INTRODUCTION — Chronic myelomonocytic leukemia (CMML) is a malignant hematopoietic disorder with clinical and pathologic features of both a myeloproliferative neoplasm (MPN) and a myelodysplastic syndrome (MDS). CMML is characterized by peripheral blood monocytosis and bone marrow dysplasia, often accompanied by cytopenias, constitutional symptoms, and/or splenomegaly. CMML is among the most aggressive chronic leukemias, with a propensity for progression to acute myeloid leukemia (AML).
Management and prognosis of CMML are discussed here.
Pathogenesis, epidemiology, clinical presentation, diagnosis, and differential diagnosis of CMML are discussed separately. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis".)
Management of other MPNs and MDS are presented separately. (See "Overview of the myeloproliferative neoplasms" and "Overview of the treatment of myelodysplastic syndromes".)
Issues specifically related to the diagnosis and treatment of myelodysplastic syndromes and myeloproliferative neoplasms during the COVID-19 pandemic are addressed by the American Society of Hematology [1,2].
PRETREATMENT EVALUATION — Pretreatment evaluation of the patient with CMML should identify disease-associated symptoms, assess medical fitness, and evaluate comorbid illnesses to aid selection of a management strategy.
Consultation with transplantation specialists to judge eligibility for allogeneic hematopoietic cell transplantation (HCT) and initiate a search for a suitable donor should be offered to medically-fit patients with higher-risk CMML.
Clinical features, initial evaluation and diagnosis, and differential diagnosis of CMML are discussed separately. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Evaluation'.)
Clinical — The history and physical examination should evaluate the presence of disease-associated findings, including constitutional symptoms (ie, unexplained fevers, weight loss, night sweats), manifestations of splenomegaly (eg, early satiety, abdominal fullness or pain), lymphadenopathy, disease-related skin lesions, complaints associated with cytopenias (eg, fatigue, infections, bleeding/bruising), and document the history of transfusions.
Laboratory — Pretreatment laboratory studies should include:
●Complete blood count (CBC) with differential, reticulocyte count, renal and liver chemistries, serum erythropoietin (EPO) level.
●Human leukocyte antigen (HLA) typing should be performed for patients who are candidates for allogeneic HCT and/or those who require HLA-matched platelets. (See 'Hematopoietic cell transplantation' below.)
●Lymphocytotoxic (anti-HLA) antibody screen is useful if there are concerns regarding alloimmunization, especially for multiparous women and multiply-transfused patients.
If a karyotype and/or mutation analysis was not performed with the diagnostic bone marrow examination, these studies should be performed on peripheral blood or marrow. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Bone marrow'.)
MEDICAL FITNESS — Assessment of medical fitness is important for determining the goals of care and choice of management of CMML. Age, per se, does not determine medical fitness, but because of age-related comorbidities, caution should be used when considering intensive therapy for patients ≥75 years old. Chronic comorbid conditions should be weighted more heavily than transient medical complications of the leukemia itself (eg, infection, heart failure exacerbated by anemia). The burden of CMML can contribute to a lack of fitness and, in some cases, treatment may alleviate consequences/complications of the leukemia and enhance the patient's ability to tolerate and benefit from subsequent treatments.
Our assessment of medical fitness includes evaluation of:
●Performance status (PS) based on the Eastern Cooperative Oncology Group (ECOG) performance scale (table 1).
●Physiologic fitness (eg, comorbid conditions, activities of daily living, physical performance tests, cognition), as measured by the Charlson comorbidity index (CCI) (table 2).
Other instruments for assessing performance status (eg, Karnofsky scale (table 3)) or physiologic fitness (eg, the short physical performance battery [SPPB] https://geriatrictoolkit.missouri.edu/SPPB-Score-Tool.pdf [3] or hematopoietic cell transplantation-specific comorbidity index [HCT-CI] (table 4)) are also acceptable.
Following are our suggestions for classifying the medical fitness of a patient with CMML. It should be recognized that there are no clear distinctions between these categories and some measures of PS or physiologic fitness can apply to different categories of fitness. In selecting a category of fitness, we seek to protect frail patients from treatment that they are unlikely to survive, while not depriving a medically-unfit but not frail patient of the opportunity to achieve remission and prolonged survival. We categorize medical fitness as follows:
●Medically-fit (both of the following):
•ECOG PS: 0 to 2
•CCI: 0 to 2
●Medically-unfit, but not frail (either of the following):
•ECOG PS: 3
•CCI: 3
●Frail (both of the following):
•ECOG PS: ≥3
•CCI: ≥3
PROGNOSIS
Prognostic factors — The prognosis of patients with CMML is generally poor, but there is marked clinical heterogeneity with respect to the natural history and outcomes. Some of the clinical and laboratory features that are associated with outcomes are incorporated into prognostic models of CMML. (See 'Prognostic models' below.)
