- 101: Annals of Oncology 15:993-995, 2004 - Editorial
HIV-related non-Hodgkin's lymphoma (HIV-NHL) in the era of highly active antiretroviral therapy (HAART): some still unanswered questions for clinical management
M. Spina and U. Tirelli*
Division of Medical Oncology A, National Cancer Institute, Aviano, Italy
bone marrow transplantation • chemotherapy • HAART • HIV infection • non-Hodgkin's lymphoma
Since the beginning of the AIDS epidemic the treatment of HIV-related non-Hodgkin's lymphoma (HIV-NHL) has been a challenge. Before the introduction of highly active antiretroviral therapy (HAART) in the management of these patients, the prognosis of HIV-NHL was poor, despite a high response rate, owing to aggressive tumor behavior, increased hematological toxicity and a high rate of opportunistic infections (OIs) [1, 2]. Since the widespread use of HAART, the prognosis of HIV-NHL has improved, with a better tolerance to chemotherapy, a higher complete remission (CR) rate, a significant improvement of disease-free survival (DFS) and a significant reduction in the number of deaths related to HIV complications [3–5]. Many studies have shown that the CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) can be considered the standard approach for patients with aggressive NHL in the HIV setting [6, 7], even though a recent study of the general population demonstrated the superiority of rituximab plus CHOP in comparison with CHOP alone in patients with CD20-positive diffuse large B-cell NHL [8]. Moreover, some promising results have been reported in HIV-NHL using a protracted schedule that can overcome the resistance of tumor cells to cytotoxic agents [9].
At the present time, some questions are still unanswered in the approach of HIV-NHL, and are the subject of this review. (i) Does continuous infusion chemotherapy have an advantage in comparison with a brief intermittent schedule? (ii) Is the addition of rituximab to chemotherapy feasible and useful? (iii) Is there any difference between immunoblastic and Burkitt subtypes? (iv) Is high-dose chemotherapy (HDT) and peripheral blood stem cell (PBSC) rescue feasible and active?
Continous infusion chemotherapy
Little et al. [10] recently reported the results of a phase II study to evaluate the activity of dose-adjusted infusional EPOCH (etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin) without concomitant HAART in 39 newly diagnosed HIV-NHL patients. CR was achieved in 29 patients (74%) and partial remission (PR) in five patients (13%), for a total objective response rate of 87%. At a median follow-up of 53 months, DFS and overall survival (OS) were 92% and 60%, respectively. Despite the suspension of HAART, no OIs occurred during the treatment. The results of this study indicate the activity and safety of this approach, stressing the importance of testing the addition of rituximab to infusional chemotherapy.
Rituximab plus chemotherapy
We previously reported the promising results of a phase II study using rituximab at the standard dose of 375 mg/m2 on day 1 followed by 96 h continuos intravenous infusion of cyclophosphamide, doxorubicin and etoposide (R-CDE regimen) and concomitant HAART in 41 patients with aggressive CD20-positive HIV-NHL [11]. Twenty-nine out of 38 evaluable patients (76%) achieved a CR, two of 38 (5%) had a PR and the remaining seven patients (19%) progressed. With a median follow-up of 1 year, only three out of 29 complete responders (10%) had relapsed, and 32 out of 41 are alive. The treatment was well tolerated, without any toxic death, and only two patients developed OIs during the treatment, although 29% of patients developed manageable bacterial infections during neutropenia. The actuarial OS and DFS at 2 years were 70% and 86%, respectively, with a significant improvement over patients treated in the pre-HAART era (OS ranging from 9 to 18 months and DFS ranging from 12 to 18 months) [1, 2, 7, 9].
Based on these results, we suggested that the association of rituximab plus chemotherapy should also be strongly recommended as a front-line treatment for patients with CD20-positive high-grade HIV-NHL.
The combination of rituximab plus CHOP (R-CHOP regimen) was tested in a phase II study conducted within the Agence Nationale Recherche SIDA (ANRS) in France [12]. Sixty-one patients were enrolled, and a CR was achieved in 40 out of 52 evaluable patients (77%). Two toxic deaths were observed, three patients had OIs during the chemotherapy and bacterial infections were observed in 34% of patients. After a median follow-up of 18 months, the 2-year OS was 64% and the 2-year DFS was 83%. Similar to that observed in our study, the combination of rituximab and chemotherapy is safe and highly active, confirming the advantage of this combination versus previous experience without rituximab.
