance status of greater than 2. Other intensive regimens have also been
common as HIV-associated diffuse large B-cell lymphoma in the used, with 4-year overall survival of 70 percent, but with death in 11
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Western world, and occurs at a higher CD4 count. In a Surveillance, percent from regimen-related toxicity. 148

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