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1) Gearing up for a series of #ASH20 highlights in #AMLsm and #MDSsm and will post threads about main highlights on major topics starting with TP53-mutated AML. This subset of AML is probably the worst genetic entity. Median OS has ranged between 5-9 months from diagnosis
2) @ColemanLindsley and colleagues have shown in an analysis of the CPX-351 vs 7+3 PH3 among older patients with secondary AML that patients with TP53 mutations do not derive benefit with median OS of 5.7 months for those patients deemed for for intensive chemo
3) in an #ASH20 presentation By @NicholasShortMD including 202 patients with newly diagnosed AML and TP53 mutations who received therapy @LeukemiaMDA and showed most patients had complex karyotype. Most patients received non-intensive therapies
4) The authors identified 40% VAF as cutoff for worse outcomes regardless of therapy but especially for ARA-C based intensive chemo treated patients further supporting the notion that many of these patients, esp those with high VAF, do not benefit from intensive therapies.
5) The authors proposed use of VAF of 40% or presence of more than one TP53 mutation as trigger for investigational therapy regardless of fitness for intensive chemotherapy. Patients with lower VAF might benefit from Ara-C based chemo followed by alloBMT
6) in Another analysis in #ASH20 patients with TP53 AML had very poor outcomes with 10-day decitabine with venetoclax, further throwing cold water on previous data suggesting 10-day courses of decitabine are particularly helpful in these patients
7) Therapeutically, data with magrolimab with azacitidine has been promising for TP53 mutated AML especially reported median OS of 12 months but with small number of patients, limited follow-up duration and no control arm difficult to draw solid conclusions
8) increasing data suggest the issue with TP53 AML is high relapse rates and short survival despite intensive therapies and transplant despite high response rates to initial therapy. This is important for clinical trials to look at OS rather than CR as endpoints
9) important to emphasize that not all TP53 mutations are equal, some might be variants and not pathogenic, impact of VAF, concurrent different TP53 or other gene mutations and chromosomal abnormalities, all need to be included in consideration when thinking about therapy choices
10) we recently published a case in @TheLancet that highlights some of the challenges in management of patients with TP53 mutated AML https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32543-5/fulltext
11) please feel free to share your thoughts/experiences, retweet this thread and add any other #ASH20 abstracts or other data/insights you have about TP53 AML
12) and thanks to all the authors who shared their slides with me from #ASH20. I look forward to additional threads about important #AMLsm and #MDSsm highlights
13) Not in #ASH20 but TP53 has been found to explain Peto’s Paradox-the lack of correlation between the animal’s body size and cancer risk. For example elephants have many more cells than humans and live longer but develop cancer very rarely
14) researchers found that elephant genome encodes 20 copies of TP53 & this was coincident with the evolution of large body sizes, the evolution of extreme sensitivity to genotoxic stress, and a hyperactive TP53 signaling pathway https://elifesciences.org/articles/11994
