Molecular Pathogenesis of Chronic Myelomonocytic Leukemia and Potential Molecular Targets for Treatment Approaches

Abstract

Numerous examples in oncology have shown that better understanding the pathophysiology of a malignancy may be followed by the development of targeted treatment concepts with higher efficacy and lower toxicity as compared to unspecific treatment. The pathophysiology of chronic myelomonocytic leukemia (CMML) is heterogenous and complex but applying different research technologies have yielded a better and more comprehensive understanding of this disease. At the moment treatment for CMML is largely restricted to the unspecific use of cytotoxic drugs and hypomethylating agents (HMA). Numerous potential molecular targets have been recently detected by preclinical research which may ultimately lead to treatment concepts that will provide meaningful benefits for certain subgroups of patients.

Multistep pathogenesis of chronic myelomonocytic leukemia in patients

“…We have shown that spontaneous formation of CFU-GM is a functional surrogate parameter of RAS-pathway activation. [10][11][12] The spontaneous formation of CFU-GM in normal individuals (median 4.8/10 5 PBMNC, range 3.5-8.5) has been reported by us previously. 13 As shown in Figure 3, growth factor-independent myeloid colony formation was significantly increased in cohort TSN vs. TS and T, respectively (0.018), but there was no difference between TS and T, respectively (p = .218).…”

“…We did this to get a sufficient patient number for the third cohort. In fact, the median number of mutations was 5 [3][4][5][6][7][8][9][10][11][12][13] in this group. This represents the real-life situation since some reports have indicated that more advanced CMML shows a higher number of mutations than less advanced disease.…”

“…We have shown that spontaneous formation of CFU‐GM is a functional surrogate parameter of RAS‐pathway activation 10–12 13 .…”

“…We recently were able to show that growth factor‐independent CFU‐GM formation may be a functional surrogate of RAS‐pathway activation 10–12 26 …”

Real-World Data on Chronic Myelomonocytic Leukemia: Clinical and Molecular Characteristics, Treatment, Emerging Drugs, and Patient Outcomes

“…However, the DACOTA trial [ 52 ] proved that randomized clinical trials are feasible in CMML, and clinical trials in CMML are now ongoing. Enrollment in CMML-specific clinical trials or in exploratory trials of specific tumor biomarkers should be encouraged as the best way to clarify the molecular mechanisms behind CMML and to explore the efficacy of new drugs in this disease [ 22 , 24 , 47 , 65 , 66 ]. Nevertheless, until such time where we have reliable data from clinical trials, studies such as ours, based on real-world data, can provide valuable insight into the CMML mutational landscape and treatment outcomes.…”