Chronic Myeloid Neoplasms: Comparison
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Please note this is a comparison between Version 2 by Catherine Yang and Version 1 by THEODOROS KARANTANOS.

Chronic myeloid neoplasms are clonal diseases with variable clinical course and outcomes and despite the introduction of novel therapies, patients with high-risk disease continue to have overall poor outcomes. 

  • myeloid neoplasms
  • sex-related differences

1. Introduction

Chronic myeloid neoplasms represent a broad spectrum of disorders ranging from myelodysplastic syndrome (MDS) characterized by dysplasia in the marrow and cytopenias in the peripheral blood to myeloproliferative neoplasms (MPN) characterized by hyperplasia in the marrow and elevated counts in the peripheral blood. These diseases can lead to failure of normal hematopoiesis or transformation to acute myeloid leukemia (AML). Despite the variability in their pathology and clinical presentation these neoplasms arise from malignant stem and progenitor cells carrying somatic mutations [1]. The cure of these patients is challenging since malignant stem cells are resistant to chemotherapy and can result in relapse following remission even after allogeneic transplantation [2]. The better understanding of the pathophysiology of chronic myeloid neoplasms is a necessity for the development of new therapeutic approaches to improve the survival of these patients.

21. Sex-Related DiffereInces in the Presentation and Outcomes of Patients with Chrtroductionic Myeloid Neoplasms

Chronic myeloid neoplasms represent a broad spectrum of disorders ranging from myelodysplastic syndrome (MDS) characterized by dysplasia in the marrow and cytopenias in the peripheral blood to myeloproliferative neoplasms (MPN) characterized by hyperplasia in the marrow and elevated counts in the peripheral blood. These diseases can lead to failure of normal hematopoiesis or transformation to acute myeloid leukemia (AML). Despite the variability in their pathology and clinical presentation these neoplasms arise from malignant stem and progenitor cells carrying somatic mutations [1]. The cure of these patients is challenging since malignant stem cells are resistant to chemotherapy and can result in relapse following remission even after allogeneic transplantation [2]. The better understanding of the pathophysiology of chronic myeloid neoplasms is a necessity for the development of new therapeutic approaches to improve the survival of these patients.

2. Sex-Related Differences in the Presentation and Outcomes of Patients with Chronic Myeloid Neoplasms

Patient characteristics, such as age, performance status and comorbidities, affect the clinical presentation and outcomes of chronic myeloid neoplasms and have been included in risk assessment tools used in the clinic [3][4]. Various reports have highlighted an independent impact of sex in the presentation and outcomes of these patients [5][6][7]. In this section we will summarize the data from a number of MDS, MDS/MPN, MPN, and chronic myeloid leukemia (CML) cohorts supporting a possible implication of sex in the presentation and outcomes of these diseases.

2.1. Precursor States (CHIP, ICUS, CCUS)

Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the presence of at least one somatic mutation that is relevant clinically and is otherwise found in MDS (or other myeloid neoplasms) without the presence of persistent cytopenias or diagnosis of myeloid neoplasms [8]. Male sex has been associated with a modestly increased risk of CHIP [9] but there is no strong evidence to support that sex affects significantly the outcomes of these individuals [10]. Idiopathic cytopenia of undetermined significance (ICUS) is defined as relevant cytopenia which is persistent for at least 6 months not explained by another disease and clonal cytopenia of undetermined significance (CCUS) is defined as persistent cytopenia for at least 4 months not explained by another disease with the presence of one or more somatic mutations [11]. Individuals with CCUS show a skewed male-to-female ratio [11] but the impact of sex on the outcomes of individuals with these precursor states has not been extensively evaluated.

2.2. MDS

Early data provided evidence that MDS is overall more common in men across various age groups [12] but the role of sex as a prognostic factor for MDS has been only recently highlighted. Nösslinger et al. analyzed 897 MDS patients to evaluate the impact of sex and age in a Cox regression model including R-IPSS score as a variable [13]. They demonstrated that among patients with low and intermediate-1 R-IPSS scores men had significantly worse survival compared to women while there was no significant difference between women and men at higher risk groups [13]. Wang et al. studied the outcomes of 34,681 patients with MDS and showed that male sex is a predictor of worse survival independent of age, race, and sub-type [5]. The authors reported that the negative impact of male sex was significant among patients with refractory anemia, refractory cytopenia with multilineage dysplasia, and MDS with 5q deletion while no significant differences were noted in higher-risk sub-types such as refractory anemia with excess blasts and treatment related MDS [5]. These results indicate an important implication of sex in the outcomes of patients with MDS warranting further evaluation. Based on these data, the introduction of sex as an independent predictor of outcomes in risk assessment tools used in clinical trials and everyday practice is a reasonable consideration.

