AIDS-Related Burkitt's Lymphoma Versus Diffuse Large-Cell Lymphoma in the Pre–Highly Active Antiretroviral Therapy (HAART) and HAART Eras: S
http://www.100md.com
《临床肿瘤学》
the Norris Comprehensive Cancer Center
Department of Epidemiology and Biostatistics
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA
National Cancer Centre, Singapore
ABSTRACT
PURPOSE: To compare outcomes of patients with HIV-Burkitt's lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre–highly active antiretroviral therapy (HAART) versus HAART eras.
PATIENTS AND METHODS: Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART.
RESULTS: There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm3 independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era.
CONCLUSION: Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.
INTRODUCTION
The two major categories of aggressive AIDS-related lymphomas (ARLs) are Burkitt's lymphoma (HIV-BL) and diffuse large-cell lymphoma (HIV-DLCL). In non-HIV infected patients, BL is a rapidly progressing disease with a poor outcome when treated with standard regimens used for other subtypes of aggressive non-Hodgkin's lymphoma (NHL). 1 These patients fare better when treated with multiagent, dose intensive regimens, which lead to long-term, disease-free survival in the majority. 2-9 While intensive chemotherapy is recommended for the treatment of BL in the general population, optimal management of patients with HIV-BL is not currently well defined.
In the pre–highly active antiretroviral therapy (HAART) era, therapy of patients with HIV-BL using less intensive, low-dose chemotherapy was associated with median overall survival time similar to that of patients with HIV-DLCL, suggesting that dose-intensive therapy was not required in the treatment of HIV-BL. 10,11 Thus, the AIDS Clinical Trials Group (ACTG) in the United States compared standard-dose chemotherapy consisting of methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD) and granulocyte macrophage colony-stimulating factor (GM-CSF) support with reduced-dose M-BACOD without GM-CSF in 198 patients with ARL. 11 No differences were found in either response rate (standard dose, 52% v reduced dose, 41%), or median survival (standard dose, 6.8 months v reduced dose, 7.7 months) in patients receiving standard-dose or reduced-dose chemotherapy. However, reduced-dose M-BACOD was associated with a statistically superior toxicity profile. Importantly, there were no differences in response or survival in terms of pathologic type of lymphoma. Thus, outcome of the 85 patients with large-cell lymphoma and the 83 patients with BL in either dose arm was similar, 11 although the prognosis of both groups of patients was equally poor, with median survival of approximately 6 months. Other studies have also treated patients with HIV-BL and HIV-DLCL similarly, with no statistically significant differences in response or survival. 10,12-14 In contrast, the factors that have been associated with poor survival in patients with ARL include CD4 cells less than 100/mm3, stage III or IV disease, age older than 35 years, history of injection drug use, and elevated lactate dehydrogenase (LDH). 10,15,16 Nonetheless, it should be noted that these studies have included primarily patients in the pre-HAART era.
The advent of HAART has resulted in a dramatic reduction in the development of opportunistic infections and a remarkable improvement in overall survival among patients with AIDS. 17 At the same time, prognosis of patients with ARL has also improved; the median overall survival of these patients is now comparable to that of patients with aggressive NHL in the general population. 18-22 Further, with improved immune function due to HAART, patients are better able to tolerate standard dose regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and others. 22,23 Additionally, in the HAART era, several studies have also shown that it is possible to successfully salvage patients with relapsed or refractory ARL using high-dose chemotherapy and progenitor stem-cell support. 24-26
Several small retrospective series in the HAART era have also suggested that it may be feasible to administer intensive regimens such as CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) 27 and hyperCAVD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) 28 to patients with HIV-BL. Nonetheless, it remains uncertain whether these intensive strategies are necessary or optimal for these patients. With the ability to administer safely such therapy to patients with ARL, it may be important to reassess the previous understanding that HIV-infected patients with BL and DLCL should be treated similarly.
We thus sought to compare the outcomes of patients with HIV-BL and HIV-DLCL who were treated with either CHOP- or M-BACOD–based chemotherapy in either the pre-HAART or HAART eras, to determine whether differences in outcome were apparent, and to reevaluate the question of optimal therapy for HIV-BL in the HAART era. We also wished to determine factors that were independently associated with decreased survival in both time frames.
PATIENTS AND METHODS
This study was approved by the institutional review board of our institution.
The diagnostic criteria for determining the various subtypes of lymphoma, including ARL, have evolved over time. In this analysis, we used the Lukes-Collins classification system of malignant lymphomas, which divided the lymphomas into B-cell, T-cell and null cell types. Details of this classification have been published previously. 29,30 The advantage of this system is its applicability to all cases of lymphoma diagnosed over the last two decades, and the fact that our center has used this system consistently over the past three decades. For this study, the Lukes and Collins diffuse large cleaved, large noncleaved, and B immunoblastic were considered as DLCL, while small noncleaved cell lymphoma was considered as BL.
Using these diagnostic criteria, we retrospectively identified 363 patients diagnosed with HIV-BL or HIV-DLCL at Los Angeles County-University of Southern California (LAC-USC) Medical Center and USC/Norris Cancer Hospital between 1982 and December 2003. Thus, there were 135 patients with biopsy-confirmed HIV-BL and 228 patients with HIV-DLCL. Patients with all other histologic subtypes and unclassifiable subtypes were excluded from this analysis. These 363 patients came from a total cohort of 414 patients that also included an additional 51 patients diagnosed with other histologic subtypes. All cases in this study were reviewed and diagnosed by a single, expert hematopathologist (B.N.N.). All patients were HIV seropositive by enzyme-linked immunosorbent assay with confirmation by Western blot.
Patients were staged before treatment using the Ann Arbor staging system, which included a history; physical examination; standard laboratory tests; computed tomography scans of chest, abdomen, pelvis, and other relevant sites; gallium scans; and bilateral bone marrow biopsy. Lumbar puncture was performed routinely in all patients, and assessment of cerebrospinal fluid (CSF) cytology was performed in all.
