Incidence and diagnosis of Richter transformation: transition from the era of chemoimmunotherapy to novel targeted agents

Richter transformation (RT) is the pathological and clinical transformation of chronic lymphoid leukemia (CLL) to an aggressive lymphoma. Incidences vary across the different studies and have been reported from one to just over 15%. Most of the epidemiological data are derived from retrospective studies with varying lengths of follow-up. The largest cohort data from the MD Anderson Cancer Center (MDACC) and Mayo Clinic established incidence rates of 2.3–5% [1,2]. A more recently published population study from Norway including over 2600 patients diagnosed between 2003–2012, reported an incidence of 2.9% [3]. Taking into consideration all available epidemiological data conclude the annual incidence rate of RT in CLL stands at 0.5%/year [2]. In this issue of Leuk Lymphoma Ben-Dali et al. [4] report the findings of one of the largest population cohorts ever studied, based on data from the Danish National CLL registry; 113 histologically-confirmed cases of RT were identified amongst 3667 patients diagnosed with CLL between 2008–2016 and followed over a median of 4.6 years. The five-year cumulative incidence of RT was 2.8%. Approximately half of those who developed RT had received prior chemo-immunotherapy (CIT) for CLL, and the five-year cumulative incidence in this population was 7.1%. This study highlights several aspects relating to RT that need to be considered. First, they report a lower incidence of RT, compared to other studies and common knowledge; the authors propose that variability in reported incidences between published studies may stem from the differences in terms of risk profile and that the CLL cohort presented here may represent a population with more indolent disease (i.e. nationwide vs. trial populations). However, it has also been argued that the incidence of RT may be underestimated in some series due to differing biopsy policies [5]. The lower incidences mentioned above are in contrast to results of a prospective study reported by Rossi et al. [5] in 2008, where a more ‘aggressive’ diagnostic policy was adopted and biopsy performed whenever RT was clinically suspected (lymph node size > 5 cm, rapidly enlarging lymph nodes, suspicious extra nodal lesions, appearance of B-symptoms, and significantly elevated LDH). The cumulative incidence at five and 10 years in that particular study was 13.6 and 16.25%, respectively. The main question to be asked would probably be whether the introduction of novel agents has in fact affected the incidence of RT. Results of clinical trials using ibrutinib and or venetoclax in R/R CLL patients reported relatively high incidences of 3–20% [6–8]. But when evaluating the same agents in treatment – naïve patients, the incidence of RT was similar to past ‘historical’ reports of 3–6%, varying according to the treatment status of the study population, and length of follow-up, which ranged from 3–6 years [6,7]. We may however conclude that, the incidence of RT in the era of novel targeted agents appears to be similar to that in the CIT era, although these results should be interpreted with caution since the patient populations used for assessing the incidence of RT during novel agent therapy included data from clinical trials and we still await ‘real world data’ as recorded in this study from Denmark. The second point to take into consideration is that in the Danish cohort, 50% of the cases of RT occur in treatment naïve patients [4]. This is an intriguing observation from a biological standpoint and implies that we need to identify risk factors which are independent of drug-induced clonal evolution. It also emphasizes the need for a risk assessment model for RT which would be relevant for all CLL patients both treatment naïve as well as in the era of novel agents.