Chronic myelomonocytic leukemia

CMML is a cancer of the blood-forming cells in the marrow, and the classification puts it in a category of its own. It is not a myelodysplastic syndrome and not a myeloproliferative neoplasm — it is an overlap between the two.

Those two words are worth unpacking. Myelodysplastic means the marrow makes blood cells that are misshapen and work poorly, so counts run low. Myeloproliferative means the marrow makes too many of a cell type, so counts run high. CMML shows both at once, in varying mixtures — one disease on a spectrum rather than two stapled together.

It is defined by monocytes. A monocyte is a white blood cell that engulfs microbes and clears debris, and CMML requires them to be persistently raised — at least 0.5 × 10⁹/L, and at least 10% of the white cells. The 2022 classification lowered that absolute threshold from 1.0, absorbing cases previously described as “oligomonocytic”.

Two labels then get applied at once, and both may appear on a report. A subtype by white cell count — myelodysplastic CMML below 13 × 10⁹/L, myeloproliferative CMML at or above it. And a grade by how many immature cells are present: CMML-1 or CMML-2.

Changes acquired in the DNA of blood-forming stem cells during a person’s life. Not inherited, not passed to children, and not caused by anything the person did or failed to do.

Recurring changes have been identified in most people with CMML, and they fall into a few functional groups: genes that control which other genes are switched on, genes that edit RNA messages before they are used, growth switches that get stuck on, and master switches controlling blood-cell development.

It is strongly age-related, with a median age at diagnosis somewhere between 65 and 75 depending on the series, and it is more common in men. Previous anticancer treatment, radiation and some chemical exposures are recognised risk factors, but for most people no cause is ever identified.

CMML has two clinical faces, and which one a person has changes both what they feel and what is offered first.

The dysplastic face behaves like a myelodysplastic neoplasm: low counts. Anemia bringing fatigue and breathlessness, low platelets bringing bruising and bleeding, and too few working neutrophils bringing repeated infections — often with a long-running need for red cell transfusions.

The proliferative face behaves like a myeloproliferative neoplasm: an enlarged spleen and liver, constitutional symptoms such as fever, weight loss and night sweats, and blood cells being made outside the marrow. Reviews describe this face as running a more aggressive course.

The feared event in either case is transformation to acute myeloid leukemia, when the immature cell count crosses 20%. Published estimates of how often that happens differ between sources and none of them names a cohort, region or period — so we give it as a range attributed to its source rather than as a figure.

One practical thing worth knowing: a full risk assessment needs chromosome studies and a molecular panel, so the risk band is not knowable on the day of diagnosis. Waiting weeks for that result is normal care, not a delay in it.

There is no single pathway. What is offered depends on the risk band and on which face — dysplastic or proliferative — dominates.

Supportive care manages the counts and the symptoms without changing the disease: transfusions, growth factors, antibiotics.

Hypomethylating agents — azacitidine and decitabine — strip chemical tags off DNA so silenced genes can switch back on. They can improve counts, reduce an enlarged spleen and relieve symptoms, with response rates reported around 30% to 60%. Response is not remission, and complete remission is uncommon.

Hydroxyurea is used to bring down high counts in proliferative disease, and there is a comparison worth knowing about. In a randomised trial of 170 people, decitabine against hydroxyurea showed no significant difference in survival. Decitabine reduced progression to acute leukemia by 38%, but that was offset by a 55% increase in deaths from other causes, usually infection. The newer drug did not beat the older one on survival.

A transplant is the only potentially curative option, and EBMT states plainly that it is applicable to only a minority of patients.

Clinical trials are a routine option at every stage here rather than a last resort.

Most people meeting this diagnosis are in their late sixties or seventies, and a good many arrive at it through a blood count that would not settle rather than through feeling suddenly ill.

Then comes a wait. The risk band cannot be known until chromosome and molecular results come back, and that band determines whether the conversation is about controlling the disease or about a transplant. Several weeks of not knowing which conversation you are in is a genuinely hard part of this illness, and it is normal.

For those on the dysplastic side, life becomes transfusions and counts. For those on the proliferative side it is more often an enlarged spleen, night sweats and weight loss — a different daily experience from the same diagnosis.

For the minority who go to transplant, it is a serious undertaking in an older population, and the decision is made against real relapse and mortality figures rather than against a hope.

For the minority of people with CMML who are transplant candidates, a donor is the only route to a potentially curative treatment. For everyone else a donor is not part of the plan, and saying that plainly is more useful than implying otherwise.

For those candidates, EBMT rates a well-matched unrelated donor as standard of care alongside a matched sibling — and rates mismatched alternative donors, including cord blood and half-matched relatives, the same way. An unrelated donor is a first-line option here rather than a fallback, and a registry match is not the only path to a transplant.

The decision rule is indexed on the CMML-specific molecular score. High-risk people who are eligible and have a donor go straight to transplant; intermediate-2 with an additional risk factor likewise; low and intermediate-1 disease is monitored closely rather than transplanted.

Upfront transplant is preferred over treating first — unless there is a delay in donor availability, or the disease is moving fast, in which case hypomethylating agents are used as a bridge. Donor availability is one of the things that can force that detour.