The evolving role of hypomethylating agents in chronic myelomonocytic leukaemia

Q. How do you currently define the role of HMAs in the management of CMML?

The approval of HMAs in CMML is based on very few patients enrolled in registrational MDS clinical trials. Dedicated evaluation of HMAs in CMML is largely unsatisfactory. It has also been convincingly demonstrated that HMAs do not significantly impact clonal burden. With these caveats, phase II single arm trial data suggest there is significant response rates with HMAs. Additionally, recent data from the UK based phase II AMMO trial (ISRCTN30808508) show that oral HMAs improve survival in patients with CMML (as well as other MDS/myeloproliferative neoplasm (MPN) overlap syndromes). Therefore for many patients, I still consider HMAs an integral part of treatment.

Q. Which CMML subtypes – myelodysplastic, myeloproliferative – derive the greatest benefit from HMAs in your experience?

Select patients in both can derive benefit, but I would consider HMAs more strongly in myelodysplastic subtype patients who have cytopenias that may be ameliorated with HMAs.

Q. What are the current limitations of the use of HMAs in CMML?

Randomized data from the phase III DACOTA trial (NCT02214407) suggest no survival benefit with decitabine as compared to hydroxyurea, although this was somewhat contradicted by the recently presented AMMO trial showing survival advantage with oral decitabine. These discrepancies may be explained by the oral administration of HMAs in the AMMO trial. However, the main limitation of HMAs in CMML is their lackluster responses and ability to significantly control disease evolution, as well as target more proliferative symptoms of the disease.

Q. How do treatment goals differ between younger, transplant-eligible patients and older or frail individuals?

CMML is incredibly heterogeneous, so it is important to understand treatment goals to design the best therapeutic strategy. Transplant is the only curative modality for the treatment of CMML, so this should be a goal in the appropriate higher risk patient. In older patients who are not eligible for transplant, the goals are diverse and include decreasing transfusion burden as well as improving symptoms or splenomegaly. Ultimately, treatments should also be aimed and preventing the disease from progressing and increasing lifespan.

Q. Do you see a future role for HMA-based combinations?

I do see a role for HMA based combinations. Venetoclax has been demonstrated to improve responses, but does not significantly improve survival in retrospective studies. JAK inhibitors are a compelling approach as they can impact the proliferative signs of the disease (e.g. splenomegaly, constitutional symptoms) and, in general, do not have significant overlapping toxicities.

Q. Which novel agents or combinations in development for CMML are you most excited about?

Thankfully there has been accelerating novel therapeutic development in CMML over the last five years. Some examples of promising agents include JAK inhibitors, such as pacritinib, which may be better suited towards CMML compared to ruxolitinib. HMA combinations with IO-202 (which targets LILRB4) and lenzilumab (which targets GM-CSF) have shown encouraging efficacy in early phase trials.

Q. What do you see as the greatest unmet need in CMML treatment today?

The biggest unmet need in CMML is for specifically designed treatments that can alter the disease course. Presently available therapies are borrowed from related, but distinct, diseases including MDS and MPN. The next generation of therapeutics are being designed specifically to treatment CMML and leverage expanding knowledge of the pathobiology of this disease to significantly improve disease control and ultimately survival.