Perspectives on drug development in chronic myelomonocytic leukemia: changing the paradigm

The past decade has witnessed a surge of therapeutic advances in oncology, driven largely by the development of immuno-oncology approaches and targeted therapies.¹ Despite this, drug development has not been equitable across disease states, with advances often concentrated in specific areas while others remain stagnant. Chronic myelomonocytic leukemia (CMML) is a representative example, with recent successes in related myeloid neoplasms, such as acute myeloid leukemia (AML), failing to translate to improvements in this myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) of lesser incidence. However, CMML incidence is predicted to increase due to more permissive diagnostic criteria by both the World Health Organization (WHO) and the International Consensus Classification (ICC).^2,3 Since 2017, the US Food and Drug Administration (FDA) has approved 13 drugs across MDS and AML indications, with just 1 oral decitabine/cedazuridine, extending to CMML. A variety of challenges, such as significant clinical heterogeneity, evolving disease classification, and the unique biology of the disease, have hindered drug development, resulting in no therapies that have clearly demonstrated disease-modifying potential specific to CMML.^2,3 To address these barriers, the FDA convened a “Mini-symposium on CMML: Current State of the Art and Trial Design” in September 2023. A panel of academic physicians with expertise in CMML preclinical and clinical drug development were invited to engage with the FDA and a patient representative of topics relevant to drug development in CMML. Herein, we summarize the key topics of discussion from this symposium, review the challenges that have limited drug development for this rare disease to date, and provide perspectives to guide future research.

The current model of drug development in CMML is largely based on the appropriation of drugs studied and used in patients with MDS, with most treatment pathways mirroring those in patients with MDS or MPNs. To date, 3 agents have been approved for the treatment of CMML in the United States: azacitidine (2004), decitabine (2006), and decitabine/cedazuridine (2020). All 3 are hypomethylating agents (HMAs), the last an oral formulation pharmacologically equivalent to parenteral decitabine. These agents were approved based on studies that predominantly enrolled patients with MDS, with only a small subset of patients with CMML included.^4-7 Smaller single-arm studies and real-world data have confirmed the clinical activity of these agents in CMML; however, the recent phase 3 DACOTA study failed to show an improvement in event-free survival in patients with advanced proliferative CMML treated with decitabine compared with hydroxyurea, and there are no convincing data that demonstrate that HMAs substantially alter the course of the disease.^8-13 Notably, DACOTA was only the second phase 3 study ever performed exclusively in patients with CMML. The first phase 3 study was performed 30 years earlier, demonstrating the superiority of the control arm hydroxyurea over etoposide in patients with advanced proliferative CMML.¹⁴ Moreover, no phase 3 study designed specifically for CMML has ever been performed in the United States.

Disease-specific clinical trials have been scarce due to a variety of challenges, including the rarity and heterogeneity of CMML and the historical lack of understanding of disease biology. This has left the standard therapy for CMML relatively unchanged over the past 15 years. Allogeneic stem cell transplantation is the only therapeutic modality known to have disease-modifying potential, although its curative potential is far from universal.¹⁵ Nevertheless, several early phase studies have been performed in recent years evaluating agents such as ruxolitinib, lenzilumab, tipifarnib, and tagraxofusp, specifically in the CMML population (Table 1).^16-19 These studies provide enthusiasm that there is capacity to change the current dogma and establish a new framework for drug development in CMML.

A variety of challenges have hindered advancements in CMML, with issues both unique to the disease and those reflecting broader challenges in the field. Key factors at the root of many disease-specific challenges include the evolution of CMML classification, heterogeneous clinical features, and a low incidence of the disease.

