Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL

Although TP53, NOTCH1, and SF3B1 mutations may impair prognosis of patients with chronic lymphocytic leukemia (CLL) receiving frontline therapy, the impact of these mutations or any other, alone or in combination, remains unclear at relapse. The genome of 114 relapsed/refractory patients included in prospective trials was screened using targeted next-generation sequencing of the TP53, SF3B1, ATM, NOTCH1, XPO1, SAMHD1, MED12, BIRC3, and MYD88 genes. We performed clustering according to both number andcombinations of recurrentgene mutations. Thenumberof genes affected by mutation was 2, 1, and 0 in 43 (38%), 49 (43%), and 22 (19%) respectively. Recurrent combinations of 2 mutations of TP53, SF3B1, and ATM were found in 22 (19%) patients. This multiplehit profilewasassociated with a medianprogression-free survival of 12monthscompared with 22.5 months in the remaining patients (P = .003). Concurrent gene mutations are frequent in patients with relapsed/refractory CLL and are associated with worse outcome.