In the group of 128 CD20-positive ARL, the combination of chemotherapy with rituximab was associated with better OS and PFS. The hazard ratio was 0.48 (95% CI 0.25–0.93) for OS and 0.47 (95% CI 0.26–0.86) for PFS (Fig. 1, Tables 2 and 3).
This was also seen in the subgroup of patients with a severely compromised immune system, as indicated by CD4 T-cell counts of less than 100 cells/μl. In this group (n = 33), the use of rituximab (n = 16) was associated with prolonged OS (hazard ratio 0.25, 95% CI 0.07–0.90; Fig. 2) and a trend toward better PFS (hazard ratio 0.35, 95% CI 0.12–1.02). Furthermore, we did not observe an increased risk of fatal infections due to the use of rituximab in these severely immunosuppressed patients.
Some baseline characteristics differed between CD20-positive patients treated with rituximab and those treated with PCT only. In the rituximab group, the median CD4 T-cell count and the proportion of Burkitt's subtype were higher than in the PCT only group (Table 1). In contrast to other cohort studies , patients with Burkitt's lymphoma had no reduced OS in our cohort (hazard ratio 0.58, 95% CI 0.30–1.12). The PFS was even better in Burkitt's lymphoma than in DLBCL (hazard ratio 0.50, 95% CI 0.27–0.95).
Survival and outcome: multivariate analysis
We evaluated a variety of prognostic parameters for their effect on OS and PFS, including demographic factors (age, sex), lymphoma-specific factors (histology, IPI score, CD20 expression, bone marrow involvement), HIV-related factors (CD4 T-cell count, detectable HIV-RNA at lymphoma diagnosis, prior ART and prior AIDS-defining illnesses) and the use of rituximab.
In univariate analysis in the entire group of CD20-positive and CD20-negative ARL, a CD4 T-cell count more than 100 cells/μl, no ART at ARL diagnosis, CD20 expression, a low IPI score, no bone marrow involvement and the use of rituximab were predictive of better OS and/or PFS. These parameters were included into the multivariate model. We did not observe any influence of histology (Burkitt's lymphoma, DLBCL or unclassified high-grade lymphoma) on OS in our cohort.
In multivariate analysis, a low IPI score, the use of rituximab and CD20 expression were associated with a strong and consistent positive effect both on OS and on PFS (Tables 2 and 3). Hazard ratios for OS were 2.85 (95% CI 1.01–8.10), 0.43 (95% CI 0.21–0.89) and 0.31 (95% CI 0.15–0.63) for a low IPI score, the use of rituximab and CD20 expression, respectively. Hazard ratios for PFS were 4.41 (95% CI 1.46–11.71), 0.44 (95% CI 0.23–0.84) and 0.24 (95% CI 0.12–0.47), respectively (Tables 2 and 3).
To differentiate between the influence of CD20 expression and the effect of rituximab, univariate and multivariate analysis had been performed furthermore in the subgroup of CD20-positive ARL. In these patients, the effect of rituximab on OS and PFS was consistently statistically significant in all analysis. In multivariate analysis, hazard ratio for OS and PFS were 0.42 (95% CI 0.20–0.87) and 0.45 (95% CI 0.23–0.88; Tables 2 and 3). Next to the use of rituximab, a CD4 T-cell count more than 100 cells/μl was associated with a positive effect both on OS and PFS [0.40 (95% CI 0.18–0.85) and 0.48 (95% CI 0.25–0.94, respectively; Tables 2 and 3].
Causes of death
After a median follow-up of 15 months, 61 of the 163 ARL patients had died (37%). Causes of death were lymphoma (n = 36, 67%), fatal infections (n = 12, 22%) and various reasons (myocardial infarction, liver failure, suicide, unknown, n = 6, 11%). The deaths due to fatal infections were considered to be treatment-related. Among these treatment-related deaths, three patients received PCT combined with rituximab and nine patients received PCT without rituximab. The median CD4 T-cell counts at baseline in patients who died due to fatal infections did not differ between patients receiving rituximab (median 104 cells/μl) and those without rituximab (median 100 cells/μl).
