Understanding Clonal Hematopoiesis in Hematologic Malignancies With Rahul Banerjee, MD, Jeremy Meier, MD, and Samuel Rubinstein, MD

Dr. Jeremy Meier and Dr. Samuel Rubinstein of the University of North Carolina (UNC) Chapel Hill are the first and senior author, respectively, of a recently published review paper entitled Game of Clones: Diverse Implications for Clonal Hematopoiesis in Lymphoma and Multiple Myeloma. In this interview for Blood Cancer Awareness Month, Oncology Data Advisor’s Editorial Board member Dr. Rahul Banerjee speaks with Dr. Meier and Dr. Rubinstein about their work in this area and the future of clonal hematopoiesis research in hematologic malignancies.

Rahul Banerjee, MD, FACP: Hi, everyone. Welcome to Oncology Data Advisor, your resource for the multidisciplinary cancer team. My name is Dr. Rahul Banerjee, and I’m on the Editorial Board for Oncology Data Advisor. Today, it is my pleasure to speak with Dr. Meier and Dr. Rubinstein about clonal hematopoiesis in hematologic malignancies as we speak about Blood Cancer Awareness Month.

Dr. Meier is a Fellow in the Division of Hematology and Oncology at UNC Chapel Hill. His research interests are in clonal hematopoiesis and hematology. Dr. Rubinstein is a Clinical Assistant Professor within the Division of Hematology and Oncology at UNC Chapel Hill. His research interests are in multiple myeloma and amyloid light chain (AL) amyloidosis. Dr. Meier, Dr. Rubinstein, pleasure to have you both here.

Samuel Rubinstein, MD: Thank you for having us.

Jeremy Meier, MD: Yes, pleasure to be here. Thank you so much.

Dr. Banerjee: Absolutely. So I think we can delve into the acronyms, but I feel like that’s probably the biggest barrier to entry for anyone in the field who wants to learn more about clonal hematopoiesis and how it affects our patients. Can you just walk us through clonal hematopoiesis of indeterminate potential (CHIP), clonal hematopoiesis (CH), variant allele fraction (VAF), clonal cytopenia of undetermined significance (CCUS), and all the other terms that someone who’s reading about this kind of topic should be familiar with?

Dr. Rubinstein: Yes, so clonal hematopoiesis is the umbrella term for disproportionate expansion of hematopoietic stem cells and their progeny following the acquisition of the somatic mutation. It’s further subcategorized into entities depending on the presence or absence of a significant abnormality in the blood counts. You’ll hear people talk about clonal hematopoiesis of indeterminate potential, or CHIP, which is clonal hematopoiesis with no identified reductions in blood counts. Then you have clonal cytopenia of uncertain significance, which is CH plus a blood count abnormality, specifically a low blood count in the absence of a hematologic malignancy. A patient has a mutation in DNMT3A and their hemoglobin’s 10.5, but they don’t have evidence of myelodysplasia or other myeloid disease morphologically.

Another acronym I think that we’ll discuss because it helps us think about the relative prevalence of CH is variant allele frequency, or VAF. That just refers to the percentage of the cells that harbor given clonal hematopoiesis mutation. Of course, clonal hematopoiesis can occur in the setting of increased blood counts and no known myeloid malignancy. My colleagues from my former fellowship at Vanderbilt have attempted to come up with acronyms for that situation, as well. It’s a little ill advised. I think CHAP is one that’s come up; I’m not going to delve into that too much. But that’s an entity that’s also recognized and has prognostic implications beyond the scope of our review.

Dr. Banerjee: Absolutely. Generally speaking, with clonal hematopoiesis, what VAFs are you talking about? Not 30% or 40%, for example; probably lower digits, single digits?

Dr. Rubinstein: There’s a range, so it’s generally lower frequency variant allele frequencies of 10% to 15%, but you can have higher. I think some of the studies we’ll talk about show that sometimes you have higher variant allele frequencies in the setting of clonally unrelated malignancies.