Hospital records, bone marrow pathology reports, laboratory data, radiology reports, treatment regimens, and response to therapy were reviewed.
HAART became available in our institution in 1997. Thus in the current study, patients in the pre-HAART era included only those who were diagnosed before December 31, 1996, and who did not receive HAART therapy during the course of their HIV disease. Patients in the HAART era included only those who were diagnosed after January 1, 1997, and who did receive HAART.
The following HIV-related and lymphoma-related characteristics were assessed: age, sex, performance status, use of injection drugs, serum lactate dehyrodenase level, CD4 count at presentation, stage of disease, prior history of AIDS, pathologic subtype of lymphoma, and response to treatment. Differences in baseline lymphoma characteristics and HIV-related characteristics were compared between the two histologic subtypes using t-test or 2 test for continuous or categoric variables, respectively (Tables 1 and 2). Comparisons were made for pre-HAART and HAART eras. The Cox proportional hazard model was fitted to determine the significant prognostic factors for survival in ARL. 31 Survival or follow-up time was calculated from the date of diagnosis to death or to the date when the patient was last seen. Factors showing significant impact in univariate analysis were tested in a multivariate model for independence of association. Survival curves were compared between HIV-BL and HIV-DLCL for pre-HAART and HAART eras using Kaplan-Meier survival analysis. 32 P values from the log-rank tests were reported for referring to statistical differences of median survival time. 33 All analyses were performed using SAS version 8.0 (SAS Institute, Cary, NC).
RESULTS
HIV and Lymphoma Characteristics
The demographic, HIV and lymphoma-related characteristics of the 135 patients with HIV-BL and 228 patients with HIV-DLCL are provided in Tables 1 and 2. There were 117 cases of HIV-BL (45%) and 145 cases of HIV-DLCL (55%) in the pre-HAART era, compared with 18 cases of HIV-BL (18%) and 83 cases of HIV-DLCL (82%) in the HAART era.
In both the pre-HAART and HAART eras, there were no statistically significant differences between the two histologic subtypes at presentation in terms of age, sex, history of injection drug use, prior history of opportunistic infection(s) or Kaposi's sarcoma, LDH level, and stage of disease at diagnosis (Tables 1 and 2).
However, in the pre-HAART era, the median CD4 count at diagnosis in patients with HIV-DLCL was significantly lower than that of patients with HIV-BL (60 cells/mm3 versus 120 cells/mm3, respectively; P = .03). In addition, more patients with HIV-DLCL had a CD4 count of less than 100 cells/mm3 at diagnosis than patients with HIV-BL (57% v 36%, P = .0009). In contrast, in the HAART era, differences in median CD4 counts at diagnosis (BL, 125 cells/mm3 v DLCL, 94 cells/mm3; P = .85) and proportions of patients with CD4 counts less than 100 cells/mm3 were similar between the two groups (BL, 39% v DLCL, 46%; P = .52). While the proportions of patients with Karnofsky performance score (KPS) less than 80 were not different between the two histologic subtypes in the pre-HAART era, more patients with HIV-BL had a KPS less than 80 (61% v 31%, P = .01) in the HAART era.
Although extranodal lymphomatous involvement was prevalent in both histologic subtypes in both pre-HAART and HAART eras, the pattern of lymphomatous involvement was different (Table 2). Bone marrow, liver, and renal involvement were statistically more common in patients with HIV-BL compared with patients with HIV-DLCL in both time periods.
Treatment
All patients receiving combination chemotherapy were treated with curative intent. The most commonly used chemotherapy regimens were M-BACOD and CHOP-based therapy in both periods (Table 3). In the pre-HAART period, a greater proportion of patients with DLCL were never treated for their lymphoma when compared with patients with BL (17% v 5%, P = .01). Nonetheless, the most commonly used regimens were CHOP- or M-BACOD–based therapies, used in 75% of patients with DLCL and 86% of those with BL (P = .01). In the HAART period, the proportion of patients receiving M-BACOD–or CHOP-based chemotherapy was not statistically different between the two groups (90% in BL v 84% in DLCL; P = .78).
Apart From CHOP- or M-BACOD–based chemotherapy, other regimens used in the HAART era included the EPOCH regimen (etoposide, oncovin, doxorubicin, and cyclophosphamide) in three patients and infusional CDE (etoposide, doxorubicin, and cyclophosphamide) in two. In the pre-HAART era, 10 patients (9%) with HIV-BL and 11 with HIV-DLCL (8%) received other regimens using varying combinations of high-dose cytarabine, doxorubicin, etoposide, vincristine, cyclophosphamide, methotrexate, and prednisone.
Outcome
In the pre-HAART era, there was no statistically significant difference in the complete response rates between patients with HIV-BL or HIV-DLCL who were treated for their lymphomas (32% v 32%; P = .99; Table 2). Additionally, overall median survival in the pre-HAART era was not statistically different between the two histologic subtypes (6.0 v 7.6 months; P = .99; Fig 1A). When analysis of median survival was limited to only those patients who received combination chemotherapy with curative intent, there was still no statistical difference between the two histologic groups in terms of overall median survival (HIV-BL, 6.4 v HIV-DLCL, 8.3 months; P = .43; Fig 1B). In the univariate analyses of poor prognostic factors for survival in the pre-HAART era among patients who were treated with curative intent, KPS less than 80, an elevated LDH, a prior history of AIDS, a median CD4 count less than 100 cells/mm3 at diagnosis, and failure to attain complete remission were each associated with decreased survival (Table 4). Pathologic type of lymphoma (DLBCL v BL) had no impact. In multivariate analyses, failure to attain complete remission and a CD4 count less than 100 cells/mm3 were independently predictive of decreased survival (Table 4).
