Since the introduction of combination antiretroviral therapy (cART), the incidence of AIDS-related lymphomas (ARLs) has remarkably declined while the prognosis has considerably improved [1,2]. However, ARLs still remain a serious cause of mortality and morbidity in HIV-infected patients . Plasmablastic lymphomas (PBLs), which are characterized by the absence of B-cell markers (CD20) and the presence of plasma cell markers, comprise a rare entity within ARL [4–8]. The aim of the present study was to describe the clinical characteristics and to analyze the outcome of HIV-infected patients with PBL enrolled in the prospective German ARL-cohort study.
The German ARL-cohort study is a prospective observational multicenter evaluation. HIV-1-infected patients with ARL diagnosed in 30 participating German centers after 1 January 2005, were included in the study. The present analysis consists of 18 patients with the histopathological diagnosis of PBL out of 302 ARL patients enrolled until June 2011. Fifteen out of 18 cases with diagnosis of PBL were confirmed by a review pathologist of one of the German lymphoma reference centers. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of ARL diagnosis until death or until the last follow-up and until lymphoma progression or death as a result of any cause. Kaplan–Meier survivor function was used to evaluate OS and PFS. Prior AIDS-defining illness, CD4 T-cell count at ARL diagnosis, cART before ARL diagnosis, suppressed HIV-RNA, age more than 60, enhanced lactate dehydrogenase (LDH), Eastern Cooperative Oncology Group (ECOG)  score >2, stage III/IV disease, extranodal involvement, and the International Prognostic Index (IPI)  were considered as potential predictors (definitions of ECOG, IPI, and Ann Arbor score  are listed in Table 1). Approval was granted by the ethic committee of the University of Cologne, Germany and of each participating site. Written informed consent was obtained.
All patients were men with a median age of 44 years. Median CD4 T-cell count at ARL diagnosis was 85/μl (range 0–1100/μl). Only five patients had an undetectable HIV-RNA at the time of PBL diagnosis. The baseline characteristics are depicted in Table 1.
With regard to histopathological findings, all PBLs were CD20-negative and at least one plasma cell marker (VS38c, CD38, MUM1, CD138) has been expressed in 82% of cases. Data on KI-67 and Epstein–Barr virus (EBV) are available for 94 and 78% of cases, respectively. A very high proliferation index (KI-67 ≥80%) was found in 13 out of 17 patients (76%) and EBV positivity was observed in 12 out of 14 cases (86%).
Protocols based on CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) were the initial regimen (CHOP-21: n = 6, CHOP-14: n = 3, CHOEP: n = 1) in 10 patients, whereas seven patients were treated according to the high-dose methotrexate-based B-ALL protocol adapted from B-ALL/NHL2002 (ClinicalTrials.gov identifiers NCT00199082/NCT00388193) of the German Multicenter Study Group for the Treatment of Adult Acute Lymphoblastic Leukemia (GMALL). Twelve patients (67%) received at least four cycles of chemotherapy according to the CHOP protocol or B-ALL protocol.
By 30 June, 2011, 12 out of 18 patients (67%) have died after a median survival time of 4 months (range 0–11 months; Table 1). None of these patients achieved a complete remission. Six patients were still alive in their first complete remission with a median follow-up of 32 months (range 21–76 months). The median survival of the entire cohort of patients was 5 months (range 0–76 months). By univariate analysis, an increased LDH, an ECOG performance >2, an age >60 years at lymphoma diagnosis, and an intermediate or high IPI score (score 2–5) were associated with a significantly lower OS and PFS (OS: P = 0.003, P = 0.006, P < 0.001 and P = 0.023, respectively; PFS: P = 0.015, P < 0.001, P < 0.001 and P = 0.011, respectively). A CD4 T-cell count less than 200/μl was associated with a lower PFS (P = 0.036). No other clinical or histopathological characteristics were found to be predictive for outcome and we did not observe any difference concerning proliferation index (KI-67 <80 vs. ≥80%) and histopathological EBV detection (EBV positivity yes or no) in patients who died or survived. The predominant cause of death was lymphoma progression (n = 8, 67%). Other reasons for death were liver failure, infection, and gastrointestinal bleeding.
PBLs predominately occur in patients with advanced HIV infection and account for approximately 3% of all ARLs [12,13]. Data from the pre-cART era showed that PBL carried a poor prognosis with a median survival of about 6 months .
The data of this cohort indicate that HIV-infected patients with PBL still have a very poor outcome and OS similar to that reported in the pre-cART era [12,13]. These findings are in contrast to the improvement in survival among patients with other HIV-associated lymphoproliferative disorders [15,16] and to the findings of a recently published large retrospective analysis of 50 HIV-infected patients with PBL. The complete response in this analysis rate was 66% and the median OS was 11 months . A possible explanation for the shorter OS of our patients could be the more profound immune deficiency (median CD4 cell count 85 vs. 206/μl). As in other studies , we observed a significantly reduced survival in patients with intermediate or high IPI score.
Most of our patients received protocols based on the CHOP regimen. Of note, there were at least three patients achieving long-term complete remissions with this approach. We were unable to identify individual factors of these patients accounting for the favorable outcome. We did not observe an improved outcome in patients treated with the more intensive B-ALL protocol (P = 0.60).
ARL patients with a good performance status may also benefit from high-dose chemotherapy followed by stem cell transplantation [19,20]. Unfortunately, this approach may apply only to a subgroup of patients. Moreover, our experiences and other observations [17,21] do not suggest that intensive chemotherapies increase prognosis in patients with HIV-associated PBL.
Thus, new strategies are needed. New options may be the use of drugs such as lenalidomide or bortezomib, which has been approved for the treatment of multiple myeloma . There are several case reports of patients with PBL in which encouraging responses were achieved with these new approaches [23–25].
In conclusion, AIDS-related PBL still has a very poor prognosis. Innovative studies focusing on more specific treatment approaches are warranted.
Conflicts of interest
This work was funded by the Federal Ministry of Education and Research (BMBF), Germany; Grant: 01 KI 0771. 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. 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. B.J. has received consulting fees from Boehringer Ingelheim, fees for speaking engagements from Janssen-Cilag. M.H. has received support for travel to meetings from Harlachinger Krebshilfe, Celgene, Janssen-Cilag, Novartis, Pfizer, Roche Pharma, consulting fees from Takeda Pharma GmbH and fees for speaking engagements from Boehringer Ingelheim, Celgene, Gilead Sciences, MSD, Novartis, Pfizer, Roche Pharma. G.F. has received consulting fees from Abbott, Bristol-Myers Squibb, 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, ViiV Healthcare, fees for board membership from Abbott, BMS, Gilead Sciences, Janssen-Cilag, MSD, Roche, ViiV Healthcare and fees for speaking engagements from Abbott, BMS, Gilead Sciences, Janssen-Cilag, MSD, Roche, ViiV Healthcare. A.Z. received fees for speaking engagements and a research grant from MSD, and support for travel to meetings from Boehringer Ingelheim, Gilead Sciences, and MSD. J.T. received fees for speaking engagements from Gilead Sciences, Bristol-Myers Squibb, Actelion, and Pfizer. For the remaining authors, none were declared.
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