The challenge of unavailable IGH mutational status in CLL in resource-limited settings

Chronic lymphocytic leukemia (CLL), the most common leukemia in the Western world, has a very heterogeneous clinical course and numerous factors providing prognostic information have been documented over the years. Some of these clinical and biological factors have been integrated into scoring systems such as the CLL International Prognostic Index (CLL-IPI), which is based on five factors: age, clinical stage, serum B2 microglobulin, Immunoglobulin gene heavy variable (IGHV) mutational status, and TP53 abnormalities (deletion or mutation) [1]. A meta-analysis of the CLL-IPI applied to CLL patients entered into clinical trials allowed for the stratification of patients into four risk groups that showed significant different times to first treatment (TTFT) and overall survival (OS). These findings were validated in a Danish population-based cohort of 1514 patients with CLL [2]. An issue that still needs to be considered relates to the feasibility to investigate all the parameters included in the CLL-IPI prognostic model, in the context of standard care for CLL patients. A registry with a large number of patients across the USA, which included both academic and community centers, showed that about 90% of patients with CLL were not screened for IGHV mutations [3]; even in the CLL-IPI meta-analysis referred to earlier, one-third of the patients lacked this information. This is indeed a matter of some concern when it comes to, the worldwide applicability of the CLL-IPI particularly considering the fact that unmutated IGHV status has a major impact in the CLL-IPI, scoring 2 points, which is double that of clinical stage and age, two parameters that are readily available for all the community. In this issue of the journal, Lad et al. [4] proposes a prognostic index for CLL designated CLL-LIPI where the IGHV mutational status is replaced by the lymphocyte doubling time (LDT) (greater or under 6months). When this score was applied as risk stratification in a cohort of 218 patients diagnosed and followed in a single institution, and in whom all parameters were available, it was shown to have prognostic significance in terms of TTFT and OS. The disease features and biological markers in the cohort of patients included in this study were not essentially different from those of patients included in the CLL-IPI analysis, except for a slightly higher proportion of patients with del17p in the CLL-LIPI group. There were also no differences in the proportion of patients allocated to each of the four risk groups. However, a significantly higher proportion of patients (60%) in the CLL-IPI study had unmutated IGHV compared to the number of patients with a shorter LDT (40%) in the CLL-LIPI. This is unfortunate, as it would have been interesting to have examined both the LDT and IGHV mutational status in this cohort, to ascertain how much overlapping or independence there actually was between these two variables and what their respective impact was on the prognosis of CLL. LDT reflects the proliferation rate of the malignancy and is an easy parameter to record and evaluate in CLL. It is an ‘old’ parameter that entered the CLL ‘prognostic scenario’ prior to the era of immunological markers such as CD38, ZAP-70 and CD49d and the availability of fluorescence in situ hybridization (FISH) to detect chromosomal abnormalities with prognostic impact or recent more complex molecular genetic assays. The impact of LDT in the prognosis of CLL was first illustrated by Galton in the early 1960s [5] and later by Bergsagel [6] who documented the poor outcome of CLL patients with short LDT. Since this seminal observation, there have been several studies showing the impact of LDT in the progression of CLL