Recently, Kaplan et al. [13] reported, in abstract form, the results of a large phase III randomized trial comparing the CHOP regimen (group A, 95 patients) with a combination of rituximab plus CHOP followed by 3-monthly doses of the antibody (group B, 47 patients). CR was achieved in 55 of 95 (58%) and 23 of 47 (50%) patients in arms A and B, respectively (P=0.371). Toxicity was higher in the rituximab arm: in fact, death due to infection occurred in seven out of 95 (7%) in group A, and only in one out of 47 (2%) in group B patients. Moreover, documented sepsis in the setting of neutropenia were observed in 10 and zero patients in groups A and B, respectively (P=0.031). With a median follow-up of 6 months, median CR duration has not yet been reached. The authors concluded that the high incidence of infections during neutropenia and death in patients who received rituximab raises concerns regarding the safe use of this approach in the HIV setting. However, the two groups were not well balanced with regard to CD4 cell count at baseline: more patients with lower counts were included in the rituximab arm, which probably influenced the high rate of infections observed in this group. Moreover, the CR rate was significantly lower in comparison with the other studies (50–58% versus 74% of EPOCH versus 76% of R-CDE versus 77% of R-CHOP), suggesting some kind of bias or selection. Finally, fatal infections occurred in six out of 15 (40%) patients during the maintenance phase of rituximab; therefore, it was not demonstrated to be useful in the management of aggressive NHL.
Burkitt versus diffuse large B-cell
Before the introduction of HAART, the Burkitt subtype showed a similar poor outcome to diffuse large B-cell NHL and, unlike in the general population, the same chemotherapy regimens have been used to approach Burkitt's lymphoma in the HIV setting. The have been no prospective studies that aimed to evaluate the outcome of HIV-related Burkitt in HAART era. Within the R-CDE study, we analyzed the factors that negatively influenced the OS. In univariate analysis, Burkitt subtype [hazard ratio (HR) 2.48; 95% confidence interval (CI) 1.15–5.37; P=0.02], homosexual man as risk factor for HIV infection (HR 2.54; 95% CI 1.17–5.51; P=0.02) and a detectable HIV viral load at the end of chemotherapy (HR 2.48; 95% CI 1.15–5.37; P=0.02), whereas in a Cox model Burkitt subtype (HR 2.17; 95% CI 0.99–4.76; P=0.05) and the risk factor for HIV infection (HR 2.34; 95% CI 1.07–5.11; P=0.03), were associated with a significantly worse OS, suggesting that the combination of rituximab and chemotherapy could be insufficient to treat Burkitt's lymphoma, and the use of more intensive regimens may be required.
Finally, the possibility of using aggressive chemotherapy regimens in HIV-Burkitt has recently been reported, suggesting that the use of short intensive courses could lead to a high level of control of the disease without a significant increase in toxicity [14–16].
High-dose chemotherapy
Around half of all patients with HIV-NHL needs second-line chemotherapy as a result of progression or relapse of their lymphoma. Until now, the results of salvage treatment in this setting have been very poor, with an objective response rate of 30% and a median survival of only few months [17–19]. Recently, preliminary results of the use of HDT and PBSC rescue have been published. Gabarre et al. [20] reported the results of this approach in eight patients with refractory or relapsed lymphoma. Collection and grafting of PBSC was feasible, the hematological population was not different from that of young patients of the general population, and five patients out of eight achieved a CR. Moreover, the use of HAART significantly reduced the risk of OI, making the overall risk of this treatment similar to that for HIV-negative patients. Promising results were obtained by Molina et al. [21], who reported an 80% CR rate and a 79% OS and event-free survival rate in 15 patients with relapsed or refractory HIV-related lymphoma. Within the Italian Cooperative Group on AIDS and Tumors (GICAT), we are running a prospective phase II study aiming to evaluate the feasibility and activity of HDT and PBSC rescue both in HIV-related NHL and in Hodgkin's disease. Up to now, 16 consecutive patients have entered the program. Adequate collection of PBSC was obtained in 80% of patients (median CD34+ cells 6.8x106/kg). Three patients had early disease progression, one before PBSC collection and two before transplantation. Ten patients (62%) actually received HDT and PBSC transplantation, and engraftment promptly occurred in all patients. No patient died from OIs or other infections or treatment-related complications. All evaluable patients (two are too early) achieved a CR (one after radiotherapy on residual disease). Two patients relapsed and died at +10 and +14 months. Six are alive and disease-free at a median of 8 months after transplantation [22].
Conclusions
Considerable progress has been made in the treatment of NHL in the HIV setting. HAART in particular has improved the outcome of this disease, suggesting for the first time in clinical trials that the manipulation of the immune system has a significant impact on the management and outcome of cancer, especially specific immunological tumors like NHL. Whether or not rituximab has a significant impact on the management of CD20+ NHL in the HIV setting deserves further study, although in our hands and in those of French hematologists, this seems to be the case. Also, Burkitt's lymphoma in patients with HIV deserves an intensive approach as in the general population, because the change in the natural history of this subtype with HAART therapy allows more intensive chemotherapy. Finally, HDT and PBSC rescue is a safe and effective approach, and should be the standard treatment in relapsed or resistant HIV-NHL, when HIV infection is under control.
Acknowledgements
The authors wish to thank Ms Daniela Furlan for her editorial support in the preparation of the manuscript. This manuscript was supported by ISS (30 D.79) and AIRC grants.
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