Chronic myelomonocytic leukemia (CMML) is a rare and biologically complex hematologic malignancy that shares features of both myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) [1]. It primarily affects older adults, with a median age at diagnosis ranging from 70 to 75 years, and accounts for approximately 15–20%of all MDS/MPN overlap syndromes. CMML is characterized by a clonal proliferation of hematopoietic stem and progenitor cells, leading to sustained peripheral blood monocytosis (≥ 0.5 × 10/L) and bone marrow dysplasia [2, 3]. The clinical presentation is highly variable, reflecting the diverse genetic and molecular landscapes underlying the disease [4]. Patients can present with either a myelodysplastic phenotype, characterized by cytopenias and ineffective hematopoiesis, or a myeloproliferative phenotype, marked by leukocytosis, splenomegaly, and constitutional symptoms such as fever, weight loss, and night sweats [5].

The pathogenesis of CMML is driven by a complex interplay of genetic, epigenetic, and environmental factors. Key mutations frequently implicated in CMML include ASXL1, TET2, SRSF2, RUNX1, and NRAS, which contribute to clonal hematopoiesis and disease progression [6]. Notably, ASXL1 mutations are associated with a particularly poor prognosis, while TET2 mutations, when present without ASXL1 co-mutation, are linked to a more indolent disease course [7]. The combination of these mutations and additional genetic lesions can lead to progressive bone marrow failure and transformation to acute myeloid leukemia (AML), a common cause of death in patients with CMML [8, 9]. Recent insights into the role of clonal hematopoiesis of indeterminate potential (CHIP) and age-related clonal hematopoiesis (ARCH) have further highlighted the importance of early mutational events in CMML pathogenesis, highlighting the need for early detection and intervention [10].

Despite advances in supportive care and targeted therapies, allogeneic stem cell transplantation (allo-HCT) remains the only potentially curative option, offering the possibility of long-term disease-free survival through the eradication of the malignant clone and restoration of normal hematopoiesis [11, 12]. However, the decision to proceed to allo-HCT is complex, given the advanced age, frequent comorbidities, and the substantial risks associated with the procedure, including graft-versus-host disease (GVHD) and non-relapse mortality (NRM). For carefully selected patients, particularly those with high-risk disease and adverse molecular profiles, allo-HCT represents the most effective approach to achieving durable remission and potential cure.

Epidemiology

CMML is relatively rare, with an estimated annual incidence of 0.3 to 0.4 cases per 100,000 individuals, accounting for 10–20%of MDS/MPN overlap syndromes [13]. Its rarity has historically limited robust clinical trial data, necessitating careful extrapolation from related diseases.

Classification of CMML

The recently updated International Consensus Classification (ICC, 2022) and the 2022 World Health Organization (WHO) classification have introduced similar modifications to the diagnostic criteria for CMML [14, 15]. These updates include the elimination of the CMML-0 subtype, a reduction in the monocyte threshold to ≥ 0.5 × 109/L, and a continued emphasis on distinguishing between myelodysplastic and myeloproliferative subtypes. Despite these changes, both systems have maintained the same blast count thresholds and, as a result, can be used interchangeably for CMML diagnosis. However, neither classification currently incorporates subtyping based on specific mutational signatures [16].

Notably, both the ICC and WHO classifications have revised the criteria for AML to account for specific genetic mutations. For example, AML with NPM1 mutations is now defined without a minimum blast count threshold (WHO 2022), while AML with CEBPA mutations requires at least 10%blasts (ICC 2022). Given this, patients with CMML harboring these specific mutations should be considered and managed as AML, regardless of blast percentage.

Additionally, the ICC 2022 has introduced a new disease category, MDS/AML, characterized by 10–19%blasts and the presence of high-risk mutations such as TP53, ASXL1, BCOR, EZH2, RUNX1, SF3B1, STAG2, U2AF1, or ZRSR2. This category acknowledges the overlapping features of MDS and AML in certain patients but does not currently extend to CMML, which remains classified separately despite potential molecular overlaps.

Risk Stratification for Identifying Transplant Candidates

Effective risk stratification is critical for determining which patients with CMML are most likely to benefit from allo-HCT [7, 17,18,19,20]. Selecting appropriate transplant candidates involves balancing the potential for long-term remission against the significant risks of transplantation, including GVHD and NRM (Fig. 1) [21].

