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P. Schommers et al.
Introduction
Over the last two decades, the incidence of AIDS-relat- ed lymphomas (ARL) has markedly declined due to the introduction of combination antiretroviral therapy (cART). However, ARL remain a major cause of morbidity and mortality, and represent the highest proportion of all AIDS-related deaths.1 Patients with ARL are usually treat- ed with the same chemotherapy protocols established in the HIV-negative setting,2 and the rates of complete remis- sion (CR) achieved are comparable to those reported in their HIV-negative counterparts.3,4 However, available data on the incidence and potential risk factors of recurrent dis- ease in ARL are scarce, and treatment of disease relapse remains challenging.4,5 In recent studies on HIV-negative patients with diffuse large B-cell lymphoma (DLBCL), R- CHOP-based regimens (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) resulted in CR rates of around 65-80%. Differences in response rates largely depend on the pre-treatment International Prognostic Index (IPI) for aggressive lymphomas.6,7 In patients who had achieved a CR, relapse rates ranged from 6-10%.6,8 The second most common ARL are Burkitt or Burkitt-like lymphomas (BL).9,10 In the HIV-negative set- ting, CR and overall survival (OS) rates of around 80-90% were reported by different groups.10-12 In a large prospec- tive trial on short-intensive chemotherapy combined with rituximab for patients with BL, the relapse rate was 12%.10 Although this approach also proved feasible in HIV-relat- ed BL,9 it remains unclear whether relapse rates reported in HIV-negative DLBCL and BL are different to those in ARL. Thus, we investigated the risk factors and incidence of relapse in a large cohort of ARL patients who had achieved a CR after first-line treatment.
Methods
Study design
The German HIV Lymphoma Cohort is an ongoing, prospective observational multicenter study including all adult HIV infected patients who are diagnosed with biopsy- or cytology-proven malignant lymphoma in 33 participating centers since January 2005. Data on HIV-infection and lymphoma characteristics, treat- ment and outcome are recorded. From the time of lymphoma diagnosis, patients are followed every six months. Ethics approval was obtained from the ethics committees of the University of Cologne (IRC Cologne: 05-174), Germany, and written informed consent was given by each participating patient.
The present analysis includes only patients with aggressive B- cell lymphoma in first CR. Lymphomas were grouped in DLBCL, BL, plasmablastic lymphoma (PBL) and ARL, not further classifi- able, the latter group representing aggressive B-cell non-Hodgkin lymphomas (B-NHL) that could not be classified into any subtype. To study the impact of chemotherapy dose intensity on the risk of relapse in patients treated with either R-CHOP-based regimens or the short intensive GMALL protocol,10 we performed an analysis of dose reductions and delays in chemotherapy cycles. (Information about the GMALL and R-CHOP protocol can be found in the Online Supplementary Tables S1 and S2, respectively). A full-intensity treatment was considered to consist of six cycles of chemotherapy according to the R-CHOP or GMALL protocol administered at 3-week intervals without dose reductions and within a period of 120 days (5x21 days for 6 cycles plus a maxi- mum of 3 days delay per cycle). Less than 6 cycles of chemother-
apy were classified as “cycle reduction” and the treatment dura- tion was calculated according to the number of cycles given. If the dose of any chemotherapy drug was reduced by 20% or more, treatment intensity was considered to be reduced.
As positron emission tomography (PET) scans were not routine- ly performed, the 1999 standardized response criteria for non- Hodgkin’s lymphomas13 were used rather than the 2007 criteria.14 CR was defined as the disappearance of all disease manifestations for at least three months. This definition also includes uncertain complete remission (CRu) that implied a residual mass of 1.5 cm or smaller that remained unchanged over at least three months.
Statistical analysis
Statistical analyses were performed using IBM SPSS Statistics software (IBM, Armonk, NY, USA), v.24.0. Univariate statistics were performed using Pearson’s χ2, Fisher’s exact one-way Analysis of Variance (ANOVA) with Bonferroni-corrected post- hoc test, or Kruskal-Wallis test depending on data. For the multi- variate Cox regression analysis, continuous clinically meaningful breakpoints that showed P-values below 0.1 in the univariate analysis were considered. Kaplan-Meier curves were used to illus- trate the relapse-free survival (RFS) and overall survival. Differences between subgroups were assessed with the log-rank test. RFS was defined as the period between first diagnosis and any lymphoma relapse according to the STEEP criteria.15 OS was defined as the period between first diagnosis and death from any cause. All-cause deaths as well as “lost to follow up” were cen- sored. All P-values were two-sided. P<0.05 was considered statis- tically significant.
Results
Patients' characteristics and outcome
Numbers and characteristics of patients included in the present analysis are depicted in Figure 1. In total, 254 of 399 (63.7%) patients with high-grade NHL of B-cell origin (classified as ARL) reached a CR with their first-line chemotherapy. Of those, 127 had DLBCL, 91 BL, 29 PBL, and 7 ARL, not further classified. ARL was CD20-negative in 24 of 254 cases (9.5%), among them 22 PBL and 2 DLBCL cases. Among 22 PBL cases with information on Epstein-Barr-Virus (EBV) status, EBV was present in 15 (68%). Overall, 86.2% of patients with CD20+ lym- phomas received rituximab. Notably, patients diagnosed before 2010 were less frequently treated with rituximab than those diagnosed from 2010 onwards (79% vs. 96%, P<0.001). Further, 73% of patients with CD4 cell counts less than 50/μl received rituximab compared to 88% with CD4 counts 50/mL or over (P=0.096). Patients' character- istics with respect to treatment outcomes are listed in Table 1. OS of patients who achieved CR with first-line therapy was significantly better than that of patients in other response groups (Figure 2). After a median follow up of 4.6 years, 5-year OS of the entire group of all 262 patients in first CR was 87.1% [standard error (SE) 2.3%] (Figure 3A) with differences between lymphoma sub- types: 87.8% (SE 3.1%) in DLBCL, 87.6% (SE 3.7%) in BL, 79.6% (SE 11.3%) in PBL, and 83.3% (SE 15.2%) in ARL, not further classified (P=0.994) (Figure 3B).
Incidence of recurrent disease in ARL
After a median follow up of 4.6 years, a relapse of the ARL had occurred in 29 of 254 patients (11.4%). Relapses were observed in 14 patients with DLBCL (11.0%), 9 with
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