Patients with CMML are at risk for complications of the disease (eg, cytopenias), transformation to acute myeloid leukemia (AML), and treatment-related toxicity. Median survival for patients with CMML is generally 20 to 40 months, and approximately 15 to 30 percent progress to AML, but outcomes vary with an individual's prognostic features [4-12].
The features most closely associated with survival in patients with CMML are white blood cell (WBC) count, percentage of blasts in peripheral blood and bone marrow, hemoglobin (Hb) level, red blood cell (RBC) transfusion-dependence, karyotype, and certain mutations [4-10,13-15]. Other findings that have been associated with outcomes in CMML include thrombocytopenia, lymphocytosis, serum lactate dehydrogenase (LDH), and splenomegaly.
Mutations of specific genes are present in nearly all cases of CMML, and some mutations are independently associated with outcomes [16,17]. The most common mutations include genes that encode splicing factors (eg, SRSF2), epigenetic regulators (eg, ASLX1, TET2, DNMT3A, IDH2, EZH2, UTX), tyrosine kinases (eg, NRAS, KRAS, CBL, JAK2), and transcription factors (eg, RUNX1) [18-23]. Nonsense and frameshift mutations, but not missense mutations, of ASXL1 are consistently reported to be an adverse prognostic feature [24,25]. Other mutations are less closely linked to outcomes, while some mutations are associated with better prognosis. As an example, in one study, loss-of-function mutations of TET2 were present in more than half of 1084 patients with CMML and those patients had more favorable outcomes compared to patients with no TET2 mutation (median survival 49 versus 30 months, respectively) [26]. Mutations also differ according to the CMML subtype. Mutations in JAK2, NRAS, and SETBP1 are more common with the proliferative subtype, whereas TET2 and SF3B1 mutations are more closely associated with the dysplastic subtype [16]; CMML subtypes are described below. (See 'CMML subtype' below.)
CMML subtype — The CMML subtype is based on peripheral blood WBC count [27]. WBC count is independently associated with outcomes in CMML and is incorporated into prognostic models, as described below. (See 'Prognostic models' below.)
CMML subtypes are categorized as:
●Proliferative (CMML-MPN) – WBC count ≥13,000/microL (≥13 x 109/L)
●Dysplastic (CMML-MDS) – WBC count <13,000/microL
CMML stage — The CMML stage is determined by the percentage of blasts in peripheral blood and bone marrow. CMML staging was revised in the 2022 World Health Organization scheme to exclude the CMML-0 subgroup [28]:
●CMML-1 – <4 percent blasts plus promonocytes in peripheral blood and <9 percent blasts in bone marrow
●CMML-2 – 5 to 19 percent blasts plus promonocytes in peripheral blood and 10 to 19 percent blasts in bone marrow and/or the presence of Auer rods
PROGNOSTIC MODELS — There is no consensus regarding a preferred tool for risk stratification in CMML. Various prognostic models have been developed, some of which were designed exclusively for CMML while others were developed more broadly for myelodysplastic syndromes (MDS). Most models have comparable performance, but some are more likely to upstage patients (ie, reclassify a patient from a lower-risk group in one model to higher-risk disease with another model).
We consider any of the models that incorporate cytogenetic and molecular features to be acceptable, including:
Mayo molecular model — The Mayo molecular model includes the monocyte count, circulating immature myeloid cells, hemoglobin (Hb) level, platelet count, and ASXL1 mutation status [24].
Points are assigned as follows:
●Absolute monocyte count (AMC) – >10,000/microL (10 x 109/L) (1 point)
AMC = white blood cell (WBC) count x percentage of monocytes ÷ 100
●Circulating immature cells – Presence of myeloblasts, myelocytes, metamyelocytes, and/or promyelocytes in peripheral blood (1 point)
●Decreased Hb – <10 g/dL (<100 g/L) (1 point)
●Decreased platelets – <100,000/microL (1 point)
●ASXL1 frameshift or nonsense mutation (1 point)
The Mayo molecular model stratifies patients into four risk groups (based on the sum of the points above) with the following rates of median overall survival (OS):
●Low risk (0 points): OS 97 months
●Intermediate-1 risk (1 point): OS 59 months
●Intermediate-2 risk (2 points): OS 31 months
●High risk (≥3 points): OS 16 months
The earlier Mayo prognostic model (which did not include ASXL1 mutational status) is described below. (See 'Other models' below.)
CPSS-Mol — The CMML-specific prognostic scoring system with molecular features (CPSS-Mol) includes the CMML subtype and stage, transfusion-dependence (or Hb level), cytogenetic features, and mutation status [16]. CMML subtype and stage are described above. (See 'CMML subtype' above.)
