WHO-Defined Chronic Myelomonocytic Leukemia-2 (CMML-2) Patients Rapidly Progress to AML Suggesting This Entity Represents a Transitory Clinical State (2019)

Introduction: CMML is a heterogenous myeloid neoplasm with an estimated median overall survival (OS) of 31 months with 20% of patients transforming to acute myeloid leukemia (AML). It is subclassified by the WHO into CMML-0, CMML-1 and CMML-2 based upon bone marrow and peripheral blood blast percentage, with this distinction carrying variable prognostic relevance across published reports. CMML-2 is characterized by 10-19% bone marrow myeloblasts and/or 5-19% peripheral blood myeloblasts. However, whether this represents a distinct clinical entity or a transitional state inevitably leading to AML has not been explored. Methods: CMML patients with baseline disease classification and detailed treatment information were identified from the Moffitt Cancer Center CMML database. Baseline demographic, clinical and molecular information was evaluated. The Kaplan-Meier method was used to determine OS, progression free survival (PFS) and AML transit time, defined as the time from diagnosis to AML transformation. Treatment naïve patients with a baseline diagnosis of myelodysplastic syndrome with excess blasts-2 (MDS-EB2) were identified from an existing MDS clinical database as a comparator. Statistical analysis was performed using Graphpad Prism and SPSS. Results: Between 1/1/2000 and 7/1/2019, 623 patients with a pathologic diagnosis of CMML were identified. The median age was 71 and 68.4% were male. At the time of diagnosis, 356 patients were classified as CMML-0, 156 as CMML-1 and 111 as CMML-2. Median OS was calculated after stratifying patients by WHO category identifying 3 distinct prognostic groups with a median OS of 40 months in CMML-0, 22.4 months in CMML-1 and 14.0 months in CMML-2 (p&lt;0.0001). The rate of transformation to AML was 18.5% in CMML-0, 26.9% in CMML-1 and 42.3% in CMML-2 (p&lt;0.0001) with a median PFS of 37.2, 16.8 and 8.2 months, respectively (p&lt;0.0001). CMML-2 patients transforming to AML had a lower baseline WBC (16.0 vs 27.0, p=0.03), lower baseline monocyte count (2.86 vs. 4.8, p=0.02) and increased transfusion dependency (63.8% vs. 45%, p=0.04). Comprehensive molecular data was available in a subset of patients with no mutations statistically different, although a trend toward a higher frequency of EZH2 (21.1% vs. 4.4%, p=0.15) and SETBP1 (11% vs. 0%, p=0.19) mutations was observed in patients that transformed. No differences in NPM1 mutation were observed in CMML-2 transforming cases (4 vs 3 cases). In patients with CMML-2 who progressed to AML the median time to transformation was 7.5 months (vs. 23.7 months in CMML-0 and 9.5 months in CMML-1, p&lt;0.0001). However, because a large fraction of CMML-2 patients received hypomethylating agent (HMA) therapy, CMML-2 cases were further stratified into those who received HMA (n=61) vs. those who received no treatment (n=30) prior to AML transformation. While no OS advantage was identified with HMA treatment (mOS of 15.4 vs. 13 months, p=0.58), untreated patients displayed an extremely high rate of AML transformation (66.3% vs. 36.1%, p=0.02), a shorter PFS (2.8 vs 12.2 months, p&lt;0.0001) and transit time to AML (3.4 vs. 11.6 months, p=0.002). Untreated patients who did not transform were older (median age of 72 vs. 66, p=0.06) with higher ECOG performance status (36% ECOG &gt;2 vs 5.2%, p=0.08) and demonstrated a dismal median OS of 1.9 months. Untreated patients with CMML-2 were then compared to 85 patients with MDS-EB2 who did not receive therapy. While no significant difference in OS was identified, CMML-2 patients had a significantly higher rate of transformation to AML (66.3% vs. 22.3%, p&lt;0.0001) and inferior PFS (2.8 vs. 5.1 months, p=0.0008). Conclusion: Subclassification of CMML by the WHO system based on bone marrow and peripheral blood blast content effectively stratifies patients into three groups with a distinct risk of AML transformation, PFS, and OS. Untreated CMML-2 patients display a rapid and extremely high rate of transformation supporting a transitional phase to AML. Further, the majority of untreated CMML-2 patients that did not pathologically transform had a particularly poor prognosis clinically consistent with aggressive AML. This is distinct from patients with MDS-EB2 in whom the risk of AML transformation and PFS were far lower. HMA effectively reduced the risk of AML transformation, PFS, and significantly delayed transit time to AML. Disclosures Sallman: Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Sweet:Stemline: Consultancy; Celgene: Speakers Bureau; Jazz: Speakers Bureau; Incyte: Research Funding; Pfizer: Consultancy; Abbvie: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees. Kuykendall:Celgene: Honoraria; Incyte: Honoraria, Speakers Bureau; Janssen: Consultancy; Abbvie: Honoraria. Talati:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Speakers Bureau; Pfizer: Honoraria; Celgene: Honoraria; Agios: Honoraria. List:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lancet:Agios, Biopath, Biosight, Boehringer Inglheim, Celator, Celgene, Janssen, Jazz Pharmaceuticals, Karyopharm, Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Other: fees for non-CME/CE services . Komrokji:celgene: Consultancy; pfizer: Consultancy; DSI: Consultancy; Incyte: Consultancy; Agios: Consultancy; JAZZ: Consultancy; Novartis: Speakers Bureau; JAZZ: Speakers Bureau.