Despite the initial descriptions of CMML dating back to 1937, for decades, it was classified simply as a subtype within MDS.²¹ Only recent versions of the WHO and ICC classifications have classified CMML as a unique disease within the MDS/MPN category of myeloid neoplasms, with updates to the diagnostic criteria as recently as 2022.^2,3 Undoubtedly, this lack of recognition as a distinct entity has had untold repercussions on CMML drug development. The previously discussed historical treatment paradigm is at least in part a demonstration of this. Yet even since the updated classifications have been in place, CMML-specific trials have been limited, likely reflecting the lingering impacts of this historical classification. Indeed, in many aspects, CMML has been difficult to “detach” from MDS and is still viewed by many as analogous to MDS. This is evident at research conferences and even in the National Comprehensive Cancer Network guidelines, where CMML has been grouped within MDS sessions and guidelines. In clinical practice, patients with CMML are often incorrectly labeled as having MDS due to misdiagnosis or under-recognition, which limits their ability to define CMML incidence and identify these patients for incorporation into clinical trials or real-world studies. Until CMML is properly recognized and viewed as a unique disease by the broader community, this will continue to hinder advancements.

Biologically, a relatively limited understanding of CMML persists, particularly in relation to disease initiation and drivers of progression. This renders the identification of novel candidate therapies, and even the appropriate time at which to initiate therapy, challenging. As a result of this and other factors, no therapies exist that have proven to be disease-modifying for CMML. This itself poses problems for clinical trial design, including the selection of appropriate comparator arms in randomized studies, identifying backbones for combination approaches, and determining appropriate eligibility criteria. Although HMAs are considered by many to be the standard of care for CMML, recent data have challenged this paradigm and their benefits may vary by subgroup. Response rates are modest, ranging from ∼30% to 60% (complete remission ∼10%-20%), and the median overall survival (OS) is ∼18 to 30 months.^8-13 The TET2 mutated/ASXL1 wild-type genotype is associated with improved outcomes, whereas inferior outcomes are observed in patients displaying proliferative features, differences not always considered when determining whether arms of clinical trials are balanced. These data call into question the acceptance of HMAs as the “standard” in the clinical trial setting, as it relates to the selection of comparator arms and eligibility criteria regarding the requirement of prior therapies.

Aligning with its classification as an MDS/MPN, colloquially referred to as “overlap syndromes,” CMML displays significant clinical heterogeneity. This has led to the distinction of 2 CMML subtypes, MDS-CMML and MPN-CMML, which are delineated by white blood cell (WBC) count and display unique molecular biology, clinical features, and outcomes.^2,22 MDS-CMML, defined as WBC <13 × 10⁹/L, typically manifests with peripheral blood cytopenia and related symptoms, whereas MPN-CMML, defined by WBC ≥13 × 10⁹/L, is typified by proliferative features such as leukocytosis, splenomegaly, and constitutional symptoms. These disparate presentations can prove challenging in drug development and trial design and support the need for a more clinically rigorous CMML classification that takes the clinical heterogeneity of the disease into account. A drug designed to improve cytopenias may prove effective in MDS-CMML while having little efficacy in MPN-CMML. Indeed, many historical MDS trials that have included patients with CMML have excluded patients with MPN-CMML. The logical decision to restrict by subtype in trials only further limits the number of eligible patients with an already rare disease. This is similarly a challenge for clinical trials using molecularly targeted therapies, where the eligible patient pool will be limited, and these trials are further hindered by the lack of FDA-approved molecular assays required to identify such patients.

Risk stratification is complex in CMML, with at least 10 prognostic systems developed over the last 2 decades.^23,24 Initial systems were those developed largely in MDS, with expected limitations in capturing the unique clinical course of patients with CMML. Several disease-specific systems have now been developed, but none has proven superior, and intrapatient heterogeneity in risk group assignment is often observed between these systems.²⁵ Three disease-specific models incorporating molecular data have more recently been developed, but their performance has not been compared.^26-28 There remain unanswered questions in how to best risk stratify patients with CMML and the lack of uniformity across the CMML community, which poses challenges to clinical trial patient selection.