In the HAART era, the complete response rate was higher in patients with HIV-DLCL when compared with similarly treated patients with HIV-BL, although the difference was not statistically significant (57% v 35%, P = .2; Table 2). Importantly, the median survival of patients with HIV-DLCL was significantly longer than that of patients with HIV-BL (38.1 months v 5.1 months; P = .0005; Fig 2A). This difference in median survival was even more remarkable if only patients who received combination chemotherapy with curative intent were considered (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003; Fig 2B). In the univariate analyses, poor prognostic factors for survival in patients treated with curative intent included KPS less than 80, elevated LDH level, a prior history of AIDS, advanced disease stage at presentation, failure to attain complete remission of disease, and a pathologic diagnosis of HIV-BL (Table 4). On multivariate analysis, pathologic diagnosis of HIV-BL was an independent poor prognostic factor for survival, together with failure to attain complete remission (Table 4).
It has been our practice to treat all patients with negative CSF cytology with four weekly doses of prophylactic intrathecal (IT) cytarabine for prophylaxis. Patients with positive CSF cytology were treated with IT cytarabine on alternate days until clearance of malignant cells was achieved. Thereafter, the patient was treated with weekly IT chemotherapy for a month, followed by monthly IT therapy for a year. Among the 23 patients with HIV-BL treated for positive CSF cytology, 5 (23%) achieved complete remission of disease, including clearance of CSF. Among the 19 patients with HIV-DLCL and positive CSF cytology, 4 (22%) achieved complete remission of disease, including clearance of CSF. The remaining patients died as a result of progressive disease.
DISCUSSION
We have demonstrated that the survival of patients with HIV-DLCL has improved dramatically from 8.3 months in the pre-HAART era to 43.2 months in the HAART era when these individuals are treated with CHOP- or M-BACOD–based regimens. In contrast, after similar types of chemotherapy, survival of patients with HIV-BL has remained unchanged and poor, at a median of 6.4 months in the pre-HAART and 5.7 months in the HAART eras. The finding that HAART did not improve the survival of patients with HIV-BL has not previously been reported.
Earlier studies, before the advent of HAART, demonstrated that age, CD4 count, stage, a history of injection drug use, and LDH were predictive of survival. In contrast, pathologic-type lymphoma was not shown to be of prognostic significance. 12,15,16, 34-37 Univariate analyses of prognostic factors in our study also demonstrated the same poor prognostic characteristics. On multivariate analyses in both the pre-HAART and HAART eras, failure to attain complete response was an independent predictor of poor survival. Of importance is our finding that when analyses were confined to the HAART era, BL pathologic type was also shown to be independently associated with shorter survival.
It is conceivable that the use of HAART, through decreasing other competing causes of mortality such as opportunistic infections, has allowed the natural history of the various pathologic subtypes of ARL to be expressed. Indeed, the median survival of 43.2 months in our patients with HIV-DLCL after treatment with CHOP or M-BACOD is similar to that of HIV-uninfected patients in the general population with aggressive NHL of similar stages. 36 Likewise, the poor survival in similarly treated patients with HIV-BL is consistent with the poor outcome observed in HIV-uninfected patients with BL treated with standard dose chemotherapy. 1 Although survival of patients with HIV-BL after CHOP- or M-BACOD–based chemotherapy was short in the pre-HAART era, results were similarly poor in patients with DLCL, potentially obscuring any differences in the natural history of these two pathologic types.
Experience over the last three decades has confirmed the efficacy of dose-intensive chemotherapy in improving the survival of patients with BL. 3-9 The current study and others 27,28 indicate the need for prospective trials to determine whether HIV-BL should be treated with similar intensive strategies, now that such therapy can be given safely. 26-28 For example, Cortes et al 28 investigated the use of the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen in 13 patients with HIV-BL, nine of whom also received HAART. Results were encouraging, with a complete remission (CR) rate of 92%, although median survival was only 12 months. Of interest, six of seven patients who received HAART from the start of chemotherapy were alive and in CR after a median of 29 months (range, 7 to 45 months), whereas all four patients who did not receive HAART subsequently died. Toxicity in patients with HIV-BL was similar to that reported in non-HIV-infected patients with BL treated with the same regimen. 8 In another study, Wang et al 27 retrospectively compared 14 HIV-infected patients with BL with 24 non-HIV-infected patients with BL who received CODOX-M/IVAC or less intensive regimens. HIV status had no negative impact on either CR (HIV infected, 64% v non–HIV infected, 63%) or 2-year event-free survival rates (HIV infected, 59% v non–HIV infected, 62%). When event-free survival was evaluated according to the chemotherapy regimen and independent of HIV status, patients receiving CODOX-M/IVAC had a better 2-year event-free rate compared with those receiving less intensive chemotherapy (80% v 38%, respectively). Further, rates of myelosuppression and infection were similar among HIV-infected and HIV-uninfected patients treated with CODOX-M/IVAC. These studies, as well as the current work, suggest that the approach of using a uniform regimen for all pathologic subtypes of aggressive ARL should be re-evaluated.
This current study reported a decline in the incidence of HIV-BL over time, contrary to expectation. As BL in the setting of HIV infection tends to present in patients with higher CD4 counts, its incidence should theoretically increase in the HAART era, commensurate with the rise in CD4 counts following effective use of antiretroviral therapy. However, in one large epidemiologic study conducted by the International Collaboration on HIV and Cancer, 37 there was no evidence that the incidence of HIV-BL has changed over time, although the authors did caution that the number of cases of BL observed in the report was small. In another epidemiologic study from France, Beeson et al 38 noted an increase in the proportion of patients with HIV-BL from 17.7% in the pre-HAART era to 26.8% in the HAART era; however, this increase was not statistically significant (P = .17). Of importance, in the large EuroSIDA study of AIDS-related lymphoma, the incidence of BL decreased from the pre-HAART to the HAART eras, whereas that for diffuse large cell/immunoblastic lymphoma increased. 39 In another recent retrospective study 40 involving 214 patients with AIDS-related lymphomas from the Frankfurt AIDS cohort (FACS), treated between January 1981 and May 2003, the incidence rate of BL decreased from 24% in the pre-HAART era to 12.9% in the HAART era. Interestingly, 39% of the patients in the cohort had CD4 counts less than 100 cells/mm3 in the HAART era, compared with 74% of patients with CD4 counts less than 100 cell/mm3 in the HAART era. Thus, the incidence of BL was lower in the HAART era despite an increase in CD4 counts.
