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Gerke, M.B.; Christodoulou, I.; Karantanos, T. Myelodysplastic/Myeloproliferative Neoplasms. Encyclopedia. Available online: https://encyclopedia.pub/entry/47800 (accessed on 10 September 2024).
Gerke MB, Christodoulou I, Karantanos T. Myelodysplastic/Myeloproliferative Neoplasms. Encyclopedia. Available at: https://encyclopedia.pub/entry/47800. Accessed September 10, 2024.
Gerke, Margo B., Ilias Christodoulou, Theodoros Karantanos. "Myelodysplastic/Myeloproliferative Neoplasms" Encyclopedia, https://encyclopedia.pub/entry/47800 (accessed September 10, 2024).
Gerke, M.B., Christodoulou, I., & Karantanos, T. (2023, August 08). Myelodysplastic/Myeloproliferative Neoplasms. In Encyclopedia. https://encyclopedia.pub/entry/47800
Gerke, Margo B., et al. "Myelodysplastic/Myeloproliferative Neoplasms." Encyclopedia. Web. 08 August, 2023.
Myelodysplastic/Myeloproliferative Neoplasms
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15153815

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are hematological disorders characterized by both proliferative and dysplastic features. According to the 2022 International Consensus Classification (ICC), MDS/MPN consists of clonal monocytosis of undetermined significance (CMUS), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), MDS/MPN with SF3B1 mutation (MDS/MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocytosis not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. These disorders exhibit a diverse range of genetic alterations involving various transcription factors (e.g., RUNX1), signaling molecules (e.g., NRAS, JAK2), splicing factors (e.g., SF3B, SRSF2), and epigenetic regulators (e.g., TET2, ASXL1, DNMT3A), as well as specific cytogenetic abnormalities (e.g., 8 trisomies, 7 deletions/monosomies). 

myelodysplastic/myeloproliferative neoplasms MDS/MPN overlap syndromes CMML aCML MDS/MPN-T-SF3B1 MDS/MPN-RS-T-NOS MDS/MPN-NOS

1. Introduction

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are a distinct group of hematological disorders characterized by overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Both elements are required to diagnose MDS/MPN, with the identification of the hyperproliferation of hematopoietic cells in conjunction with bone marrow dysplasia and ineffective hematopoiesis, which occasionally leads to cytopenia. In instances where cytopenia is not present, morphological analysis of the bone marrow may show dysplastic changes in one or more lineages, fulfilling the criteria for MDS/MPN diagnosis.
In recent years, the classification and understanding of MDS/MPN overlap syndromes have evolved, shedding light on their complex biology and genetic abnormalities. Traditionally, the classification of MDS/MPN was based on the fourth edition of the WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues (WHO4), first released in 2008 and updated in 2016, which divided MDS/MPN into four subdivisions: chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), myelodysplastic/myeloproliferative neoplasm with ringed sideroblasts and thrombocytosis (MDS/MPN-RS-T), MDS/MPN-unclassifiable (MDS/MPN-U), and Juvenile myelomonocytic leukemia (JMML) [1]. In 2022, the most recent edition (5th-WHO5) was released, which still included CMML but introduced changes: JMML was removed, aCML was renamed to MDS/MPN with neutrophilia (mainly to avoid confusion with CML), MDS/MPN-RS-T was renamed as MDS/MPN with thrombocytosis and SF3B1 mutation (MDS/MPN-T-SF3B1), and MDS/MPN-unclassifiable was termed as MDS/MPN not otherwise specified (MDS/MPN-NOS) [2]. The same year, the International Consensus Classification (ICC) of Myeloid Neoplasms and Acute Leukemias divided MDS/MPN into seven subdivisions: CMML, clonal monocytosis of undermined significance (CMUS), aCML, MDS/MPN-T-SF3B1, MDS/MPN-RS-T-not otherwise specified (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS [3]. Given the absence of identifiable dysplastic features, JMML was excluded from the most recent MDS/MPN classifications and was included in MPN on the WHO5 and in pediatric/germline mutation-associated disorders on the ICC, highlighting the evolving nature of classification systems.