Fig. 1

Factors influencing decision for transplant or no transplant

Historically, the prognostic models used to stratify CMML patients were adapted from MDS scoring systems, including the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R). Over time, more CMML-specific tools have been developed, such as the Düsseldorf score, MD-Anderson Prognostic Score, modified Bournemouth score, CMML-specific Prognostic Scoring System (CPSS), and the Mayo model. These models, while broadly effective, often lacked incorporation of molecular data, which has become increasingly relevant for predicting disease progression and overall survival [18, 22].

In recent years, molecularly integrated scoring systems have been introduced to improve prognostic accuracy. These include the Groupe Francophone des Myelodysplasies score (GFM, focused on ASXL1 mutations), Mayo Molecular Model (MMM), and the CPSS-Molecular (CPSS-Mol), which considers mutations in ASXL1, RUNX1, NRAS, and SETBP1. The European LeukemiaNet (ELN) and 2018 European Hematology Association (EHA) guidelines currently recommend five key scoring systems for CMML, including the MD-Anderson Prognostic Score, CPSS (in the absence of molecular data), GFM, MMM, and CPSS-Mol when molecular data is available.

While these newer molecular models offer significant improvements, it is important to recognize that many of them were developed based on untreated historical cohorts and have not been extensively validated for predicting transplant-specific outcomes. Recent retrospective analyses have suggested that IPSS-M, for instance, correlates well with post-transplant outcomes in MDS [23, 24], indicating its potential applicability to CMML. Similarly, the CPSS-Mol has demonstrated superior predictive power over traditional scoring systems in identifying patients likely to benefit from early transplantation, as shown in studies involving large CMML transplant cohorts [25].

Most recently, a study developed a simple, clinically based survival model for CMML, called BLAST, using 457 molecularly annotated patients [18]. The model incorporates circulating blasts ≥ 2%, leukocytes ≥ 13 × 10⁹/L, and anemia severity, stratifying patients into low (0 points), intermediate (1 point), and high-risk (2–4 points) groups with median overall survival of 63, 28, and 13 months, respectively. BLAST showed strong predictive accuracy (AUC 0.77/0.85 at 3/5 years), comparable to existing molecular models. Unfavorable mutations (e.g., DNMT3A, ASXL1, TP53) [26] and favorable ones (e.g., TET2, PHF6) were identified and incorporated into a combined clinical-molecular model, BLAST-mol, improving performance (AUC 0.80/0.86). Both models were validated in external cohorts. Risk factors for leukemic transformation included adverse mutations, leukocytosis, and elevated blast counts. BLAST and BLAST-mol offer accessible, effective tools for global CMML risk stratification.

However, applying these risk models to real-world clinical decision-making remains complex. For patients with lower-risk CMML, the immediate risks associated with allo-HCT may outweigh potential long-term benefits, as these patients can often have prolonged survival without early intervention. In contrast, patients with high-risk features, including adverse genetic mutations or elevated blast percentages, are more likely to benefit from early transplantation, as delaying allo-HCT in this group can lead to disease progression, loss of transplant eligibility, and worse overall outcomes.

A most recent retrospective study analyzed a large international cohort of 3,182 CMML patients, including 769 (24%) who underwent allo-HCT [27]. To evaluate the impact of different transplant timing strategies, the researchers constructed flexible parametric survival models to assess key transition hazards, including the risk of AML transformation, non-transplant mortality, post-transplant relapse, and death without disease recurrence. These models incorporated patient age and various prognostic scoring systems (CPSS, CPSS-Mol, and iCPSS) as explanatory variables. A semi-Markov multi-state model based on microsimulation was then developed to estimate optimal transplant timing, using Restricted Mean Survival Time (RMST) over an 8-year period to compare different stratification strategies. The analysis revealed that patients classified as very low or low risk by the iCPSS (n = 1998, 62%) had better outcomes with delayed transplantation (24–36 months after diagnosis). In contrast, those in the intermediate, high, and very high-risk groups (n = 1184, 38%) benefited from early transplantation (3–6 months after diagnosis), resulting in longer RMST. Notably, the iCPSS approach led to a change in recommended transplant timing for 31%and 35%of patients compared to CPSS and CPSS-Mol, respectively. Specifically, 726 patients (22%) who would have been advised to delay allo-HCT under the CPSS strategy were found to benefit from immediate transplantation under the iCPSS model, while 855 patients (26%) identified as immediate HSCT candidates by CPSS-Mol actually had better outcomes with delayed transplantation. Overall, these shifts in transplant timing strategies resulted in significant gains in life expectancy, averaging 1.2 to 1.4 years, depending on the risk model used (p < 0.01). The findings highlight the value of integrating clinical and molecular data into transplant decision-making for CMML. The iCPSS-based Decision Support System effectively refines risk stratification and individualizes transplant timing, offering a data-driven alternative to traditional clinical judgment. This personalized approach significantly improves patient outcomes, demonstrating the potential of iCPSS to guide more precise, life-extending transplantation strategies (Fig. 2).

