The ASCO Post is pleased to present Hematology Expert Review, an ongoing feature that quizzes readers on issues in hematology. In the concluding half of this two-part installment, which began in our November 25 issue, Drs. Syed Ali Abutalib and Mrinal M. Patnaik continue to 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.

GUEST EDITORS

Syed Ali Abutalib, MD

Mrinal M. Patnaik, MD

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

Introduction

As we noted in part 1, chronic myelomonocytic leukemia (CMML) is a myeloid neoplasm characterized by a pathologic accumulation of monocytic cells manifesting with coexisting signs of myeloproliferation along with 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 and a male:female predominance of 2:1.^1,2 

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). Here, 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 the treatment of CMML-related symptomatic/massive splenomegaly is correct?

A. Hydroxyurea may be preferred over a hypomethylating agent in such cases.

B. Unlike in primary myelofibrosis, there is no role for ruxolitinib.

C. Splenectomy should be considered.

D. Both B and C

Question 2

Which of the following statements about the prognosis and treatment of intermediate-2 and high-risk categories in the CMML-specific prognostic model (CPSS-Mol) and the Mayo Molecular Model (MMM) and high-risk category of the Groupe Français des Myélodysplasies (GFM) model is correct?

A. On average, these patients have a median overall survival of less than 2 years.

B. Hydroxyurea and hypomethylating agents are noncurative therapeutic options.

C. Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative option.

D. All of the above

Question 3

Which of the following statements about allo-HCT in the treatment of CMML is correct?

A. The best outcomes are achieved in patients with the lowest disease burden at the time of allo-HCT.

B. Registry data from the European Society for Blood and Marrow Transplantation (EBMT) reported a 4-year overall survival rate of 33%.

C. Allo-HCT should be considered in eligible
patients with advanced CMML.

D. All of the above

Question 4

Which of the following agents is/are in clinical trial(s) for patients with CMML?

A. Anti–granulocyte macrophage colony-stimulating factor (GM-CSF) monoclonal antibody

B. Farnesyl transferase inhibitor

C. JAK1/2 inhibitor

D. Protein conjugate involving IL-3 and truncated components of the diphtheria toxin

E. MEK inhibitor

F. All of the above 

Answers to Hematology Expert Review Questions

Question 1

Which of the following statements about the treatment of CMML-related symptomatic/massive splenomegaly is correct?

Correct Answer: A. Hydroxyurea may be preferred over a hypomethylating agent in such cases.

Expert Perspective

Hydroxyurea may be preferred over hypomethylating agents in the management of symptomatic/massive splenomegaly from CMML. If hydroxyurea is well tolerated, it should be used in the first line for the management of proliferative CMML, including in patients with massive splenomegaly.^2-6 Patients with CMML who have massive splenomegaly are often symptomatic, have a hypercatabolic state, and are at risk for spontaneous splenic rupture, which can result in catastrophic intra-abdominal hemorrhage.

Recent data using the JAK1/2 inhibitor ruxolitinib in patients with CMML have been encouraging, with splenic response rates of 43%. Ruxolitinib was well tolerated, with the two most common grade 3 and 4 treatment-related toxicities being anemia (10%) and thrombocytopenia (6%). Hypomethylating agents, splenic radiation therapy, and splenectomy are generally avoided for spleen control, given inherent complications such as worsening cytopenias with hypomethylating agents, lack of durable responses with radiation therapy, and surgical morbidity and mortality associated with splenectomy, respectively.⁶

Question 2

Which of the following statements about the prognosis and treatment of intermediate-2 and high-risk categories in the CMML-specific prognostic model (CPSS-Mol) and the Mayo Molecular Model (MMM) and high-risk category of the Groupe Français des Myélodysplasies (GFM) model is correct?