2. Definitions

2.1. Chronic Myelomonocytic Leukemia

CMML is defined as monocytosis (absolute monocytes ≥ 0.5 × 109/L and ≥10% of the WBC) with cytopenia and the presence of <20% of blasts in the peripheral blood (PB) and bone marrow (BM) [3]. A clonal population with abnormal cytogenetics or myeloid neoplasm-associated mutation is needed for diagnosis unless monocytes > 1 × 109/L [3][4]. BM typically demonstrates hypercellularity due to the proliferation of myeloid lineage without the pathological features of AML, MPN, or other monocytosis-associated conditions [3]. Moreover, BCR-ABL1 translocation or other genetic abnormalities of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions should not be detected [3]. Of note, two subgroups of CMML have been defined based on blast percentage: CMML-1 with <5% blasts in PB and <10% in BM, and CMML-2 with 5–19% blasts in PB and 10–19% in BM [3]. Finally, the amount of total WBC classifies CMML into two additional groups: the myeloproliferative subtype (MP-CMML) with WBC of >13 × 109/L and the myelodysplastic group (MD-CMML) with lower WBC counts [3].

2.2. Atypical Chronic Myeloid Leukemia

ACML is defined as leukocytosis 13 × 109/L due to an increased number of neutrophils and their precursors, cytopenia, and blasts less than 20% of the composition of cells in PB and BM. Dysgranulopoiesis is present in PB, including hyposegmented and/or hypersegmented neutrophils and hypercellular BM with granulocytic proliferation and dysplasia [3]. Monocytes and eosinophils constitute <10% of PB leukocytes each [3]. Like CMML, BCR-ABL1 translocation or other genetic abnormalities of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions should not be detected [3].

2.3. Clonal Monocytosis of Undetermined Significance

CMUS is a premalignant precursor to CMML defined by monocytosis (absolute monocytes ≥ 0.5 × 109/L and ≥10% of the WBC) with the presence or absence of cytopenia, in the presence of myeloid neoplasm-associated mutation [3]. No morphological findings of CMML, dysplasia, or blasts should be identified in bone marrow, and no other criteria for hematologic neoplasm should be met, while other causes of reactive monocytosis should be excluded [3]. In the presence of cytopenia, CMUS can be re-named as Clonal Cytopenia with Monocytosis of Undetermined Significance (CCMUS) [3].

2.4. Myelodysplastic/Myeloproliferative Neoplasm with Thrombocytosis and SF3B1 Mutation

MDS/MPN with thrombocytosis and SF3B1 mutation (MDS/MPN-T-SF3B1) is defined as thrombocytosis (platelets > 450,000 × 109/L) with anemia with minimal blasts (<1% in PB and <5% in BM) [3]. The S3FB1 mutation is necessary for diagnosis, with or without other myeloid neoplasm-associated mutations or abnormal cytogenetics, but always without BCR-ABL1 translocation or other genetic abnormalities of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusion [3]. MDS, MPN, or other MDS/MPN should be excluded, along with a history of growth factors which could be responsible for myeloproliferative features or cytotoxic therapy responsible for myelodysplasia [3].

2.5. Myelodysplastic/Myeloproliferative Neoplasm with Ring Sideroblasts and Thrombocytosis, Not Otherwise Specified

MDS/MPN-RS-T, NOS is defined as thrombocytosis (platelets > 450,000 × 109/L) with minimal blasts (<1% in PB and <5% in BM) and anemia with erythroid-lineage dysplasia and >15% ring sideroblasts [3]. A clonal population with abnormal cytogenetics or somatic mutation(s) but no S3FB1 mutation, BCR-ABL1 translocation, or other genetic abnormalities of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusion should be identified. The presence of other MDS, MPN, or MDS/MPN needs to be excluded [3].

2.6. Myelodysplastic/Myeloproliferative Neoplasm, Not Otherwise Specified

MDS/MPN-NOS entails cytopenias, thrombocytosis, or leukocytosis (as above) and blasts in PB and BM < 20% [3]. Clonality, as displayed by clonal cytogenetic and/or somatic mutation(s), must be present, but not the BCR-ABL1 translocation or other genetic abnormalities of myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusion [3]. The absence of any other MDS/MPN, MDS, MPN, or history of prior cytotoxic or growth factor therapy is required [3].