Fig. 2

Benefit of timing of HCT according to age

Risk Stratification for Predicting Post-Transplant Outcomes

While the CPSS and CPSS-Mol scoring systems are commonly used to assess relapse risk and overall survival in CMML patients undergoing allo-HCT, they have notable limitations when it comes to predicting post-transplant outcomes [19, 20]. These models, primarily designed to guide initial disease prognosis, may not fully capture the complex factors influencing post-HCT survival, as they were not specifically developed for the transplant setting. Importantly, using these scores dynamically at the time of transplant, rather than relying solely on initial diagnosis assessments, may offer more accurate predictions of post-transplant outcomes. However, this approach remains largely unvalidated and requires further clinical research.

Additionally, certain high-risk genetic mutations, such as TP53, are known to significantly impact post-transplant survival but are not comprehensively included in current molecularly integrated scores like the CPSS-Mol [28,29,30,31]. This highlights a critical gap in existing models, emphasizing the need for more sophisticated, transplant-specific risk stratification tools.

To address these limitations, several dedicated transplant-specific prognostic models have been developed. One example is the CMML-specific transplant score, which was designed and validated in a cohort of 240 CMML patients undergoing allo-HCT [25]. This model integrates both molecular data (e.g., ASXL1 and NRAS mutations) and clinical parameters (such as bone marrow blast percentage and comorbidity index) to provide a more precise post-transplant risk assessment. It stratifies patients into five distinct risk groups, with 5-year survival rates ranging from 81%for the lowest-risk group to 19%for the highest-risk group, and non-relapse mortality rates spanning from 5 to 51%. This model has demonstrated superior predictive performance compared to more generalized tools like the CPSS-Mol, which were not specifically designed for transplant patients.

Other transplant-focused tools have also been proposed, including the endothelial activation and stress index (EASIX), which aims to predict NRM by assessing markers of endothelial damage. However, some of these newer models have faced criticism for not being realizable in every day clinical practice by being too complex to calculate and including factors like GVHD without appropriately accounting for inherent statistical biases, underscoring the need for careful model refinement [32, 33].

To further improve predictive accuracy, future transplant-specific scoring systems may need to incorporate additional variables such as donor type, stem cell source, and conditioning regimen intensity. These factors, which significantly influence transplant outcomes, could enhance the precision of risk assessment and better guide personalized post-transplant care.

Pretransplant Management of Splenomegaly

Splenomegaly is a common finding in patients with CMML, often reflecting the underlying myeloproliferative component of the disease. In many cases, splenomegaly is mild and can be managed conservatively without specific intervention. However, a subset of patients presents with massive splenomegaly, which can significantly complicate the transplant process. Large spleens are associated with delayed neutrophil and platelet engraftment, increased transfusion requirements, and higher NRM.

Splenectomy is one approach for managing severe splenomegaly before allo-HCT, as it can improve hematopoietic recovery by reducing splenic sequestration of blood cells and enhancing donor cell engraftment [34]. Studies in myelofibrosis have shown that splenectomy can significantly accelerate neutrophil and platelet recovery. However, splenectomy is a high-risk procedure in the context of CMML, with reported perioperative morbidity rates of approximately 43%and mortality rates around 13%, making this option suitable only for carefully selected patients. For those who avoid splenectomy, it is important to note that spleen size often gradually decreases after successful engraftment, reflecting disease control.

Splenic irradiation presents a less invasive alternative to splenectomy, offering the potential to reduce spleen volume and control disease symptoms prior to transplantation [35]. However, this approach carries its own set of challenges. Splenic irradiation can induce severe, prolonged pancytopenia, which may complicate the transplant process if not carefully managed. Given this risk, it is generally recommended that splenic irradiation be used as an adjunct to conditioning regimens, where the pancytopenia it induces can be mitigated by rapid donor engraftment. Splenic irradiation is associated with reduced relapse risk and similar NRM compared to splenectomy, and appears as much more attractive approach. However, more studies particularly in CMML are needed.

For patients in whom splenectomy or splenic irradiation are deemed too risky, medical therapies such as JAK2 inhibitors may offer an alternative means of controlling splenomegaly. These agents, including ruxolitinib, have been shown to reduce spleen size and improve disease-related symptoms in myelofibrosis and may have a role in selected CMML patients, particularly those with JAK2 mutations or proliferative disease features [36]. However, their use in the pretransplant setting remains investigational, and further studies are needed to define their optimal role in this context.

