Characterization of Indolent Chronic Myelomonocytic Leukemia Phenotypes and Identification of Dynamic Disease Features of Progression and Need for Treatment
Authors: Aguirre Luis E. , Ball Somedeb , Jain Akriti G , Al Ali Najla , Sallman David A. , Kuykendall Andrew T. , Sweet Kendra , Lancet Jeffrey E. , Padron Eric , Komrokji Rami S. 
Published: November 2021

Abstract
Background
CMML is a markedly heterogenous clinical entity exhibiting features innate to both, myeloproliferative neoplasms (MPN) and myelodysplasia (MDS). Generally associated with poor outcomes, median overall survival (mOS) is 3 years (yrs). Multiple prognostic models consider cardinal clinical, cytogenetic and molecular features critical in estimating individual risk and outlining treatment. Identification and longitudinal assessment of features of interest become important to predict which patients tend to have a more indolent course compared to those who will progress.
Methods
Clinical and molecular data was collected retrospectively from a proprietary database of 729 patients with CMML treated at Moffitt Cancer Center (MCC). Pts were stratified into 2 cohorts: those remaining in observation for &gt;3 yrs (indolent CMML) and those who required treatment &lt;3 yrs after presentation (NI-CMML). Treatment-naïve pts lost to f/u within 3 yrs were excluded. For those pts with indolent disease who required treatment eventually, we aimed to identify changes in clinical and molecular features from baseline immediately anteceding the need for treatment to establish whether they predicted evolution of disease. Marrow features were examined at baseline and at specific time intervals prior to the initiation of therapy.
Results
Between August 1995 and October 2020, 729 pts with a diagnosis of CMML were identified at MCC. Out of these, 68.3% (498) were male and 88.5% (645) were Caucasian. Median age at diagnosis was 71 (17-95). A total of 123 pts (17%) did not require treatment within 3 yrs of diagnosis. mOS was 70 mo among those who did not require early treatment compared to 25 mo for those who did (p&lt;.001).
Clinically, higher platelet count at baseline was associated with longer time to treatment (p=0.022). Elevated WBC (proliferative CMML), lymphocytes, monocytes, ANC, marrow blasts and cellularity, as well as low baseline Hb were associated with earlier initiation of treatment (p&lt;.005). Pts not needing immediate treatment had lower risk disease by IPSS, R-IPSS and all CMML risk models (Table 1).
JAK2, SF3B1 and IDH2 mutations were associated with more indolent course obviating the need for intervention within 3 yrs (p&lt;.005). NRAS portended a more aggressive course (p=0.004). Pts harboring ASXL1 showed a trend towards early progression (p=0.067) (Table 2).
Of the 123 pts with indolent disease, 37.4% (46) required intervention at some point. Need for treatment was secondary to worsening clinical symptoms and/or cytopenias in most cases. From a molecular perspective, 7 of the 46 pts had NGS assessment prior to and after starting treatment for comparison of clonal evolution.
Interestingly, pts with indolent CMML who progressed differed from baseline compared to those with static disease: they tended to harbor CBL (p=0.005), U2AF1 (p=0.022) and ETV6 mutations (p=0.05).
Histopathologically, the presence of ALIP (abnormally localized immature precursors), when reported, was an important feature in a significant number of cases needing treatment (77.8%, n=7), that was not present early in the course of the disease. Presence of ALIP prompted initiation of treatment and mirrored clinical decline. Also, changes in the M:E ratio from baseline always heralded abnormality, but whether that ratio was abnormally high or low was irrelevant and merely a reflection of the underlying pathophysiology (proliferative vs dysplastic). Change was synonymous with abnormality and was more prominent 1 month prior to treatment.
From a molecular standpoint, clonal evolution mirrored the need to start treatment usually in the form of new mutations: 5 (71.4%) of cases developed new or additional TET2 mutations, 2 (28.6%) gained EZH2 mutations, 1 ABL1 and yet another developed multiple mutations in TET2, SRSF2, STAG2 and CBL.
Conclusion
A small subset of CMML patients (17%) have a more indolent disease course associated with better outcomes. Clinical and molecular features at diagnosis can be assessed to identify them. Dynamic changes in M:E ratio from baseline (regardless of direction) and presence of ALIP heralded and/or mirrored clinical decline and need to start or switch treatment. Similarly, gain of mutations mirroring clonal evolution heralded need to start treatment.
Figure 1 Figure 1.

Disclosures
Sallman: Kite: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Incyte: Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kuykendall: PharmaEssentia: Honoraria; Abbvie: Honoraria; Novartis: Honoraria, Speakers Bureau; Prelude: Research Funding; BluePrint Medicines: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Lancet: ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Astellas: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Jazz: Consultancy. Padron: Stemline: Honoraria; BMS: Research Funding; Taiho: Honoraria; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; Geron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees.