XPO1 Mutation Presence May Result in Increased Proliferation in Early CLL

There were a few select transcriptomic features that were associated with B-cell receptor and cytokine signaling in those with XPO1-mutated early-stage CLL. In pathways with upregulated genes, these features included early response to B-cell receptor activation, TGFβ and EGF-EGFR signaling, FOSB expression, and MAPK regulation via DUSP.

Investigators report that the presence of XPO1 mutations in patients with early-stage chronic lymphocytic leukemia (CLL) appears to correlate with more robust B-cell receptor signaling that may result in more proliferation and a decreased time to first treatment (TTFT), according to findings from an analysis published in the British Journal of Haematology.¹

Investigators only included patients with early-stage disease who were initially treated using a watch-and-wait strategy when assessing how XPO1 mutations affect clinical proliferation. The analysis included several cohorts. Cohort 1 was comprised of 276 patients with newly diagnosed Rai 0 and 1 disease; cohort 2 had a multicenter population of 286 patients with Binet A CLL; and the third multicenter cohort, which was previously described in an earlier report,² had 395 patients with Rai 0 disease.

Investigators identified XPO1 mutations in 2.9% of patients in cohort 1, 4.2% of those in cohort 2, and 2.0% in cohort 3. The rate of TTFT was 0% at 10 years in cohort 1 among those with an XPO1 mutation vs 69.8% in those with XPO1 wild-type disease (HR, 9.8; 95% CI, 4.35-22.14; P <.001); the median follow-up was 10.4 years. The independent association between shorter TTFT and XPO1 mutations was maintained during the multivariate analysis, which accounted for unmutated IGHV genes, palpable lymph nodes, and lymph node counts that exceeded 15,000 per μL (HR, 2.79; 95% CI, 1.16-6.71; P = .022).

The 6-year TTFT rate was 25.0% among those with an XPO1 mutation in cohort 2 vs 61.3% among those with XPO1 wild-type disease at a median follow-up of 5.6 years (P = .025; HR, 2.24; 95% CI, 1.09-4.61; P = .029). Moreover, at a median follow-up of 6.7 years, the 7-year TTFT rate in those with XPO1 mutations in cohort 3 was 0% vs 73.4% in those with XPO1 wild-type disease.

Among those with XPO1-mutant disease, investigators reported that 236 genes were upregulated and 296 were downregulated. There were a few select transcriptomic features that were associated with B-cell receptor and cytokine signaling in this population. In pathways with upregulated genes, these features included early response to B-cell receptor activation, TGFβ and EGF-EGFR signaling, FOSB expression, and MAPK regulation via DUSP.

In the overall cohort (n = 957), those with XPO1 E571 (n = 25) or XPO1 D624 mutations (n = 3) demonstrated “superimposable outcomes in terms of TTFT,” investigators wrote (P = .594).

To conduct the analysis, investigators tested patients with monoclonal B-cell lymphocytosis (MBL; n = 95), early-stage CLL (n = 957), CLL that relapsed following chemoimmunotherapy or pathway inhibitors (n = 81), and CLL with Richter syndrome (n = 55). Patients were re-analyzed both at the time of requirement (n = 61) and at Richter transformation (n = 29) to assess XPO1 mutations’ potential clonal evolution. Moreover, investigators examined the XPO1 gene via next-generation sequencing with a target resequencing gene panel in cohorts 1 and 3, as well as with Sanger sequencing in cohort 2.

Investigators reported XPO1 mutations in 3 patients with MBL, 28 with early-stage CLL, 4 with relapsed CLL, and 7 with CLL that transformed to diffuse large B-cell lymphoma. Compared with those who had MBL, XPO1 mutations occurred more often, respectively, in those with Richter transformation (12.7% vs 3.1%; P = .03) and early-stage CLL (12.7% vs 2.9%; P = .002).

References

1. Moia R, di Terzi Bergamo L, Talotta D, et al. XPO1 mutations identify early-stage CLL characterized by shorter time to first treatment and enhanced BCR signaling. B J Haem. Published online August 14, 2023. doi:10.1111/bjh.19052
2. Cohen JA, Rossi FM, Zucchetto, et al. A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia. Haematologica. 2020;105(6):1613-1620. doi:10.3324/haematol.2019.228171