3. Biology

3.1. Genetic Mutations

The genomic profile of patients with MDS/MPN defines the disease biology and strongly affects patients’ outcomes [5]. Palomo et al. demonstrated that TET2 and SRSF2 mutations are the most common founder mutations in CMML, while ASXL1/SETBP1 mutations co-occur frequently in aCML [5]. The authors demonstrated that MDS/MPN-NOS (formerly, MDS/MPN-unclassifiable) is the most heterogeneous group with the molecular profile defining disease progression and outcomes [5]. Finally, it was highlighted that TP53 mutation defines a separate phenotype characterized by dismal outcomes [5]. The researchers' group showed that men with MDS/MPN neoplasms have a higher number of somatic mutations and a greater number of high-risk mutations (ASXL1, EZH2, RUNX1, SETBP1, NRAS, STAG2), which were associated with a higher risk of AML transformation and worse survival [6].
Somatic genetic mutations are present in over 90% of patients with CMML, can aid in the confirmation of diagnosis, are predictive of the disease course, and present opportunities for developing novel therapeutics [3][7]. Some of the most frequently mutated genes in CMML are implicated in cellular processes, including epigenetic control, such as TET2 and ASXL1; RNA splicing, including SRSF2; cell signaling, such as CBL and NRAS; and transcription and nucleosome assembly, including RUNX1 and SETBP1 [7][8][9][10][11][12][13][14][15]. SRSF2, TET2, and ASXL1 are reported to be the most frequently mutated of these genes, present in approximately 40% of patients with CMML [5][16]. TET2 is thought to be the initial driver mutation responsible for monocytosis, but it has not been shown to impact OS or LFS in CMML [7][8][17]. The accumulation of additional mutations such as ASXL1, along with DNMT3A, RUNX1, SETBP1, NRAS, KRAS, CBL, and JAK2, is associated with increased proliferation, dysplasia, and progression to AML [5][7][18][19][20]. Nonsense/frameshift ASXL1 mutations are the only mutations independently and consistently associated with poor prognosis [7]. ASXL1 mutations have been incorporated as a predictive component in several prognostic CMML scoring systems, including the Groupe Francophone des Myelodysplasias (GFM) Model, Mayo Molecular Model, and Spanish CMML specific cytogenetic risk stratification model (CPSS) [7][8][16][21][22][23]. In CMUS, these listed myeloid mutations and their frequency are associated with an increased risk of disease progression to CMML [3][24].
In aCML, the absence of MPN-associated driver mutations, such as JAK2, CALR, and MPL, and the presence of SETBP1 and ASXL1 mutations can provide additional support for aCML diagnosis, according to ICC guidelines [3][25]. Palomo et al. found that approximately 90% of 71 aCML patients have an ASXL1 mutation, found in the ancestral clone in 79% of cases [5]. Patnaik et al. analyzed 25 aCML patients reporting ASXL1 (28%), TET2 (16%), NRAS (16%), SETBP1 (12%), and RUNX1 (12%) as the most prevalent mutations [26]. In this study, TET2, NRAS, and PTPN11 mutations, along with the presence of more than three mutations, were found to adversely impact survival in univariate analysis, while ASXL1, SETBP1, and ETNK1 were not found to impact prognosis [26]. In contrast with genetic prognostic studies in CMML, TET2 was the only mutation that retained association with a worse prognosis outcome in multivariate analysis [26].
The SF3B1 spliceosome mutation is commonly a founder mutation in MDS/MPN-RS-T, and thus, the 2022 ICC recognized the mutation as a requirement in the diagnosis of MDS/MPN-T-SF3B1, as mentioned [3][27]. Other spliceosome mutations, including U2AF1 and SRSF2, are frequent founder mutations in patients without SF3B1 mutation in MDS/MPN-RS-T NOS [27]. The JAK2V617F mutation is reported in 58% of MDS/MPN-RS-T patients and associated with myeloproliferative features [28]. Additional mutations in genes implicated in kinase signaling pathways, such as NF1, SETBP1, CBL, FLT3, and MPL, have also been frequently reported in MDS/MPN-RS-T neoplasms [28]. Due to the high frequency of JAK2V617F mutation, the IWG suggests that its presence supports the diagnosis of MDS/MPN-RS-T [3].