Similarly, in an earlier report involving patients seen from 1982 to 1998, Levine et al 41 first reported a decrease in HIV-BL over time. With further follow-up, this current report has demonstrated a continued decline in the incidence of HIV-BL over time. Because the median CD4 counts among patients with HIV-BL has not changed over time, whereas the median CD4 count among patients with HIV-DLCL has increased, the decline in incidence of HIV-BL is unlikely to result from a decline in CD4 counts among our patients.
This current study represents data from a single institution. Therefore, it may potentially be biased by the specific referral patterns in our center. Nonetheless, the LAC-USC Medical Center is a government-operated facility, is one of the largest hospitals in the United States, and serves a largely indigent patient population, which is not specifically referred to our center. The inclusion of patients from the USC/Norris Cancer Hospital (n = 79), a private facility with a large referral base, serves to broaden the scope of patients included in this report. Thus, the observation that HIV-BL has decreased over time is indeed provocative. Interestingly, in the recently completed trial of CHOP versus R-CHOP (rituximab-CHOP) by the AIDS Malignancy Consortium (AMC), which included 150 patients accrued in the HAART era, only 14 patients (9%) had a diagnosis of HIV-BL (personal communication, March 2005), consistent with the possibility that the incidence of HIV-BL is declining over time. Nevertheless, our current study does not represent a population-based, epidemiologic study; thus, firm conclusions regarding the incidence of HIV-BL over time cannot be made from this work. Further epidemiologic study will be required to elucidate the true incidence of HIV-BL in the HAART era and the influence of HAART on the incidence of this subtype of lymphomatous disease.
Previous studies have suggested that BL occurs in HIV-infected patients with better immunity and higher CD4 counts 38,42 compared with HIV-DLCL. Thus, in one such study, the median CD4 cell count among cases of HIV-BL and HIV-DLBCL were 195 cells/mm3 and 66 cells/mm3, respectively. 38 While the median CD4 counts (120 cell/mm3) among patients with HIV-BL in our study appeared somewhat lower than expected for patients with HIV-BL, they are consistent with published data. Pluda et al 43 reported a median CD4 count of 120 cells/mm3 in patients with HIV-BL, while others 27,28,39 have reported CD4 counts at presentation ranging from 77 to 168 cells/mm3. Consistent with previous studies, 38,42 patients with HIV-BL in our study had statistically higher median CD4 counts when compared with patients with HIV-DLCL. However, although the median CD4 count in patients with HIV-BL remained unchanged over time, the median CD4 count in patients with HIV-DLCL increased from 60 to more than 94 cells/mm3, such that the difference in median CD4 counts between the two groups was no longer statistically significant in the HAART period. This improvement in CD4 counts in patients with HIV-DLCL is presumably due to better immune reconstitution in the era of HAART, whereas the CD4 counts remained greater than 100 cells/mm3 in patients with BL in both periods.
Consistent with the clinicopathologic characteristics that have been described for patients with AIDS-related lymphoma, 34,41,44 the majority of patients in our study presented with disseminated disease with a high frequency of extranodal involvement in both the pre-HAART and HAART eras. However, involvement of the bone marrow, liver, and kidney were statistically more common, particularly in the HAART era, in patients with HIV-BL, which is in keeping with the known aggressive nature of BL in both HIV-negative and positive patients. 34,44-46
Our current study has several limitations. Because cytogenetic or molecular analyses were not routinely performed on tissue samples, some cases may have been wrongly identified by morphology alone. Although the diagnosis of lymphoma on morphologic features is prone to interobserver discrepancy, 47 all cases in this study were reviewed by one expert hematopathologist (B.N.N.), making this variability less likely. Further, although some patients received low-dose as opposed to standard dose chemotherapy in the pre-HAART era, prospective trials demonstrated no difference in response or survival with these regimens. 11 Additionally, because this was a retrospective study, detailed information on each individual's response to HAART, in terms of both virologic response and specific change in CD4 counts and the duration of HAART use before developing lymphoma, was not uniformly available. Nonetheless, the significant improvement in survival in our patients with HIV-DLCL in the HAART era, despite use of the same therapies, would indicate the beneficial effects of HAART in this subgroup.
In conclusion, we have shown that the survival of patients with HIV-DLCL has improved dramatically in the HAART era. In comparison, the survival of similarly treated patients with HIV-BL remains poor. The current practice of using a uniform regimen in treating HIV-infected patients with aggressive ARL should be re-evaluated through conduct of prospective therapeutic trials.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Presented as an oral presentation at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004; published in abstract form.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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NCI Non-Hodgkin's Lymphoma Classification Project Writing Committee: Classification of non-Hodgkin's lymphomas: Reproducibility of major classification systems. Cancer 55:91-95, 1985(Soon Thye Lim, Roksana Ka)
Department of Epidemiology and Biostatistics
Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA
National Cancer Centre, Singapore
ABSTRACT
PURPOSE: To compare outcomes of patients with HIV-Burkitt's lymphoma (HIV-BL) and HIV-diffuse large-cell lymphoma (HIV-DLCL) after treatment with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or M-BACOD (methotrexate, bleomycin, cyclophosphamide, etoposide) in pre–highly active antiretroviral therapy (HAART) versus HAART eras.