Out of 54 deaths in patients with curative treatment intention, 37 deaths (69%) occurred in patients with CD4 T-cell counts less than 200 cells/μl and 19 deaths (35%) occurred in patients with CD4 T-cell counts less than 100 cells/μl. Not only the ARL-related mortality (insufficient response to PCT or relapse, 20 of 36 deaths, 55%) but also the infection-related mortality (10 of 12 fatal infections) occurred predominately in patients with CD4 T-cell counts less than 200 cells/μl (five of 12 fatal infections occurred with CD4 T-cell counts <100 cells/μl).
In our multicenter cohort of patients with ARL, CD20 expression, CD4 T-cell count at ARL diagnosis and the use of rituximab had strong impact on survival. Rituximab was beneficial in ARL even in the setting of severe immune deficiency and was not associated with an increased risk of fatal infections. Sixty-one out of 163 patients (37%) had died after a median follow-up of 15 months. These data are in accordance with the findings of other cohorts, demonstrating that the mortality of ARL patients remains high, even with suppressive ART and despite the increasing use of standard PCT protocols [17–20].
The majority of patients with ARL did not receive ART at the time of lymphoma diagnosis, and only 24% had a HIV-RNA of less than 50 copies/ml. Approximately half of our patients had a CD4 T-cell count lower than 200 cells/μl and 27% of the patients had a CD4 T-cell count lower than 100 cells/μl at ARL diagnosis. One hundred and two of 156 patients had the ARL diagnosis as their initial AIDS-defining event (65%). In 35 of 156 patients (22%), HIV and ARL were diagnosed concurrently (time frame <4 weeks). Thus, a relevant proportion of our patients were late presenters. Next to severe immune suppression and delayed initiation of ART, HIV viremia has been identified as a risk factor for the development of lymphomas [21,22].
After the diagnosis of ARL, immunological and virological response to ART had been shown to be important prognostic factors [23,24]. In contrast to other investigators , we did not observe an influence of antiretroviral pretreatment on survival (Table 2). In contrast to pretreated patients, ART-naive patients starting ART after ARL diagnosis may have an additional beneficial effect on the control of lymphoma. However, this effect could not be observed in our cohort.
In contrast to other cohort studies , patients with Burkitt's lymphoma had a better outcome than patients with DLBCL in our cohort, probably reflecting the frequent use of more intensive and effective approaches such as the GMALL protocol in Burkitt's lymphoma in Germany. Consistently with previous studies [17,25], we found an influence of the degree of the immunodeficiency on survival. In the multivariate analysis, a CD4 T-cell count more than 100 cells/μl was associated with better OS and PFS. Out of 54 deaths in patients with curative treatment intention, 37 deaths (69%) occurred in patients with CD4 T-cell counts less than 200 cells/μl and 19 deaths (35%) occurred in patients with CD4 T-cell counts less than 100 cells/μl.
The second factor, which was associated with better outcome, was CD20 expression of lymphomas. As shown in a previous study , patients with CD20-negative lymphomas had a poorer OS and PFS in comparison to CD20-positive cases. As the therapeutic option of using a CD20 antibody does not exist in this entity, distinct therapeutic strategies for these types of lymphomas are urgently needed.
For a long time, it was not clear whether rituximab was well tolerated and effective in HIV-infected patients with BCL. In the AIDS-Malignancies Consortium (AMC) 010 trial, 143 patients with CD20-positive ARL were randomized to CHOP or R-CHOP . The slightly better response in the R-CHOP arm was outweighed by a higher incidence of severe infections with the majority of deaths occurring in those with CD4 cell counts less than 50 cells/μl. Of note, some baseline characteristics of patients differed between the prospective randomized AMC 010 trial and our cohort study. In the AMC 010 trial, the median CD4 T-cell (133 vs. 205 cells/μl) was lower and the proportion of patients with a CD4 T-cell count less than 50 cells/μl was higher (25 vs. 18%), More patients of the AMC 010 trial have had an advanced stage disease (stage III/IV, 79 vs. 60%) and only 26% of patients have been ART-naive at ARL diagnosis (vs. 55% of patients in our cohort). These unfavorable differences in baseline parameters might be account for difference in outcome between these trials.
