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Understanding leukemia

Rare types of leukemia

AML, ALL, CML and CLL make up the great majority of leukemia cases. But there are also a number of rarer types. Hearing a rare diagnosis can feel isolating — this topic introduces these types briefly and simply, and explains why experienced centres, second opinions and clinical trials matter so much.

Last updated: ~6 min read
Around a translucent human figure on a dark navy background, a softly glowing constellation of cells of different shapes and colours: granular, hairy, large-nucleated and small cells, with a faint DNA helix behind.
Figure 1.Concept: the leukemia family has many rare and very different members.

01Short answer

Most leukemias belong to the four main types, but the WHO classification recognises dozens of rarer forms. They include chronic myelomonocytic leukemia (CMML), a disease with features of both MDS and myeloproliferation, most common at ages 65–75; juvenile myelomonocytic leukemia (JMML), mainly in children around age 2; large granular lymphocyte (LGL) leukemia, often a slow-growing disease of T or NK cells; prolymphocytic leukemia; mixed phenotype acute leukemia (MPAL), in which blasts carry both myeloid and lymphoid markers; blastic plasmacytoid dendritic cell neoplasm (BPDCN), often with skin lesions; adult T-cell leukemia/lymphoma (ATLL), linked to the HTLV-1 virus; chronic neutrophilic and eosinophilic leukemias; and mast cell leukemia. With rare types, an experienced laboratory and centre, often a second opinion, and clinical trials are especially important.

02Simple explanation

Leukemia is not one disease but a family. Its four “big” members — AML, ALL, CML and CLL — are the best known. But the family also has rarer relatives: each one arises from a particular type of cell and particular genetic changes.

Some rare types are “borderline” diseases. For example, CMML combines features of faulty cell maturation (like MDS) and overproduction (myeloproliferation). JMML, which affects young children, belongs to the same group.

Some types are very slow and may need only monitoring for years — for example, many cases of LGL leukemia. Others are fast and aggressive — for example BPDCN, mast cell leukemia or prolymphocytic leukemia — and need urgent, specialised treatment.

Diagnosing rare leukemias can be difficult: under the microscope, the cells can look like other diseases. That is why flow cytometry, genetic tests and an experienced hematopathologist matter so much. Sometimes samples are sent to another centre for a second opinion — this is normal and helpful practice.

A rare disease does not mean a hopeless one. New targeted drugs have appeared for many rare types in recent years, and clinical trials offer new possibilities. If you are facing a rare diagnosis, ask your doctor about centres with experience of the disease and about available trials.

03Scientific explanation

CMML is the main member of the MDS/MPN group: persistent monocytosis in the blood, no BCR::ABL1 or PDGFRA/PDGFRB rearrangement, blasts <20% and dysplasia or a clonal abnormality (WHO 2022 lowered the monocyte threshold). According to the NCI, median age at diagnosis is 65–75, with a male predominance; progression to AML worsens the outlook. Hypomethylating agents can help symptoms and low counts; an allogeneic stem cell transplant is the only potential cure. JMML, according to the NCI, is most common in children around age 2 and more common in boys; it is linked to disruption of the RAS signalling pathway and can be associated with conditions such as neurofibromatosis type 1 and Noonan syndrome; in most cases, treatment is an allogeneic transplant.

LGL leukemia can be T-cell (T-LGL) or NK-cell; the NCI describes it as a chronic disease that may last a long time and get worse. T-LGL is often accompanied by neutropenia, anemia and autoimmune conditions such as rheumatoid arthritis, and is frequently treated with immunosuppressive drugs; monitoring may be enough when there are no symptoms. Prolymphocytic leukemia (PLL) is a form with increased prolymphocytes in the blood and marrow that progresses faster than classic CLL; T-PLL is a separate aggressive disease, while WHO 2022 no longer recognises B-PLL as a separate category.