3.2. Chromosomal Abnormalities

Cytogenic abnormalities are present in approximately 30% of all patients with CMML [3][7][24]. An analysis of 414 CMML patients found cytogenetics to be an independent prognostic factor for OS and AML transformation (p = 0.001) [29]. In this analysis, the highest risk cytogenetics included the presence of trisomy 8, abnormalities of chromosome 7, or complex karyotype; an intermediate risk constituted all other chromosome abnormalities; and a low risk included a normal karyotype or the loss of the Y chromosome [29]. Stratification by these cytogenetic abnormalities divided patients into the 5-year OS of 4%, 26%, and 35% (p < 0.001), respectively [29]. The Mayo Clinic–French consortium studied 409 patients with CMML, also finding that 30% of patients had chromosomal abnormalities [30]. High-risk (complex and monosome karyotypes), intermediate (abnormalities not included in the high or low groups), and low-risk (normal and sole Y- or 3q) displayed median survivals of 3, 20, and 41 months, respectively [30]. ASXL1 mutations were detected in 37% of patients with abnormal karyotypes, while SP3B1 mutations were detected in 46% of patients with normal karyotypes [30].
In an analysis of 367 patients with different subsets of MDS/MPN, aCML and MDS/MPN-NOS were associated with the highest genomic instability: 42% and 47% of patients had chromosomal abnormalities, respectively [5]. Palomo et al. reported the most common cytogenetic abnormalities in aCML and MDS/MPN-NOS to be trisomy 8, −7/del7q, and -Y [5]. Patnaik et al. found trisomy 8, trisomy 9, and trisomy 21 to be the most common karyotype abnormalities in an analysis of 25 patients with aCML [26]. An analysis of 71 patients with MDS/MPN-RS-T demonstrated karyotype abnormalities in only 10% of patients, the most common of which being trisomy 8 (4%) and the loss of chromosome Y (4%) [31].

3.3. Current Therapeutic Strategies in MDS/MPN

3.3.1. Hypomethylating Agents

To date, the mainstay of first-line chemotherapy for MDS/MPN includes hypomethylating agents (HMA). HMA, including 5-azacitidine (AZA) and decitabine (DAC), decrease oncogenesis-related DNA methylation by irreversibly binding to DNA methyltransferase and can also cause direct DNA damage [32][33][34][35]. HMA remains the only FDA-approved chemotherapy agent for CMML, with approval primarily gained by including patients with CMML in MDS-focused clinical trials [7][36][37][38]. In a hallmark study, Silverman et al. reported outcomes for 14 CMML patients in a randomized trial of AZA in patients with MDS, reporting that 8% of patients had a complete response (CR), 15% had a partial response (PR), and 38% demonstrated improvement within the overall study population [36]. Fenaux et al. included 11 CMML patients in a randomized phase III trial of high-risk MDS patients, reporting a median overall survival (OS) of 24.5 months with AZA treatment compared to 15 months for conventional care [37]. The overall response rate (ORR) was 29% with AZA treatment, compared to 12% in conventional care regimes [37]. Kantarjian et al. reported a 17% response rate to DAC in MDS patients compared to 0% in the supportive care group, including 14 patients with CMML among 170 total patients [38]. These studies supporting FDA approval primarily focused on MD-CMML subset patients.
HMA are also used as a first-line treatment in non-CMML MDS/MPN, with their rationale for use drawn mainly from CMML studies. Case reports have explored the use of DAC in aCML, with pooled data identifying a complete hematologic remission (CHR) in seven of eight patients, with two patients being bridged to transplant [39][40][41][42][43]. Despite the small sample size, HMA are recommended in aCML as bridge-to-transplant or in cases of ineligibility for transplant or clinical trial enrollment [39]. In the analysis of 135 patients with MDS/MPN-NOS, 27 patients received ≥six cycles of HMA; 1 patient achieved a CR, 2 patients achieved a PR, 2 patients achieved a marrow response (MR), and 1 patient achieved a complete cytogenetic remission, together leading to an ORR of 19% (n = 5) [44]. Of these five respondents, two patients eventually progressed to AML [44]. In a retrospective analysis of 52 MDS/MPN-RS-T patients, 12 had received HMA therapy [45]. The ORR was 25%, with a median duration of response of 7 months, with one CR, two patients with hematological improvement, and three patients proceeding to allo-HSCT after treatment failure [45].
HMA must be given IV due to cytidine deaminase, an enzyme that breaks down DAC and AZA in the small intestine and liver, reducing HMA effectiveness when taken orally. This poses challenges for patients limited by transportation and can reduce quality of life due to the excess time spent in hospitalization receiving care [46]. Cedazuridine inhibits cytidine deaminase, preventing DAC degradation and allowing for efficient delivery when co-taken orally. Savona et al. investigated the combination of DAC with cedazuridine in a phase I trial including six CMML patients, identifying similar pharmacokinetics with IV DAC and a similar safety profile [47].
Other enhancements to HMA therapy include guadecitabine, a next-generation hypomethylating agent with prolonged metabolic activity. Guadecitabine has been tolerated in a study of high-risk myelodysplastic syndromes including 22 CMML patients [48]. The ORR for patients with CMML was 45% (10 out of 22) [48]. Phase III investigation is ongoing (NCT02907359).