The CPSS-Mol score results from adding points from the clinical features plus points assigned to the genetic risk group:
●Clinical features:
•CMML-proliferative subtype – WBC count ≥13,000/microL (1 point)
•CMML stage – Bone marrow blasts ≥5 percent (1 point)
•Red blood cell (RBC) transfusion-dependence (≥1 unit per 8 weeks over a 4-month period) or Hb <9 g/dL for men and <8 g/dL for women (1 point)
plus
●Genetic risk group score (the sum of cytogenetic risk plus mutation risk), as follows:
•Cytogenetic risk group [29]:
-Low cytogenetic risk (0 points) – Normal karyotype or isolated -Y
-Intermediate cytogenetic risk (1 point) – Other cytogenetic abnormalities, exclusive of high cytogenetic risk features (below)
-High cytogenetic risk (2 points) – Trisomy 8, complex karyotype (≥3 abnormalities), or abnormalities of chromosome 7
plus
•Mutation risk:
-Mutation of ASXL1, NRAS, or SETBP1 (1 point each)
-Mutation of RUNX1 (2 points)
CPSS-Mol stratifies patients into four risk groups (based on the sum of the points above), with the following rates of median OS and 48-month cumulative incidence of leukemia (CIL):
●Low: OS not reached; CIL 0 percent
●Intermediate-1: OS 68 months; CIL 8 percent
●Intermediate-2: OS 30 months; CIL 24 percent
●High: OS 17 months; CIL 52 percent
Compared with other prognostic models, CPSS-Mol was superior for predicting survival and it upstaged the risk category for a substantial proportion of patients, but it has not yet been independently validated [16]. The original CPSS from which CPSS-Mol was developed is described below. (See 'Other models' below.)
GFM (Groupe Francophone des Myélodysplasies) — The GFM model stratifies risk according to age, WBC count, Hb, platelet count, and ASXL1 mutation [30]. Points are assigned as follows:
●Age – >65 years (2 points)
●WBC count – >15,000/microL (>15 × 109/L) (3 points)
●Hb – <10 g/dL for women or <11 g/dL for men (2 points)
●Platelet count – <100,000/microL (2 points)
●ASXL1 mutation – (2 points)
The GFM model stratifies patients into three risk groups (based on the sum of the points above) with the following rates of median OS among 312 patients in a training set (32 month median follow-up) and 165 patients in a validation cohort (27 month median follow-up):
●Low risk (0 to 4 points): OS not reached
●Intermediate risk (5 to 7 points): OS 22 to 39 months
●High risk (8 to 12 points): OS 14 to 18 months
Other models — We favor use of one of the prognostic models described above, but other models have been developed that do not incorporate molecular features.
●CMML-specific prognostic scoring system (CPSS) – CPSS includes four clinical variables that are independently associated with survival and progression to acute myeloid leukemia (AML), including CMML subtype, CMML stage, RBC transfusion-dependence, and cytogenetic features [29]. The scoring system uses the same criteria as CPSS-Mol, except it does not include mutation status. (See 'CPSS-Mol' above.)
CPSS was created with a training cohort of 532 patients and validated with an independent cohort of 231 patients. There are four risk groups, with the following rates of median and five-year OS and five-year CIL:
•Low: median OS 61 to 72 months; five-year OS 51 to 55 percent; five-year CIL 13 to 24 percent
•Intermediate-1: median OS 31 months; five-year OS 25 to 29 percent; five-year CIL 29 to 41 percent
•Intermediate-2: median OS 13 to 15 months; five-year OS 10 to 11 percent; five-year CIL 52 to 60 percent
•High: median OS 5 to 9 months; five-year OS 0 percent; five-year CIL 73 to 100 percent
●Mayo model – The Mayo model is calculated with four laboratory parameters from peripheral blood (ie, monocyte count, circulating immature myeloid cells, Hb level, platelet count) (calculator 1) [31]. Unlike the Mayo molecular model (described above), it does not include ASXL1 mutation status. (See 'Mayo molecular model' above.)
The Mayo model stratifies patients into three categories with the following rates of median OS [31]:
•Low risk (0 points): OS 32 months
•Intermediate risk (1 point): OS 19 months
•High risk (2 to 4 points): OS 10 months
●The Global MD Anderson Cancer Center (MDACC) scoring system – The MDACC is a complex model that includes a large number of variables, but online calculators are available (calculator 2) [32]. It is valid for both MDS and CMML. The four risk groups and respective rates of median OS are:
•Low: OS 54 months
•Intermediate-1: OS 25 months
•Intermediate-2: OS 14 months
•High: OS 6 months
Other prognostic models for CMML that do not include molecular features have also been created [15,33].
RISK STRATIFICATION — Management of CMML is guided by the risk category, which is derived from one of the prognostic models described above. (See 'Prognostic models' above.)
