Ioannis Kotsianidis, MD Mrinal M. Patnaik, MBBS
The U.S. Food and Drug Administration has approved two hypomethylating agents (HMAs), azacitidine and decitabine, for the treatment of chronic myelomonocytic leukemia (CMML), a rare and aggressive myeloid malignancy with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN).1,2 Despite being widely used for MDS, there is a lack of strong clinical evidence supporting the use of these agents in patients with CMML, and outcomes can be variable between patients.
In this edition of “Drawing First Blood,” Ioannis Kotsianidis, MD, of Democritus University of Thrace in Greece, and Mrinal M. Patnaik, MBBS, of Mayo Clinic in Rochester, Minnesota, debate the evidence, or lack thereof, supporting the use of azacitidine and decitabine in CMML and whether these agents should be used, as options are limited. Dr. Kotsianidis was asked to argue in favor of HMAs and Dr. Patnaik was asked to argue against.
Dr. Kotsianidis: This is a difficult question. Decitabine is not approved in Europe and azacitidine is restricted to patients with dysplastic CMML. The best first-line choice for CMML will depend on the patient’s status and disease status; this includes considering the patient’s age, severity of symptoms, fitness, risk according to scoring symptoms, possibility of secondary CMML, and molecular features. If I have a high-risk patient, I will go for first-line azacitidine or decitabine – off-label. I would consider a transplant for a young and fit patient with intermediate- to high-risk CMML, but that is a different question.
Dr. Patnaik: I have a different take on this concept. CMML has long been an orphan disease that has suffered a lot of injustice. This disease has often been lumped with MDS, which has higher incidence and prevalence rates. That is how azacitidine and decitabine were approved in the U.S., based on trials primarily designed for patients with MDS.
I am referring to two pivotal studies. The AZA-001 trial was conducted in Europe and randomly assigned patients to azacitidine or conventional care regimens.3 The CALGB 9221 study, which was conducted in North America, looked at patients with MDS and randomly assigned them to azacitidine versus best supportive care.4 In these two large studies, there were only a handful of patients with CMML. Additionally, these patients had to have a white blood cell (WBC) count lower than 12,000, so they all had, by definition, dysplastic CMML. Based on these two studies, the drug was approved for MDS and CMML.
CMML is a heterogeneous disease that we classify as myeloproliferative (WBC ≥13 x 109/L) and myelodysplastic (WBC <13 x 109/L) variants. I agree with Dr. Kotsianidis that you must stratify patients by age and performance status, and I do think there is a subset of patients with CMML who will benefit from HMAs. There is also a subset who will not benefit from them.
That is why I am constantly championing newer, rationally defined clinical trials for the myeloproliferative CMML subtype. Our approach to treating these patients must acknowledge that the existing standard of care has not been thoroughly vetted and does not universally apply to every patient with CMML.
This is best highlighted by the European DACOTA study that randomly assigned patients with higher risk myeloproliferative CMML to receive decitabine or hydroxyurea.5 There were more objective responses in the decitabine arm, but those responses did not translate into a survival benefit.6 At the end of the day, if these responses do not translate into a survival benefit or a meaningful improvement in quality of life (QoL), then you have to question the appropriateness of the agent. With time, the toxicity of the agents, including cardiac toxicities, are slowly unraveling.
Dr. Kotsianidis: I agree that the DACOTA study was a nice and much-needed trial because we don’t have CMML-exclusive trials. We do have retrospective data, though, including our data from Greece, showing that the WBC count had no independent impact on survival; either we use it as a continuous value or at the cutoff of 13,000 WBC.6 The DACOTA study had a rather problematic definition of progression. The first endpoint of the trial was event-free survival, and that definition included doubling of baseline bone marrow blasts after six cycles or best response. This increase can be potentially meaningless, i.e., if a patient goes from 2% to 4% or from 3% to 6% blasts. Also, doubling of blasts has never formally been shown to affect survival.
