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TP53 aberrations [del(17p) or TP53 mutation] predict poor survival with chemoimmunotherapy in patients with chronic lymphocytic leukaemia (CLL). We evaluated long-term efficacy and safety of first-line ibrutinib-based therapy in patients with CLL bearing TP53 aberrations in a pooled analysis across four studies: PCYC-1122e, RESONATE-2 (PCYC-1115/16), iLLUMINATE (PCYC-1130) and ECOG-ACRIN E1912. The pooled analysis included 89 patients with TP53 aberrations receiving first-line treatment with single-agent ibrutinib (n = 45) or ibrutinib in combination with an anti-CD20 antibody (n = 44). All 89 patients had del(17p) (53% of 89 patients) and/or TP53 mutation (91% of 58 patients with TP53 sequencing results available). With a median follow-up of 49·8 months (range, 0·1-95·9), median progression-free survival was not reached. Progression-free survival rate and overall survival rate estimates at four years were 79% and 88%, respectively. Overall response rate was 93%, including complete response in 39% of patients. No new safety signals were identified in this analysis. Forty-six percent of patients remained on ibrutinib treatment at last follow-up. With median follow-up of four years (up to eight years), results from this large, pooled, multi-study data set suggest promising long-term outcomes of first-line ibrutinib-based therapy in patients with TP53 aberrations. Registered at ClinicalTrials.gov (NCT01500733, NCT01722487, NCT02264574 and NCT02048813).

Summary: TP53‐disrupted chronic lymphocytic leukaemia (CLL) patients show a suboptimal long‐term response to ibrutinib. We hereby report that ibrutinib‐induced in vitro apoptosis and proliferation inhibition were significantly lower in TP53‐mutated (TP53‐M) CLL cells compared to TP53 wild‐type cells. Contrariwise, venetoclax effectively killed TP53‐M cells. Gene expression profile analysis of TP53‐M cells revealed a downmodulation of B‐cell receptor (BCR)‐related genes and an upmodulation of genes with anti‐apoptotic/pro‐survival activity, suggesting that the survival and proliferation of TP53‐M cells are less dependent on the BCR pathway. These observations further support the use of drug combinations for the optimal management of TP53‐M CLL patients. [ABSTRACT FROM AUTHOR]

To identify the molecular signatures that predict responses to decitabine ( DAC), we examined baseline gene mutations (28 target genes) in 109 myelodysplastic syndrome ( MDS) patients at diagnosis. We determined that TP53 mutations predicted complete response ( CR), as 10 of 15 patients (66·7%) who possessed TP53 mutations achieved a CR. Univariate and multivariate analyses showed that TP53 mutations are the only molecular signatures predictive of a CR to DAC in MDS. Among the ten patients with TP53 mutations who achieved a CR, nine presented with complex karyotypes due to abnormalities involving chromosome 5 and/or chromosome 7, and eight possessed monosomies. Although TP53 mutations were associated with a higher frequency of CRs, they were not associated with improved survival. Poor outcomes were attributed to early relapses and transformation to acute myeloid leukaemia after CR. Post- DAC therapy patient gene mutation profiles showed that most CR patients exhibited fewer gene mutations after achieving a CR. It seems that suppression of these gene mutations was facilitated by DAC, resulting in a CR. In summary, TP53 mutations might predict decitabine-induced complete responses in patients with MDS. DAC-induced responses may result from partial suppression of malignant clones containing mutated TP53 genes. [ABSTRACT FROM AUTHOR]

Treatment success in patients with acute myeloid leukaemia ( AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation ( HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival ( OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval ( CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) ( P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML. [ABSTRACT FROM AUTHOR]

The article discusses a study on the impact of hypomethylating agents (HMA) treatment in TP53-mutated acute myeloid leukaemia (AML) patients. Topics covered include the prevalence of TP53-overexpression at baseline using a validated immunohistochemistry method, overall response rates between TP53-positive and TP53-negative AML patients, and time to response and response duration between TP53-positive and TP53-negative AML patients.

In chronic lymphocytic leukaemia ( CLL), TP53 mutation and deletion are strongly associated with one another and with adverse clinical outcome. Mutant TP53 protein typically accumulates to high levels and has been reported to have transcriptional regulatory activity distinct from that of wild-type TP53. To investigate whether such an effect is relevant to CLL, carefully balanced primary CLL samples with or without TP53 mutation/deletion were compared for their gene expression profiles using high-density DNA microarrays. Ninety-six and eight differentially expressed genes were identified, respectively, using two alternative statistical approaches with different stringencies. None of the differentially expressed genes were known to be regulated by mutant TP53, and only four of the 67 under-expressed genes were known transcriptional targets of wild-type TP53. Significantly, both approaches showed that gene under-expression was the dominant feature of TP53-mutant CLL samples. Furthermore, a disproportionate number of the under-expressed genes were located on chromosome 17p, the most significant being TP53 itself. Together, these results indicate that any transcriptional regulatory effects of mutant TP53 in CLL cells are overshadowed by the under-expression of co-deleted TP53 and other genes on chromosome 17p. Our findings have implications for emerging therapeutic strategies that target mutant TP53. [ABSTRACT FROM AUTHOR]

Hairy cell leukaemia variant ( HCL-variant) and splenic marginal zone lymphoma ( SMZL) are disorders with overlapping features. We investigated the prognostic impact in these disorders of clinical and molecular features including IGH VDJ rearrangements, IGHV gene usage and TP 53 mutations. Clinical and laboratory data were collected before therapy from 35 HCL-variant and 68 SMZL cases. End-points were the need for treatment and overall survival. 97% of HCL-variant and 77% of SMZL cases required treatment ( P = 0·009). Survival at 5 years was significantly worse in HCL-variant [57% (95% confidence interval 38-73%)] compared with SMZL [84% (71-91%); Hazard Ratio 2·25 (1·20-4·25), P = 0·01]. In HCL-variant, adverse prognostic factors for survival were older age ( P = 0·04), anaemia ( P = 0·01) and TP 53 mutations ( P = 0·02). In SMZL, splenomegaly, anaemia and IGHV genes with >98% homology to the germline predicted the need for treatment; older age, anaemia and IGHV unmutated genes (100% homology) predicted shorter survival. IGHV gene usage had no impact on clinical outcome in either disease. The combination of unfavourable factors allowed patients to be stratified into risk groups with significant differences in survival. Although HCL-variant and SMZL share some features, they have different outcomes, influenced by clinical and biological factors. [ABSTRACT FROM AUTHOR]