For treatment purposes, we stratify risk for patients with CMML as follows:
●Higher risk:
•CPSS-Mol – High risk and Intermediate-2 risk
•Mayo molecular model – High risk and Intermediate-2 risk
•Groupe Francophone des Myélodysplasies (GFM) – High risk and selected patients with Intermediate risk
●Lower risk:
•CPSS-Mol – Low risk and Intermediate-1 risk
•Mayo molecular model – Low risk and Intermediate-1 risk
•GFM – Low risk and selected patients with Intermediate risk
Importantly, assignment to either the higher-risk or lower-risk category is not absolute, especially for those individuals in an intermediate-risk category. A clinician may judge that other prognostic variables (eg, disease subtype or stage, lymphocytosis, serum lactate dehydrogenase [LDH], splenomegaly) may modify the assignment of a risk category. Various factors that are associated with prognosis are discussed above. (See 'Prognostic factors' above.)
Within each risk category, treatment choices are informed by medical fitness, the nature and severity of disease-related symptoms, and individual values and preferences. Age, per se, does not determine the choice of treatment, but older patients generally have more comorbid illnesses that may influence eligibility for intensive treatments (eg, transplantation). Determination of medical fitness is described above. (See 'Medical fitness' above.)
HIGHER-RISK PATIENTS — For all patients with CMML, we encourage participation in a clinical trial, whenever possible. Outside of a clinical trial, management of patients with higher-risk CMML is informed by medical fitness, availability of a suitable donor for hematopoietic cell transplantation (HCT), and patient values and preferences.
Medically-fit — Criteria for patients who are considered medically-fit are presented above. (See 'Medical fitness' above.)
For medically-fit patients with higher-risk CMML and a low percentage of myeloblasts/promonocytes in blood and bone marrow (ie, <5 percent) who have a suitable donor, we suggest allogeneic HCT rather than symptom-directed therapy with hydroxyurea (HU) or a hypomethylating agent (HMA) or supportive care alone.
For higher-risk patients with higher myeloblast/promonocytes percentages, we suggest HMA-based therapy in an attempt to reduce the blast percentage prior to allogeneic HCT. Long-term disease control and the potential for cure outweigh the short-term and long-term toxicities of allogeneic HCT; other treatments are less effective for controlling symptoms and no other approach offers the potential for long-term disease control. For some patients who will undergo allogeneic HCT, treatment with HU or HMA may be given prior to transplantation, as discussed. (See 'Hematopoietic cell transplantation' below.)
There is no consensus regarding an upper age limit for allogeneic HCT. Practices vary between institutions, and some centers limit allogeneic HCT to patients who are ≤65, ≤70, or ≤75 years of age. Selection of patients for HCT, conditioning regimens, graft source, and other aspects of transplantation are discussed below. (See 'Hematopoietic cell transplantation' below.)
For patients who do not have a suitable transplant donor or who decline transplantation because they place greater weight on the adverse effects of HCT than on its benefits, we offer symptom-directed therapy, as described for lower-risk patients. (See 'Lower-risk patients' below.)
Medically-unfit or HCT declined — Criteria for patients who are considered medically-unfit are presented above. (See 'Medical fitness' above.)
For patients whose medical fitness would not permit allogeneic HCT or who decline transplantation because they place greater weight on its adverse effects (including toxicity, isolation, dependence on a caregiver, financial burden) than the benefits, management is informed by the nature and severity of disease-related symptoms, as described for lower-risk patients. (See 'Lower-risk patients' below.)
Frail — Criteria for medical frailty are presented above. (See 'Medical fitness' above.)
For frail patients, we generally offer supportive care alone. (See 'Supportive care' below.)
LOWER-RISK PATIENTS — Patients with lower-risk CMML may experience proliferative symptoms (eg, constitutional symptoms, complaints related to splenomegaly), findings associated with cytopenias (eg, anemia-related, infections, bleeding/bruising), a combination of the two, or they may be asymptomatic. (See "Chronic myelomonocytic leukemia: Clinical features, evaluation, and diagnosis", section on 'Clinical features'.)
Indications for treatment — Indications for treatment of CMML are not clearly defined, and the choice of therapy varies with the degree of symptomatic distress and/or indications of organ involvement. We consider the following when considering treatment for patients with CMML:
●For asymptomatic patients who have no critical cytopenias, we generally observe while monitoring for evidence of disease progression, as described below. (See 'Patient follow-up' below.)
●For other patients, we consider the following to be indications for symptom-directed treatment:
•Constitutional/systemic symptoms (eg, fever, weight loss)
•Organ involvement (eg, symptomatic splenomegaly, skin disease, renal dysfunction, pulmonary involvement)
•Alterations in blood counts (eg, worsening cytopenias, increasing blast percentage, hyperleukocytosis, leukostasis)
Choice of therapy — For patients with lower-risk CMML who have troublesome symptoms or significant cytopenias, we suggest treatment with hydroxyurea (HU) or a hypomethylating agent (HMA) rather than allogeneic hematopoietic cell transplantation (HCT) or supportive care alone. For most patients with lower-risk CMML, such treatments provide symptomatic relief with an acceptable toxicity profile, whereas the morbidity and potential premature mortality of allogeneic HCT outweigh its benefits.
