The ASCO Post is pleased to present Hematology Expert Review, an ongoing feature that quizzes readers on issues in hematology. In this installment, Drs. Syed Ali Abutalib and Mrinal M. Patnaik explore the current treatment and prognosis of chronic myelomonocytic leukemia. For each quiz question that follows, select the one best answer. The correct answers and accompanying discussions appear below.

Introduction

Chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by a pathologic accumulation of monocytic cells manifesting with coexisting signs of myeloproliferation and myelodysplasia and associated with an increased risk of transformation to secondary acute myeloid leukemia (AML). The incidence of CMML has been approximated at 12.8 cases per 100,000 people per year, with the median age of diagnosis being from 73 to 75 years old and a male:female predominance of 2:1.^1,2

GUEST EDITORS

Syed Ali Abutalib, MD

Mrinal M. Patnaik, MD

Dr. Abutalib is Co-Director, Hematology and BMT/Cellular Therapy Programs; Director, Clinical Apheresis Program, Cancer Treatment Centers of America and NMDP Midwest Apheresis Program, Zion, Illinois; Associate Professor, Rosalind Franklin University of Medicine and Science; and Founder of Advances in Cell & Gene Therapy. Dr. Patnaik is Professor of Internal Medicine, Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Patients with CMML have features overlapping those of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), making it a disease with two main phenotypes.¹ Those with an MDS phenotype present with or develop peripheral blood cytopenias, effort intolerance, easy bruisability, and transfusion dependence (dysplastic CMML). Those with an MPN phenotype present with or develop leukocytosis, monocytosis, hepatomegaly, splenomegaly, and features of myeloproliferation (proliferative CMML). Herein, we highlight some of the common and unique features related to the treatment and prognosis of both types of CMML.

Question 1

Which of the following statements about CMML is correct?

A. Cytogenetic abnormalities are observed in 90% of cases.

B. A CMML-specific prognostic model (CPSS-Mol) is superior to the other two utilized models.

C. Complete responses with hypomethylating agents are observed in fewer than 20% of patients.

D. Molecular mutations are observed in 30% of cases.

E. All the above

Question 2

Which of the following statements about the prognosis of patients in low- and intermediate-1 risk categories, based on the MMM and the CPSS-Mol models, or the low-risk category of the GFM model is correct?

A. Patients with splenomegaly or cytopenia(s) are excluded from these risk groups.

B. Patients in these groups should be observed closely without therapy.

C. On average, these patients have a median overall survival of 2 years.

D. Patients in this and other risk groups may have rheumatologic and/or renal issues.

E. All of the above

Question 3

Which of the following is not a widely accepted treatment option in patients with dysplastic and proliferative CMML who present with autoimmune phenomena including immune-mediated thrombocytopenia?

A. Corticosteroids for dermatologic manifestations and immune-mediated thrombocytopenia

B. DNA methyltransferase (DNMT) inhibitors in conventional or low doses for autoimmune manifestations in dysplastic CMML

C. Rituximab for immune-mediated thrombocytopenia

D. Eltrombopag for immune-mediated thrombocytopenia

E. Splenectomy for hypersplenism

Question 4

Which of the following statements about CMML-related anemia is correct?

A. The prospective data to treat anemia in CMML are limited.

B. Unlike the setting of MDS, response rates are independent of serum erythropoietin levels.

C. As in MDS, the addition of granulocyte colony-stimulating factor (G-CSF) is a reasonable approach in patients who are unresponsive to erythropoiesis-stimulating agents.

D. Luspatercept is contraindicated in CMML-related anemia.

E. All of the above

Answers to Hematology Expert Review Questions

Question 1

Which of the following statements about CMML is correct?

Correct Answer: C. Complete responses with hypomethylating agents are observed in fewer than 20% of patients.

Expert Perspective

Clonal cytogenetic abnormalities occur in approximately 20% to 30% of patients with CMML, whereas more than 90% have somatic molecular mutations.^1,2 The diagnosis of CMML still remains one of exclusion, as no clinical, pathologic, or molecular findings are specific for this disease. Molecularly integrated prognostic models are not limited to the CMML-specific prognostic model (CPSS-Mol) but also include the Groupe Français des Myélodysplasies (GFM) and Mayo Molecular Model (MMM). In practice, any of the three molecularly integrated CMML prognostic models can be utilized for risk stratification; there is no international consensus statement with a preference of one over the other.^2-5

Hypomethylating agents are commonly prescribed in CMML, especially in patients showing relevant cytopenia(s) and/or intermediate- and high-risk disease. The overall response rates fall in the range of 40% to 50%, with complete remission rates of less than 20%.^2,6

Question 2

Which of the following statements about the prognosis of low- and intermediate-1 risk categories, based on the MMM and the CPSS-Mol models, or the low-risk category of the GFM model is correct?

Correct Answer: D. Patients in this and other risk groups may have rheumatologic and/or renal issues.

