Significance of hypergammaglobulinemia in patients with chronic myelomonocytic leukemia

Chronic myelomonocytic leukemia (CMML) is a rare, genotypically and phenotypically heterogenous hematologic malignancy of elderly people with an intrinsic risk to progress and transform into secondary acute myeloid leukemia (AML). With regard to the presence of myeloproliferation, CMML was originally subdivided into myeloproliferative disorder (MP-CMML; white blood cell count [WBC] count > 13 × 10⁹/L) versus myelodysplastic syndrome (MD-CMML; WBC count ≤ 13 × 10⁹/L MD-CMML) by the FAB criteria [1, 2]. Since CMML is characterized by features of both MDS and MPN, the World Health Organization (WHO) classification of 2002 assigned CMML to the mixed category, MDS/MPN [3]. CMML is further subclassified by WHO into three groups based on blast equivalents (blasts plus promonocytes) in peripheral blood (PB) and bone marrow (BM) as follows: CMML‑0 if PB < 2% and BM < 5% blast equivalents; CMML‑1 if PB 2–4% or BM 5–9% blast equivalents; and CMML‑2 if PB 5–19% or BM 10–19% blast equivalent, and/or Auer rods are present [4]. CMML patients may have a highly variable outcome, suggesting that several factors can determine the course of disease and the cause of death in these patients [5‐9]. There are a number of established prognostic parameters that have been incorporated into several prognostic models [10‐21]. In clinical practice, chronic inflammation is often indicated by a relative increase in the gamma globulin fraction of the electrophoresis. The potential contribution of chronic inflammation to the clinical outcome of CMML patients is poorly investigated. Using the database of the Austrian Biodatabase for Chronic Myelomonocytic Leukemia (ABCMML), we analyzed 60 CMML patients in whom serum electrophoresis was available in patient records.

Serum electrophoresis is an excellent tool for analyzing the inflammation status in patients. In the early phase of acute inflammation, the α1 and α2 fractions are increased, whereas changes in albumin and the γ fraction are not regularly seen [25]. In the late phase of acute inflammation, the serum albumin starts to decrease and the γ fraction to increase. Chronic inflammatory disorders are characterized by increased gamma globulins and by decreased serum albumin, whereas the α1 and α2 fractions are not altered anymore.

Since serum electrophoresis is not routinely performed in myeloid disorders, it was available in only a subgroup of patients in our ABCMML database. In these patients, we have seen relative polyclonal hypergammaglobulinemia in 42%. There was a clear inverse correlation to albumin levels, indicating opposite changes of gamma globulins and albumin in chronic inflammation. In a subgroup of patients, α1 and/or α2 fractions were increased in the electrophoresis, suggesting a persistent acute-phase pattern in these patients.

The mechanism behind hypergammaglobulinemia in CMML patients remains to be determined. Polyclonal hypergammaglobulinemia has already been described in previous series of patients with CMML [26]. We have looked for possible correlations of hypergammaglobulinemia with phenotypic and molecular features. Regarding laboratory features including leukocyte count, hemoglobin value, platelet value, and circulating blasts, we could not find any differences in patients with or without hypergammaglobulinemia, indicating that the mechanisms leading to changes in these parameters are different from the mechanism leading to hypergammaglobulinemia. Regarding molecular parameters, we observed an association of hypergammaglobulinemia and molecular aberrations of the NRAS and ZRSFR genes. These findings are unexpected, but have to be considered with caution due to the small number of CMML patients who had molecular analysis. However, in this context, it has to be mentioned that recently, a functional link between molecular aberrations and activation of the inflammasome was reported in a preclinical model [27]. In this mouse model, Kras-driven myeloproliferation was reversed by functional inactivation of NLRP1, a major component of the inflammasome. A similar phenotypic improvement was seen with therapeutic IL‑1 receptor blockade.

Most strikingly, patients with hypergammaglobulinemia had inferior survival as compared to CMML patients without hypergammaglobulinemia. This adverse impact on survival was found in univariate analysis and was retained in the multivariate analysis in the presence of thrombocytopenia, which was the only adverse blood parameter, indicating that the pathophysiologic basis for the two alterations are different. In larger series, all parameters including leukocytosis, anemia, thrombocytopenia, and circulating blast cells are established prognostic parameters. The lack of prognostic impact of these parameters, except thrombocytopenia, is most likely the result of the small patient cohort in this study. Therefore, the prognostic impact of hypergammaglobulinemia in this study deserves even more attention. There is clear evidence in the literature that IL‑6 is one of the main stimulatory factors of IgG production [28, 29]. On the other hand, it has been shown that CMML cells can produce IL‑6 in vitro and stimulate CMML cell growth in an autocrine manner [30]. One attractive hypothesis of our exploratory findings could be that IL‑6 may provide a common basis for hypergammaglobulinemia and the adverse outcome in these patients. This hypothesis must be further explored in future studies.

We are aware of the limitations of our study. For example, most of the information used in this study was derived from retrospective real-world data that were not collected systematically or prospectively. Thus, not every parameter was available in all patients. In addition, data from patient records were obtained over many years and from many different centers. Moreover, the patients included in this study were a relatively heterogenous population regarding the blast cell counts, and there was a lack of molecular data in a significant number of patients. However, real-world data have recently been recognized as an important way to get insights into the routine management and natural history of rare diseases [31]. CMML is a rare disease and adequate patient numbers for a systematic and prospective study are not easy to collect within a limited timeframe. Moreover, the ABCMML provides information derived from molecular as well as from functional studies and therefore allows a more comprehensive view and deeper insight into the complex pathophysiology of this hematologic malignancy [22].