PATIENTS AND METHODS: Three hundred sixty-three patients with AIDS-related lymphoma diagnosed from 1982 to 2003 were reviewed retrospectively, including 262 in the pre-HAART (HIV-BL, 117; HIV-DLCL, 145) and 101 in the HAART era (HIV-BL, 18; HIV-DLCL, 83). Pre-HAART included those who did not receive HAART, and HAART era included those diagnosed after January 1997 who received HAART.
RESULTS: There were no significant differences between groups in terms of age, sex, history of injection drug use, prior AIDS, lactate dehydrogenase level, and disease stage at diagnosis. Compared with HIV-BL, HIV-DLCL was associated with significantly lower CD4 counts in the pre-HAART but not the HAART era. Although the overall median survival was similar for both groups in the pre-HAART era (HIV-BL, 6.4 months v HIV-DLCL, 8.3 months; P = .43), survival was significantly worse in patients with HIV-BL in the HAART era (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003). Failure to attain complete remission and CD4 count less than 100 cells/mm3 independently predicted for poor survival in the pre-HAART era. In comparison, histology of HIV-BL and no attainment of complete remission were independent poor prognostic factors in the HAART era.
CONCLUSION: Survival of patients with HIV-DLCL has improved in the HAART era, along with CD4 count, whereas survival of similarly treated patients with HIV-BL remained poor. The current practice of using the same regimen for both groups of patients should be re-evaluated.
INTRODUCTION
The two major categories of aggressive AIDS-related lymphomas (ARLs) are Burkitt's lymphoma (HIV-BL) and diffuse large-cell lymphoma (HIV-DLCL). In non-HIV infected patients, BL is a rapidly progressing disease with a poor outcome when treated with standard regimens used for other subtypes of aggressive non-Hodgkin's lymphoma (NHL). 1 These patients fare better when treated with multiagent, dose intensive regimens, which lead to long-term, disease-free survival in the majority. 2-9 While intensive chemotherapy is recommended for the treatment of BL in the general population, optimal management of patients with HIV-BL is not currently well defined.
In the pre–highly active antiretroviral therapy (HAART) era, therapy of patients with HIV-BL using less intensive, low-dose chemotherapy was associated with median overall survival time similar to that of patients with HIV-DLCL, suggesting that dose-intensive therapy was not required in the treatment of HIV-BL. 10,11 Thus, the AIDS Clinical Trials Group (ACTG) in the United States compared standard-dose chemotherapy consisting of methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD) and granulocyte macrophage colony-stimulating factor (GM-CSF) support with reduced-dose M-BACOD without GM-CSF in 198 patients with ARL. 11 No differences were found in either response rate (standard dose, 52% v reduced dose, 41%), or median survival (standard dose, 6.8 months v reduced dose, 7.7 months) in patients receiving standard-dose or reduced-dose chemotherapy. However, reduced-dose M-BACOD was associated with a statistically superior toxicity profile. Importantly, there were no differences in response or survival in terms of pathologic type of lymphoma. Thus, outcome of the 85 patients with large-cell lymphoma and the 83 patients with BL in either dose arm was similar, 11 although the prognosis of both groups of patients was equally poor, with median survival of approximately 6 months. Other studies have also treated patients with HIV-BL and HIV-DLCL similarly, with no statistically significant differences in response or survival. 10,12-14 In contrast, the factors that have been associated with poor survival in patients with ARL include CD4 cells less than 100/mm3, stage III or IV disease, age older than 35 years, history of injection drug use, and elevated lactate dehydrogenase (LDH). 10,15,16 Nonetheless, it should be noted that these studies have included primarily patients in the pre-HAART era.
The advent of HAART has resulted in a dramatic reduction in the development of opportunistic infections and a remarkable improvement in overall survival among patients with AIDS. 17 At the same time, prognosis of patients with ARL has also improved; the median overall survival of these patients is now comparable to that of patients with aggressive NHL in the general population. 18-22 Further, with improved immune function due to HAART, patients are better able to tolerate standard dose regimens such as CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) and others. 22,23 Additionally, in the HAART era, several studies have also shown that it is possible to successfully salvage patients with relapsed or refractory ARL using high-dose chemotherapy and progenitor stem-cell support. 24-26
Several small retrospective series in the HAART era have also suggested that it may be feasible to administer intensive regimens such as CODOX-M/IVAC (cyclophosphamide, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine) 27 and hyperCAVD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) 28 to patients with HIV-BL. Nonetheless, it remains uncertain whether these intensive strategies are necessary or optimal for these patients. With the ability to administer safely such therapy to patients with ARL, it may be important to reassess the previous understanding that HIV-infected patients with BL and DLCL should be treated similarly.
We thus sought to compare the outcomes of patients with HIV-BL and HIV-DLCL who were treated with either CHOP- or M-BACOD–based chemotherapy in either the pre-HAART or HAART eras, to determine whether differences in outcome were apparent, and to reevaluate the question of optimal therapy for HIV-BL in the HAART era. We also wished to determine factors that were independently associated with decreased survival in both time frames.
PATIENTS AND METHODS
This study was approved by the institutional review board of our institution.
The diagnostic criteria for determining the various subtypes of lymphoma, including ARL, have evolved over time. In this analysis, we used the Lukes-Collins classification system of malignant lymphomas, which divided the lymphomas into B-cell, T-cell and null cell types. Details of this classification have been published previously. 29,30 The advantage of this system is its applicability to all cases of lymphoma diagnosed over the last two decades, and the fact that our center has used this system consistently over the past three decades. For this study, the Lukes and Collins diffuse large cleaved, large noncleaved, and B immunoblastic were considered as DLCL, while small noncleaved cell lymphoma was considered as BL.
