1 Definition, Epidemiology, Diagnosis, and Classification

The myelodysplastic-myeloproliferative neoplasms (MDS/MPNs) are a heterogeneous group of hematologic malignancies characterized by dysplastic and myeloproliferative clinical, laboratory, and morphological overlapping features, both in marrow and in blood. The MDS/MPN category, recently updated by the last revision to the WHO classification of myeloid and histiocytic/dendritic neoplasms (Khoury et al. 2022), includes chronic myelomonocytic leukemia (CMML), MDS/MPN with neutrophilia (previously called atypical CML), MDS/MPN with SF3B1 mutation (in its absence with ringed sideroblasts) and thrombocytosis (MDS/MPN-SF3B1-T), as well as MDS/MPN not otherwise specified (MDS/MPN-NOS) (Table 76.1).

Table 76.1 Classification and diagnostic criteria of MDS/MPNs
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MDS/MPN are typically diagnosed in elderly age with CMML being definitely the most frequent subtype (incidence of around 0.3–0.4 case/100,000 inhabitants per year, median age 74–79 years) (Benzarti et al. 2019). Being very uncommon, data concerning the incidence of MDS/MPN with neutrophilia, MDS/MPN-SF3B1-T, and MDS/MPN-NOS are currently unknown.

2 Risk Factors and Prognostic Index

The clinical course of MDS/MPN varies from an indolent course over several years for a minor fraction of patients with CMML and MDS/MPN-SF3B1-T to a more rapid progression with dismal prognosis and frequent transformation into secondary acute myeloid leukemia in the preponderance of patients with CMML and in the vast majority of patients with MDS/MPN with neutrophilia and MDS/MPN-NOS, for whom allo-HCT still represents the only curative option (Onida and Beran 2008; Onida 2017; Patnaik and Tefferi 2022, 2023).

CMML is highly heterogeneous, with clinical and hematological characteristics varying from mainly myelodysplastic to predominantly myeloproliferative which has led both the last version of the WHO classification (Khoury et al. 2022) and the International Consensus Classification (Arber et al. 2022) to retain the distinction of MD-CMML and MP-CMML variants, on the base of total WBC count < or ≥13 × 109/L, respectively (Bennett et al. 1994). Based on marrow and peripheral blood blast percentage, there are now only two disease subtypes (CMML-1, and CMML-2), associated to a corresponding decreasing life expectations (Khoury et al. 2022; Arber et al. 2022). Over the latest years, a number of disease-specific prognostic systems have been developed in CMML in order to allow the best treatment strategy allocation (Onida 2017). The most recent ones are listed in Table 76.2.

Table 76.2 Prognostic systems in MDS/MPN
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MDS/MPN with neutrophilia, previously called atypical CML, is a rare hematologic malignancy with an overall dismal prognosis (median 24 months). Age, hemoglobin level, and leukocyte count have been identified as variables with independent prognostic significance, allowing the stratification of two groups with significantly different life expectations. Likewise, for MDS/MPN-SF3B1-T, three risk categories of patients were recently differentiated by a Mayo Clinic prognostic model including molecular investigations (Table 76.2).

MDS/MPN-NOS is the most heterogeneous and the least well-characterized entity, with no currently recognized specific molecular findings. Some description of the biological and clinical characteristics have been reported in two series (DiNardo et al. 2014; Wang et al. 2014), with median survival of 12.4 and 21.8 months, respectively, and possible association of thrombocytosis with a more favorable outcome. More recently, a retrospective analysis including 88 patients from the Mayo Clinic and 47 from the Moffitt Cancer Center reported median OS of 26 and 33 months, respectively (Mangaonkar et al. 2020).

3 Pretransplantation Treatment

For this rare group of diseases, there are few prospective studies on therapy, most being either retrospective analyses or case reports, making it difficult to give recommendations. Similarly to MDS, in high-risk patients with MDS/MPN and low blast count (<10%), upfront transplantation is the most frequently preferred strategy. In general, because apart from allo-HCT, no therapy has been shown to modify the disease course, pretransplantation treatments point toward symptom control rather than the achievement of disease remission (Odenike et al. 2015).

3.1 CMML

In general, treatment strategies in patients with CMML with symptomatic or progressive disease are based on the dysplastic versus proliferative features and the percentage of marrow blasts (Onida et al. 2013; Itzykson et al. 2018). In the presence of rising leukocytosis and/or organ infiltration (mostly splenomegaly) with low marrow blast percentage, hydroxyurea (HU) remains the drug of choice. Patients showing high blast percentages may be bridged to transplant through AML-like induction chemotherapy or by means of hypomethylating agents (HMAs), with a reported 40–50% overall response rate (Patnaik and How 2022). New treatment strategies based on the combination of HMAs with other agents (e.g., lenalidomide, venetoclax) or innovative modalities including targeted therapies (e.g., JAK2 inhibitors, MEK1/2 inhibitors, IDH1/2 inhibitors) or receptor agonists/antagonists immunotherapy approaches currently under experimental phase (Renneville et al. 2021) may further increase the response rate leading to an overall improvement of post-transplantation outcomes.