Dr. Meier: I think it depends on your sequencing technique. You can detect variant allele frequencies well below 1%, but clinically, how relevant those are is unclear at this time.

Dr. Banerjee: That’s an excellent point, especially, as you alluded to, in patients with cancer who have many, many other mutations going on and it’s hard to tell what’s clonal and what’s not. Since we’re giving this talk during September and Blood Cancer Awareness Month, let’s talk about blood cancers and clonal hematopoiesis. It sounds like it’s somewhat of a chicken and egg in that the clonal hematopoiesis can predispose patients to developing blood cancers; but for patients who have blood cancers with higher rates of CH, can you talk us through which comes first? Or is there is a little bit of both?

Dr. Meier: I think it is probably a little bit of both. It’s hard to determine one over the other, and I think it comes back to talking about clonal hematopoiesis as kind of a context-dependent effect. Certainly, when you look broadly, patients with CH have a much higher risk of developing a hematological malignancy, particularly as that variant allele frequency increases. Studies have shown that if you have a VAF that’s over 10%, your risk could be up to 50 times that of somebody who doesn’t have clonal hematopoiesis, in terms of developing hematological malignancy.

If you look a little bit deeper, such as in cases of lymphoma, there’s an excellent study that looked at immunoblastic T-cell lymphoma, which we talked about a bit in the review. It’s interesting that if you look at the malignant T-cell clones and compare that to the myeloid compartment that you’d see in the bone marrow, there was remarkable consistency in shared mutations between the two compartments. They had 22 patients who had clonal hematopoiesis in this study, and 15 of the 22 had shared mutations between myeloid cells and the bone marrow and those malignant T cells.

The thought is that there’s potentially a kind of hematopoietic progenitor clone that can then evolve over time, acquiring immune mutations and other things that lead it down a malignant tract. That’s why they saw that the malignant T cells had developed new clones or divergent mutations like RHOA that are prominent in that cancer. It’s likely that clonal hematopoiesis, if anything, may set up almost a niche, or a microenvironment, that can support the development of a hematologic malignancy as additional mutations are acquired and accrued.

Dr. Banerjee: That’s a good point. It’s not just the clonal hematopoiesis itself, but you’re right, it’s kind of making the other immune cells dysfunctional, which would normally do some immune surveillance or prevent this malignant pre-clone from growing. That’s a really good point.

Dr. Meier: Right. Then if you take it a step further, and I think we’ll get into this a little bit, they also had patients who developed therapy-related myeloid neoplasms after treatment for their T-cell lymphoma. Again, they shared very similar mutations between the T-cell lymphoma and that therapy-related myeloid neoplasm. But the myeloid neoplasm had acquired new mutations that drove it down that path.

Dr. Banerjee: Fair, which is interesting. Dr. Rubinstein, we’ve talked about T-cell lymphoma; anything similar to that in myeloma?

Dr. Rubinstein: This is obviously an evolving story, and I think it probably is the case that clonal hematopoiesis and the underlying, unrelated hematologic malignancy both modify the microenvironment and may promote development of the other disease process. In myeloma, there are definitely more proposed mechanisms by which myeloma can promote the development of clonal hematopoiesis as opposed to the other way around.

There are a few potential mechanisms that may contribute to this. There’s a study demonstrating that myeloma cells may release extracellular vesicles that dysregulate hematopoietic stem cell growth. Specifically in the presence of myeloma-released extracellular vesicles, you have dose-dependent reductions of hematopoietic stem cell viability and colony formation, as well as a relative reduction in healthy myeloid progenitor cells. You may have a mechanism there by which multiple myeloma cells release extracellular vesicles into the microenvironment and promote expansion of clonal hematopoiesis clones.