Using these diagnostic criteria, we retrospectively identified 363 patients diagnosed with HIV-BL or HIV-DLCL at Los Angeles County-University of Southern California (LAC-USC) Medical Center and USC/Norris Cancer Hospital between 1982 and December 2003. Thus, there were 135 patients with biopsy-confirmed HIV-BL and 228 patients with HIV-DLCL. Patients with all other histologic subtypes and unclassifiable subtypes were excluded from this analysis. These 363 patients came from a total cohort of 414 patients that also included an additional 51 patients diagnosed with other histologic subtypes. All cases in this study were reviewed and diagnosed by a single, expert hematopathologist (B.N.N.). All patients were HIV seropositive by enzyme-linked immunosorbent assay with confirmation by Western blot.
Patients were staged before treatment using the Ann Arbor staging system, which included a history; physical examination; standard laboratory tests; computed tomography scans of chest, abdomen, pelvis, and other relevant sites; gallium scans; and bilateral bone marrow biopsy. Lumbar puncture was performed routinely in all patients, and assessment of cerebrospinal fluid (CSF) cytology was performed in all.
Hospital records, bone marrow pathology reports, laboratory data, radiology reports, treatment regimens, and response to therapy were reviewed.
HAART became available in our institution in 1997. Thus in the current study, patients in the pre-HAART era included only those who were diagnosed before December 31, 1996, and who did not receive HAART therapy during the course of their HIV disease. Patients in the HAART era included only those who were diagnosed after January 1, 1997, and who did receive HAART.
The following HIV-related and lymphoma-related characteristics were assessed: age, sex, performance status, use of injection drugs, serum lactate dehyrodenase level, CD4 count at presentation, stage of disease, prior history of AIDS, pathologic subtype of lymphoma, and response to treatment. Differences in baseline lymphoma characteristics and HIV-related characteristics were compared between the two histologic subtypes using t-test or 2 test for continuous or categoric variables, respectively (Tables 1 and 2). Comparisons were made for pre-HAART and HAART eras. The Cox proportional hazard model was fitted to determine the significant prognostic factors for survival in ARL. 31 Survival or follow-up time was calculated from the date of diagnosis to death or to the date when the patient was last seen. Factors showing significant impact in univariate analysis were tested in a multivariate model for independence of association. Survival curves were compared between HIV-BL and HIV-DLCL for pre-HAART and HAART eras using Kaplan-Meier survival analysis. 32 P values from the log-rank tests were reported for referring to statistical differences of median survival time. 33 All analyses were performed using SAS version 8.0 (SAS Institute, Cary, NC).
RESULTS
HIV and Lymphoma Characteristics
The demographic, HIV and lymphoma-related characteristics of the 135 patients with HIV-BL and 228 patients with HIV-DLCL are provided in Tables 1 and 2. There were 117 cases of HIV-BL (45%) and 145 cases of HIV-DLCL (55%) in the pre-HAART era, compared with 18 cases of HIV-BL (18%) and 83 cases of HIV-DLCL (82%) in the HAART era.
In both the pre-HAART and HAART eras, there were no statistically significant differences between the two histologic subtypes at presentation in terms of age, sex, history of injection drug use, prior history of opportunistic infection(s) or Kaposi's sarcoma, LDH level, and stage of disease at diagnosis (Tables 1 and 2).
However, in the pre-HAART era, the median CD4 count at diagnosis in patients with HIV-DLCL was significantly lower than that of patients with HIV-BL (60 cells/mm3 versus 120 cells/mm3, respectively; P = .03). In addition, more patients with HIV-DLCL had a CD4 count of less than 100 cells/mm3 at diagnosis than patients with HIV-BL (57% v 36%, P = .0009). In contrast, in the HAART era, differences in median CD4 counts at diagnosis (BL, 125 cells/mm3 v DLCL, 94 cells/mm3; P = .85) and proportions of patients with CD4 counts less than 100 cells/mm3 were similar between the two groups (BL, 39% v DLCL, 46%; P = .52). While the proportions of patients with Karnofsky performance score (KPS) less than 80 were not different between the two histologic subtypes in the pre-HAART era, more patients with HIV-BL had a KPS less than 80 (61% v 31%, P = .01) in the HAART era.
Although extranodal lymphomatous involvement was prevalent in both histologic subtypes in both pre-HAART and HAART eras, the pattern of lymphomatous involvement was different (Table 2). Bone marrow, liver, and renal involvement were statistically more common in patients with HIV-BL compared with patients with HIV-DLCL in both time periods.
Treatment
All patients receiving combination chemotherapy were treated with curative intent. The most commonly used chemotherapy regimens were M-BACOD and CHOP-based therapy in both periods (Table 3). In the pre-HAART period, a greater proportion of patients with DLCL were never treated for their lymphoma when compared with patients with BL (17% v 5%, P = .01). Nonetheless, the most commonly used regimens were CHOP- or M-BACOD–based therapies, used in 75% of patients with DLCL and 86% of those with BL (P = .01). In the HAART period, the proportion of patients receiving M-BACOD–or CHOP-based chemotherapy was not statistically different between the two groups (90% in BL v 84% in DLCL; P = .78).
Apart From CHOP- or M-BACOD–based chemotherapy, other regimens used in the HAART era included the EPOCH regimen (etoposide, oncovin, doxorubicin, and cyclophosphamide) in three patients and infusional CDE (etoposide, doxorubicin, and cyclophosphamide) in two. In the pre-HAART era, 10 patients (9%) with HIV-BL and 11 with HIV-DLCL (8%) received other regimens using varying combinations of high-dose cytarabine, doxorubicin, etoposide, vincristine, cyclophosphamide, methotrexate, and prednisone.
