By Paul Kleutghen | Posted - Jul 13th, 2020

 

 

 

 

What is CHIP? Genetic Mutations in Older Myeloma Patients Who May be More Likely to Develop a second Blood Cancer or Cardiovascular Disease

An interesting article was published in the Journal Nature Communications a few weeks ago, authored by a team from Dana Farber Cancer Institute, reminding us of something that we tend to not hear about in our travels: the relationship between multiple myeloma and CHIP. But what is this CHIP? CHIP stands for Clonal Hematopoeisis of Indeterminate Potential, and is very nicely explained in information provided on the Dana Farber website (and I highly recommend you read the full blog post on the link just provided): 

As people age, it is normal for their blood-forming cells, known as hematopoietic stem cells (HSCs), to acquire genetic mutations, or misspellings, in their DNA. Most of these mutations do not affect how HSCs function or cause disease. In some cases, however, the mutations give certain HSCs an edge in survival, granting them an outsized role in producing blood cells. When this situation arises in people who are otherwise healthy, it’s known as clonal hematopoiesis of indeterminate potential (CHIP). [Note : the ‘edge in survival’ just mentioned does not refer to the survival of the patient but survival of these potentially harmful cells.]

Individuals with CHIP do not have symptoms of disease or markedly abnormal blood counts, but their risk of developing a blood cancer such as leukemia is 10 times higher than average, Dana-Farber researchers have found. That translates into a 1 percent chance per year of developing one of these diseases. People with CHIP also have an increased risk of cardiovascular disease and of leukemia resulting from treatment for other cancers.’

The article builds on the prior understanding of the negative impact CHIP may have on multiple myeloma patients who are or will be undergoing Stem Cell Transplants (SCT). The Dana Farber team studied the prevalence of 224 mutated genes that tend to be present in the blood of those with hematological malignancies. This was done by sequencing the DNA of purified stem cell product, harvested before transplant, from 629 transplant patients treated over an 8-year period. 

Here are some of the reported conclusions :

  • CHIP was present in close to 22 % of the 629 myeloma patients studied.
  • DNMT3A was the most frequently mutated gene followed by TET2, TP53, ASXL1 and PPM1D. [Note : and this alphabet soup is how genes in our DNA are coded.]
  • The median age at ASCT in patients with CHIP was 61 years, compared to 57 years in those without CHIP. 
  • The presence of CHIP was associated with a history of smoking, past medical history of cancer and a decreased efficiency of stem cell mobilization (5.8 million CD34+ cells/kg/day in those with CHIP compared to 8.3 million CD34+ cells/kg/day in those without CHIP. 
  • ...the presence of CHIP was not associated with abnormalities in the peripheral blood parameters at diagnosis or post-induction. [emphasis added]
  • patients with CHIP responded less well to induction therapy such that CHIP was associated with a higher post-induction median level of β2-microglobulin (2.3 mg/dL in those with CHIP compared to 2.0 mg/dL in those without [p = 0.008]), and a smaller percentage decrease in M-spike level (p = 0.008) post-induction [compared to the level at time of diagnosis].
  • The median overall survival (OS) of patients with CHIP was 5.3 years, significantly lower than in those without CHIP (7.5 years. Interestingly, CHIP was also associated with a lower median progression free survival (PFS) of 2.2 years compared to 2.6 years in those without CHIP. We also observed a worse OS and PFS in patients carrying more than one mutation. 
  •  … the presence of CHIP prior to ASCT was not associated with an increased risk of Therapy related Myeloid Neoplasms (TMN).n [Emphasis added. Note: in other words, if you have CHIP prior to transplant you do not have a higher risk of another hematological cancer compared to patients who do not have CHIP.]
  • However, IMiD maintenance was significantly associated with developing a subsequent TMN …[Note : in other words when you go onto a maintenance regimen with an immunomodulator you will have a higher risk of developing a hematological cancer, regardless of whether you have CHIP or not].
  • … and the presence of CHIP did not increase the risk among those receiving first-line IMiD maintenance or IMiD maintenance at any point post-ASCT. [Note : or in other words, the likelihood of a patient developing a second hematological malignancy with immunomodulator maintenance after SCT is similar regardless of whether you have CHIP or not.

And I am already hearing some say, ‘Well, that does it for me ! I am going to take myself off maintenance with [Revlimid, Pomalyst, Thalomid] ! And save me a bundle in the process !’ Before you do so, however, you need to be aware of a few other conclusions of this study :

  • Maintenance with immunomodulators is associated with improved outcome for ALL patients (CHIP or not) and that is despite the fact that maintenance with an IMiD may result in a higher risk to end up with a second hematological cancer. ‘First-line IMiD maintenance was associated with a longer median OS of 8.5 years compared to 5.6 years in those not receiving IMiD maintenance. As expected, IMiD maintenance was associated with a longer PFS of 3.4 years compared to 1.5 years in those not receiving IMiD maintenance.’
  • ‘In patients not receiving IMiD maintenance, CHIP was associated with a significantly lower median OS of 3.6 years compared to 6.6 years in those who did not have CHIP mutations.’
  • 'However, there was no significant difference in those who received maintenance (median OS of 7.7 and 8.9 years for CHIP and no CHIP.'
  • Similarly, in patients not receiving IMiD maintenance, CHIP was associated with a significantly lower median PFS of 1.1 years compared to 1.8 years. There was also no difference in PFS among patients with and without CHIP who received IMiD maintenance (median PFS of 3.3 and 3.6 years for CHIP and no CHIP, respectively).
  • These results suggest the presence of an interaction between the effect of having CHIP and IMiD maintenance, which is significant when it comes to PFS outcome. 

In other words : If you have had a stem cell transplant, it is wise to stay on your IMiD’s maintenance, unless your physician tells you otherwise for this or that medical reason.

The bottom-line conclusion at the end of the Dana Farber study is plain and simple:

‘Altogether, these data suggest that the presence of CHIP at time of transplant does not increase the risk of TMN (secondary cancers) associated with IMiD maintenance and that patients with CHIP, when treated with IMiD maintenance, obtain a survival benefit similar to that seen in multiple myeloma patients generally.’ … ‘ In fact, IMiD maintenance was not only associated with an improvement in both PFS and OS but it completely abrogated the deleterious effects of CHIP in the post-ASCT setting.’

And there you have it : some of us have CHIP, others do not. Your chance to have CHIP increases with increasing age. You may wish to talk to your physician if you have not yet been tested for CHIP, get tested and find out the result. If you have CHIP and you are not yet refractory to IMiD’s, you may wish to make sure to continue life with maintenance Revlimid (or one of the other immunomodulators).

 
Paul Kleutghen
About the Author

Paul Kleutghen - I am a patient diagnosed in 2014 with primary plasma cell leukemia (pPCL), a rare and aggressive variant of multiple myeloma and have been very fortunate to find treatment at the division of Cellular Therapy at the Duke University Cancer Institute. My wife, Vicki, and I have two adult children and a grandson who is the ‘light of my life’. Successful treatment has allowed Vicki and I to do what we love best : traveling the world, albeit it with some extra precautions to keep infections away. My career in the pharmaceutical industry has given me insights that I am currently putting to use as an advocate to lower drug pricing, especially prices for anti-cancer drugs and, very specifically, CAR-T therapies, with recent contributions posted by Health affairs, the Institute for Clinical and Economic Review and the Centers for Medicare and Medicaid Services.

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