Q&A: Clinical implications of clonal hematopoiesis

Question: What do you think about TET2 mutations being among the most frequent mutations in CH, but IDH being relatively rare?

Dr. Viny: Great question. Both are affecting demethylation and epigenetic instability. While I don’t think the answer is known, perhaps the IDH mutations have a more dominant effect on hematopoietic output. The majority of the CH data uses blood; maybe the marrow tells a different story.

Question: Can we cure clonal hematopoiesis with vitamin C?

Dr. Viny: You clearly know the recent work by Iannis Aifantis, PhD, showing the effects of vitamin C on TET enzyme activity, published here: Cell. 2017 Sep 7;170(6):1079-95. For CH patients with TET2 mutations, a high-dose vitamin C regimen sounds very exciting. There is also complementary work by Sean Morrison, PhD, published in Nature (2017 Sep 28;549[7673]:476-81).

Question: Is there a limit to the sequencing depth and variant allele fraction needed to identify clonal hematopoiesis? At what point is CH not CH?

Dr. Viny: So this is as much a technical question as it is a biological question. As of now we can reliably detect variant allele fraction in CH to 0.1%, at best. What is detectable and what is clinically relevant are questions that still need to be answered.

Question: There seems to be a lot of good research going on in CH. What are the big knowledge gaps that future studies should be targeting?

Dr. Viny: First, what are the functional and molecular consequences of the varying alleles in CH? Second, are there other clinical risks to CH beyond leukemia and cardiovascular disease? And third, does inflammation cause CH or does CH cause inflammation?

Dr. Viny is with the Memorial Sloan Kettering Cancer Center, New York, where he is a clinical instructor; is on the staff of the leukemia service; and is a clinical researcher in the Ross Levine Lab. Connect with him on Twitter at @TheDoctorIsVin.