Outcome
In the pre-HAART era, there was no statistically significant difference in the complete response rates between patients with HIV-BL or HIV-DLCL who were treated for their lymphomas (32% v 32%; P = .99; Table 2). Additionally, overall median survival in the pre-HAART era was not statistically different between the two histologic subtypes (6.0 v 7.6 months; P = .99; Fig 1A). When analysis of median survival was limited to only those patients who received combination chemotherapy with curative intent, there was still no statistical difference between the two histologic groups in terms of overall median survival (HIV-BL, 6.4 v HIV-DLCL, 8.3 months; P = .43; Fig 1B). In the univariate analyses of poor prognostic factors for survival in the pre-HAART era among patients who were treated with curative intent, KPS less than 80, an elevated LDH, a prior history of AIDS, a median CD4 count less than 100 cells/mm3 at diagnosis, and failure to attain complete remission were each associated with decreased survival (Table 4). Pathologic type of lymphoma (DLBCL v BL) had no impact. In multivariate analyses, failure to attain complete remission and a CD4 count less than 100 cells/mm3 were independently predictive of decreased survival (Table 4).
In the HAART era, the complete response rate was higher in patients with HIV-DLCL when compared with similarly treated patients with HIV-BL, although the difference was not statistically significant (57% v 35%, P = .2; Table 2). Importantly, the median survival of patients with HIV-DLCL was significantly longer than that of patients with HIV-BL (38.1 months v 5.1 months; P = .0005; Fig 2A). This difference in median survival was even more remarkable if only patients who received combination chemotherapy with curative intent were considered (HIV-BL, 5.7 months v HIV-DLCL, 43.2 months; P = .0003; Fig 2B). In the univariate analyses, poor prognostic factors for survival in patients treated with curative intent included KPS less than 80, elevated LDH level, a prior history of AIDS, advanced disease stage at presentation, failure to attain complete remission of disease, and a pathologic diagnosis of HIV-BL (Table 4). On multivariate analysis, pathologic diagnosis of HIV-BL was an independent poor prognostic factor for survival, together with failure to attain complete remission (Table 4).
It has been our practice to treat all patients with negative CSF cytology with four weekly doses of prophylactic intrathecal (IT) cytarabine for prophylaxis. Patients with positive CSF cytology were treated with IT cytarabine on alternate days until clearance of malignant cells was achieved. Thereafter, the patient was treated with weekly IT chemotherapy for a month, followed by monthly IT therapy for a year. Among the 23 patients with HIV-BL treated for positive CSF cytology, 5 (23%) achieved complete remission of disease, including clearance of CSF. Among the 19 patients with HIV-DLCL and positive CSF cytology, 4 (22%) achieved complete remission of disease, including clearance of CSF. The remaining patients died as a result of progressive disease.
DISCUSSION
We have demonstrated that the survival of patients with HIV-DLCL has improved dramatically from 8.3 months in the pre-HAART era to 43.2 months in the HAART era when these individuals are treated with CHOP- or M-BACOD–based regimens. In contrast, after similar types of chemotherapy, survival of patients with HIV-BL has remained unchanged and poor, at a median of 6.4 months in the pre-HAART and 5.7 months in the HAART eras. The finding that HAART did not improve the survival of patients with HIV-BL has not previously been reported.
Earlier studies, before the advent of HAART, demonstrated that age, CD4 count, stage, a history of injection drug use, and LDH were predictive of survival. In contrast, pathologic-type lymphoma was not shown to be of prognostic significance. 12,15,16, 34-37 Univariate analyses of prognostic factors in our study also demonstrated the same poor prognostic characteristics. On multivariate analyses in both the pre-HAART and HAART eras, failure to attain complete response was an independent predictor of poor survival. Of importance is our finding that when analyses were confined to the HAART era, BL pathologic type was also shown to be independently associated with shorter survival.
It is conceivable that the use of HAART, through decreasing other competing causes of mortality such as opportunistic infections, has allowed the natural history of the various pathologic subtypes of ARL to be expressed. Indeed, the median survival of 43.2 months in our patients with HIV-DLCL after treatment with CHOP or M-BACOD is similar to that of HIV-uninfected patients in the general population with aggressive NHL of similar stages. 36 Likewise, the poor survival in similarly treated patients with HIV-BL is consistent with the poor outcome observed in HIV-uninfected patients with BL treated with standard dose chemotherapy. 1 Although survival of patients with HIV-BL after CHOP- or M-BACOD–based chemotherapy was short in the pre-HAART era, results were similarly poor in patients with DLCL, potentially obscuring any differences in the natural history of these two pathologic types.
Experience over the last three decades has confirmed the efficacy of dose-intensive chemotherapy in improving the survival of patients with BL. 3-9 The current study and others 27,28 indicate the need for prospective trials to determine whether HIV-BL should be treated with similar intensive strategies, now that such therapy can be given safely. 26-28 For example, Cortes et al 28 investigated the use of the hyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) regimen in 13 patients with HIV-BL, nine of whom also received HAART. Results were encouraging, with a complete remission (CR) rate of 92%, although median survival was only 12 months. Of interest, six of seven patients who received HAART from the start of chemotherapy were alive and in CR after a median of 29 months (range, 7 to 45 months), whereas all four patients who did not receive HAART subsequently died. Toxicity in patients with HIV-BL was similar to that reported in non-HIV-infected patients with BL treated with the same regimen. 8 In another study, Wang et al 27 retrospectively compared 14 HIV-infected patients with BL with 24 non-HIV-infected patients with BL who received CODOX-M/IVAC or less intensive regimens. HIV status had no negative impact on either CR (HIV infected, 64% v non–HIV infected, 63%) or 2-year event-free survival rates (HIV infected, 59% v non–HIV infected, 62%). When event-free survival was evaluated according to the chemotherapy regimen and independent of HIV status, patients receiving CODOX-M/IVAC had a better 2-year event-free rate compared with those receiving less intensive chemotherapy (80% v 38%, respectively). Further, rates of myelosuppression and infection were similar among HIV-infected and HIV-uninfected patients treated with CODOX-M/IVAC. These studies, as well as the current work, suggest that the approach of using a uniform regimen for all pathologic subtypes of aggressive ARL should be re-evaluated.