There is no optimal treatment for all symptomatic patients with CMML. Patients may have proliferative symptoms, complications of cytopenias, or a combination of the two. The choice of therapy should be individualized, based on the nature and severity of symptoms, toxicity profile, comorbid illnesses, ease of administration, and patient preferences. Examples of how symptoms inform the choice of treatment follow:
●Proliferative symptoms – For patients with predominantly proliferative symptoms, such as splenomegaly, soaking sweats, weight loss, or renal dysfunction (due to high lysozyme levels) we generally treat with HU (see 'Hydroxyurea' below). Several studies have also demonstrated that the JAK2 inhibitor, ruxolitinib, may have efficacy in this subsets of CMML patients comparable to that seen in primary myelofibrosis.
●Transfusion-dependence – For transfusion-dependent patients and those with symptoms that are predominantly related to cytopenias (eg, fatigue, dyspnea, infections, bleeding/bruising), we favor treatment with an HMA. (See 'Hypomethylating agents' below.)
●Mild or no symptoms – Mildly symptomatic or asymptomatic patients may choose initial supportive care (as needed) with observation for disease progression rather than immediately beginning therapy. (See 'Supportive care' below.)
Some patients with isolated anemia may benefit from treatment with an erythropoiesis-stimulating agent or lenalidomide, as described separately. (See "Management of the hematologic complications of myelodysplastic syndromes", section on 'Treatment'.)
Some younger, medically-fit patients with lower-risk CMML may instead choose to pursue allogeneic HCT because they place greater weight on the possibility of long-term disease control and potential cure than on the adverse effects. (See 'Hematopoietic cell transplantation' below.)
Frail patients are generally treated with supportive care alone. (See 'Supportive care' below.)
HEMATOPOIETIC CELL TRANSPLANTATION — Allogeneic hematopoietic cell transplantation (HCT) is the only curative option for patients with CMML, but it is associated with substantial complications, including acute and chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), and disease relapse.
All patients who may be candidates for allogeneic HCT should be offered the opportunity to discuss this procedure with a transplantation physician soon after diagnosis. A decision to proceed with allogeneic HCT should consider the CMML risk category, medical fitness, availability of a suitable donor, and individual values and preferences. The risk of transplantation should be assessed using the hematopoietic cell transplantation-specific comorbidity index (HCT-CI) (table 4) or a similar instrument. Determination of CMML risk category and eligibility for allogeneic HCT are discussed above and separately. (See 'Risk stratification' above and "Determining eligibility for allogeneic hematopoietic cell transplantation".)
There is no consensus regarding a preferred conditioning regimen for transplantation in CMML. Most studies have used myeloablative conditioning (MAC), but historical comparisons suggest that nonmyeloablative (NMA) or reduced intensity conditioning (RIC) can achieve similar results. When available, a matched related donor is the preferred graft source, but a matched unrelated donor, haploidentical donor, or umbilical cord blood may be an acceptable graft source. (See "Preparative regimens for hematopoietic cell transplantation" and "Donor selection for hematopoietic cell transplantation".)
The optimal timing of transplantation is uncertain. Most experts propose transplantation soon after higher-risk CMML is diagnosed or after achieving the best possible remission status [34]. In general, outcomes are better when patients are transplanted in remission, but there is no persuasive evidence that cytoreductive therapy prior to transplantation can improve outcomes. The best pre-HCT treatment is not defined and preferences vary by institution; some experts favor pretransplant hypomethylating agent (HMA) treatment while others favor intensive chemotherapy.
Outcomes with allogeneic HCT vary considerably between studies. Broadly, approximately one-third of patients with CMML are cured by transplantation, but similar proportions of patients relapse or die from transplant-related mortality (TRM). Examples of studies that reported outcomes with allogeneic HCT for CMML include:
●A multicenter study that included 513 patients with CMML (median age 53 years) reported that four years after HCT, overall survival (OS) was 33 percent, disease-free survival (DFS) was 27 percent, NRM was 41 percent, and relapse rate was 32 percent [34]. Nearly equal numbers of patients in this study underwent MAC versus RIC.
●In another study, among 85 patients with CMML (median age 51 years), allogeneic HCT achieved 40 percent 10-year OS [35].
●In a study in which 43 of 73 patients underwent NMA conditioning, three-year OS, NRM, and cumulative rate of relapse were 32, 36, and 35 percent, respectively [36].