In contrast to AMC 010, some nonrandomized studies did not show an increased rate of fatal infections under rituximab in combination with different PCT protocols [8,11]. A recent published randomized trial compared rituximab either concurrently or sequentially with the EPOCH regimen in HIV-associated BCLs, with promising complete remission rate and no increased toxicity in both the concurrent and sequential arm . The proportion of patients with a CD4 T-cell count lower than 100 cells/μl was 31% and comparable to our cohort (26%). However, comparisons between R-EPOCH and other immunochemotherapy regimens are lacking in ARL and data about the feasibility of rituximab therapy in the setting of severe immune deficiency are limited. There are also some retrospective cohort studies [4,17,27] addressing prognostic factors of survival in ARL. In these studies, however, information about the immunophenotype, chemotherapy or the use of rituximab was not available or insufficient. In an attempt to overcome these limitations, we included not only HIV-related prognostic factors in the analysis, but also lymphoma-specific factors (histological subtype, CD20 expression, bone marrow involvement) and the application of rituximab. In contrast to the AMC 010 study, we found an improved OS and PFS in patients receiving rituximab. This was observed both in the entire group of high-grade ARL as well as in the subgroup of CD20-positive cases and remained evident even in the setting of a severe immune deficiency.
In accordance with other studies [3,8,13], we did not observe an increased risk of fatal infections due to the use of rituximab in our cohort. However, the patients who died from treatment-associated infections had lower CD4 T cells than the entire group. These findings emphasize the need for prospective trials evaluating the benefits of intensified supportive care (e.g. use of granulocyte-colony stimulating factor, early or prophylactic use of anti-infective agents).
This study has some limitations. The uncontrolled design resulted in differences in baseline characteristics between patients with or without rituximab. However, there were no differences in IPI score between patients receiving and not receiving rituximab. The median CD4 T-cell counts were higher in patients receiving rituximab, indicating a potential confounding bias arising from the treating physician's decision of whether or not to add rituximab to PCT in an individual patient. In addition, the proportion of ART-naive patients was higher in patients receiving rituximab. Although only further and larger randomized clinical trials can prove the efficacy and safety of rituximab in this setting, our study strongly indicates a positive effect.
In conclusion, in this multicenter cohort study of HIV-infected patients presenting with ARL, the use of rituximab improved OS and PFS. This effect was seen even in the setting of severe immune deficiency and without an increased risk of fatal infections. The substantial mortality rate, especially in those patients with severe immune deficiency and with lack of CD20 expression, emphasizes the need for further clinical research in ARLs.
First, the authors thank all the patients participating in our cohort for providing their data and biomaterials to the cohort. The authors are grateful for all the work and dedication of the documentation officers and of the heads of the participating sites: Axel Adam (Hamburg), Johannes Bogner (Munich), Hans-Reinhard Brodt (Frankfurt am Main), Thomas Buhk (Hamburg), Andrea Eberhardt (Munich), Stefan Fenske (Hamburg), Holger Gerigk (Hamburg), Daniel Gillor (Cologne), Ingo Greiffenburg (Krefeld), Georg Haerter (Ulm), Stefan Hansen (Hamburg), Angela Hammond (Augsburg), Christian Hoffmann (Hamburg), Heinz-August Horst (Kiel), Andreas Humpe (Kiel), Eva Jaegel-Guedes (Munich), Hans Jäger (Munich), Ulf Kloenne (Muenster), Heribert Knechten (Aachen), Gisela Kremer (Cologne), H. Lehmann (Dresden), Jan van Lunzen (Hamburg), Franz Mosthaf (Karlsruhe), Birgit Ross (Essen), Bernhard Schaaf (Lubeck), Carl Knud Schewe (Hamburg), B. Sonntag (Munich), Hans-Jürgen Stellbrink (Hamburg), Thomas Sternfeld (Munich), Albrecht Stoehr (Hamburg), Jan Thoden (Freiburg), Mathias Vierbuchen (Hamburg), Jan-Christian Wasmuth (Bonn), Lutwin Weitner (Hamburg), Timo Wolf (Frankfurt) and Kathrin Zuchold (Berlin).