Another point is that the DACOTA trial was not properly powered to show a difference in overall survival (OS). Survival in this cohort of elderly patients is highly influenced by extra hematologic comorbidities, as reflected by the higher rate of cardiovascular events in the decitabine arm. Having said that, the most reliable and biologically relevant endpoint was the cumulative incidence of progression to acute myeloid leukemia (AML) transformation. This was superior in the decitabine arm compared with hydroxyurea. However, it also appears that toxicity was too high in the decitabine arm, which had a significantly higher two-year cumulative death without progression or transformation, and this may be an obvious reason for the absence of differences in OS.
DACOTA was a very good trial, but I am not sure you can apply the findings of this trial to every patient with myeloproliferative CMML.
Dr. Patnaik: I agree. No trial is perfect. There were limitations, but we must acknowledge a trial of this magnitude carried out exclusively for CMML. In the U.S., this would have been a difficult task, especially since the comparator arm had single-agent hydroxyurea. We would have struggled to accrue.
At Mayo Clinic and some other centers, we now have a database with more than 1,000 patients with CMML. What is clear is that one subtype of CMML does better than others – these patients have a TET2 mutant/ASXL1 wild-type genotype. They not only have better survival rates, but also have more durable responses to HMAs.7
TET2, ASXL1, and SRSF2 are the three most common somatic mutations in CMML. TET2 occurs in approximately 60% of patients, ASXL1 in about 40%, and SRSF2 in about 40% to 50%. When you see patients with CMML who have a mutation in TET2 and do not have an ASXL1 mutation, they will do well in general, but when you treat them with HMAs, median responses can be quite prolonged, much more than median responses seen in CMML in general.
These findings from the database mirror prior basic research published that showed TET2 mutations impaired the ability to oxidize methylcytosine and decrease 5-hydroxymethylcytosine levels, providing a biological rationale for using HMAs in this group.8 By default, a lot of the patients with the TET2 mutant/ASXL1 wild-type genotype have MDS-CMML.
In addition to the DACOTA study, there is also a smaller phase II trial that showed that although the overall response rates (ORR) to HMAs can be in the 40% to 50% range, the true complete remission rates were less than 20%.9 For proliferative CMML, responses are sometimes less than 10%. Although the DACOTA study is not perfect, it is the only randomized, prospective study that we have dedicated to CMML and is a great start to build on.
Dr. Kotsianidis: I agree. Most of the data are retrospective and most of the retrospective series are pretty small, but most of them show the same results. The ORRs are about 30% to 50%, and the OS ranges from 17 to 30 months. We do have one more prospective phase II trial out of the U.K., but it was very small with only 32 patients.10
In reference to the 13,000 WBC cutoff, I was wondering ... if we use this threshold for a trial, might we have a lead-time bias? For instance, a patient might have a count of 11,000 and in three months it could be 13,000. So, we may introduce lead-time bias if we select patients based only on the 13,000 cutoff. What is urgently needed is a better molecular characterization of the disease.
Dr. Patnaik: Yes, I fully agree. The 13,000 WBC threshold is somewhat arbitrary. If you check a patient’s complete blood count twice a week, it may be 12,000 one day and 14,000 the next.
We published a paper in Nature Communications where we raised the same question.11 We did extensive genomic, transcriptomic, and epigenetic work and found there is a biological basis for proliferative and dysplastic disease that is inherently driven by signaling mutations. Seventy percent of patients had RAS pathway mutations (NRAS, CBL, PTPN11, KRAS, and NF1), and there was a subset that was also driven by JAK2V61F7. If you look at patients who have RAS pathway mutations, they have a unique gene expression profile enriched in genes regulating cell cycle and cell division and they also have a unique epigenetic profile. We hope that moving forward, genetic signatures might replace WBC cutoffs in identifying MPN-CMML from MDS-CMML, also resulting in rationally designed and chosen drug therapies for affected patients.
Dr. Kotsianidis: Another important point to mention about HMAs is that we don’t even know how these drugs work. We don’t know the mechanisms of action, but equally importantly, we don’t know the mechanisms of resistance; thus, we don’t know how to overcome resistance. If a patient has MDS, CMML, or AML and is refractory to HMAs, there will be a grave outcome, so how these drugs work is a principal question for me.
