Research Article: HIV-Associated Burkitt Lymphoma: Good Efficacy and Tolerance of Intensive Chemotherapy Including CODOX-M/IVAC with or without Rituximab in the HAART Era

Date Published: November 14, 2012

Publisher: Hindawi Publishing Corporation

Author(s): J. A. Rodrigo, L. K. Hicks, M. C. Cheung, K. W. Song, H. Ezzat, C. S. Leger, J. Boro, J. S. G. Montaner, M. Harris, H. A. Leitch.

http://doi.org/10.1155/2012/735392

Abstract

Background. The outcome of HIV-associated non-Hodgkin lymphoma (NHL) has improved substantially in the highly active antiretroviral therapy (HAART) era. However, HIV-Burkitt lymphoma (BL), which accounts for up to 20% of HIV-NHL, has poor outcome with standard chemotherapy. Patients and Methods. We retrospectively reviewed HIV-BL treated in the HAART era with the Magrath regimen (CODOX-M/IVAC±R) at four Canadian centres. Results. Fourteen patients with HIV-BL received at least one CODOX-M/IVAC±R treatment. Median age at BL diagnosis was 45.5 years, CD4 count 375 cells/mL and HIV viral load (VL) <50 copies/mL. Patients received PCP prophylaxis and G-CSF, 13 received HAART with chemotherapy and 10 rituximab. There were 63 episodes of toxicity, none fatal, including: bacterial infection, n = 20; grade 3-4 hematologic toxicity, n = 14; febrile neutropenia, n = 7; oral thrush; and ifosfamide neurological toxicity, n = 1 each. At a median followup of 11.7 months, 12 (86%) patients are alive and in remission. All 10 patients who received HAART, chemotherapy, and rituximab are alive. CD4 counts and HIV VL 6 months following BL therapy completion (n = 5 patients) were >250 cells/mL
and undetectable, respectively, in 4. Conclusion.
Intensive chemotherapy with
CODOX-M/IVAC±R
yielded acceptable toxicity and good survival rates in patients
with HIV-associated Burkitt lymphoma receiving
HAART.

Partial Text

Burkitt lymphoma (BL) is a highly aggressive B-cell non-Hodgkin Lymphoma (NHL) associated with chromosomal translocations resulting in upregulation of the proto-oncogene C-MYC, which drives progression through the cell cycle [1]. It has an estimated incidence of 1200 patients per year in the United States [2]. Immunodeficiency associated BL is more commonly seen with human immunodeficiency virus (HIV) infection than other forms of immunodeficiency [3] though its incidence is lowest in patients with a CD4 count <50 cells/mL [4]. NHL accounts for approximately one third of AIDS-related malignancies and the frequency of BL is 2.4–20% of HIV-associated NHL [5]. Patients treated with the Magrath regimen were identified from the database of the hematology practices [30]. Patients from two centers in Toronto, Ontario and two centers in Vancouver, British Columbia (BC) were included. All patients had biopsy proven BL and were HIV positive at lymphoma diagnosis. Clinical data collected were HIV risk (sexual, injection drug use (IDU), etc.), CD4 count and HIV viral load at lymphoma diagnosis, prior AIDS, coinfection with the hepatitis B and/or hepatitis C viruses, and HAART use. HAART was defined as two nucleoside/nucleotide analogues and at least one protease inhibitor or a nonnucleoside reverse transcriptase inhibitor [31]. Fourteen patients with HIV-associated BL diagnosed between December 2004 and August 2009 who received at least one treatment from the Magrath protocol were identified [30]. Patients were from St. Paul's Hospital, n = 7; Vancouver General Hospital, n = 3 (Vancouver); St. Michael's Hospital, n = 2; Sunnybrook Hospital, n = 2; (Toronto). One patient had features intermediate between DLBCL and BL according to the 2008 World Health Organization (WHO) classification, including a documented t(8;14) and a proliferation rate of 80% in the pericardial fluid. The clinical features were considered to be more in keeping with BL than DLBCL and he was treated as such. The C-MYC translocation was confirmed by FISH for MYC in nine patients, t(8;14) in eight, and FISH was unsuccessful in one. The t(8;14) was confirmed by karyotype analysis in one patient. The t(14;18) or BCL-2 was negative by: FISH for t(14;18) in four patients; FISH for BCL-2 in six patients and immunohistochemistry (IHC) for BCL-2 in three patients (one of these patients had focal weak positivity for BCL-2 by IHC, which is accepted in the WHO 2008 classification) [3]. The t(14;18) was negative by karyotype analysis in two patients, and BCL-2 and t(14;18) were not reported in two patients. At a median followup of 11.7 (2.0–53.2) months, 12 of 14 patients (86%) are alive and in remission (Figure 1). All 10 patients who received HAART, intensive chemotherapy, and rituximab are alive. Eleven of 12 survivors had high-risk BL and 10 had a CD4 count >200 cells/mL at BL diagnosis. There were 2 deaths, at 2.9 and 6.9 months from lymphoma diagnosis, both from progressive lymphoma. The CD4 count at BL diagnosis in these patients was 140 and 180 cells/mL. One patient presented with CNS involvement by BL and received chemotherapy without HAART or rituximab. The second patient received chemotherapy and HAART but no rituximab, and received only two cycles of therapy as he suffered anoxic brain injury secondary to sepsis, prompting a change in direction of care to palliative management. He ultimately died of progressive BL.

