TP53 Mutation and Survival in Chronic Lymphocytic Leukemia

Abstract

CLL with TP53 mutation carries a poor prognosis regardless of the presence of 17p deletion when treated with F-based chemotherapy. Thus, TP53 mutation analysis should be incorporated into the evaluation of patients with CLL before treatment initiation. Patients with TP53 mutation should be considered for alternative treatment approaches.

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…The regimens to which TP53 mutations predicted drug resistance included treatment with purine (pentostatin) or pyrimidine (fludarabine) analogues, as well as combination regimens containing anthracycline, cyclophosphamide, cytosine arabinoside, vincristine and/or etoposide. [18][19][20][21][22][23] Considering primary (pre-surgical) treatment of breast cancer, TP53 mutations have been associated with anthracycline and mitomycin resistance, 12,[24][25][26] but not with taxane resistance; 26,27 similarly, one study evaluating efficacy of taxanes in the adjuvant setting 28 and two studies evaluating anthracyclines and taxanes administered in concert, or sequentially, found no effect of TP53 mutation status on response. 29,30 Yet, there is evidence at variance.…”

The SF3B1 inhibitor spliceostatin A (SSA) elicits apoptosis in chronic lymphocytic leukaemia cells through downregulation of Mcl-1

“…Progressive disease is characterised by unmutated immunoglobulin heavy variable (IGHV) genes, ZAP70 and CD38 expression. 1 Genetic markers including deletions of 17p, 11q and 13q, trisomy 12 and TP53 mutations [2][3][4] have been known to impact prognosis for some time, however with the emergence of next generation sequencing, a plethora of new genetic alterations have been identified including NOTCH1 (10-15%) [5][6][7][8] and SF3B1 (10-17%) [8][9][10] mutations which identify patients with progressive disease. 8 SF3B1 is one of the proteins that make up the spliceosome and regulates excision of introns from premRNA 11 .…”

Evaluation of 230 patients with relapsed/refractory deletion 17p chronic lymphocytic leukaemia treated with ibrutinib from 3 clinical trials

“…Deletion of chromosome 17p [del(17p)] distinguishes a subgroup of patients with chronic lymphocytic leukaemia (CLL) and an exceptionally poor prognosis (Hillmen et al , 2007; Hallek et al , 2010; Zenz et al , 2010, 2012; Badoux et al , 2011). Although uncommon at the time of diagnosis (generally <5%) (Juliusson et al , 1990), the percentage of patients with CLL whose disease harbours del(17p) increases to as much as 10% when therapy is first indicated and can be identified in >40% of multiply relapsed and/or heavily pre‐treated patients (Zenz et al , 2012).…”

“…Del(17p) is a cytogenetic abnormality resulting in loss of TP53 function, leading to resistance to chemotherapy and increased risk of Richter transformation (RT) (Hallek et al , 2010; Badoux et al , 2011; Tam & Stilgenbauer, 2015). Because median survival for patients with del(17p) CLL has typically been ≤3 years from initiation of therapy, younger, fit patients (with an otherwise long life expectancy) with del(17p) CLL have often been referred for allogeneic stem cell transplantation (Hallek et al , 2010; Zenz et al , 2010, 2012; Tam & Stilgenbauer, 2015). Until recently, safe and highly effective therapies for most patients with del(17p) have been limited, representing an important unmet medical need (O'Brien et al , 2016a).…”