PF659 MYELOMONOCYTIC SKEWING IN VITRO DISCRIMINATES SUBGROUPS OF PATIENTS WITH MYELOFIBROSIS WITH A DIFFERENT PHENOTYPE, A DIFFERENT GENOTYPE AND DIFFERENT PROGNOSIS
Authors: K. Geissler, B. Gisslinger, E. Jäger, E. Bogner, E. Fuchs, F. Schischlik, D. Alpar, R. Jäger, R. Kralovics, H. Gisslinger
Journal: HemaSphere (2019)

Background: Normal hematopoietic function is maintained by a well controlled balance of myelomonocytic, megaerythroid and lymphoid progenitor cell populations. This balance may be skewed during pathologic conditions such as hematological malignancies, infections and autoimmunity. Moreover skewed hematopoiesis can be found in aged hematopoiesis. Since semisolid in vitro cultures from peripheral blood mononuclear cells (PBMNC) of normal individuals usually contain a higher concentration of erythroid colonies (BFU-E) as compared to myelomonocytic colony forming units (CFU-GM) this test may be useful for investigating skewed differentiation towards the myelomonocytic over erythroid committment in patients. The role of myelomonocytic skewing in patients with myelofibrosis has not been studied so far. Aims: Our aim was to study the role myelomonocytic skewing in patients with myelofibrosis. Methods: In this retrospective study the frequency of myelomonocytic skewing, its prognostic impact and its correlation to hematologic and molecular parameters was investigated in 104 patients with myelofibrosis in whom semisolid in vitro cell cultures from PBMNC have been performed between 2001 and 2012. In vitro cell cultures have been performed as previously described (Geissler K et al, Blood 1996). Results: Myelomonocytic skewing as indicated by an inverse ratio of BFU-E/CFU-GM was found in 36/104 (35%) patients (as compared to 2/54 [4%] in normal individuals). Patients with myelomonocytic skewing were older (70 years [42–87) vs 64 [21–88], p = 0.0182), had lower hemoglobin levels (9.8 g/dL [7.6–14.3] vs 12.5 [7.7–16.2], p < 0.0001) and platelet counts (224 x 109/L [15–1450] vs 489 [18–1226], p = 0.0019), and higher blast cell counts in PB (1% [0–14] vs 0 [0–8], p = 0.0085) whereas WBC counts were not significantly different (11.9 x 109/L [2.8–59.3] vs 8.54 [1.8–72], p = 0.0672). As shown in Figure 1 the presence of myelomonocytic skewing was associated with a significantly shorter survival (30 vs 123 mo, p < 0.0001). There was no difference between MF-patients with and without myelomonocytic skewing, respectively, with regard to the frequency of MF driver mutations of JAK2 (58% vs 60, p = 0.8928), CALR (29% vs 33, p = 0.7391) and MPL (0% vs 15, p = 0.5360), respectively. A mutational profile investigated by next generation sequencing was available in 39 patients. The frequency of mutations of genes of the splicing and/or epigenetic machinery was higher in patients with as compared to patients without myelomonocytic skewing (69% vs 23%, p = 0.0052).Summary/Conclusion: The results of this study show that the in vitro detection of myelomonocytic skewing can discriminate subgroups of patients with myelofibrosis with a different hematologic phenotype, a different genotype and a different prognosis. Our findings may be important for the understanding and management of myelofibrosis.