There’s also a shared reliance on interleukin-6 (IL-6) in multiple myeloma. It’s a critical growth factor, and it’s mechanistically behind a lot of the cardinal findings in multiple myeloma. Multiple calcium elevation, renal insufficiency, anemia, and bone lesion (CRAB) features are driven more by IL-6 than anything else. That IL-6 dysregulation is a cardinal feature of clonal hematopoiesis. Then, additionally, you have changes in the immune surveillance cells in the myeloma microenvironment, specifically regulatory T cells and gamma delta T cells that may promote viability of clonal hematopoiesis clones, as well. So, I don’t know which is first, the chicken or the egg, but it may be that myeloma may play more of a role in promoting and sustaining CH than the other way around.

Rahul Banerjee: Absolutely so. To both of your points, it seems kind of a snowball effect that as immune surveillance gets worse as a myeloma clone grows and grows, those problems are severe, a little bit out of control. And that’s just a diagnosis. You mentioned briefly, Dr. Meier, about the idea of therapy-related neoplasm and so forth. Maybe we can pivot to therapy. I’m sure almost any therapy that we use for lymphoma or myeloma—but in particular, chemotherapy or so forth—probably does put cells at risk of developing more mutations, including hematopoietic cells.

Let’s focus on transplant. Obviously in myeloma, we use melphalan, typically as a single drug, as a mainstay of therapy for eligible patients with lymphoma, although the world is kind of changing a little bit. But for both Hodgkin and non-Hodgkin lymphoma, for example, you might talk about a BEAM (carmustine/etoposide/cytarabine/melphalan) autologous (auto) transplant for refractory disease. Can you talk about how transplant affects the landscape of clonal hematopoiesis in hematologic malignancy?

Dr. Meier: I can start first and talk briefly about the lymphoma side. Certainly, when you’re talking about bone marrow transplant, there’s a lot that goes into how you’re affecting the bone marrow microenvironment. An interesting thing is that when you’re talking about inflammation outside of what we do to deplete the bone marrow, there’s increased inflammation post-transplant. What they’ve shown is that these clones that emerge from clonal hematopoiesis actually have a selective growth advantage under those conditions. They upregulate antioxidant genes and anti-inflammatory genes.

With all this going on, you’re depleting the bone marrow and you’re increasing inflammation in the setting of a transplant. Any of those clones that are persisting automatically have a head start in terms of their growth post-transplant.

When you look at studies, though, the effect of clonal hematopoiesis pre-transplant on outcomes post-transplant is kind of a mixed bag. There are studies that certainly show that there’s a negative consequence in terms of overall survival post-transplant, particularly when you’re looking at lymphoma. In a big study out of Dana-Farber looking at over 400 patients, 120 of those had evidence of CHIP or clonal hematopoiesis at the time of diagnosis ahead of autologous transplant. In those patients who had increased incidence of therapy-related myeloid neoplasms—a 10% increase over those who didn’t—their overall survival was halved at five to 10 years, compared with those who didn’t have CH. That was attributed both to increased instances of therapy-related neoplasms but also non-relapse mortality.

There’s a huge impact that we know of on clonal hematopoiesis on other health effects, particularly cardiovascular disease. In that study, increased cardiovascular disease and cardiovascular disease–related deaths were a big factor in those increased deaths that they saw. On the other side, in a large Danish study of close to 600 patients, 20% to 25% of them had evidence of clonal hematopoiesis before transplant, and there wasn’t any difference in overall survival in that cohort post–autologous transplant. Again, it’s context-dependent. It depends on what mutations you’re calling or ascertaining here are important. So, it’s still a mixed bag, and more research is certainly needed.

Dr. Banerjee: Absolutely. It’s a good reminder that I think we all think about transplant-related mortality or the lymphoma coming back because of the clonal hematopoiesis or secondary malignancy. But you’re right, the cardiovascular risk factors of clonal hematopoiesis are kind of screaming out at us that we have to keep an eye on them, especially after transplant. Dr. Rubinstein, how about for myeloma?