This current study reported a decline in the incidence of HIV-BL over time, contrary to expectation. As BL in the setting of HIV infection tends to present in patients with higher CD4 counts, its incidence should theoretically increase in the HAART era, commensurate with the rise in CD4 counts following effective use of antiretroviral therapy. However, in one large epidemiologic study conducted by the International Collaboration on HIV and Cancer, 37 there was no evidence that the incidence of HIV-BL has changed over time, although the authors did caution that the number of cases of BL observed in the report was small. In another epidemiologic study from France, Beeson et al 38 noted an increase in the proportion of patients with HIV-BL from 17.7% in the pre-HAART era to 26.8% in the HAART era; however, this increase was not statistically significant (P = .17). Of importance, in the large EuroSIDA study of AIDS-related lymphoma, the incidence of BL decreased from the pre-HAART to the HAART eras, whereas that for diffuse large cell/immunoblastic lymphoma increased. 39 In another recent retrospective study 40 involving 214 patients with AIDS-related lymphomas from the Frankfurt AIDS cohort (FACS), treated between January 1981 and May 2003, the incidence rate of BL decreased from 24% in the pre-HAART era to 12.9% in the HAART era. Interestingly, 39% of the patients in the cohort had CD4 counts less than 100 cells/mm3 in the HAART era, compared with 74% of patients with CD4 counts less than 100 cell/mm3 in the HAART era. Thus, the incidence of BL was lower in the HAART era despite an increase in CD4 counts.
Similarly, in an earlier report involving patients seen from 1982 to 1998, Levine et al 41 first reported a decrease in HIV-BL over time. With further follow-up, this current report has demonstrated a continued decline in the incidence of HIV-BL over time. Because the median CD4 counts among patients with HIV-BL has not changed over time, whereas the median CD4 count among patients with HIV-DLCL has increased, the decline in incidence of HIV-BL is unlikely to result from a decline in CD4 counts among our patients.
This current study represents data from a single institution. Therefore, it may potentially be biased by the specific referral patterns in our center. Nonetheless, the LAC-USC Medical Center is a government-operated facility, is one of the largest hospitals in the United States, and serves a largely indigent patient population, which is not specifically referred to our center. The inclusion of patients from the USC/Norris Cancer Hospital (n = 79), a private facility with a large referral base, serves to broaden the scope of patients included in this report. Thus, the observation that HIV-BL has decreased over time is indeed provocative. Interestingly, in the recently completed trial of CHOP versus R-CHOP (rituximab-CHOP) by the AIDS Malignancy Consortium (AMC), which included 150 patients accrued in the HAART era, only 14 patients (9%) had a diagnosis of HIV-BL (personal communication, March 2005), consistent with the possibility that the incidence of HIV-BL is declining over time. Nevertheless, our current study does not represent a population-based, epidemiologic study; thus, firm conclusions regarding the incidence of HIV-BL over time cannot be made from this work. Further epidemiologic study will be required to elucidate the true incidence of HIV-BL in the HAART era and the influence of HAART on the incidence of this subtype of lymphomatous disease.
Previous studies have suggested that BL occurs in HIV-infected patients with better immunity and higher CD4 counts 38,42 compared with HIV-DLCL. Thus, in one such study, the median CD4 cell count among cases of HIV-BL and HIV-DLBCL were 195 cells/mm3 and 66 cells/mm3, respectively. 38 While the median CD4 counts (120 cell/mm3) among patients with HIV-BL in our study appeared somewhat lower than expected for patients with HIV-BL, they are consistent with published data. Pluda et al 43 reported a median CD4 count of 120 cells/mm3 in patients with HIV-BL, while others 27,28,39 have reported CD4 counts at presentation ranging from 77 to 168 cells/mm3. Consistent with previous studies, 38,42 patients with HIV-BL in our study had statistically higher median CD4 counts when compared with patients with HIV-DLCL. However, although the median CD4 count in patients with HIV-BL remained unchanged over time, the median CD4 count in patients with HIV-DLCL increased from 60 to more than 94 cells/mm3, such that the difference in median CD4 counts between the two groups was no longer statistically significant in the HAART period. This improvement in CD4 counts in patients with HIV-DLCL is presumably due to better immune reconstitution in the era of HAART, whereas the CD4 counts remained greater than 100 cells/mm3 in patients with BL in both periods.
Consistent with the clinicopathologic characteristics that have been described for patients with AIDS-related lymphoma, 34,41,44 the majority of patients in our study presented with disseminated disease with a high frequency of extranodal involvement in both the pre-HAART and HAART eras. However, involvement of the bone marrow, liver, and kidney were statistically more common, particularly in the HAART era, in patients with HIV-BL, which is in keeping with the known aggressive nature of BL in both HIV-negative and positive patients. 34,44-46
Our current study has several limitations. Because cytogenetic or molecular analyses were not routinely performed on tissue samples, some cases may have been wrongly identified by morphology alone. Although the diagnosis of lymphoma on morphologic features is prone to interobserver discrepancy, 47 all cases in this study were reviewed by one expert hematopathologist (B.N.N.), making this variability less likely. Further, although some patients received low-dose as opposed to standard dose chemotherapy in the pre-HAART era, prospective trials demonstrated no difference in response or survival with these regimens. 11 Additionally, because this was a retrospective study, detailed information on each individual's response to HAART, in terms of both virologic response and specific change in CD4 counts and the duration of HAART use before developing lymphoma, was not uniformly available. Nonetheless, the significant improvement in survival in our patients with HIV-DLCL in the HAART era, despite use of the same therapies, would indicate the beneficial effects of HAART in this subgroup.
In conclusion, we have shown that the survival of patients with HIV-DLCL has improved dramatically in the HAART era. In comparison, the survival of similarly treated patients with HIV-BL remains poor. The current practice of using a uniform regimen in treating HIV-infected patients with aggressive ARL should be re-evaluated through conduct of prospective therapeutic trials.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Presented as an oral presentation at the 46th Annual Meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004; published in abstract form.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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