The appropriate selection of end points and response definitions has also proven difficult, with clinical heterogeneity as a contributing factor. Historically, MDS response criteria have been used in these predominantly MDS studies, but this fails to capture the potential benefits across this unique disease, particularly in patients with MPN-CMML. MDS/MPN-specific response criteria have been proposed but require validation and could likely be further improved.²⁰ Questions remain if these would be sufficient in a registrational phase 3 study in CMML. A modified version of the MDS/MPN International Working Group response criteria was used for the approval of pemigatinib in myeloid/lymphoid neoplasm with fibroblast growth factor receptor 1 (FGFR1) rearrangement but has not yet been used as part of an approval for the treatment of CMML.²⁹ Symptom responses are captured in these criteria and may be a key goal of therapy for some patients with CMML. However, validated measures are important to reproducibly quantify these subjective benefits, and disease-specific patient-reported outcome (PRO) metrics have not been developed. PROs developed in MPNs have been used, but due to differences in biology and clinical presentation (eg, pruritis is common in MPNs but rare in CMML), they may not adequately capture the benefits of CMML. Biologically relevant exploratory end points to support therapeutic activity are also challenging to assess given the incomplete understanding of complex cytokine networks and clonal hierarchy in CMML. Lastly, the absence of drugs with proven disease-modifying capacity renders the selection of early surrogate end points that accurately predict improved OS nearly impossible.

There are additional considerations that relate to the field as a whole. Cancer centers face a variety of challenges, from financial constraints to resource limitations, and have been further strained because of the COVID-19 pandemic. Clinical trials with lower anticipated accruals, such as those in rare diseases, may be deprioritized and declined altogether due to these constraints. This extends to industry partners who may decline to sponsor scientifically sound research due to perceived economic factors or other impacts, amplifying the need for academic clinical trials in CMML. Federal funding in the United States is increasingly difficult to obtain with a continued decline in total funding now nearing a 25-year low.³⁰ Although such challenges are not unique to this disease, they often disproportionately impact rare diseases such as CMML and further potentiate the challenges already posed.

Historical stagnation in CMML drug development and, by extension, patient outcomes require calculated changes to increase the armamentarium of therapies for this disease. Although significant hurdles remain, the panel feels there is optimism that this can be achieved. Rare myeloid diseases, such as chronic myeloid leukemia, primary myelofibrosis, and even systemic mastocytosis, have seen considerable breakthroughs in recent years. Although historical pessimism exists regarding the feasibility of CMML-specific clinical trials, recent years have shown the fallacy of this belief, with several disease-specific trials completed and reaching target accrual.^16-19 Although not performed in the United States, the phase 3 DACOTA trial (n = 170 patients) further demonstrates the ability to complete such trials in this disease, though such studies are challenging and innovative study designs are warranted.¹³ Looking to the future, the gold standard in CMML drug development will need to be that of disease-specific trials evaluating biologically rationale therapies (Table 2).

Building on recent momentum will be key to helping establish a blueprint for drug development in CMML, which has not truly existed to date. Importantly, several key historical challenges are becoming more myth than fact. These include the notion that CMML diagnosis is ambiguous. Although better recognition is required in wider practice settings, the CMML classification is now well defined, with both the WHO and ICC publishing updated diagnostic criteria in 2022 and even softening the monocyte threshold. This should allow for easier diagnosis and classification of such patients, and identification of a broader population to enroll in trials. Risk stratification has also evolved and improved, with disease-specific models incorporating genomic data that are now available and recognized as the current standard. Although questions regarding the optimal model to be used in trials remain, efforts are ongoing to develop a superior model to use in future research. Lastly, MDS/MPN response criteria have been developed that more robustly capture clinical benefits in patients with CMML than prior MDS-biased models and should be favored in clinical trials.²⁰ 

To truly move the field forward, broader recognition of the distinct biology and clinical outcomes of patients with CMML will be required. This includes the unique and clinically meaningful biology of clonal classical monocytosis, its differentiation capacity to macrophages, and the intersection of these factors with autoimmune symptomatology, which is often associated with CMML.^31-33 The historical dogma of simply extrapolating work from MDS to CMML needs to be minimized unless a clear biologic rationale for investigating a drug in CMML exists. The panel supported, even in such cases, that disease-specific trials should be the standard. The common exercise of simply including small cohorts of patients with CMML in MDS trials does little to move the field forward, and further upholds this historical dogma.