3.2 MDS/MPN with Neutrophilia (Previously known as Atypical CML)

Due to its absolute rarity in patients having no age or comorbidity barrier to allo-HCT, no consensus subsists on to whether any pretransplant treatment may have an impact on post-transplantation outcome and what kind of therapy should be best used. Control of leukocytosis is generally achieved with cytoreductive agents such as HU or IFN-α immunomodulation. Chemotherapy induction treatment is preferred when facing high blast count in advanced disease phases or in patients showing AML transformation.

Some efficacy of decitabine (Tong et al. 2015) and of ruxolitinib single agent (Dao et al. 2020) has also been reported, whereas a phase II trial of AZA and ruxolitinib in combination in a series of 35 MDS/MPN patients showed promising activity, with an overall response rate of 57% according to the 2015 international consortium response criteria for MDS/MPN (Savona et al. 2015), even though median survival of the few aCML included patients (n = 4) was only 8 months (Assi et al. 2018). According to recently reported data, ASXL1, SETBP1, and ETNK1 are the most frequently mutated genes, with a total of 43.2%, 29.7, and 16.2%, respectively (Fontana et al. Hemasphere 2020), whereas JAK2 mutation is rare (0–7%), and CSF3R mutations are only occasionally observed (Sun et al. 2023). Even though in future these findings may influence therapeutic approaches by means of evolving targeted therapies, currently allo-HCT remains the only treatment strategy with established curative potential in eligible patients (Dao et al. 2017; Patnaik and Tefferi 2023).

3.3 MDS/MPN-SF3B1-T

MDS/MPN-SF3B1-T generally represents the disease entity associated with the best prognosis among overlap syndromes, with a median survival of about 6 years (Kuendgen et al. 2021). Guidelines for disease management are not formally recognized, and treatment strategies are generally extrapolated from low-risk MDS and MPN, with adjusted individual management depending on presenting problems (Patnaik and Tefferi 2017). While lenalidomide has been occasionally reported to reduce transfusion need, antiplatelet, and cytoreductive treatments are often required due to the high risk of thrombosis (Kuendgen et al. 2021). Similar to lower risk MDS and MPN patients, allo-HCT is reserved for patients with refractory cytopenias, high-risk cytogenetics and/or molecular genetics, or progressive disease (Patnaik et al. 2016). Based on the different gene mutations possibly involved (SF3B1 in ~85%, JAK2V617F in ~50%, TET2 in ~25%, ASXL1 in ~20%, DNMT3A in ~15%, and SETBP1 in ~10%.), attentiveness in targeted therapies is developing.

3.4 MDS/MPN-NOS

MDS/MPN-NOS is a very rare and heterogeneous disease entity, with no consensus on which therapy (if any) should be given for patients candidate to allo-HCT. Allogeneic HCT should be encouraged in eligible patients with TP53 mutations (Patnaik and Tefferi 2023). Augmented leukocyte proliferation is generally managed by means of cytoreductive agents such as HU or through immunomodulation with IFNα, while HMAs as well as lenalidomide may represent an option in case of prevailing cytopenias. JAK inhibitors are also potential therapeutic options, either alone or in combination with HMAs (Assi et al. 2018). When patients are progressing to AML transformation, induction chemotherapy should be used as a bridge to allo-HCT.

4 Autologous HCT

Because the harvesting of polyclonal hematopoietic progenitor cells is not feasible through the currently available treatment options, autologous HCT is currently not a recommended strategy in MDS/MPN.

5 Allogeneic HCT

Currently still representing the only curative strategy, the role of allo-HCT in adult MDS/MPN patients remains controversial mainly due to the lack of prospective studies, being therefore generally considered a possible treatment option for eligible patients with high-risk diseases.

In CMML benefits and risks of allo-HCT have been analyzed retrospectively in various series, with different characteristics at transplant and much variable outcomes described (Table 76.3). Recent recommendations from an international expert panel agreed to limit indication for allo-HCT in CMML patients classified in the intermediate-2 and high-risk CPSS categories (de Witte et al. 2017), representing the preferred treatment modality for younger patients with acceptable comorbidity index (Patnaik et al. 2015; Patnaik and Tefferi 2022). This indication was recently reinforced by the results of a study comparing transplant vs no transplant strategy in a large series of CMML patients from an international collaborative analysis (Robin et al. 2022).