Dr. Patnaik: We also need to look at regulatory endpoints. With CMML, we look at response rates and OS. Can you prolong survival with existing and experimental agents? Can you reduce the rate of leukemia transformation – leukemia-free survival? However, there are elderly patients with significant QoL issues. These patients have splenomegaly, poor appetites, drenching night sweats, and persistent bone pain. QoL endpoints should also be incorporated into drug therapies and their approvals. Similar to myelofibrosis, where spleen volume reduction and total symptom score improvements have led to the approval of Janus kinase inhibitors, we need to explore therapies and these endpoints in CMML too. HMAs do not modify the biology of the disease. Even if the disease goes into remission, it has not gone away. If we cannot get patients access to treatments that change the biology of the disease, we should be working to find treatments that allow them to live with dignity.
Additionally, when looking at ways to improve survival, given that this is a disease of aging, we must find ways to reduce toxicity and improve tolerability. It is important to note that I am not sure we even know how best to dose azacitidine and decitabine. We are dosing them like cytotoxic chemotherapy, while a lot of their response mechanisms are epigenetic in origin. We need to revisit the dosing of these drugs and ensure that rational approaches are chosen that optimize efficacy and minimize toxicity.
We must revolutionize our approach. We must look at survival endpoints and QoL endpoints and then present data to regulatory agencies, showcasing that these must be considered for CMML-related drug approvals.
Dr. Kotsianidis: I agree. We need to do more basic research on these issues and also perform CMML-specific trials. CMML is a different disease and cannot be lumped with MDS.
Dr. Patnaik: This is music to my ears. It is difficult to find funding for CMML,* and drug companies do not want to work on CMML because it’s a rare disease. We can’t keep grouping patients living with CMML with those living with MDS and including them in MDS trials. Biologically, these are very different entities. Rare diseases are not rare for those afflicted by them, and I can assure all patients living with CMML that I will work with my colleagues to make sure that we do justice to the field.
Dr. Kotsianidis: Yes, it’s time for this disease to be a separate disease in trials and not only in classifications.
*Note: The Leukemia and Lymphoma Society recently launched a CMML Special Initiative to fund research into CMML. More information is available at www.lls.org/research/cmml-special-initiative.
- U.S. Food and Drug Administration. VIDAZA (azacitidine for injection), for subcutaneous or intravenous use. Initial U.S. Approval: 2004. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/050974s034lbl.pdf.
- U.S. Food and Drug Administration. FDA approves new therapy for myelodysplastic syndromes (MDS) that can be taken at home. July 7, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-new-therapy-myelodysplastic-syndromes-mds-can-be-taken-home.
- Fenaux P, Mufti G, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223-232.
- Silverman LR, Demakos E, Peterson BL, et al. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002;20(10):2429-2440.
- Itzykson R, Santini V, Thepot S, et al. Decitabine versus hydroxyurea for advanced proliferative chronic myelomonocytic leukemia: results of a randomized phase III trial within the EMSCO Network. J Clin Oncol. 2023;41(10):1888-1897.
- Pleyer L, Leisch M, Kourakli A, et al. Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study. Lancet Haematol. 2021;8(2)e135-e148.
- Coltro G, Mangaonkar AA, Lasho TL, et al. Clinical, molecular, and prognostic correlates of number, type, and functional localization of TET2 mutations in chronic myelomonocytic leukemia (CMML) – a study of 1084 patients. Leukemia. 2020;34(5):1407-1421.
- Bejar R, Lord A, Stevenson K, et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood. 2014;124(17):2705-2712.
- Santini V, Allione B, Zini G, et al. A phase II, multicentre trial of decitabine in higher-risk chronic myelomonocytic leukemia. Leukemia. 2018;32(2):413-418.
- Drummond MW, Pocock C, Boissinot M, et al. A multi-centre phase 2 study of azacitidine in chronic myelomonocytic leukaemia. Leukemia. 2014;28(7):1570-1572.
- Carr RM, Vorobyev D, Lasho T, et al. RAS mutations drive proliferative chronic myelomonocytic leukemia via a KMT2A-PLK1 axis. Nat Commun. 2021;12(1):2901.
The following positions were assigned to the participants and do not necessarily reflect ASH opinions, the participants’ opinions, or what they do in daily practice.
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