Dr. Rubinstein: Myeloma is a similar story of having some conflicts in the data. Regarding the prognostic implications, there was a similar study out of the same institution, Dana-Farber—they’ve led a lot of the CH work, including defining it as a disease entity—demonstrating inferior overall survival after autologous transplant for patients who have clonal hematopoiesis. Very interestingly, it’s a heterogeneously-treated cohort. As you and many listening will know, standard of care is to offer lenalidomide maintenance after autologous stem cell transplant. It seems that the adverse prognostic implications of clonal hematopoiesis were disproportionately limited to those who do not receive lenalidomide maintenance after a stem cell transplant on that study. Patients with CH and no maintenance had the worst prognosis. Maintenance with lenalidomide, in the vast majority of cases, may overcome some of the impairment in prognosis associated with CH prior to transplant.

As for the story on whether melphalan conditioning promotes clonal expansion of CH clones, there are conflicting studies to that effect. There is one relatively large study of a heterogeneous population of patients with myeloma and patients with non-Hodgkin lymphoma, but many with myeloma did not have significant evidence of clonal evolution longitudinally after transplant. There’s a larger clonal tracing study that followed patients for longer that demonstrated, in an immediate peri-transplant period, about a sixfold expansion in clonal hematopoiesis clones that remained relatively stable thereafter. It stands to reason that you would get some modest selection by the mechanisms Dr. Meier was mentioning of CH clones. The impact of that expansion in and of itself on prognosis is not entirely clear.

One twist in the story in which myeloma diverges from lymphoma: Dr. Meier mentioned that in patients with lymphoma, the adverse prognostic implications of CH are driven mostly by non-relapse mortality, cardiovascular events, etc. In myeloma, by contrast, increased myeloma relapse seems to be associated with more of the mortality events that are seen in clonal hematopoiesis patients. They’re at risk for earlier relapse of disease. The interesting common thread surprised me. We spent a lot of time reviewing the literature for this, and if you’d asked me what I thought we would come up with, I would’ve said some of the mortality differences that are seen may be due to more therapy-related myeloid neoplasms (TMNs) in patients with CH. Interestingly, that’s not really the major contributor to the adverse prognostic implications of CH in the clonally-unrelated hematologic malignancy space.

Dr. Banerjee: To pivot on that point of secondary neoplasms, I’m surprised to hear that in the first study you mentioned, in patients who got lenalidomide maintenance, CH wasn’t worse for those patients. I would imagine that lenalidomide is probably worse than everything.

Dr. Rubinstein: It’s a little off topic, but it does somewhat fit with the DETERMINATION story, which shows transplant itself driving most of the increase in myeloid malignancies. Unfortunately, patients who don’t get a transplant seem to make up for it with more lymphoid malignancies. It’s a bit surprising that we worked on this before DETERMINATION read out. But I would say that story is concordant.

Dr. Banerjee: I completely agree. That’s a really good segue to some of the trials coming out in terms of auto transplant. I’m biased; I love auto transplant, but I love chimeric antigen receptor (CAR) T therapy even more. Your review is a very great review; I think all of you in the audience should take a look at it, because it’s really compelling. A lot of background that Dr. Meier and Dr. Rubinstein are summarizing here is the story of CH and chronic lymphoid leukemia (CLL) and CAR T therapy. One example is that patient who actually had a better response paradoxically because of their CH. Can you just walk us through that story?

Dr. Meier: This is a very interesting story, and I’m also quite interested in CAR T cells and CAR T-cell research, so I was very intrigued by this. This came out of the University of Pennsylvania, and it was early on in their CD19 CAR T trials. They had one patient in particular, a 78-year-old who had multiply relapsed/refractory CLL who received CAR Ts on this study. Interestingly, he actually got two infusions of CAR T cells. He got the first infusion, he had severe cytokine release syndrome (CRS), they gave tocilizumab shut that down, and then he had progressive disease. There was concern that maybe the anti–IL-6 therapy had affected the expansion of the CAR Ts and how they were functioning. He got a second infusion, and even after the second infusion, he initially showed signs of disease progression. It was unclear what the course was going to be.