3.3.2. Ruxolitinib

Ruxolitinib is a JAK1/2 inhibitor with approved use in polycythemia vera, myelofibrosis, and acute and chronic graft-versus-host disease. A preclinical study of CMML found that the pro-neoplastic JAK1/2 pathway can be induced by the granulocyte-macrophage-colony-stimulating factor (GM-CSF) in CMML primary samples and can be successfully targeted by JAK inhibitors, including ruxolitinib [49]. Several clinical studies have explored the use of ruxolitinib in MDS/MPN. Padron et al. reported in a phase I clinical trial of CMML patients that 20 mg of ruxolitinib twice daily led to an ORR of 35% (defined by a greater than 50% spleen reduction or MDS IWG criteria) and no hematological toxicities and was associated with patient-reported symptom improvement [50]. In contrast, Abaza et al. did not observe a clinical response in a phase I trial of ruxolitinib in CMML patients [51]. These outcome differences may stem from the heterogeneity of CMML; 70% of patients in the Padron et al. study had MP-CMML, while only 16% of patients had MP-CMML in Abaza et al. [50][51]. A combined phase I/II clinical trial reported an ORR of 38% using MDS/MPN IWG criteria and a 43% spleen reduction response in CMML patients receiving 20 mg of ruxolitinib twice daily [52]. Patient-derived murine xenografts supported this finding in a combined clinical/preclinical study [52].
The identification of mutations of the colony-stimulating factor 3 (CSF3R) in aCML has prompted the consideration of ruxolitinib to halt the aberrant signaling through JAK inhibition [53]. T618I, a specific mutation of CSF3R, causes a lethal myeloproliferative disease in mice, and the degree of splenomegaly and leukocytosis has been demonstrated to be reversed by ruxolitinib [54]. In a case report of a patient with mutated CSF3R-T618I, hydroxyurea-refractory aCML, the use of ruxolitinib led to a reduction in constitutional symptoms, leucocytosis, and the spleen size, as well as an improvement in anemia and thrombocytopenia [55]. Another case study of ruxolitinib in an 11-year-old patient with aCML resulted in a reduction in leukocytosis and served as a bridge to HSCT [56]. Dao et al. included 23 aCML patients in a phase II trial of ruxolitinib in aCML and CNL patients [57]. Six patients with aCML were found to have the CSF3R mutation; two patients were non-responders, while four patients reached the end of cycle six of ruxolitinib treatment [57]. In addition, two patients with aCML had PRs [57]. It is recommended that JAK inhibition with ruxolitinib is used as a bridge to HSCT in aCML patients, especially those with CSF3R T618I or JAK2V617F mutations [39][58].

3.3.3. Venetoclax

Venetoclax is a BCL-2 inhibitor used in chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), and AML patients who are not eligible for standard chemotherapy. Montalban-Bravo et al. retrospectively investigated the activity of venetoclax-based therapy in 27 CMML patients and 26 patients with AML-MRC with anteceding CMML [59]. Ventoclax was given in combination with HMA in 70–60% of patients with CMML. The ORR among CMML patients was 67% with a CR of 4%, a marrow CR with a hematologic improvement of 11%, and a marrow CR of 48% with an overall median duration response of 4 months [59]. All treatment-naïve patients achieved a response, with 28% of patients bridged to allo-HSCT [59]. Interestingly, BCL2 expression was not associated with a therapeutic response [59]. Clinical trials using venetoclax, including NCT04550442, are actively enrolling patients with CMML.