2.3. MDS/MPN

MDS/MPN overlap syndromes is a heterogeneous group of malignancies with overlapping features of both MDS and MPN showing a male predominance which is more prominent in chronic myelomonocytic leukemia (CMML) [14]. Wang et al. highlighted that among 1666 patients with MDS/MPN syndromes men have worse survival compared to women [5]. Our group recently studied retrospectively the outcomes of 167 patients with MDS/MPN and confirmed that men have worse overall survival independent of the specific disease sub-type (Karantanos et al., under review).

2.4. MPN

MPN are clonal myeloid neoplasms including essential thrombocytosis (ET), polycythemia vera (PV) and myelofibrosis (MF) sharing common driver mutations in the JAK2, CALR or MPL genes but with a notable variability in the clinical presentations and outcomes [15]. For ET and PV it remains challenging to predict which patients are going to progress to MF and for MF patients the acquisition of additional somatic mutations by itself does not fully explain the variability in the incidence of AML transformation and survival outcomes [16].
Sex is an important factor affecting the presentation of patients with MPN. Women have overall a higher prevalence of MPN, they are younger at diagnosis but they predominate in ET while men predominate in PV and PMF [17][6][18]. Interestingly, women tend to develop worsening symptoms especially abdominal discomfort, headaches, dizziness and fatigue with overall higher total symptoms score [17]. Similarly, women have higher incidence of vascular complications and particularly abdominal venous thrombosis [6][19]. Of note, based on a single center study of 84 consecutive MPN cases with splachnic vein thrombosis, 67% of these patients are women and median age at diagnosis is 54 years supporting that abdominal venous thrombosis is particularly common among young women [19]. Given that younger women have higher estrogen levels and the known impact of estrogens on thrombosis development it is possible that this is the underlying mechanism implicated in these differences. On the contrary, men have higher red blood cell transfusion requirements and worsening thrombocytopenia [17]. Barraco et al. showed that men with secondary MF present not only with lower platelets but also bigger spleens, higher percentage of circulating blasts and higher incidence of complex karyotype [20]. These results support that men tend to have more aggressive MPN phenotypes compared to women who are more symptomatic and carry a higher risk of thrombosis.
The impact of sex in the clinical outcomes of MPN patients has been studied by different groups over the last decade. Tefferi et al. analyzed 1494 patients with ET demonstrating that male sex is associated with worse survival independent of patients’ age, leukocyte count and IPSET score [21]. Our group has also found that men with MPN have worse survival compared to women independent of their age at diagnosis, disease sub-type and driver mutation [6]. Moreover, among ET and PV patients, male sex was associated with a more rapid progression to MF independent of age and disease sub-type at diagnosis [6]. Consistently, men with post-ET and post-PV secondary MF have worse survival independent of their age at the time of disease transformation and their disease sub-type at diagnosis [20]. Finally, a recent retrospective analysis of >2000 individuals with MPN showed that male sex is an independent predictor of higher incidence of transformation to MF and worse overall survival for all disease sub-types [22]. These results support an independent impact of male sex in the outcomes of MPN patients suggesting that adding sex to the risk assessment tools that are used in the clinic to predict the outcomes of MPN patients may be needed particularly for ET and PV patients.

2.5. CML

The natural history of CML has been altered significantly following the introduction of tyrosine kinase inhibitors (TKI) with a tremendous improvement of patients’ survival [23]. Given that CML is a molecularly defined neoplasm, significant sex-based alterations in the outcomes would not be expected. However, the review of studies performed in the pre-TKI era reveals interesting sex-related differences in the presentation and outcomes of patients with CML.
Sokal et al. in an early study highlighted that male sex is a negative prognostic indicator independent of spleen size, hemoglobin, levels, platelet counts and percentage of circulating blasts among young (<45 years) patients with CML [24]. Berger et al. analyzed 856 patients with CML and found that women presented with higher platelet counts, and smaller spleen sizes [7]. Moreover, men with CML had a higher incidence of additional chromosomal aberrations and worse survival [7]. This was independent of the risk assessment based on the Sokal score and the difference was more prominent among patients with low and intermediate risk [7]. During the TKI-era, despite that the incidence of TKI switching is higher among women based on data from the SIMPLICITY study [25] there is no strong evidence of sex disparities in the efficacy of TKI with regards to achievement of deep cytogenetic and molecular remissions. Similarly, no sex-related differences in the overall survival of CML patients during the TKI-era have been demonstrated [23][26].
Based on the sex-related differences in the presentation and outcomes of CML patients before the use of TKIs, it could be hypothesized that male sex may be implicated in the acquisition of secondary molecular events driving disease progression.
The observed differences in the presentation and outcomes between women and men with chronic myeloid neoplasms are summarized in Table 1.
Patient characteristics, such as age, performance status and comorbidities, affect the clinical presentation and outcomes of chronic myeloid neoplasms and have been included in risk assessment tools used in the clinic [9,10]. Various reports have highlighted an independent impact of sex in the presentation and outcomes of these patients [5,6,11]. In this section we will summarize the data from a number of MDS, MDS/MPN, MPN, and chronic myeloid leukemia (CML) cohorts supporting a possible implication of sex in the presentation and outcomes of these diseases.