Clinical success in other rare diseases has followed key scientific breakthroughs. Indeed, stronger investment in preclinical investigation will be required to advance our understanding of CMML and identify therapeutic targets that have true disease-modifying potential. Within clinical trials, thorough correlative studies should be designed to enhance our understanding of the disease and candidate agents. A key to success in rare diseases, particularly evident in pediatric oncology, has been the commitment to treat all patients in a clinical trial. Given the lack of effective therapies or a true standard of care for CMML, a similar commitment will be key to progress.

Careful attention to appropriate clinical trial design, early involvement, and discussion with the FDA is recommended to optimize drug development. Trials should be as simple and broad as possible to allow for successful study execution and more rapid patient accrual. In early phase studies, adaptive trial designs could be considered to optimize dose selection more rapidly and identify early futility.³⁴ This is particularly critical in a rare disease such as CMML, to maximize resources. Moreover, drugs being repurposed from other settings should draw from lessons learned in prior trials to maximize efficiency. Careful consideration regarding the target population and eligibility criteria is important so as not to overly restrict the number of potential patients in an already-limited patient pool. This poses some challenges given the clinical heterogeneity and distinct subtypes observed in CMML. The panel discussed the inclusion of a broad CMML population when feasible, limiting trials to a specific subgroup only when preclinical or early clinical activity supports that the efficacy will be restricted to that setting. Indeed, given the distinct biologic features of CMML subtypes, this may be necessary in some studies when there is a clear rationale to do so. This is especially true in the case of future studies aimed at repurposing approved targeted agents from other myeloid malignancies.

To capture clinical benefit with investigational agents, prudent selection of end points is required. Early phase studies could target the identification of a dosage(s) that maximizes not only efficacy but also safety and tolerability, that is, an “optimal dosage,” as opposed to the “maximum tolerated dose,” using the totality of pharmacokinetic, pharmacodynamic, safety, and exposure-response data.³⁵ As previously noted, MDS/MPN response criteria have been developed. Although the validation of these criteria using data from prospective trials is warranted, the clinical benefits are more broadly captured with these criteria. Thus, the MDS/MPN response criteria should be used in CMML clinical trials over the MDS response criteria, which do not fully account for the unique manifestations of CMML. Of note, marrow responses are included in these criteria and critical consideration and evaluation of associated outcomes is needed given the lack of benefit that has been demonstrated in other myeloid diseases with strictly marrow response.³⁶ These criteria do not have a category for stable disease and do not account for effective cytoreduction or improvement of autoimmune symptomatology, which may be important goals in highly proliferative CMML and patients presenting with associated systemic inflammatory and autoimmune diseases, respectively.³⁷ PRO measures should be considered in all CMML studies given the symptomatology patients experience and the potential impact on quality of life. Standardized metrics can corroborate clinical benefit and are vital from the patient perspective; however, no CMML-specific PROs currently exist. Until such a metric was developed or clearly validated in CMML, the MPN symptom assessment form has been the most widely used to date.

In later-phase studies, particularly in registrational trials, OS remains a key end point. However, event-free survival may be an alternative in CMML, given the high rate of AML transformation and the clinical relevance of AML transformation regarding prognosis. Earlier surrogate end points are needed but are not clearly defined in CMML due to a lack of agents proven to prolong survival. Complete remission is perhaps the most impactful early end point, but prospective studies could continue to evaluate and identify surrogate end points of survival and disease progression to be used in future research.