In recent years, there has been a shift in treatment goals for patients with HIV-associated NHL. Prior to the HAART era, infectious deaths occurred frequently, as immunosuppression and myelosuppression from HIV made intensive chemotherapy regimens needed to effectively treat aggressive lymphomas difficult to deliver and lower-dose chemotherapy regimens given with palliative intent were recommended [24]. In the HAART era, it has become clear that standard dose chemotherapy for DLBCL [16, 34], and now intensive regimens for BL can be considered and used with success [26, 28, 35–37]. In this study, we reviewed 14 HIV-positive patients with BL treated with CODOX-M/IVAC±R. Most of our patients were receiving HAART at BL diagnosis and this was reflected in their relatively preserved immune parameters; the median CD4 count was 375 cells/mL and HIV VL <50 copies/mL. Previous series [38] have shown some success with intensive chemotherapy in HIV-associated BL. Wang et al. compared patients infected with HIV (n = 8 patients) to HIV-negative patients treated with the same regimen and found that toxicity from CODOX-M/IVAC was similar between groups, with similar rates of myelosuppression and infectious complications to HIV-negative patients [38]. A recent study of 30 patient receiving CODOX-M/IVAC and HAART showed a 3-year OS rate of 52% [39]. In addition, in a recent update from the AMC, 33 patients with HIV-associated BL were treated with modified CODOX-M/IVAC-R in which high dose MTX was given at 3000 mg/m2. At a median followup of 9 months, the one year OS was 82% with no treatment related mortality [40]. Similarly, in 29 BL patients treated with dose-adjusted EPOCH-R, 10 of whom were HIV-positive, at a median followup of 57 months, the OS was 100% [41]. Our CR rate of 86% compares favorably with this experience, as does the projected one and two year OS of 83% (median followup 11.7 months) and tolerability of the regimen. The outcomes are similar to those described in HIV-negative patients with BL [42]. Relapses of BL tend to occur early, within a few months of diagnosis [43]. At a median followup of 11.7 months, only two patients died, both within seven months of diagnosis, and both of BL. Of the twelve other patients, none have relapsed, though two are less than six months from BL diagnosis. Moreover, ten of twelve survivors had high-risk features at presentation by Magrath criteria and all twelve survivors were high risk by BCCA criteria, suggesting that this therapeutic approach can overcome high-risk BL. In this review of patients with HIV-associated BL treated with the intensive Magrath (CODOX-M/IVAC) chemotherapy regimen and HAART, patients had acceptable tolerance of therapy even when it included rituximab. Of ten patients who received chemotherapy, rituximab, and HAART, none has died. Eleven of twelve survivors had high-risk features, suggesting that this therapeutic approach can overcome high-risk BL. These results suggest that if HIV control is optimized, patients with HIV-associated BL who receive intensive chemotherapy and rituximab could achieve survival similar to HIV-negative BL patients without undue therapy-related toxicity.   Source: http://doi.org/10.1155/2012/735392

 

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