Expert Perspective

Patients with lower-risk CMML include low- and intermediate-1 risk categories in the CPSS-Mol and MMM models or the low-risk category of the GFM model. Symptomatic splenomegaly can be a significant issue regardless of risk group. Thrombocytopenia can be observed in lower-risk CMML attributed to diverse etiologies including hypersplenism, immune-mediated thrombocytopenia, and bone marrow progressive disease. Anemia can also be observed regardless of risk group due to ineffective erythropoiesis, leading to significant morbidity and mortality. Autoimmune and systemic inflammatory manifestations such as erythema nodosum, leukocytoclastic vasculitis, Sweet syndrome, polymyalgia rheumatica, seronegative arthritis, and mixed connective tissue disorder–like syndromes can also be seen in 20% to 30% regardless of the risk group.^1,2

Of note, in proliferative CMML, permissive leukocytosis/monocytosis may be associated with increased lysozyme levels, with a higher prevalence of chronic kidney disease (termed lysozyme nephropathy), more commonly seen in patients with white blood cell counts higher than 30 × 10⁹/L. Hydroxyurea is the preferred agent in proliferative CMML. Patients with lower-risk CMML, on average, have a median overall survival of 60 to 100 months (5–8 years). Several, but not all, lower-risk patients can be observed without any CMML-directed therapy.²

Question 3

Which of the following is not a widely accepted treatment option in patients with dysplastic and proliferative CMML who present with autoimmune phenomena including immune-mediated thrombocytopenia?

Correct Answer: D. Eltrombopag for immune-mediated thrombocytopenia.

Expert Perspective

Although corticosteroids and steroid-sparing/disease-modifying agents are often used in the management of autoimmune manifestations, it is reasonable to administer DNMT inhibitors at conventional or low doses for more durable responses. For immune-mediated thrombocytopenia, corticosteroids and rituximab have been used; the use of thrombopoietin analogs—especially eltrombopag in CMML—requires caution, particularly in proliferative CMML. There are reports of patients with proliferative CMML demonstrating worsening proliferative features, circulating blasts, and bone marrow fibrosis on exposure to eltrombopag.⁷ The GFM group, however, has completed a yet to be published phase II trial (ClinicalTrials.gov identifier NCT02323178) assessing the safety of eltrombopag in patients with CMML patients who have thrombocytopenia (platelet count < 50 × 10⁹/L). In this study, eltrombopag was relatively well tolerated (median dose = 150 mg; range = 100–300 mg), with 46.7% of patients achieving a platelet response (10 with dysplastic CMML and 4 with proliferative CMML) that in general was not durable (median duration = 3.4 months; range = 1.7–11.6 months). Other options for thrombocytopenia include splenectomy when immune-mediated thrombocytopenia or splenic sequestration is suspected and DNMT inhibitors if the etiology is disease-related bone marrow dysfunction or failure.

Question 4

Which of the following statements about CMML-related anemia is correct?

Correct Answer: A. The prospective data to treat anemia in CMML are limited.

Expert Perspective

There are limited prospective CMML-specific data for anemia management. Akin to MDS, the management of anemia largely revolves around red blood cell transfusions and erythropoiesis-stimulating agents.

Erythropoiesis-stimulating agents are more likely to be effective in lower-risk patients, especially when endogenous erythropoietin levels are lower than 200 U/L, and in patients with low or no dependency on red blood cell transfusions. Response rates of 40% to 70% have been observed. The median duration of response is 12 to 18 months. The use of granulocyte G-CSF is avoided for several reasons, including an elevated risk of splenic rupture. Luspatercept may be used in a select group of patients with SF3B1-mutant CMML and ring sideroblasts in the bone marrow. Other options for CMML-related anemia management, outside of a clinical trial, include danazol (an anabolic steroid), lenalidomide (an immunomodulatory agent; note: isolated del5q is seen in up to 1% of CMML cases), and hypomethylating agents, such as azacitidine, intravenous decitabine, and oral decitabine combined with cedazuridine (a cytidine deaminase inhibitor), given in either conventional or attenuated dose schedules.²

Part 2 of this Hematology Expert Review quiz will appear in the December 25 issue of The ASCO Post. 

DISCLOSURE: Dr. Abutalib has served on an advisory board for AstraZeneca. Dr. Patnaik has received research funding from Kura Oncology and Stem Line Pharmaceuticals.

REFERENCES

1. Khoury JD, Solary E, Abla O, et al: The 5th edition of the World Health Organization classification of haematolymphoid tumours: Myeloid and histiocytic/dendritic neoplasms. Leukemia. 36:1703-1719, 2022.

2. Patnaik MM: How I diagnose and treat chronic myelomonocytic leukemia. Haematologica 107:1503-1517, 2022.

3. Itzykson R, Kosmider O, Renneville A, et al: Prognostic score including gene mutations in chronic myelomonocytic leukemia. J Clin Oncol 31:2428-2436, 2013.

4. Patnaik MM, Padron E, LaBorde RR, et al: Mayo prognostic model for WHO-defined chronic myelomonocytic leukemia: ASXL1 and spliceosome component mutations and outcomes. Leukemia 27:1504-1510, 2013.

5. Elena C, Galli A, Such E, et al: Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 128:1408-1417, 2016.

6. Hunter AM, Newman H, Dezern AE, et al: Integrated human and murine clinical study establishes clinical efficacy of ruxolitinib in chronic myelomonocytic leukemia. Clin Cancer Res 27:6095-6105, 2021.

7. Pleyer L, Leisch M, Kourakli A, et al: Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: A retrospective cohort study. Lancet Haematol 8:e135-e148, 2021.