Studies that analyzed factors associated with transplant outcomes in CMML include:
●A retrospective registry study that included 209 adults with CMML who underwent allogeneic HCT (median age 57 years) reported that, with median follow-up of 51 months, inferior survival was associated with higher-risk disease, impaired performance status, and bone marrow as the graft source [37].
●A retrospective survey reported that among 83 patients, pretransplantation HMA therapy was associated with a lower rate of relapse at one year (22 versus 35 percent), without an increase in TRM [38].
●In a study of 141 patients with CMML who underwent transplantation, extensive chronic GVHD was associated with better survival and lower leukemia-associated mortality [39].
●A retrospective study reported that allogeneic HCT prior to transformation to AML in patients with lower-risk CMML was associated with increased mortality [40]. This study reported on 1114 patients with CMML (risk-stratified by CPSS-mol) and underwent allogeneic HCT. Transplantation before transformation to AML in lower-risk disease was associated with increased the risk of death within two years of transplantation (hazard ratio [HR] 3.19 [95% CI 2.30-4.42), but no significant change in long-term survival.
SYMPTOM-DIRECTED THERAPIES
Hydroxyurea — Treatment with hydroxyurea (HU) can relieve splenomegaly, constitutional symptoms, renal dysfunction associated with high lysozyme levels, and other proliferative-type symptoms.
A typical starting dose of HU is 500 mg twice daily or 1000 mg once daily by mouth [41]. Doses should be adjusted to an absolute neutrophil count of 500 to 1000/microL, with a goal of achieving a balance between reducing symptoms and exacerbating neutropenia, anemia, and thrombocytopenia. The onset of action is usually within three to five days of treatment initiation and the effect is short-lived after HU is stopped; accordingly, dose adjustments should not be made more frequently than once per week to prevent wide fluctuations in the platelet count.
Toxicity of HU is usually mild and may include oral ulcers, hyperpigmentation, skin rash, and nail changes [42]. A small percentage of patients develop leg ulcers (eg, over the medial or lateral malleolus), nausea, diarrhea, or alopecia. Rare complications of HU include fever and abnormal liver function tests. Varying degrees of megaloblastic anemia and elevated mean corpuscular volume (MCV) reflect appropriate drug action and is not a reason to modify the dose. HU should not be used in pregnancy, in women with child-bearing potential who are unwilling to use highly effective contraception, and in women who are breastfeeding.
Complete blood count (CBC) and liver function tests should be obtained frequently during the first three months of treatment to monitor for rapid changes in blood counts due to dose modifications and to assess effects on liver function tests.
Persistent symptoms in a patient who cannot tolerate HU may benefit from an alternative oral antimetabolite (eg, 6-thiopurine), ruxolitinib, or a hypomethylating agent (HMA). The combination of HU plus supportive measures (eg, transfusions of red cells and platelets, erythropoiesis-stimulating agents) was shown to be superior to etoposide [41,43,44].
There is not a demonstrated benefit for intensive induction chemotherapy, such as that used for acute myeloid leukemia (AML). However, some patients with proliferative findings that are refractory to HU or with bone marrow myeloblast counts that approach 20 percent can benefit from such intensive treatment, especially to reduce tumor burden prior to allogeneic HCT [41,44]. For most patients, intensive induction therapy will not restore normal hematopoiesis, but they may instead recover with monocytosis and clonal hematopoiesis. Intensive AML-like induction regimens are discussed separately. (See "Induction therapy for acute myeloid leukemia in medically-fit adults".)
Hypomethylating agents — Azacitidine and decitabine are HMAs that can provide symptomatic relief in patients with CMML, especially for patients with complaints related to cytopenias.
The regimens for azacitidine and decitabine are the same as those used for myelodysplastic syndromes (MDS). (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Hypomethylating agents'.)
Treatment with an HMA achieves a response in 30 to 60 percent of patients with CMML and complete response (CR) in <15 percent, but such responses are often not durable; median survival is generally one to three years [45]. No trial has directly compared decitabine and azacitidine for CMML.
Trials of HMA therapy in CMML include:
●A trial that included 53 patients with CMML (median age 70 years) randomly assigned treatment with azacitidine (75 mg/m2/day on days 1 to 7) alone versus azacitidine plus lenalidomide (10 mg/day on days 1 to 21) versus azacitidine plus vorinostat (300 mg twice daily on days 3 to 9) [46]. Overall response rate (ORR) was 38 percent, but those receiving azacitidine plus lenalidomide achieved 68 percent ORR versus 28 percent for azacitidine alone. Median overall survival (OS) was not reached after 23 months follow-up. There were more rashes in patients who received lenalidomide and more gastrointestinal toxicity in those receiving vorinostat.