3.3.4. Immune-Modulatory Agents (IMiDs)

Lenalidomide and thalidomide are immune-modulatory agents with several mechanisms of action, including antiangiogenic properties, the repression of IL-6 production, and the activation of apoptotic pathways [60]. Lenalidomide is highly effective in the treatment of multiple myeloma as well as mantle cell lymphoma, chronic lymphocytic leukemia, and some MDS subtypes and has been investigated in MDS trials that included CMML patients [61][62][63]. In a phase I study of 20 CMML patients, PR was achieved in one patient and stable disease (SD) was achieved in nine patients, with a median OS of 28.9 months without significant toxicities [64]. Buckstein et al. studied low-dose melphalan and lenalidomide as possible antiangiogenic therapies in CMML (n = 12) and higher-risk MDS (n = 8) patients [65]. In the 19 patients evaluated, three total responses were seen, all in CMML-1 patients [65]. The ORR for CMML was reported as 25%, with 33% in MP-CMML [65]. Overall, severe thrombocytopenia and neutropenia were associated with therapy, along with other non-hematological toxicities [65].
Lenalidomide has also been used in patients with MDS/MPN-RS-T [66]. Based on a report of two patients with MDS/MPN-RS-T treated with lenalidomide, one patient became transfusion-independent, and one attained complete molecular remission [67]. Other case reports of lenalidomide in patients with MDS/MPN-RS-T demonstrate some clinical response (spleen reduction and/or transfusion independence), albeit with significant side effects [68][69]. In a retrospective analysis of 33 patients with MDS/MPN-RS-T, 12 patients received lenalidomide, showing a hematological improvement rate of 50% with a median duration of lenalidomide treatment of 10.3 months [70]. In a retrospective analysis of 167 patients with MDS/MPN-RS-T, 47 patients (28%) received lenalidomide, with a hematological improvement rate of 53% and a median treatment duration of 11 months [71]. Naqvi et al. found that three out of seven patients with MDS/MPN-RS-T treated with lenalidomide responded to treatment (ORR 42%); two patients achieved transfusion independence; and one patient had improvement in blood cell counts [72]. Among the patients without hematological improvement, three patients had SD, and one patient stopped after two cycles due to dermatologic toxicity [72].

3.3.5. PARP Inhibitors

PARP inhibitors like veliparib are FDA-approved breast and ovarian cancer treatments and have demonstrated preclinical efficacy in primary MPN samples [73]. PARP enzymes repair single-strand DNA break, and their inhibition results in cellular apoptosis [74]. Neoplasms with mutations in DNA damage repair genes such as BRCA1 and BRCA2, which prevent effective homologous recombination, can accumulate mutations, leading to reliance on PARP1 for DNA repair and survival [74][75].

3.3.6. RAS Pathway Inhibition

Trametinib is a mitogen-activated protein kinase 1 MEK1/MEK2 inhibitor that inhibits ERK phosphorylation in the RAS pathway and has demonstrated a reduction in NRAS-mutated AML proliferation in pre-clinical studies [76]. Approximately 70% of MPN-CMML patients have RAS mutations which may contribute to the CMML transformation to AML [18]. Borthakur et al. investigated trametinib in a study including 11 patients with relapsed or refractory CMML [77]. The CMML cohort had the highest ORR (27%) in comparison to the AML and MDS cohorts, with 3 of 11 CMML patients responding to treatment [77]. Two CMML patients were included in a phase I study of salirasib, an oral RAS inhibitor that dislodges RAS molecules from their membranes [78]. One of two patients with CMML demonstrated improvements in platelet counts from 12 × 109 to 110 × 109 for 22 weeks [78]. A randomized controlled trial of 299 patients with high-risk myelodysplastic syndromes after the failure of AZA or DAC, which included 11 CMML patients, investigated rigosertib, a synthetic benzyl sulfone that binds to the Ras-binding domain of various intracellular proteins, including RAF and PI3K [79][80]. No difference in the median OS was reported between the two groups (8.2 months in the rigosertib vs. 5.9 months in the best supportive care group) [80].