Mixed phenotype acute leukemia (MPAL) is part of the acute leukemias of ambiguous lineage: the blasts carry myeloid and lymphoid (B or T) markers at the same time, or there are two separate blast populations; some cases carry BCR::ABL1 or a KMT2A rearrangement. It is often treated with ALL-type protocols, and a transplant is frequently discussed. BPDCN, according to the NCI, is a rare, fast-growing cancer affecting the blood, marrow and skin; most patients have red-brown or deep purple skin lesions, and it usually occurs in older adults; the cells carry CD123, and a CD123-directed drug (tagraxofusp) is one treatment option.

ATLL is an aggressive T-cell lymphoma/leukemia caused by the HTLV-1 virus; the NCI notes bone and skin lesions, high calcium and enlarged lymph nodes, spleen and liver; it is more common where the virus is widespread (for example parts of Japan and the Caribbean). Chronic neutrophilic and chronic eosinophilic leukemias are myeloproliferative neoplasms; they can stay stable for years or progress quickly. Mast cell leukemia is a very rare, aggressive form of systemic mastocytosis. In newborns with Down syndrome, transient abnormal myelopoiesis (TAM) usually goes away on its own within the first 3 months, but raises the later risk of AML (NCI).

04What happens in the body?

Rare branches of the family tree

Each rare leukemia arises from a particular branch of the blood “family tree”: myeloid (CMML, JMML, chronic neutrophilic/eosinophilic leukemias, mast cell leukemia), lymphoid (LGL, PLL, ATLL), dendritic cells (BPDCN) or combining features of both lines (MPAL). Knowing the branch helps choose treatment.

A glowing tree branching from a stem cell on a dark background; the main branches are bright, and small cells of different colours glow faintly at the tips of a few thin side twigs.
Figure 2.Each rare leukemia arises from a particular branch of the blood family tree.

Slow and fast rare types

LGL leukemia and some chronic myeloid neoplasms can remain stable for years. BPDCN, mast cell leukemia, T-PLL and acute ATLL progress quickly. So the word “rare” by itself says nothing about how serious a disease is.

Accurate diagnosis: experience matters

With rare types, flow cytometry, cytogenetics, molecular tests and the eye of an experienced hematopathologist can be decisive. Sending a sample to a specialised laboratory or getting a second opinion can improve accuracy without delaying treatment.

A laboratory specialist in a mask and gloves looking through a microscope
Figure 3.With rare types, an experienced laboratory is decisive for an accurate diagnosis.

Clinical trials and support

In rare diseases there is less information about standard treatment, so clinical trials are often one of the best options. Patient organisations and online communities can help you connect with people who have a similar diagnosis.

05What to do with a rare diagnosis

With a rare leukemia, the path usually goes through these steps.

Which branch? — Myeloid, lymphoid, dendritic or mixed.1Which branch?Myeloid, lymphoid, dendritic or mixed.
Precise markers — Flow cytometry and genetic tests.2Precise markersFlow cytometry and genetic tests.
Expert review — An experienced laboratory or a second opinion.3Expert reviewAn experienced laboratory or a second opinion.
A personal plan — Monitoring, targeted treatment, transplant or a trial.4A personal planMonitoring, targeted treatment, transplant or a trial.
Accurate diagnosisThe foundation of the right treatment.
An experienced teamEspecially important in rare diseases.
Clinical trialsAccess to new treatments.

06Some rare types of leukemia at a glance

TypeWho is more often affected?Key feature
CMMLOlder adults (median 65–75), more often menMonocytosis; features of MDS and MPN; can progress to AML
JMMLYoung children (most often around age 2), more often boysRAS pathway disruption; sometimes with NF1 or Noonan syndrome
LGL leukemia (T or NK)Mainly adultsOften slow; neutropenia, autoimmune conditions
Prolymphocytic leukemiaMainly older adultsProlymphocytes; faster than classic CLL
MPALChildren and adultsBlasts carry both myeloid and lymphoid markers
BPDCNMainly older adultsSkin lesions; CD123; fast course
ATLLAdults carrying HTLV-1Skin and bone lesions, high calcium
Chronic neutrophilic / eosinophilic leukemiaMainly adultsExcess neutrophils or eosinophils; the spleen may enlarge
Mast cell leukemiaAdultsAn aggressive form of systemic mastocytosis
TAMNewborns with Down syndromeOften goes away on its own; later AML risk

* This table is only a general overview and not a complete list. The diagnostic criteria and treatment of each type are complex and are assessed by a specialist.

