How I treat chronic myelomonocytic leukemia

Abstract

Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic malignancy that may deserve specific management. Defined by a persistent peripheral blood monocytosis ≥1 × 109/L and monocytes accounting for ≥10% of the white blood cells, this aging-associated disease combines cell proliferation as a consequence of myeloid progenitor hypersensitivity to granulocyte-macrophage colony-stimulating factor with myeloid cell dysplasia and ineffective hematopoiesis. The only curative option for CMML remains allogeneic stem cell transplantation. When transplantation is excluded, CMML is stratified into myelodysplastic (white blood cell count <13 × 109/L) and proliferative (white blood cell count ≥13 × 109/L) CMML. In the absence of poor prognostic factors, the management of myelodysplastic CMML is largely inspired from myelodysplastic syndromes, relying on erythropoiesis-stimulating agents to cope with anemia, and careful monitoring and supportive care, whereas the management of proliferative CMML usually relies on cytoreductive agents such as hydroxyurea, although ongoing studies will help delineate the role of hypomethylating agents in this patient population. In the presence of excessive blasts and other poor prognostic factors, hypomethylating agents are the preferred option, even though their impact on leukemic transformation and survival has not been proved. The therapeutic choice is illustrated by 4 clinical situations among the most commonly seen. Although current therapeutic options can improve patient’s quality of life, they barely modify disease evolution. Improved understanding of CMML pathophysiology will hopefully lead to the exploration of novel targets that potentially would be curative.

How I investigate chronic myelomonocytic leukemia

“…Such cases should be regarded as “ JAK2 mutated CMML.” Giving these possible scenarios, quantification of JAK2 VAF is pivotal in CMML particularly in cases with overlapping clinical and pathologic features. Moreover, JAK2 mutated CMML may benefit from JAK2 inhibitors …”

“…Of these, ASXL1 mutations are of particular importance as they have been correlated with adverse prognosis and a poor overall survival . Such mutational profile may have clinical repercussions in the near future, as target molecules targeting the RAS signaling pathway and the spicing machinery are under investigation …”

“…Hypomethylating agents represent the most common therapeutic approach in CMML, especially in patients showing relevant cytopenia/s and/or intermediate‐ and high‐risk disease . Cytoreductive therapies (such as hydroxyurea) are instead preferred in case of marked leukocytosis, constitutional symptoms and/or splenomegaly.…”

“…3 Hypomethylating agents represent the most common therapeutic approach in CMML, especially in patients showing relevant cytopenia/s and/or intermediate-and high-risk disease. [4][5][6] Cytoreductive therapies (such as hydroxyurea) are instead preferred in case of marked leukocytosis, constitutional symptoms and/or splenomegaly. Immune and other cell-based therapies remain largely unexplored in CMML, thus providing opportunities for future novel disease-modifying therapies.…”

CMML/JMML PDXs: as easy as 1, 2, NSG-SGM3

“…8 A number of mouse models genetically engineered to harbor mutations common to CMML and JMML have provided important mechanistic insights into disease pathogenesis. 2,3 However, these models lack the tumor heterogeneity inherent to human hematological malignancies. The capacity of xenograft models to recapitulate this heterogeneity opens the door for investigations of clonal hierarchy, including the potential to identify, functionally characterize, and define the underlying molecular drivers of the elusive disease-initiating cells.…”