Q&A: Clinical implications of clonal hematopoiesis

 

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Dr. Viny: So to start, CH is the detection of somatic mutations in the blood or bone marrow of patients without any hematologic disorder – normal counts, no dysplasia, no abnormal cells; whereas clonal cytopenia of undetermined significance is a patient with a detectable somatic mutation, no dysplasia or abnormal cells, but a decrease in hematopoietic output of one or more lineages. It is inferred, but not proven, that the mutation is causing the cytopenia.

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

 

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.

 

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Dr. Viny: So to start, CH is the detection of somatic mutations in the blood or bone marrow of patients without any hematologic disorder – normal counts, no dysplasia, no abnormal cells; whereas clonal cytopenia of undetermined significance is a patient with a detectable somatic mutation, no dysplasia or abnormal cells, but a decrease in hematopoietic output of one or more lineages. It is inferred, but not proven, that the mutation is causing the cytopenia.

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

 

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.

 

There is growing literature around clonal hematopoiesis (CH) but many questions persist about its clinical significance. On June 14, Hematology News hosted a Twitter question-and-answer session with Aaron Viny, MD, who is on the staff of the leukemia service at Memorial Sloan Kettering Cancer Center in New York and is a member of the Hematology News editorial advisory board, to answer questions about CH and interpret the latest research. The following is an edited version of the Q&A session.

Question: Can you get us started by explaining the difference between clonal hematopoiesis (CH) and clonal cytopenia of undetermined significance?

Dr. Viny: So to start, CH is the detection of somatic mutations in the blood or bone marrow of patients without any hematologic disorder – normal counts, no dysplasia, no abnormal cells; whereas clonal cytopenia of undetermined significance is a patient with a detectable somatic mutation, no dysplasia or abnormal cells, but a decrease in hematopoietic output of one or more lineages. It is inferred, but not proven, that the mutation is causing the cytopenia.

Question: So are there differences in CH depending on the gene mutated?

Dr. Viny: Hard to say. The most common mutations found in CH are DNMT3A, TET2, PPM1D, and ASXL1, as shown in the Cell Stem Cell paper by Catherine C. Coombs, MD, and Ross Levine, MD (2017 Sep 7;21[3]:374-82.e4). So in the setting of patients with acute myeloid leukemia, there are data from several groups showing that persistence of DNMT3A, TET2, and ASXL1 have less recurrence risk, compared with the field. This, of course, does not apply to CH in the absence of a hematologic disorder.

Question: Are you aware of any screening programs for clonal hematopoiesis?

Dr. Viny: Currently at Memorial Sloan Kettering, patients who undergo MSK-IMPACT testing of their solid tumor have a germ line control from blood that is also sequenced. These samples are screened for CH mutations. In fact, there are two recent papers showing one key issue with tumor sequencing and CH: A blood sample is necessary to resolve the compartment of the CH mutation (that is, not in the solid tumor). The papers are JAMA Oncol. 2018 Jun 5. doi: 10.1001/jamaoncol.2018.2297 and Clin Cancer Res. 2018 Jun 4. doi: 10.1158/1078-0432.CCR-18-1201.

Question: Will patients with CH in screened samples be notified of the results?

Dr. Viny: Yes. The patients are being referred to the Memorial Sloan Kettering clonal hematopoiesis clinic run by Dr. Levine and Kelly Bolton, MD.

Question: Once you screen and detect CH, how should these patients be followed?

Dr. Viny: First, what are the risks these patients face? Extensive work by Siddhartha Jaiswal, MD, PhD, shows that there is an increased risk of cardiovascular disease and an increased risk for leukemia. So with regards to the latter, following with serial complete blood counts seems sufficient, with a bone marrow biopsy at the detection of any cytopenias. With regard to cardiovascular risk, I consider CH akin to an unmodifiable cardiac risk factor. Patients should be counseled to exercise, and depending on any other cardiac risk factors, interventions such as blood pressure control, lipid control, and daily aspirin use should be addressed accordingly.

Question: Is this BRCA1 all over again?

Dr. Viny: Perhaps. With BRCA1, we now have a few decades of follow-up to better understand the risks and even intervene with preventive interventions. Clonal hematopoiesis needs the follow-up and research to support clinical action.

Question: Could you please refer your readers to your favorite review on clonal hematopoiesis?

Dr. Viny: An outstanding review of the mechanisms and molecular consequences of clonal hematopoiesis is in Cell Stem Cell (2018 Feb 1;22[2]:157-70).

Question: Are there any effects of previous radiation on the development of CH?

Dr. Viny: Let’s start by saying that CH in the absence of prior cancer is probably a different entity. Radiation, tobacco use, and increased age all increase the risk for detection of a CH somatic mutation.

Question: What are the clinical implications of CH?

Dr. Viny: While I think it is still too soon to say if these are the only clinical implications, both increased risk of hematologic malignancy and increased risk of cardiovascular disease are the best studied and described to date. Here’s an excellent article on the cardiovascular risk: N Engl J Med. 2017 Jul 13;377(2):111-21. Of interest, it seems that the increased risk, while being relatively low, does not plateau over time.

 

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.