07Key terms

CMML
Chronic myelomonocytic leukemia — a disease with features of MDS and MPN.
JMML
Juvenile myelomonocytic leukemia — a rare leukemia of young children.
MDS/MPN
A group of diseases with features of both dysplasia and overproduction.
LGL leukemia
A leukemia of large granular T or NK lymphocytes.
Prolymphocyte
An immature form of lymphocyte.
MPAL
Mixed phenotype acute leukemia.
BPDCN
Blastic plasmacytoid dendritic cell neoplasm.
HTLV-1
A virus that can cause ATLL.
Mastocytosis
An excess build-up of mast cells in tissues.
Second opinion
A review of the diagnosis or treatment plan by another specialist.

08Key points

  • Besides the four main types, the leukemia family has many rare types.
  • Each rare type arises from a particular cell branch and genetic changes.
  • Some rare types progress slowly, others quickly.
  • Accurate diagnosis relies on flow cytometry, genetics and an experienced laboratory.
  • A second opinion is normal and helpful practice with rare diagnoses.
  • New targeted drugs have appeared for many rare types.
  • Clinical trials are an especially important option in rare diseases.

09Frequently asked questions

I have a rare type of leukemia. Does that mean a worse outlook?

Not necessarily. Some rare types progress very slowly and need only monitoring for years, while others are aggressive. The outlook depends on the type of disease, its genetic features and your general health — your hematologist will explain this.

Will my doctor be offended if I ask for a second opinion?

No. In rare diseases, a second opinion is common and recommended practice. Most doctors understand and will help provide the necessary records and samples.

How can I find a clinical trial for a rare leukemia?

Ask your doctor; you can also search international trial registries (such as ClinicalTrials.gov). Trial criteria differ, so discuss suitable options with your team.

My child has been diagnosed with JMML. What does that mean?

JMML is a rare leukemia of young children. In many cases, treatment includes a stem cell transplant. The pediatric hematologist and transplant team will explain the situation and the options in detail.

Are rare leukemias inherited?

In most cases, no. But some rare forms (such as JMML) can be linked to certain inherited syndromes. Discuss any questions about family history with your doctor.

Where can I find people with a similar diagnosis?

International patient organisations and online support groups bring together people with rare leukemias. Always check online information against reliable sources and make medical decisions with your team.

10Questions for your doctor

Take these questions to your appointment. The ones you save are collected on the “My questions” page and stay on this device only.

  1. If my leukemia is a rare type, is there a centre experienced in it?

  2. Is there a standard treatment for this type, or should a clinical trial be considered?

  3. Would a second opinion be helpful?

  4. Where can I find reliable information on this rare type?

My questions

12Sources

  1. National Cancer Institute (NCI). Myelodysplastic/Myeloproliferative Neoplasms Treatment (PDQ®) — Health Professional Version
  2. National Cancer Institute (NCI). Myelodysplastic/Myeloproliferative Neoplasms Treatment (PDQ®) — Patient Version
  3. National Cancer Institute (NCI). Childhood Acute Myeloid Leukemia and Other Myeloid Malignancies Treatment (PDQ®) — Patient Version
  4. National Cancer Institute (NCI). Chronic Myeloproliferative Neoplasms Treatment (PDQ®) — Patient Version
  5. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: T-cell large granular lymphocyte leukemia
  6. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: prolymphocytic leukemia
  7. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: blastic plasmacytoid dendritic cell neoplasm
  8. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: adult T-cell leukemia/lymphoma
  9. National Cancer Institute (NCI). NCI Dictionary of Cancer Terms: mast cell leukemia
  10. American Cancer Society. Childhood Leukemia
  11. Leukemia (Nature) — WHO 5th edition. WHO Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms
  12. Leukemia (Nature) — WHO 5th edition. WHO Classification of Haematolymphoid Tumours: Lymphoid Neoplasms
Medical disclaimerThis information is for educational purposes only and does not replace medical advice.
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