C.W., G.F. and C.H. conceived and designed the study; C.W., B.J., M.H., J.S., M.S., S.E., M.M., J.V.L., T.M., J.R.B., J.C.W., G.F. and C.H. provided patients. C.W., D.G. and C.H. collected and assembled the data. C.W., H.C., G.F. and C.H. analyzed and interpreted data. All authors wrote the manuscript, had access to the primary clinical data and gave final approval of the manuscript.
Furthermore, the authors would like to thank Philipp Schommers, Cologne for administrative assistance and Hartmut Stützer, Cologne for performing the statistical analyses.
This work was funded by the BMBF (Federal Ministry of Education and Research, Germany; grant number 01 KI 0771).
Conflicts of interest
C.W. has received consulting fees from Boehringer Ingelheim, fees for speaking engagements from Bristol-Myers Squibb, Gilead Sciences, ViiV Healthcare, MSD, Janssen-Cilag, Essex, Pfizer and Abbott. M.M. has received fees for speaking engagements from MSD. J.V.L. has received fees for board membership from BMS, Boehringer, Abbott, ViiV, MSD, Bionor AS and Gilead, Janssen; consulting fees from BMS, Boehringer, Abbott, ViiV, MSD, Bionor AS, Gilead and Janssen; grants from BMS, Gilead and Janssen; fees for speaking engagements from BMS, Boehringer, Abbott, ViiV, MSD, Bionor AS, Gilead, Janssen and Roche; and payments for development of educational presentations from MS, Gilead and MSD. J.R.B. has received consulting fees from Abbott, Boehringer Ingelheim, MSD, Janssen-Cilag and fees for speaking engagements from Abbott, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen-Cilag, ViiV Healthcare, MSD, Pfizer, Roche and Novartis. T.M. has received support for travel to meetings from MSD, Gilead and BMS. M.S. has received consulting fees from BMS, ViiV-Healthcare, Abbott, Janssen-Cilag and fees for speaking engagements from BMS, ViiV-Healthcare and Abbott, Janssen-Cilag. B.J. has received consulting fees from Boehringer Ingelheim and fees for speaking engagements from Janssen-Cilag. M.H. has received support for travel to meetings from Harlachinger Krebshilfe, Celgene, Janssen-Cilag, Novartis, Pfizer and Roche Pharma, consulting fees from Takeda Pharma GmbH and fees for speaking engagements from Boehringer Ingelheim, Celgene, Gilead Sciences, MSD, Novartis, Pfizer and Roche Pharma. S.E. has received consulting fees from Abbott, BMS, Boehringer, Gilead, Janssen, MSD, Roche and ViiV, support for travel to meetings from Abbott, BMS, Boehringer, Gilead, Janssen, MSD, Roche and ViiV and fees for board membership from Abbott, BMS, Boehringer, Gilead, Janssen, MSD and ViiV. G.F. has received consulting fees Abbott, Boehringer Ingelheim, MSD, Janssen-Cilag, Gilead and ViiV Healthcare and fees for speaking engagements from Abbott, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Janssen-Cilag, ViiV Healthcare, MSD, Pfizer and Roche. C.H. has received consulting fees from Abbott, Bristol-Myers Squibb, Gilead Sciences, Janssen-Cilag, MSD, Roche and ViiV Healthcare, fees for board membership from Abbott, BMS, Gilead Sciences, Janssen-Cilag, MSD, Roche and ViiV Healthcare and fees for speaking engagements from Abbott, BMS, Gilead Sciences, Janssen-Cilag, MSD, Roche and ViiV Healthcare. For the remaining authors, no conflicts of interest are declared.
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Keywords:© 2012 Lippincott Williams & Wilkins, Inc.
AIDS-related lymphoma; HIV; multicenter cohort study; rituximab