●A matched-pair analysis compared azacitidine (42 patients) versus HU (22 patients) versus best supportive care (BSC, 42 patients) [47]. Azacitidine achieved 54 percent ORR and 13 month median OS; median OS did not differ between azacitidine and HU. Compared with BSC, there was a trend toward superior two-year OS with azacitidine (62 versus 41 percent) that did not reach statistical significance.
●A single-institution study of decitabine in 19 patients with CMML reported 68 percent ORR, 58 percent CR, and 48 percent two-year OS; toxicity was minimal [48]. Another study of decitabine in 39 patients with CMML and poor prognostic features reported 39 percent ORR (11 percent CR) [49].
An oral preparation of decitabine-cedazuridine (an inhibitor of cytidine deaminase in the gut and liver) emulated the pharmacokinetic, pharmacodynamic, and safety profiles of intravenous decitabine, based on a phase 1 study of 43 evaluable patients [50]. A phase 2 study that included 21 patients with CMML and 59 patients with MDS used a fixed-dose preparation (35 mg decitabine plus 100 mg cedazuridine by mouth, daily for 5 days every 28 days) alternating with cycles of intravenous decitabine (20 mg/m2 for 5 days) [51]. With median follow-up of 24 months and median treatment duration of 7 months, among all patients in the study (ie, both CMML and MDS), 18 percent achieved CR (with 9 month median duration of response) and 49 percent converted to red blood cell- and/or platelet-transfusion independence for ≥56 days. Larger studies and longer-term data will be needed to determine if clinically meaningful endpoints (eg, OS) for CMML are similar to those with intravenous decitabine for CMML.
The US Food and Drug Administration (FDA) has approved oral decitabine-cedazuridine for treatment of CMML and MDS [51].
Outcomes with HMAs may be lower in patients with more advanced CMML. A retrospective study showed that improved OS was associated with an absolute monocyte count <10,000/microL (<10 x 109/L), and peripheral blood blasts <5 percent at the start of therapy with an HMA [52]. In another study, patients with palpable splenomegaly or bone marrow blasts >10 percent had inferior survival, but several reports indicate that mutation status is not predictive of a response to an HMA [49,53,54].
Azacitidine and decitabine are approved by the FDA for treatment of CMML.
SUPPORTIVE CARE — Supportive care should be provided to all patients with CMML, whether they receive another treatment or not. Patients should be treated with antibiotics for infections and transfusions with red blood cells or platelets for symptomatic anemia or thrombocytopenia, respectively. Supportive care for CMML is similar to that for patients with myelodysplastic syndromes. (See "Management of the hematologic complications of myelodysplastic syndromes".)
RESPONSE ASSESSMENT — Response to treatment should be judged by relief of disease-associated symptoms, hematologic response, and achievement of transfusion-independence.
Outside of a clinical trial, we assess the response to therapy based on relief of symptoms, improvement of blood counts, reduced transfusion needs, and improved quality of life. Expert consensus suggests that symptoms are best captured by using the myeloproliferative neoplasms symptom assessment total symptom score (MPN-SAF TSS). Response assessment can also apply criteria used for clinical trials, in which specific end points have been proposed to measure hematologic response, resolution of hepatosplenomegaly and other extramedullary disease, and morphologic response in bone marrow (table 5A-B) [55]. Discontinuation of therapy is indicated for patients who either fail to tolerate therapy or who experience progressive disease as manifest by two major criteria, one major and two minor criteria, or three minor criteria as follows:
●Major criteria – Increase in blast count; cytogenetic evidence of clonal evolution; new extramedullary disease (either worsening splenomegaly or extramedullary disease outside of the spleen).
●Minor criteria – Transfusion dependence; decrease in granulocytes or platelets by at least 50 percent from maximum response; decrease in hemoglobin by 1.5 g/dL or more from best response or baseline; increasing symptoms; molecular evidence of clonal evolution.
PATIENT FOLLOW-UP — Patients should be followed to assess response to therapy and monitor for disease progression.
There is no consensus regarding the optimal schedule and protocol for patient follow-up. We generally schedule follow-up visits every one to six months, which include clinical evaluation and complete blood count (CBC) and differential count.
Routine bone marrow examinations are not required, unless blood counts deteriorate unexpectedly or there is other evidence of possible progression to acute myeloid leukemia (eg, rising blast counts) [56]. Alternatively, some clinicians perform a bone marrow biopsy and aspirate after two to four cycles of hypomethylating agent therapy to guide further treatment decisions.
All patients with CMML should receive age-appropriate health monitoring and smoking should be discontinued. Other aspects of follow-up are presented separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'Monitoring'.)
Patients with CMML can receive killed or recombinant immunizations, but live vaccines should generally not be given to immunocompromised individuals. Specific recommendations regarding immunizations for patients with cancer and other immunocompromised conditions are summarized (figure 1) and discussed in greater detail separately. (See "Immunizations in adults with cancer".)