The role of HMAs in drug development is complex. Although clinical responses are seen and they have become the de facto standard of care, this is in part due to their position as the only therapies currently approved for CMML. FDA approval was based on studies predominantly on patients with MDS, and the subpopulation of CMML in these trials was small, limiting the interpretability of the results. Disease modification has not yet been clearly demonstrated in the patient population with CMML. Consequently, prior HMA therapy as a qualification for clinical trial enrollment may be necessary only when there is a clear reason to do so. Otherwise, the informed consent document would include a discussion of the risks and benefits of therapies that a patient may be foregoing to participate in the clinical trial, including HMA therapy. Likewise, investigational agents need not be combined with HMA simply as a matter of course and should be combined only when preclinical or prior clinical rationale exists. The disappointing results from numerous HMA combination approaches observed in MDS in recent years reinforce the need for careful consideration of the use of HMA in combination trials of MDS/MPNs. The selection of comparator arms in randomized studies also needs to be taken into consideration. Although HMA may be appropriate for some studies, this should not be viewed as a requirement given the current data on HMA therapy, particularly in proliferative CMML. Studies evaluating patients with MDS-CMML may be more appropriate for the use of HMA as a “standard of care” in the clinical trial setting.

Importantly, close collaboration within the CMML community will be vital to bring novel therapies from “bench to bedside.” Multicenter clinical trials are essential to adequately accrue patients in this rare disease. Collaboration with industry partners to develop novel agents is necessary and will require ongoing demonstration of the dire clinical needs. Likewise, efforts to expand our knowledge of CMML using real-world data will require partnerships between centers with expertise. Real-world data are a valuable tool to aid drug development and determine whether a phase 2 efficacy signal may warrant a randomized study, but the panel supported that this should not be used in lieu of a randomized definitive study.

There is a critical need for novel therapies with the ability to improve outcomes in CMML. Although there are significant challenges in drug development for this rare disease, the ability to carry out disease-specific trials and establish a new blueprint in CMML has been demonstrated. Cross-center academic, FDA, patient advocate, and industry collaboration, as well as a commitment to treating patients in clinical trials, will be vital to success. There are numerous considerations in clinical trial design that have been reviewed, and early discussion with the FDA is recommended to effectively move trials forward.

This publication reflects the views of the authors and should not be construed to represent the views or policies of the US Food and Drug Administration.

Contribution: E. Pulte and E. Padron conceptualized and chaired the symposium; A.M.H. and E. Padron wrote the manuscript; all authors participated in the symposium and provided input on the topics of discussion; all authors reviewed and edited the manuscript, and the final manuscript reflects the consensus opinion of all the authors; and all the authors approved the final manuscript.

Conflict-of-interest disclosure: A.M.H. has received honoraria from GlaxoSmithKline, Cogent Biosciences, PharmaEssentia, Blueprint Medicines, and CTI BioPharma and declares research funding from Incyte, Cogent Biosciences, Ascentage Pharma, Blueprint Medicines, Syntrix Biosystems, Novartis, and PharmaEssentia. M.M.P. has received research funding from Kura Oncology, Stemline Pharma, Epigenetix, Polaris, and Solu Therapeutics. R.I. has received research support from Novartis, Johnson & Johnson, and AbbVie and declares honoraria (consultancy) from Stemline Pharma, Bristol Myers Squibb/Celgene, and Syndax. R.M. declares honoraria (consultancy) from Novartis, Sierra Oncology, Genentech, Blueprint Medicines, Geron, Telios, CTI BioPharma, Incyte, Bristol Myers Squibb, AbbVie, GlaxoSmithKline, and MorphoSys. Y.L. declared that her spouse had received milestone payments from Selexys-Novartis for licensed patents. E. Padron has received research funding from Bristol Myers Squibb and Incyte, and reports advisory panel roles for Stemline Pharma, Blueprint Medicines, GlaxoSmithKline, Sobi, Bristol Myers Squibb, Taiho Oncology, and Novartis. The remaining authors declare no competing financial interests.

Correspondence: Eric Padron, H. Lee Moffitt Cancer Center, Hematologic Malignancies, 12902 USF Magnolia Dr, Tampa, FL 33612; email: eric.padron@moffitt.org.