Then, all of a sudden, about two months after the second infusion, they were tracking his CAR T population and they saw a spike in the number of CAR T cells, and then a month, two months after that. By six months, his CLL was completely eradicated. When they looked deeper and sequenced the T-cell receptors and the clones that were present that made up the CAR T population, it was pretty striking that 94% of the CAR T cells that peaked were from a single clone, which is insane when you think about it. In looking at that clone, what was particularly interesting is that the CAR T—because we have to virally introduce it—where it inserted in a genome, because it can be random, was in an intron of TET2. When they did more elaborate in vitro studies, they showed that resulted in an early stop codon, so you got a loss-of-function TET2 impact there.

When they sequenced the other allele that was present on his cells, they found that he carried a hypomorphic TET2 mutation, as well. You have now biophilic TET2 effects. What they showed, which is quite interesting, is in that context from a CAR T standpoint, it resulted in epigenetic modification of the CAR T cells that favored cell cycle progression and proliferation of the CAR T-cells. But at the same time, it restricted their differentiation to a more stem-like state. They were more central memory T cells, which we know from a T-cell and a CAR T-cell standpoint is advantageous for a couple things. We know that they proliferate better, and they also have a higher antitumor potential. They can be kind of pluripotent as compared with other patients that they looked at, where the CAR T cells were mostly effector memory or effector T cells, which have less of that potential.

This clonal evolution and clonal hematopoiesis that occurred in this patient, where you had emergence of the single clone, was a good thing. Essentially, it eradicated the CLL. What I thought was even more interesting is when they looked five years out, 15% of his cells were still restricted to that one clone, which is unbelievable when you’re talking about T-cell persistence. When you’re talking about CAR T cell, which is kind of the holy grail of T-cell work, how can we get these cells to persist longer to carry out their antitumor effects? Now, whether this is going to shift how we think about incorporating or designing CAR T therapy is yet to be determined.

Other newer studies have shown that CAR T cells in the context of clonal hematopoiesis may have better rates of complete response (CR) and better rates of overall survival, but at the expense of potentially more toxicity—more CRS, more neurotoxicity. Mechanistically, is there more inflammation with CH present that’s propelling CAR T and its effect forward? We don’t know. It’s an interesting question, and it’ll be very exciting to see where it goes in the future.

Dr. Banerjee: I think for the journalists of the world, it’s kind of like fighting fire with fire. You have the cells that are growing out of control, and you tell the CAR T cell, “All right, you guys start growing out of control now and see what happens.” It’s essentially a good point that it was not so much that they were proliferating uncontrollably, it’s that they were expanding. But as you’re saying, it’s maintaining that memory phenotype, not getting exhausted, not becoming effector T cells as much, and I think that’s important.

There’s obviously so much more that we could talk about here. I think one of the big topics in clonal hematopoiesis is how it affects allogeneic transplant, not just for lymphoma or myeloma, but for all blood cancers like leukemia in terms of donor-related clonal hematopoiesis. But again, that’s a whole other hour lecture in and of itself, so we’ll save that for another day. Any other parting words or thoughts about CH or CHIP or CCUS that you want to convey to the audience?

Dr. Rubinstein: It’s a fruitful area of research, and there are a lot more questions that we have now than answers. How all these considerations tangibly impact management of clonally unrelated hematologic malignancies is at this time very unclear. I think it’s very interesting. Hopefully, we will learn better how to make use of this information to optimize management for patients in the coming years.

Rahul Banerjee: Agreed, and if the testing becomes available and we have a utility for attaching, it’ll have to be made accessible for patients practically. Right now, understandably, it’s more of a research lab setting. But the potential is there, and once we figure out how to use it, I think there are a lot of things we could do with that type of knowledge.

Thank you, Dr. Meier, and thank you, Dr. Rubinstein, for your time. This has been an excellent podcast. I learned quite a bit from this, and I’m sure the audience did as well, about this alphabet soup of acronyms—most importantly, CH and how it affects our care and our prognostication of patients with blood cancers.

My name is Dr. Banerjee, and this has been a podcast for Oncology Data Advisor. Thank you all for your time and have a good day.