RELAPSED OR REFRACTORY DISEASE — We encourage participation in a clinical trial for patients with relapsed or refractory CMML.
There is no consensus regarding a preferred treatment for relapsed or refractory CMML and management is informed by prior therapy.
●Medically-fit – For all medically-fit patients who were previously treated with symptom-directed therapy, we seek to proceed to allogeneic hematopoietic cell transplantation (HCT). Given the grave prognosis of relapsed/refractory CMML, we broaden medical eligibility for transplantation and consider various alternative graft sources, including matched unrelated donors, haploidentical donors, and umbilical cord grafts.
●Less-fit
•For patients who progressed on or were intolerant of hydroxyurea (HU), we generally offer treatment with another oral antimetabolite (eg, 6-thiopurine), ruxolitinib, or a hypomethylating agent (HMA).
•For patients who progressed on or were intolerant of an HMA, we treat with HU if there are proliferative symptoms (eg, troublesome splenomegaly, constitutional symptoms) and the blood counts are adequate. For patients who did not respond to one HMA, we do not treat with an alternative HMA, because there is no evidence of benefit.
There are few effective treatments for the management of relapsed or refractory CMML. Agents that are under investigation for treatment of relapsed or refractory CMML include guadecitabine and atezolizumab, lenzilumab, tagraxofusp, NMS-035290288 (multikinase inhibitor), AZD6738 (ATR inhibitor), MBG453 (TIM3 inhibitor), CPX351, CB839 (glutaminase inhibitor), venetoclax, pevonedistat, and eltrombopag [57].
CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov). For interested patients, relatives, and physicians, both the Myelodysplastic Syndromes Foundation (www.mds-foundation.org/) and the Aplastic Anemia and MDS International Foundation (www.aamds.org) maintain websites that contain additional information as well as listings of clinical trials in this disorder [58].
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 2), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)
SUMMARY AND RECOMMENDATIONS
●Description – Chronic myelomonocytic leukemia (CMML) is a malignant hematopoietic disorder characterized by monocytosis and bone marrow dysplasia, often accompanied by cytopenias and splenomegaly. CMML has features of both a myeloproliferative neoplasm (MPN) and a myelodysplastic syndrome (MDS).
●Pretreatment evaluation – Identify disease-related symptoms and assess medical fitness (based on performance status (table 6) and comorbidities (table 4)) that might influence treatment decisions. (See 'Pretreatment evaluation' above and 'Medical fitness' above.)
●Risk stratification – Patients are classified with higher-risk or lower-risk disease, using a CMML-specific prognostic scoring system, such as CMML-specific prognostic scoring system with molecular features (CPSS-Mol), the Mayo molecular model, or the Groupe Francophone des Myélodysplasies (GFM) instrument. (See 'Prognostic models' above and 'Risk stratification' above.)
●Higher risk – For patients with higher-risk CMML, the choice of treatment is informed by medical fitness, availability of a suitable donor for hematopoietic cell transplantation (HCT), and patient values and preferences (see 'Higher-risk patients' above):
•Medically fit – Stratified according to myeloblasts/promonocytes in blood and bone marrow:
-Blasts <5 percent – For low percentage of blasts (ie, <5 percent) with a suitable donor, we suggest allogeneic HCT rather than symptom-directed therapy with hydroxyurea (HU), a hypomethylating agent (HMA), or supportive care (Grade 2C). (See 'Hematopoietic cell transplantation' above.)
-Higher blasts – For higher blast counts, we generally treat with HMA-based therapy prior to transplantation to reduce the burden of blasts.
•Other patients – For medically-unfit or frail patients, management is informed by the nature and severity of symptoms, as for lower-risk disease.
●Lower risk – For patients with lower-risk CMML, management is guided by the nature and severity of symptoms (see 'Lower-risk patients' above):
•Asymptomatic and no critical cytopenias – Observe while monitoring for disease progression.
•Symptomatic – We suggest treatment with HU or HMA, rather than allogeneic HCT or supportive care alone (Grade 2C).
Treatment is individualized according to symptoms, toxicity, comorbidities, and patient preference (see 'Choice of therapy' above):
-Proliferative symptoms – For splenomegaly, sweats, weight loss, or kidney dysfunction (from high lysozyme levels), we generally treat with HU.
-Cytopenias – For fatigue, dyspnea, infections, or bleeding/bruising, we favor treatment with an HMA.
Some patients with isolated anemia may benefit from an erythropoiesis-stimulating agent or lenalidomide.
-Mild/no symptoms – Observe for progression and supportive care, as needed.
●Relapsed/refractory disease – Management is informed by prior therapy and medical fitness, as described above. We encourage participation in a clinical trial. (See 'Relapsed or refractory disease' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge David P Steensma, MD, who contributed to an earlier version of this topic review.
