Secondary Leukemia After Non-Hodgkin Lymphoma: A Systematic Review and a Meta-Analysis

The risk of second leukemia/myelodisplastic syndrome (MDS) in non-Hodgkin lymphoma (NHL) survivors has been described in several studies, but the available evidence has yielded different results. Thus, we performed a systematic review and a meta-analysis on population-based and cohort studies to provide a quantitative assessment of the risk of secondary leukemia/MDS after NHL. Aims of our research were to estimate the pooled Relative Risk (RR) of secondary leukemia/MDS and the RRs associated with impact of different therapies in particular the effect of radiation treatments.

A Medline search of articles published between January 1985 and December 2010 was conducted to identify relevant observational studies. We included studies that met each of the following criteria: 1) published in English-language; 2) original papers (no reviews, comments, letters, or editorials); 3) including naïve patients with any stage of NHL; 4) investigating the risk of secondary leukemia/MDS in NHL survivors; 5) reporting RR, specified as standardized incidence ratios or data allowing such outcomes to be derived. The reference lists of the selected articles were inspected to identify additional papers. When two or more articles reported duplicate data, we included the most recently updated data or most informative study. We did not exclude papers on the base of therapeutic regimens. The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed. Pooled RR and 95% confidence interval (CI) were calculated using random effect models. Meta-regression and tests on heterogeneity and sensitivity analysis was conducted. The publication bias was also evaluated.

Fifteen papers met the inclusion criteria reporting RRs for leukemia/MDS. These studies included 278,782 patients affected by NHL of which 575 presented a second leukemia/MDS. RRs ranged from 2.0–251.8 and we found a meta-RR for secondary leukemia/MDS of 8.69 (95%CI: 3.66–20.64). In addition, we evaluated the effect of therapeutic regimens and radiotherapy (RT) and/or total body irradiation (TBI) exposure, limiting the analysis to the studies that clearly described the chemotherapies (CHT) and RT and/or TBI. We found a significant increased risk of second leukemia/MDS for patients exposed to irradiation (considering studies where the % of patients treated with RT and/or TBI was >30%) in comparison with unexposed patients: meta-RR was 20.20 (95%CI: 4.65–87.89) and 6.48 (95%CI:2.41–17.39) respectively. By regression analysis we identified a significant association between RT and/or TBI and secondary leukemia/MDS (P=0.004). No publication bias was observed. Regarding CHT with alkylating agents we found a meta-RR of 9.83 (95%CI: 2.45–58.84), and in a sub-group analysis of the studies that reported informations of CHT plus RT in comparison with the studies that reported data of CHT alone we found an increased risk for the patients undergoing CHT plus RT: meta-RR 13.35 (95%CI: 1.75–19.46) and 5.83 (95%CI: 1.75–19.46) respectively.

Our comparative analysis on the incidence of second leukemia/MDS presents several issues including the heterogeneity of NHL, the source of data, the time during which the studies were performed, the different schedule of CHT, the dose of RT used in the different period of time and the length of follow-up. Although these problems could reduce the accuracy of the meta-analysis, our results indicate that NHL treatment is associated with a significantly higher risk of second leukemia/MDS, in particular after RT and/or TBI.

No relevant conflicts of interest to declare.

the study has been supported by funds of the Italian Ministry of Education (FIRB 2011, CINECA code RBAP11TF7Z) and the Italian Association “Angela Serra per la Ricerca sul Cancro”, Modena.

No relevant conflicts of interest to declare.