What Is the WHO vs ICC Difference in CMML Diagnosis?

A pathology report might classify your chronic myelomonocytic leukemia (CMML) differently than a second opinion because hematologists currently use two overlapping rulebooks: the 2022 World Health Organization (WHO) 5th Edition and the 2022 International Consensus Classification (ICC). While they are very similar, they weigh certain criteria—like the physical appearance of bone marrow cells and the presence of genetic markers—differently. This means a patient might be diagnosed with CMML under the WHO system, but given a different diagnosis (like a myelodysplastic syndrome, or MDS) under the ICC system.

The Lowered Monocyte Threshold

Both the WHO and ICC updated their criteria in 2022 to recognize “oligomonocytic” (low-monocyte) CMML. Previously, an absolute monocyte count of 1.0 x 10^9/L was required. Now, both systems have lowered this prerequisite threshold to 0.5 x 10^9/L, provided that monocytes make up at least 10% of your total white blood cells (the relative monocyte count) and the elevation has persisted for over 3 months ^[1][2].

However, having these monocyte counts is not enough on its own to be diagnosed with CMML. In this lower count range, both systems require additional evidence to confirm the diagnosis, and this is where the two rulebooks disagree ^[1].

Where the Guidelines Disagree: Dysplasia and Clonality

The main reason for conflicting reports is how each system handles dysplasia (when blood cells look physically abnormal under a microscope) and clonality (a population of cells descended from a single genetically altered cell).

• The ICC Approach: The ICC requires strict morphological (physical) evidence of dysplasia in the bone marrow to diagnose CMML in patients with borderline low monocyte counts ^[1].
• The WHO Approach: The WHO criteria are more flexible. If you lack definitive physical signs of dysplasia but have a qualifying genetic mutation indicating clonality, the WHO may still classify your disease as CMML ^[1][2].

Because of these differences, research comparing the two systems found that the WHO classified roughly 1.5 times as many borderline low-count cases as CMML compared to the ICC, which classified many of those same cases as MDS or as unclassifiable ^[3].

Required Exclusion Tests

Before confirming CMML, doctors must rule out other causes of high monocytes. This includes non-cancerous causes like chronic infections, inflammation, or autoimmune diseases ^[4][5].

They must also perform genetic testing to exclude other specific blood cancers, such as chronic myeloid leukemia (defined by the BCR::ABL1 fusion gene) and neoplasms involving rearrangements in genes like PDGFRA, PDGFRB, FGFR1, or PCM1::JAK2 ^[6][7]. Finding common mutations like TET2, SRSF2, or ASXL1 supports a CMML diagnosis, but because these mutations can occur in other diseases or even in healthy aging, they do not prove you have CMML on their own ^[8][9].

MD-CMML vs. MP-CMML

Both systems divide CMML into two main categories based on your total white blood cell (WBC) count at the time of assessment:

• MD-CMML (Myelodysplastic CMML): Your WBC count is less than 13 x 10^9/L ^[2][10].
• MP-CMML (Myeloproliferative CMML): Your WBC count is 13 x 10^9/L or higher ^[2][10].

This classification describes a clinical pattern. Because blood counts can fluctuate, this label can sometimes change over time. Notably, because the ICC excludes many lower-count patients from a CMML diagnosis entirely, studies show fewer patients receive an MD-CMML diagnosis under ICC rules than under WHO rules ^[1][3].

Blasts and CMML Subtypes (CMML-1 and CMML-2)

To be diagnosed with CMML, blasts (immature leukemia cells) and promonocytes (slightly more developed but still abnormal cells) must make up less than 20% of the cells in your blood and bone marrow ^[2][10]. Promonocytes are counted together with blasts for this limit.

Depending on the exact percentage, your CMML is classified into subtypes to help estimate risk:

• CMML-1: Blasts and promonocytes are less than 5% in the blood AND less than 10% in the bone marrow ^[10].
• CMML-2: Blasts and promonocytes are between 5-19% in the blood OR between 10-19% in the bone marrow ^[10].

Summary of Diagnostic Criteria

Does the Label Change Your Treatment?

Finding out that two reports classify your disease differently can be incredibly stressful. While the immediate treatment plan may often be similar regardless of the label, a difference in classification can sometimes affect your prognostic grouping, your eligibility for certain clinical trials, or discussions around stem cell transplants ^[1][11].

Treatment decisions rely on your whole clinical picture. Doctors use comprehensive molecular risk models that combine your clinical symptoms, blood counts, and genetic profile to estimate your risk ^[12]. When reports conflict, it is essential to have an experienced hematopathologist review your original bone marrow slides, and to discuss with your hematologist how the specific label might change your follow-up care or treatment options ^[13].