3.3.7. Histone Deacetylases Inhibitors

Histone deacetylases inhibitors (HDACIs), including panobinostat (PAN), entinostat, and vorinostat, can lead to an increased expression of genes, inducing apoptosis, cellular differentiation, and cell-cycle arrest, that are aberrantly suppressed in oncogenesis [81]. HDACIs have shown promising preclinical and clinical results in MDS and AML [82][83][84]. Kobayashi et al. investigated PAN and AZA in MDS and CMML patients. Four CMML patients were enrolled; SD was reported as the best response, with tolerable side effects [85]. A phase Ib/IIb clinical trial of PAN and AZA included 4 CMML patients in Ib and 13 CMML patients in the IIb arm [86]. The MDS/CMML patients had a CR of 29.0% in the PAN+AZA arm compared to 10.3% in the AZA arm, with a similar safety profile [86]. However, no significant improvement in OS or time to progression was reported [86].
In contrast, a phase II randomized trial (n = 149, including five patients with CMML) investigated entinostat with AZA, which resulted in a median OS of 22.2 months for treatment with AZA alone as opposed to 14.7 months with AZA and entinostat [87]. The combination of AZA and entinostat led to decreased demethylation compared to that observed in the AZA monotherapy arm, suggesting an antagonistic therapeutic effect [87]. As mentioned in the lenalidomide section, the study of Sekeres et al. showed no significant differences in ORR in CMML patients treated with AZA and vorinostat compared to AZA alone [88].

3.3.8. Other Therapies

Other targeted therapies have been evaluated in a few clinical studies of MDS/MPN—mainly, CMML. Lenzilumab is a monoclonal antibody against GM-CSF, which induces apoptosis in cells with high GM-CSF receptor expression, which is a protein often found on myeloid progenitor cells [49][89]. As mentioned, 90% of CMML patient samples have demonstrated increased proliferation and dependent phospho-STAT5 signaling induced from GM-CSF [49]. When treated with the anti-GM-CSF antibody, CMML BM cells demonstrated apoptosis, particularly in samples with Ras/CBL/KAK2 signaling mutations [49]. A phase I clinical trial of lenzilumab in patients with CMML showed a durable clinical benefit in 33% of treated patients, without grade III or IV adverse events, with one patient qualifying for allo-HSCT [89]. CD123, the α chain of the IL3 receptor, is highly expressed in CMML progenitor cells and can be targeted by tagraxofusp, a truncated form of the diphtheria toxin with IL-3 [90]. Preliminary data from 36 patients with CMML treated with tagraxofusp showed a marrow CR in 11% of patients, 42% of patients achieved a >50% reduction in spleen size, and one patient was bridged to allo-SCT [91].
Pevonedistat is a small molecule inhibitor of the neural precursor cell (NEDD8)-activating enzyme leading to downstream protein ubiquitination [92]. Pevonedistat treatment has led to AML regression in murine models and has demonstrated a 50% complete response rate (CRR) in treatment-naïve AML patients [93][94].
Omacetaxine mepesuccinate (OM) is a semi-synthetic form of hemoharringtonine (HHT), a plant alkaloid with historical significance as an antineoplastic therapy in China [95]. HHT prevents protein synthesis elongation via interaction with the ribosomal A site and consequentially induces the creation of proteins with a short half-life [95]. Studies of relapsed/refractory AML and MDS show that 16–25% CR rates have been documented, albeit with adverse side effects, including hypotension, diarrhea, and tumor lysis syndrome [96]. OM has FDA approval for chronic or accelerated phase CML resistant to two or more tyrosine kinase inhibitors [97][98].
PEG-IFN-alpha was utilized in CML before imatinib development and may have some limited utility in MDS/MPN, including in aCML and MDS/MPN-RS-T. In a retrospective analysis of aCML patients, only one of seven patients treated with IFN-alpha responded (complete hematological response for 100+ months) [99]. In a phase II study of PEG-IFN-α-2b therapy in BCR-ABL-negative myeloproliferative disorders, CR was observed in two of five patients with aCML [100]. Both patients experienced drug toxicities at 36 and 38 months and were taken and then taken off the study [100]. PegIFN-alpha has limited evidence for use in MDS/MPN-RS-T but may be useful in patients needing cytoreductive therapy [66]. PegIFN-alpha treatment should be weighed against the potential to worsen anemia [66].

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Subjects: Biology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Margo B. Gerke
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Ilias Christodoulou
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Theodoros Karantanos
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Update Date: 09 Aug 2023
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