Table 76.3 Summary of selected studies on allo-HCT in CMML
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As MDS/MPN with neutrophilia is extremely rare in people younger than 65 years, outcome after allo-HCT has been described only in small single-institution series. A 5-years OS and RFS of 51% and 36%, respectively, were recently reported by the EBMT-CMWP in a retrospective analysis of 42 patients transplanted between 1997 and 2006. With an RR of 40%, a better OS was recognized in young patients with low EBMT risk score (Onida et al. 2017).

In MDS/MPN-SF3B1-T allo-HCT is generally not indicated, being reserved for patients developing refractory cytopenias or accelerated/blastic transformation (Sharma et al. 2017), whereas eligible patients with MDS/MPN-NOS should always be considerate as potential candidate for allo-HCT due to the general dismal prognosis (Mangaonkar et al. 2020).

6 Source of HSC

No impact of HSC source on the transplant outcome has been observed in the largest CMML series reported by the EBMT-CMWP (Symeonidis et al. 2015). This was in contrast to the CIBTMR study, in which the survival was statistically better with PBMC than with BM, with no clear explanation outside the small proportion of BM transplants (16%) (Liu et al. 2017). The source of stem cell is therefore left open, but PBSC may potentially be preferred to decrease the risk of graft failure and the relapse risk, particularly with the use of RIC.

For MDS/MPN with neutrophilia, MDS/MPN-SF3B1-T, and MDS/MN-NOS, data are too scarce to make clear recommendations.

7 Conditioning and GvHD Prophylaxis

In MDS/MPN patients, the choice of conditioning regimen depends on many different conditions, the major ones being comorbidities, patient age, disease phase at transplant, type of donor, and HSC source. In the two largest retrospective series of CMML patients (Symeonidis et al. 2015; Liu et al. 2017), MAC and RIC were almost equal in proportion, with no outcome difference. Likewise, in the largest reported series of MDS/MPN with neutrophilia patients, conditioning intensity had no impact on the outcome (MAC were used in 76%). Noteworthy, an improved outcome following a combined fractionated 6–8 Gray TBI/FLU-conditioning regimen was reported in advanced CMML (Radujkovic et al. 2017).

In general, for young patients (<60 years), with a HCT-CI (Sorror et al. 2005) less than 3, MAC regimens such as BU-CY, TT/BU/FLU (TBF), TT/TREO/FLU (TTF), or the reduced-toxicity FLU/BUx4 (FB4) may be advisable, particularly in the proliferative variant of CMML and in other MDS/MPN with predominant proliferative features, whereas a RIC regimen such as BU/FLU, TREO10/FLU, or reduced TBF/TTF may be preferred for patients with older age or comorbidities and for patients undergoing transplant with disease remission following pretransplant treatment.

8 Maintenance/Post Transplant Strategies

As disease recurrence represents the major cause of transplant failure in MDS/MPN, there is a growing interest toward post transplant strategies, although few data are currently available in this particular setting.

Indirect evidence of a graft versus CMML by a reduced incidence of relapse in patients with chronic GvHD has been recently reported (Itonaga et al. 2018). Some effect of DLI has also been reported in patients with relapsing CMML and low disease burden.

With more molecular markers potentially available, cell therapy-based interventions may be planned on the base of residual or increasing MRD.

Potential interest both as preemptive and as maintenance strategy derive from the use of post transplant HMAs, alone or in combination with DLI, as reported in AML and MDS.

The use of lenalidomide and checkpoint inhibitors, but also JAK2 or PARP inhibitors, alone or even in combination, together with post transplant targeted therapies represents areas of growing interest under development.

Key Points

  • MDS/MPNs include heterogeneous hematologic malignancies with mostly dismal prognosis (except low-risk CMML and MDS/MPN-SF3B1-T), for which allogeneic HCT still represents the only curative treatment option.

  • In the absence of major comorbidities, allo-HCT is recommended for patients with high-risk CMML according to the CPSS or CPSS-Mol, MDS/MPN with neutrophila, and MDS/MPN-NOS up to 75 years of age.

  • For young patients with a HCT-CI less than 3, MAC regimens may be advisable, particularly in the proliferative variant of CMML and in other MDS/MPN with predominant proliferative features, whereas a RIC regimen may be preferred for patients with older age or comorbidities.

  • Although there is no evidence from dedicated trial, in patients with CMML-2 or other MDS/MPN with marrow blast higher than 10%, a pretransplant treatment based on HMAs or AML-like induction chemotherapy may be discussed.