2.1. Precursor States (CHIP, ICUS, CCUS)

Clonal hematopoiesis of indeterminate potential (CHIP) is defined as the presence of at least one somatic mutation that is relevant clinically and is otherwise found in MDS (or other myeloid neoplasms) without the presence of persistent cytopenias or diagnosis of myeloid neoplasms [12]. Male sex has been associated with a modestly increased risk of CHIP [13] but there is no strong evidence to support that sex affects significantly the outcomes of these individuals [14]. Idiopathic cytopenia of undetermined significance (ICUS) is defined as relevant cytopenia which is persistent for at least 6 months not explained by another disease and clonal cytopenia of undetermined significance (CCUS) is defined as persistent cytopenia for at least 4 months not explained by another disease with the presence of one or more somatic mutations [15]. Individuals with CCUS show a skewed male-to-female ratio [15] but the impact of sex on the outcomes of individuals with these precursor states has not been extensively evaluated.

2.2. MDS

Early data provided evidence that MDS is overall more common in men across various age groups [16] but the role of sex as a prognostic factor for MDS has been only recently highlighted. Nösslinger et al. analyzed 897 MDS patients to evaluate the impact of sex and age in a Cox regression model including R-IPSS score as a variable [17]. They demonstrated that among patients with low and intermediate-1 R-IPSS scores men had significantly worse survival compared to women while there was no significant difference between women and men at higher risk groups [17]. Wang et al. studied the outcomes of 34,681 patients with MDS and showed that male sex is a predictor of worse survival independent of age, race, and sub-type [5]. The authors reported that the negative impact of male sex was significant among patients with refractory anemia, refractory cytopenia with multilineage dysplasia, and MDS with 5q deletion while no significant differences were noted in higher-risk sub-types such as refractory anemia with excess blasts and treatment related MDS [5]. These results indicate an important implication of sex in the outcomes of patients with MDS warranting further evaluation. Based on these data, the introduction of sex as an independent predictor of outcomes in risk assessment tools used in clinical trials and everyday practice is a reasonable consideration.

2.3. MDS/MPN

MDS/MPN overlap syndromes is a heterogeneous group of malignancies with overlapping features of both MDS and MPN showing a male predominance which is more prominent in chronic myelomonocytic leukemia (CMML) [18]. Wang et al. highlighted that among 1666 patients with MDS/MPN syndromes men have worse survival compared to women [5]. Our group recently studied retrospectively the outcomes of 167 patients with MDS/MPN and confirmed that men have worse overall survival independent of the specific disease sub-type (Karantanos et al., under review).

2.4. MPN

MPN are clonal myeloid neoplasms including essential thrombocytosis (ET), polycythemia vera (PV) and myelofibrosis (MF) sharing common driver mutations in the JAK2, CALR or MPL genes but with a notable variability in the clinical presentations and outcomes [19]. For ET and PV it remains challenging to predict which patients are going to progress to MF and for MF patients the acquisition of additional somatic mutations by itself does not fully explain the variability in the incidence of AML transformation and survival outcomes [20].
Sex is an important factor affecting the presentation of patients with MPN. Women have overall a higher prevalence of MPN, they are younger at diagnosis but they predominate in ET while men predominate in PV and PMF [4,6,21]. Interestingly, women tend to develop worsening symptoms especially abdominal discomfort, headaches, dizziness and fatigue with overall higher total symptoms score [4]. Similarly, women have higher incidence of vascular complications and particularly abdominal venous thrombosis [6,22]. Of note, based on a single center study of 84 consecutive MPN cases with splachnic vein thrombosis, 67% of these patients are women and median age at diagnosis is 54 years supporting that abdominal venous thrombosis is particularly common among young women [22]. Given that younger women have higher estrogen levels and the known impact of estrogens on thrombosis development it is possible that this is the underlying mechanism implicated in these differences. On the contrary, men have higher red blood cell transfusion requirements and worsening thrombocytopenia [4]. Barraco et al. showed that men with secondary MF present not only with lower platelets but also bigger spleens, higher percentage of circulating blasts and higher incidence of complex karyotype [23]. These results support that men tend to have more aggressive MPN phenotypes compared to women who are more symptomatic and carry a higher risk of thrombosis.
The impact of sex in the clinical outcomes of MPN patients has been studied by different groups over the last decade. Tefferi et al. analyzed 1494 patients with ET demonstrating that male sex is associated with worse survival independent of patients’ age, leukocyte count and IPSET score [24]. Our group has also found that men with MPN have worse survival compared to women independent of their age at diagnosis, disease sub-type and driver mutation [6]. Moreover, among ET and PV patients, male sex was associated with a more rapid progression to MF independent of age and disease sub-type at diagnosis [6]. Consistently, men with post-ET and post-PV secondary MF have worse survival independent of their age at the time of disease transformation and their disease sub-type at diagnosis [23]. Finally, a recent retrospective analysis of >2000 individuals with MPN showed that male sex is an independent predictor of higher incidence of transformation to MF and worse overall survival for all disease sub-types [25]. These results support an independent impact of male sex in the outcomes of MPN patients suggesting that adding sex to the risk assessment tools that are used in the clinic to predict the outcomes of MPN patients may be needed particularly for ET and PV patients.

