Association of gene mutations with time‐to‐first treatment in 384 treatment‐naive chronic lymphocytic leukaemia patients

Abstract

Summary This study correlated somatic mutation results and known prognostic factors with time‐to‐first treatment (TTFT) in 384 treatment‐naïve (TN) chronic lymphocytic leukaemia (CLL) patients to help determine disease‐specific drivers of early untreated CLL. CLL DNA from either peripheral blood or bone marrow underwent next generation targeted sequencing with a 29‐gene panel. Gene mutation data and concurrent clinical characteristics, such as Rai/Binet stage, fluorescence in situ hybridisation (FISH), ZAP70/CD38, karyotype and IGHV mutation, status were analysed in univariable and multivariable analyses to identify associations with TTFT. TTFT was defined as time from diagnosis to initial treatment. In univariable analyses, mutated ATM (P < 0·001), NOTCH1 (P < 0·001) and SF3B1 (P = 0·002) as well as unmutated IGHV (P < 0·001), del(11q) (P < 0·001) and trisomy 12 (P < 0·001) by hierarchal FISH and advanced Rai (P = 0·05) and Binet (P < 0·001) stages were associated with shorter TTFT. Importantly, del(17p), mutated TP53 and complex karyotype were not associated with shorter TTFT. In a reduced multivariable analysis, mutated ATM (P < 0·001) and unmutated IGHV status (P < 0·001) remained significant, showing their importance in early leukaemogenesis. High‐risk prognostic markers such as del(17p), mutated TP53 and complex karyotype, were not correlated with TTFT, suggesting that these abnormalities have limited roles in early disease progression but are more important in relapsed CLL.

Recent progress of prognostic biomarkers and risk scoring systems in chronic lymphocytic leukemia

“…The percentage of del17p cells has an impact on the prognosis of CLL patients, and the low percentage of del17p cells predicts a better TTFT [66]. However, another study revealed that neither del17p, mutated p53, nor complex karyotypes is associated with TTFT, which suggests that they have limited roles in early CLL patients but may take effect in relapsed disease [47]. Besides chromosome aberrations above, del6q, del9p21, del10q23, total or partial trisomies of chromosomes 3, 8, 18, 19, and duplications in 2p24 also have an impact on prognosis in CLL [67].…”

Precision Medicine Management of Chronic Lymphocytic Leukemia

“…In addition, by taking advantage of the genetic heterogeneity of CLL, mutations of genes involved in CLL pathogenesis have been tested as biomarkers for identifying early stage CLL patients with a higher risk of progression and treatment requirement. These studies point to mutations of SF3B1, NOTCH1, ATM, U1, and XPO1 as molecular predictors of shorter TTFT [7,56,57]. Interestingly, TP53 disruption is not associated with a shorter TTFT, in line with the notion that TP53 disruption interacts with treatment with chemotherapeutic agents, but not with a watch and wait strategy that does not expose CLL cells carrying TP53 disruption to the positive selection pressure exerted by ineffective chemotherapy [55,56].…”

“…Recent studies have tried to identify the clinical and molecular features of early stage CLL patients managed with a watch and wait approach and who might manifest treatment requirement soon after diagnosis [6,[55][56][57][58]. The pattern of tumor growth of untreated CLL has been investigated by analyzing serial longitudinal samples collected between diagnosis and the time of treatment requirement [6].…”

“…These studies point to mutations of SF3B1, NOTCH1, ATM, U1, and XPO1 as molecular predictors of shorter TTFT [7,56,57]. Interestingly, TP53 disruption is not associated with a shorter TTFT, in line with the notion that TP53 disruption interacts with treatment with chemotherapeutic agents, but not with a watch and wait strategy that does not expose CLL cells carrying TP53 disruption to the positive selection pressure exerted by ineffective chemotherapy [55,56]. The precise role of gene mutations in sorting asymptomatic CLL patients with an imminent risk of treatment requirement still needs to be clarified and is the current subject of investigations.…”

Do we need to analyse everything at diagnosis in chronic lymphocytic leukaemia?

“…An important question is how can this be added to by the more recent identification of recurrent genetic mutations in CLL. In the current paper, (Hu et al , ) the authors studied the impact on time from diagnosis to time to first treatment (TTFT) of detection of mutations in a 29 gene panel and looked for associations with a variety of standard prognostic factors in a cohort of 384 treatment naïve CLL. They demonstrate that mutated ATM ( P < 0·001), NOTCH1 ( P < 0·001) and SF3B1 ( P = 0·002) as well as unmutated IGHV ( P < 0·001), del(11q) ( P < 0·001) and trisomy 12 ( P < 0·001) by hierarchal FISH and advanced Rai ( P = 0·05) and Binet ( P < 0·001) stages were associated with shorter TTFT.…”