Pretreatment

The role of pretransplant treatment, often referred to as debulking, remains a topic of debate in CMML. The primary goal is to reduce the disease burden before allo-HCT, typically by lowering bone marrow blast percentages or achieving complete remission (CR). However, it is still unclear whether this approach significantly improves transplant outcomes in patients with CMML. While some studies suggest that reducing bone marrow blasts to less than 2–10%before transplantation might improve outcomes, this has not been consistently demonstrated, and the impact of achieving CR without minimal residual disease (MRD) negativity remains uncertain [12, 37,38,39].

The use of hypomethylating agents and venetoclax may be good for debulking but in limited retrospective series has shown no OS benefit. Retrospective studies have provided mixed results regarding the effectiveness of different pretransplant strategies. Some analyses indicate that HMA, such as azacitidine and decitabine, may offer better outcomes than intensive chemotherapy (IC) in certain subgroups [40], including patients with higher-risk disease or those with elevated bone marrow blast counts. However, other studies have found no significant difference in survival or relapse rates between HMA-based and IC-based pretransplant approaches. Importantly, several of these studies included patients who ultimately did not proceed to transplant due to disease progression or treatment-related toxicity, potentially skewing the results [41, 42].

Randomized prospective trials comparing pretransplant strategies in CMML are lacking, making it challenging to establish definitive guidelines. Nevertheless, HMAs remain a commonly used bridging therapy due to their relatively favorable toxicity profile and potential to stabilize disease until a transplant is feasible. However, it should be noted that up to 13–36%of patients who initiate HMA therapy with the intention of proceeding to transplant may never reach transplant due to disease progression, adverse events, or the development of new comorbidities.

A randomized phase III trial compared decitabine and hydroxyurea in 170 patients with newly diagnosed, advanced CMML (MP-CMML). While decitabine led to a significantly higher response rate (63%vs. 35%, P = 0.0004), it did not translate into improved event-free survival, which remained similar between the two arms (12 months for decitabine vs. 10 months for hydroxurea;P = 0.27). Median OS was also not significantly different (18 vs. 22 months;P = 0.67), and the duration of response was comparable. Notably, decitabine reduced the risk of disease progression or transformation to AML (HR 0.62;P = 0.005), suggesting some disease-modifying activity. However, this came with a trade-off:a non-significant trend toward increased death without progression (HR 1.55;P = 0.04), possibly reflecting treatment-related toxicity or frailty in this older population (median age 72–74). This study underscores a central challenge in MP-CMML:while decitabine may delay transformation, it does not improve long-term survival or event-free outcomes compared to hydroxyurea. Hydroxyurea remains a standard cytoreductive therapy but lacks disease-modifying impact. Thus, beyond cytoreduction, we currently lack effective disease-modifying therapies for MP-CMML. These findings highlight an urgent need for novel approaches that meaningfully alter disease trajectory without adding toxicity, especially for older, high-risk patients [43].

Emerging therapies, such as the combination of HMAs with venetoclax, have shown promise as potential bridging strategies. Early-phase clinical trials have demonstrated high response rates with these combinations, including in high-risk CMML and secondary AML, potentially providing a more effective means of reducing disease burden prior to allo-HCT [44, 45]. Novel oral formulations, such as decitabine/cedazuridine (ASTX727), have emerged to simplify outpatient management without compromising efficacy [46,47,48,49]. However, the use of these agents remains experimental in this setting, and further studies are needed to confirm their long-term impact on transplant outcomes.

Given the uncertainties surrounding the optimal pretransplant strategy, the current consensus among many experts is to prioritize early referral for allo-HCT without necessarily requiring pretransplant debulking, particularly for patients with aggressive disease features [21, 39]. This approach aims to reduce the risk of losing transplant eligibility due to disease progression or treatment-related complications.

Donor Selection

Stem cell donor options for patients with CMML encompass both standard and alternative sources. Standard donors include HLA-matched siblings and matched unrelated donors (MUDs), while alternative options comprise haploidentical donors, mismatched unrelated donors, and, less frequently, unrelated umbilical cord blood [50,51,52,53,54,55,56]. The use of cord blood is limited by its lower cell dose and slower engraftment kinetics. Over the past two decades, advances in donor selection criteria, HLA typing, and transplant protocols have significantly broadened the donor pool available to CMML patients, paralleling progress in allo-HCT for other hematologic malignancies [57,58,