2.5. CML

The natural history of CML has been altered significantly following the introduction of tyrosine kinase inhibitors (TKI) with a tremendous improvement of patients’ survival [26]. Given that CML is a molecularly defined neoplasm, significant sex-based alterations in the outcomes would not be expected. However, the review of studies performed in the pre-TKI era reveals interesting sex-related differences in the presentation and outcomes of patients with CML.
Sokal et al. in an early study highlighted that male sex is a negative prognostic indicator independent of spleen size, hemoglobin, levels, platelet counts and percentage of circulating blasts among young (<45 years) patients with CML [27]. Berger et al. analyzed 856 patients with CML and found that women presented with higher platelet counts, and smaller spleen sizes [11]. Moreover, men with CML had a higher incidence of additional chromosomal aberrations and worse survival [11]. This was independent of the risk assessment based on the Sokal score and the difference was more prominent among patients with low and intermediate risk [11]. During the TKI-era, despite that the incidence of TKI switching is higher among women based on data from the SIMPLICITY study [28] there is no strong evidence of sex disparities in the efficacy of TKI with regards to achievement of deep cytogenetic and molecular remissions. Similarly, no sex-related differences in the overall survival of CML patients during the TKI-era have been demonstrated [26,29].
Based on the sex-related differences in the presentation and outcomes of CML patients before the use of TKIs, it could be hypothesized that male sex may be implicated in the acquisition of secondary molecular events driving disease progression.
The observed differences in the presentation and outcomes between women and men with chronic myeloid neoplasms are summarized in Table 1.
Table 1.
Summary of the observed differences in the presentation and outcomes between women and men with chronic myeloid neoplasms.
Myeloid Neoplasm Observation Reference
MDS The frequency is higher in men compared to women [16][12]
MDS—Low and Intermediate-1 R-IPSS score Men have worse survival compared to women [17][13]
MDS—RA, RCMD, 5q Men have worse survival compared to women [5]
MDS/MPN Men have worse survival compared to women [5]
MPN Women predominate in ET and men predominate in PV and PMF [6,21][6][18]
MPN Women have higher incidence of venous thrombosis [6,22][6][19]
MPN Men have lower platelets [4,23][17][20]
PMF Men have bigger spleens, higher percentage of circulating blasts and higher incidence of complex karyotypes [23][20]
ET Male sex is an independent predictor of worse survival [24][21]
ET, PV Male sex is an independent predictor of worse survival and higher incidence of transformation to MF [6,25][6][22]
Secondary MF Male sex is an independent predictor of worse survival [23][20]
MPN Men have worse survival across all the subtypes [6,[625]][22]
CML Male sex is an independent predictor of worse survival among young patients (<45 years old) [27][24]
CML Men have bigger spleens, lower platelets, higher incidence of additional chromosomal abnormalities and worse survival among patients with low and intermediate risk groups [11][7]

Abbreviations: MDS, myelodysplastic syndrome; R-IPSS, revised international prognostic scoring system; RA, refractory anemia; RCMD, refractory cytopenia with multilineage dysplasia; MDS/MPN, myelodysplastic/myeloproliferative overlap neoplasm; MPN, myeloproliferative neoplasm; ET, essential thrombocythemia; PV, polycythemia vera; PMF, primary myelofibrosis; MF, myelofibrosis; CML, chronic myeloid leukemia.

 

Abbreviations: MDS, myelodysplastic syndrome; R-IPSS, revised international prognostic scoring system; RA, refractory anemia; RCMD, refractory cytopenia with multilineage dysplasia; MDS/MPN, myelodysplastic/myeloproliferative overlap neoplasm; MPN, myeloproliferative neoplasm; ET, essential thrombocythemia; PV, polycythemia vera; PMF, primary myelofibrosis; MF, myelofibrosis; CML, chronic myeloid leukemia.

References

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