About Dr. Banerjee, Dr. Meier, and Dr. Rubinstein

Rahul Banerjee, MD, FACP, is an Assistant Professor in the Division of Medical Oncology at the University of Washington; he also holds a faculty appointment at the Fred Hutchinson Cancer Center. His clinical interests are in multiple myeloma, AL amyloidosis, and CAR T therapy, and his research interests are in toxicity management, digital health, and the patient experience.

Jeremy Meier, MD, is a Fellow in the Division of Hematology and Oncology at UNC Chapel Hill. His research focuses on clonal hematopoiesis, immunometabolism, and CAR T-cell biology, particularly on how CAR T cells intersect with the tumor microenvironment.

Samuel Rubinstein, MD, is a Clinical Assistant Professor in the Division of Hematology and Oncology at UNC Chapel Hill. His research focuses on AL amyloidosis and multiple myeloma, including informatics and prognostic scoring tools for plasma cell dyscrasias.

For More Information

Meier J, Jensen JL, Dittus C, et al (2022). Game of clones: diverse implications for clonal hematopoiesis in lymphoma and multiple myeloma. Blood Rev, 100986. DOI:10.1016/j.blre.2022.100986

Lewis NE, Petrova-Drus K, Huet S, et al (2020). Clonal hematopoiesis in angioimmunoblastic T-cell lymphoma with divergent evolution to myeloid neoplasms. Blood Adv, 4(10):2261-2271. DOI:10.1182/bloodadvances.2020001636

Laurenzana I, Trino S, Lamorte D, et al (2021). Multiple myeloma–derived extracellular vesicles impair normal hematopoiesis by acting on hematopoietic stem and progenitor cells. Front Med (Lausanne), 8:793040. DOI:10.3389/fmed.2021.793040

Slavin TP, The JB, Weitzel JN, et al (2019). Association between clonal hematopoiesis and late nonrelapse mortality after autologous hematopoietic cell transplantation. Biol Blood Marrow Transplant, 25(12):2517-2521. DOI:10.1016/j.bbmt.2019.08.013

Ortmann CA, Dorsheimer L, Abou-El-Ardat K, et al (2019). Functional dominance of CHIP-mutated hematopoietic stem cells in patients undergoing autologous transplantation. Cell Rep, 27(7):2022-2028.e3: DOI:10.1016/j.celrep.2019.04.064

Gibson CJ, Lindsley RC, Tchekmedyian V, et al (2017). Clonal hematopoiesis associated with adverse outcomes after autologous stem-cell transplantation for lymphoma. J Clin Oncol, 35(14):1598-1605. DOI:10.1200/JCO.2016.71.6712

Husby S, Favero F, Nielsen C, et al (2020). Clinical impact of clonal hematopoiesis in patients with lymphoma undergoing ASCT: a national population-based cohort study. Leukemia, 34(12):3256-3268. DOI:10.1038/s41375-020-0795-z

Heini AD, Porret N, Zenhaeusern R, et al (2021). Clonal hematopoiesis after autologous stem cell transplantation does not confer adverse prognosis in patients with AML. Cancers (Basel), 13(13):3190. DOI:10.3390/cancers13133190

Mouhieddine TH, Sperling AS, Redd R, et al (2020). Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant. Nat Commun, 11(1):2996. DOI:10.1038.s41467-020-16805-5

Richardson PG, Jacobus SJ, Weller EA, et al (2022). Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med, 387:132-147. DOI:10.1056/NEJMoa2204925

Fraietta JA, Nobles CL, Sammons MA, et al (2018). Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature, 558:307-312. DOI:10.1038/s41586-018-0178-z

Gibson CJ, Kim HT, Zhao L, et al (2022). Donor clonal hematopoiesis and recipient outcomes after transplantation. J Clin Oncol, 40(2):189-201. DOI:10.1200/JCO.21.02286

Transcript edited for clarity. Any views expressed above are the speakers’ own and do not necessarily reflect those of Oncology Data Advisor.

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