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Journal of Clinical Oncology, Vol 23, No 33 (November 20), 2005: pp. 8538-8540 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.9512
Burkitt’s Lymphoma and Previous AIDS-Defining Illnesses Are Not Prognostic Factors in AIDS-Related Non-Hodgkin’s LymphomaDepartments of HIV Medicine and Oncology, The Chelsea and Westminster Hospital, London, United Kingdom To the Editor: The recent article by Lim et al1 in the July 1, 2005, issue of the Journal of Clinical Oncology demonstrated that the survival of patients with HIV-related diffuse large B cell lymphoma has improved in the highly active antiretroviral therapy (HAART) era, along with the CD4 count, whereas the survival of those with Burkitt’s lymphoma has remained poor (38.1 months v 5.1 months; P = .0005), despite no differences in response rate (57% v 35%; P = .2). The authors suggested that the use of HAART, through changing causes of mortality including other infections, has allowed expression of the natural history of lymphoma. In multivariable analyses, we have recently demonstrated that the previously established International Prognostic Index (IPI) for lymphomas remains clinically useful for individuals with AIDS-related systemic non-Hodgkin’s lymphoma. In addition, we have shown that the CD4 count is an independent predictor of mortality and should be combined with the IPI in HIV-infected individuals, identifying those patients who may benefit from standard therapy with curative intent, and others who may be considered for other treatments.2 Interestingly, in analyses including 104 individuals with AIDS-related systemic non-Hodgkin’s lymphoma treated before the HAART era, we observed that Burkitt’s lymphoma and previous AIDS-defining illnesses were significant independent predictors of mortality. To our surprise, and in contrast to suggestions made by Lim et al, neither of these factors were poor prognostic factors in those patients treated in the HAART era.2 For our entire cohort of 215 patients with AIDS-related systemic non-Hodgkin’s lymphoma, the actuarial overall survival at 2 years, including all causes of death, was 32% (95% CI, 25% to 39%), and at 5 years was 26% (95% CI, 19% to 33%). Comparisons of the clinicopathologic features of patients in the pre- and post-HAART eras do not immediately explain these findings. Patients in the post-HAART era had significantly higher CD4 cell counts (median, 144 cells/mm3 v 45 cells/mm3; P < .001), better Eastern Cooperative Oncology Group performance status (P = .003), and fewer previous AIDS-defining diagnoses (P < .001), although these individuals had a higher serum lactate dehydrogenase (P < .001), and importantly, more had Burkitt’s lymphoma histology (P = .020). In multivariate analyses of these patients, four variables were found to be significant independent predictors of mortality following a diagnosis of AIDS-related systemic non-Hodgkin’s lymphoma (Table 1) : a prior AIDS diagnosis (P = .016), Burkitt’s lymphoma histology (P = .026), CD4 cell countat lymphoma diagnosis (P < .001), and IPI risk group (P < .001 for high IPI v other categories).
A prognostic risk score was derived from this analysis by the addition of weightings for each of these four variables as shown in Table 2, with the group of patients with high IPI risk (score, 3.3) and CD4 cell counts of less than 100 cells/mm3 (score 2.29) having the highest scores. The prognostic risk scores were then divided into quartiles as follows: less than 1.59, 1.59 to 3.32, 3.32 to 4.45, and more than 4.45. Using these quartiles, the overall survival duration for each quartile group was derived as illustrated in Figure 1. Those individuals in the highest quartile had a likely ratio for mortality of 10.02 (hazard ratio, 1), compared with those in the lowest quartile (likelihood ratio, 0.2; hazard ratio, 0.1; 95% CI, 0.06 to 0.19).