Correct Answer: D. All of the above

Expert Perspective

On average, patients with high-risk CMML have a median overall survival of less than 2 years. It is best to use a hypomethylating agent in dysplastic CMML with higher-risk disease or clinically significant cytopenias, especially in the presence of TET2 mutations and the absence of ASXL1 mutations. For patients who respond to a hypomethylating agent, the median duration of response is 12 to 18 months.^2-6 

In the prospective phase III randomized ­DACOTA trial, which assessed the efficacy of decitabine vs hydroxyurea in patients with higher-risk proliferative (white blood cell count ≥ 13 × 10⁹/L) CMML, there was no difference in overall survival or event-free survival between the hydroxyurea and decitabine arms. However, one-third of hydroxyurea recipients subsequently received decitabine, and more decitabine-treated patients achieved a response and were taken to allo-HCT.^2-6 

Subsequently, a 2021 retrospective study using the same eligibility criteria as the DACOTA trial analyzed the outcomes of ­hypomethylating agents (n = 412) vs hydroxyurea (n = 391) vs intensive chemotherapy (n = 83). The adjusted median overall survival favored hypomethylating agents over hydroxyurea (hazard ratio = 1.39, 95% confidence interval = 1.17–1.65, P = .0002). Hypomethylating agents did not confer an overall survival advantage for patients with myelodysplastic CMML with less than 10% blasts.⁷ 

Cytoreductive intensive chemotherapy may be a reasonable option in selected younger fit patients with AML transformation or high blast counts. There are limited prospective data on the use of hypomethylating agents and the BCL2 antagonist venetoclax in CMML and transformed CMML (secondary AML).⁸ Overall, allo-HCT remains the only curative option for patients with CMML, but less than 10% of patients are eligible, given the advanced median age of diagnosis and attendant comorbidities.

Question 3

Which of the following statements about allo-HCT in the treatment of CMML is correct?

Correct Answer: D. All of the above

Expert Perspective

For patients with more than 10% bone marrow blasts, it is best to administer cytoreductive treatment before allo-HCT; the best therapy to accomplish this goal remains unclear and is a controversial area. In a retrospective study from the Mayo Clinic, allo-HCT achieved a 5-year overall survival of 51% in chronic-phase CMML vs 19% in blastic transformation of CMML, underscoring the importance of early allo-HCT, especially in higher-risk patients.^2,4

In the largest study to date of allo-HCT, the EBMT reported the outcomes of 513 patients (median age = 53 years), of whom 249 received myeloablative conditioning and 228 received reduced-intensity conditioning.⁵ The 4-year nonrelapse mortality was 41%, and the relapse rate was 32%, accounting for a 4-year relapse-free survival rate of 27% and an overall survival rate of 33%. In this study, the only factor prognostic for favorable outcomes was the achievement of a complete remission at the time of allo-HCT. 

Allo-HCT should be considered in all eligible patients with CMML. Transplant eligibility should not rely on a fixed age limit but on accurate assessment of frailty, comorbidities, and overall performance status. A recent consensus document from an expert panel recommends upfront allo-HCT for intermediate-2 and high-risk patients with CMML (CPSS risk stratification) with less than 10% bone marrow blasts.³

Question 4

Which of the following agents is/are in clinical trial(s) for patients with CMML?

Correct Answer: F. All of the above

Expert Perspective

CMML-specific trials include investigations assessing the safety and efficacy of lenzilumab (an anti–GM-CSF monoclonal antibody, ClinicalTrials.gov identifier NCT02546284), tipifarnib (a farnesyl transferase inhibitor, NCT02807272), ruxolitinib (a JAK1/2 inhibitor, NCT03722407), cobimetinib (a MEK inhibitor, NCT04409639), and tagraxofusp-erzs (a protein conjugate involving IL-3 and truncated components of the diphtheria toxin, NCT02268253).^2,6 

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. de Witte T, Bowen D, Robin M, et al: Allogeneic hematopoietic stem cell transplantation for MDS and CMML: Recommendations from an international expert panel. Blood 129:1753-1762, 2017.

4. Pophali P, Matin A, Mangaonkar AA, et al: Prognostic impact and timing considerations for allogeneic hematopoietic stem cell transplantation in chronic myelomonocytic leukemia. Blood Cancer J 10:121, 2020.

5. Symeonidis A, van Biezen A, de Wreede L, et al: Achievement of complete remission predicts outcome of allogeneic haematopoietic stem cell transplantation in patients with chronic myelomonocytic leukaemia. A study of the Chronic Malignancies Working Party of the European Group for Blood and Marrow Transplantation. Br J Haematol 171:239-246, 2015.

6. 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.

7. Itzykson R, Santini V, Chaffaut C, et al: Decitabine versus hydroxyurea for advanced proliferative CMML: Results of the EMSCO randomized phase 3 DACOTA trial. Blood 136(suppl 1):53-54, 2020.

8. DiNardo CD, Jonas BA, Pullarkat V, et al: Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med 383:617-629, 2020.