Single-Hit TP53 Associated With Prolonged OS and PFS Vs Multi-Hit TP53 in Ibrutinib-Treated CLL

Patients with chronic lymphocytic leukemia (CLL) and single-hit TP53 mutations derived long-term responses with ibrutinib (Imbruvica) monotherapy, whereas patients with multi-hit TP53 aberrations had shortened progression-free survival (PFS), according to findings from a study published in Clinical Cancer Research.

At a median follow-up of 6.3 years (range, 6.1-7.2), overall survival (OS) and PFS were prolonged in patients with single-hit TP53 (n = 9) compared with patients with multi-hit TP53 (n = 42; P ≤ .042).

The median OS was not reached (NR) in patients with multi-hit TP53,and the median PFS was 4.6 years (95% CI, 3.7 years–NR). The 5-year OS and PFS rates in the single-hit TP53 cohort were 100% each compared with 69% and 43%, respectively, in the multi-hit TP53 cohort.

Additionally, time-to-progression (TTP) and cumulative incidence of relapse (CIR) were superior in patients with single-hit TP53 vs multi-hit TP53.

“Although currently considered equal prognostic markers, patients treated with single-agent ibrutinib carrying only a single TP53 hit demonstrate excellent [PFS] and [OS] on ibrutinib compared to those with multiple TP53 hits,” wrote lead study author Christian Brieghel, MD, PhD, a clinical scientist in the Department of Hematology at Rigshospitalet of Copenhagen University Hospital in Copenhagen, Denmark, and co-authors. “Thus, testing for both del(17p) by FISH [fluorescence in situ hybridization] and TP53 mutations by deep next-generation sequencing [NGS] should be performed to improve risk stratification of and facilitate clinical trials testing novel treatment approaches in multi-hit TP53 CLL.

TP53 mutations are associated with genomic instability and adverse outcomes in patients with cancer. In CLL, the presence of these mutations predicts poor prognosis with a shorter time to treatment initiation, a high likelihood of becoming refractory to or relapsing early after chemoimmunotherapy, and poor OS.

Although more patients with relapsed/refractory CLL have TP53 mutations compared with patients with newly diagnosed CLL, international guidelines recommend universal and up-front testing for TP53 alterations.

17p deletions and TP53 mutations frequently co-occur; however, single-hit TP53 aberrations are associated with poor outcomes in patients with CLL who are treated with chemoimmunotherapy. However, mixed findings have been reported regarding the prognosis of patients with single-hit vs multi-hit TP53 aberrations, so further studies were warranted.

Moreover, since patients with TP53 mutations have a shorter duration of response to ibrutinib vs those without TP53 mutations, the study investigators aimed to develop an understanding of whether the single-hit or multi-hit TP53 aberrations influence clinical outcomes with ibrutinib.

To that end, patients with TP53-mutated CLL were accrued from a phase 2 study (NCT01500733) of ibrutinib monotherapy in patients with CLL and small lymphocytic lymphoma.

TP53 aberrations were defined by the detection of 17p deletions by FISH, TP53 mutations by targeted NGS, or tissue expression of p53 by immunohistochemistry. Single-hit TP53 was defined as having a 17p deletion or single TP53 mutation, whereas multi-hit TP53 was defined as having a 17p deletion and TP53 mutation(s).

All patients received 420 mg of daily ibrutinib until disease progression or unacceptable toxicity.

Additionally, a population-based cohort of 205 patients with ibrutinib-treated CLL was included for external validation. These data were collected retrospectively from the Danish CLL registry and patient records.

Baseline patient characteristics showed that the median age in the overall population (n = 51) was 62 years (range, 59-69), and most patients were male (n = 31; 60.8%). Most patients had high-risk disease features such as Rai stage 4 disease (n = 25; 49%) and elevated β2-microglobulin (median, 3.9 mg/L; range, 2.9-5.8). The majority of patients (n = 34; 66.7%) had unmutated IGHV status and 17p deletion (n = 47; 92.2%). 17p deletion positivity by FISH was 56% (range, 18.8%-85.8%). Finally, most patients had treatment-naïve CLL (n = 34; 66.7%) vs relapsed/refractory CLL (n = 17; 33.3%).

Between arms, the multi-hit TP53 subgroup was enriched with younger patients with relapsed/refractory CLL and unmutated IGHV.

Overall, 220 TP53 mutations were identified in 84% (n = 43) of patients with a median variant allele frequency (VAF) of 0.6% (interquartile range [IQR], 0.3%-1.6%). Most mutations (n = 177; 80%) were low burden. Most patients (n = 39; 76%) had at least one high-burden TP53 mutation, but four patients (8%) had only low-burden mutations.

Among 51 patients, 92% (n = 47) carried 17p deletion and 76% (n = 39) carried concurrent 17p deletion and TP53 mutations. The median number of mutations per individual was one (IQR, 1-3); however, in the relapsed/refractory subgroup, the median number of mutations per patient was 3 (IQR, 1-13).

Nine patients had single-hit TP53 mutations, whereas 42 had multi-hit TP53 mutations. Of these patients, 19 had only 2 TP53 aberrations, 3 carried TP53 mutations only, and 39 had 17p deletion with one (n = 19) or more (n = 20) concomitant TP53 mutations.

At the median follow-up time, 16 patients had died and 23 had progressive disease. Four patients died from causes unrelated to disease progression.

No difference in OS or PFS was observed in patients with multi-hit TP53 with only 2 vs more than 2 aberrations (P ≥ .32) or between patients with only TP53 mutations vs 17p deletion with or without TP53 mutations. TTP and CIR were similar between patients with multi-hit TP53 with only 2 vs more than 2 aberrations.

With a VAF cutoff of 1%, similar outcome and discrimination capabilities were observed vs a VAF cutoff of 0.2%. A VAF cutoff of 2% resulted in less favorable PFS and TTP and lower discrimination capabilities in patients with single-hit TP53 aberrations.

Patients with multi-hit TP53 had consistently inferior outcomes irrespective of age, prior treatment, and IGHV mutational status, but patients with relapsed/refractory CLL and multi-hit TP53 mutations had inferior outcomes vs patients with newly diagnosed, multi-hit TP53-mutated CLL.

In the external validation cohort, 92 patients were excluded because they did not harbor TP53 aberrations. An additional patient was excluded because they were receiving combination targeted therapy.

At a median follow-up of 2.3 years (IQR, 1.5-3.3), patients with multi-hit TP53 had inferior OS and PFS compared with patients with single-hit TP53 or who did not harbor a known aberration (P = .002). In patients with known TP53 mutational status only, OS and PFS were longer, but insignificant in the single-hit TP53 vs multi-hit TP53 cohorts (OS, P = .11; PFS, P = .08, respectively).

“An assessment of TP53 aberrations by using both FISH and deep NGS should be performed in all CLL patients considered for treatment with ibrutinib,” concluded Brieghel and co-authors.

Reference

Brieghel C, Aarup K, Torp MH, et al. Clinical outcomes in patients with multi-hit TP53 chronic lymphocytic leukemia treated with ibrutinib. Clin Cancer Res. Published online May 7, 2021. Accessed May 24, 2021. doi:10.1158/1078-0432.CCR-20-4890