The analysis we present here demonstrates that the presence of previous AIDS-defining illness and Burkitt’s lymphoma histology, both poor prognostic factors in the pre-HAART era, disappear as prognostic factors in the HAART era. As the incidence of Burkitt’s lymphoma has not decreased, we cannot explain these data on the basis of frequency. This is in contrast to the data presented by Lim et al1 that concentrates on retrospective survival as single pairwise variables. HAART-induced immune maintenance may explain the disappearance of previous AIDS-defining illnesses as a prognostic factor in the HAART era, despite the importance of the CD4 counts in all patient prognostic scores. However, it does not explain the issues surrounding Burkitt’s lymphoma. Most AIDS-related Burkitt’s lymphoma is Epstein-Barr virus–negative (although in Africa it is strongly associated). Sequence analysis of VDJ rearrangements at various stages of B cell differentiation has revealed hypermutations in VH genes leading to the introduction of point mutations in this region increasing the affinity of complementarity-determining regions of antibody-binding sites.3-5 If cells expressing the mutated sequences are then exposed to more antigens, this interaction results in stimulation and proliferation of those cells that bind these antigens most efficiently, with unstimulated cells undergoing apoptosis.6,7 Genomic instability due to somatic hypermutation results in deregulated expression of the mitotic uncoupling c-Myc oncoprotein, and may further enhance the transformation process.8 Interestingly, B cells were the first known latent reservoir of HIV discovered,9,10 and we suggest a model in which suppression of viremia in the HAART era leads to decreased B cell stimulation, regardless of whether those cells harbor Epstein-Barr virus or not. Here, the resulting AIDS-associated Burkitt’s lymphoma in the HAART era may have fewer associated somatic mutations and could be less "aggressive" and therefore not a poor prognostic factor. In all patients with AIDS-related systemic non-Hodgkin’s lymphoma however, regardless of the time of diagnosis, the CD4 count remains a significant independent prognostic variable. Authors’ Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Lim ST, Karim R, Nathwani BN, et al: AIDS-related Burkitt’s lymphoma versus diffuse large-cell lymphoma in the pre-highly active antiretroviral therapy (HAART) and HAART eras: Significant differences in survival with standard chemotherapy. J Clin Oncol 23:4430-4438, 2005
2. Bower M, Gazzard B, Mandalia S, et al: A prognostic index for systemic AIDS-related lymphoma treated in the era of highly active anti-retroviral therapy. Ann Intern Med 143:265-273, 2005 3. Kocks C, Rajewsky K: Stable expression and somatic hypermutation of antibody V regions in B-cell developmental pathways. Annu Rev Immunol 7:537-559, 1989[CrossRef][Medline] 4. Klein U, Klein G, Ehlin-Henriksson B, et al: Burkitt’s lymphoma is a malignancy of mature B cells expressing somatically mutated V region genes. Mol Med 1:495-505, 1995[Medline] 5. Brezinschek HP, Foster SJ, Brezinschek RI, et al: Analysis of the human VH gene repertoire: Differential effects of selection and somatic hypermutation on human peripheral CD5(+)/IgM+ and CD5(–)/IgM+ B cells. J Clin Invest 99:2488-2501, 1997[Medline] 6. Liu YJ, Joshua DE, Williams GT, et al: Mechanism of antigen-driven selection in germinal centres. Nature 342:929-931, 1989[CrossRef][Medline]
7. Bellan C, Lazzi S, Hummel M, et al: Immunoglobulin gene analysis reveals two distinct cells of origin for EBV positive and EBV negative Burkitt’s lymphomas. Blood 106:1031-1036, 2005
8. Zhu D, Qi CF, Morse HC 3rd, et al: Deregulated expression of the Myc cellular oncogene drives development of mouse "Burkitt-like" lymphomas from naive B cells. Blood 105:2135-2137, 2005 9. Lane HC, Masur H, Edgar LC, et al: Abnormalities of B-cell activation and immunoregulation in patients with the acquired immunodeficiency syndrome. N Engl J Med 309:453-458, 1983[Abstract]
10. Stebbing J, Gazzard B, Douek DC: Where does HIV live? N Engl J Med 350:1872-1880, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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