Leukemia is a type of cancer that starts in the bone marrow and can move into the blood. Staging, or determining how advanced the cancer is, is important for pinpointing effective treatments. For most cancers, the stage depends on the size and location of tumors, and how far the cancer has spread in the body.

Leukemia behaves differently from most cancers. Since leukemia is a blood cancer, it typically does not form solid tumors and has usually spread throughout the body before it is diagnosed. Therefore, the stages of leukemia are characterized differently from other types of cancer. While some types of leukemia are described using different stages, others are characterized as specific subtypes or classifications and are not staged like other types of cancers.

There are many different kinds of leukemia, which are described by how quickly the cancer progresses and the types of cells that are involved. There are subtypes within each group. The four main types of leukemia are:

• Acute lymphoblastic leukemia (ALL)
• Acute myeloid leukemia (AML, also called acute myelogenous leukemia)
• Chronic lymphocytic leukemia (CLL)
• Chronic myeloid leukemia (CML, also called chronic myelogenous leukemia)

Leukemia cells are immature white blood cells (also called blast cells) that develop certain genetic mutations. These mutations make the cells grow abnormally quickly. As the leukemia cells expand, they can crowd out other cell types — like red blood cells (RBCs) and platelets. When there are too many leukemia cells and not enough of the other blood cells, the body has a more difficult time fighting infections, transporting oxygen, and clotting properly. This imbalance of blood cell types leads to symptoms of leukemia like weakness, fatigue, swollen lymph nodes, muscle aches, bone and joint pain, shortness of breath, anemia (not enough RBCs), cuts that don’t clot well due to low platelets (thrombocytopenia), and bruising. Occasionally, leukemia cell numbers can grow to such an extent that they can obstruct blood vessels and cause heart attacks, strokes, or vascular problems. Very high numbers of leukemia cells can also produce a fever and cause weight loss.

Acute Lymphocytic Leukemia (ALL) Classification

ALL doesn’t have a standard staging system. Instead, it is classified into different subtypes. A group of French, American, and British (FAB) experts originally created a system for characterizing ALL in the 1970s. This system was based on what leukemia cells looked like under a microscope, and included the subtypes L1, L2, or L3. Newer technology and tests now let doctors classify leukemia cells more accurately. The World Health Organization (WHO) updated the ALL classification system in 2016.

The WHO system is based on which kind of white blood cells are cancerous. B cells and T cells are white blood cells that play important roles in the immune system. B cells (also called B lymphocytes) are responsible for making antibodies to fight infections. T cells (also called T lymphocytes) help protect the body from infection.

WHO classifies ALL as:

• B-cell ALL
• T-cell ALL
• Mixed lineage acute leukemia (various types of white blood cells are affected, with characteristics of both ALL and AML)

Subtypes within these categories depend on specific genetic changes seen in the cells.

Acute Myeloid Leukemia (AML) Classification

The National Cancer Institute explains that AML can be described as untreated, in remission, or recurrent.

• Untreated AML is newly diagnosed and has not been treated, except to relieve symptoms of leukemia. In untreated AML, at least 20 percent of the bone marrow cells are leukemia cells.
• AML in remission has been treated and there are no symptoms of leukemia. Blood counts are normal and fewer than 5 percent of bone marrow cells are leukemia cells.
• Recurrent AML occurs when AML that has been treated returns in the blood or bone marrow.

FAB Classification of AML

According to the American Cancer Society, a group of French, American, and British (FAB) leukemia experts worked together to categorize AML into eight subtypes in the 1970s. The subtypes were labeled M0 through M7. These subtypes are based on the type of leukemia cells present in the body and what they look like under a microscope. These FAB subtypes are:

• M0 — Undifferentiated acute myeloblastic leukemia
• M1 — Acute myeloblastic leukemia with minimal maturation
• M2 — Acute myeloblastic leukemia with maturation
• M3 — Acute promyelocytic leukemia
• M4 — Acute myelomonocytic leukemia
• M4 eos — Acute myelomonocytic leukemia with eosinophilia
• M5 — Acute monocytic leukemia
• M6 — Acute erythroid leukemia
• M7 — Acute megakaryoblastic leukemia

Subtypes M0 through M5 start from immature white blood cells. M6 starts from immature RBCs, and M7 starts from immature platelet cells.

The FAB classification system can be helpful, but it is only based on how the cells look under a microscope. The FAB system does not consider factors that can affect the outlook for AML.

WHO Classification of AML

The World Health Organization (WHO) updated a classification system for AML in 2016. The WHO system is based on genetic changes that can happen in cancer cells, which cells are affected, and how quickly the cancer cells grow. The major WHO subtypes of AML are:

• AML with recurrent genetic abnormalities
• AML with myelodysplasia-related changes
• Therapy-related myeloid neoplasms
• AML, NOS (not otherwise specified)
• Myeloid sarcoma
• Myeloid proliferations related to Down syndrome

Doctors can detect the genetic changes in the cancer cells of AML to determine a person’s prognosis. Some genetic changes have a better outlook than others.

Chronic Lymphocytic Leukemia (CLL) Stages

There are two major staging systems for CLL: Rai and Binet.

Rai Classification of CLL

The Rai classification system for CLL was developed in 1975 and is most commonly used in the United States. Rai stages are based on the number of lymphocytes, a type of white blood cell in the blood and bone marrow. Lymphocytes include T cells and B cells, which play important roles in fighting off bacteria and viruses. When there are too many lymphocytes, this is indicative of leukemia and is called lymphocytosis.

All of the Rai stages involve lymphocytosis, but the different stages depend on the enlargement of lymph tissues (lymph nodes, spleen, and liver), and the number of red blood cells and platelets. An enlarged spleen, enlarged lymph nodes, or an enlarged liver can be found during a physical exam. Blood cell counts can be determined using a blood test.

Enlarged lymph tissues, more lymphocytes, and fewer red blood cells and platelets occur with more severe CLL. The five Rai stages are:

• Stage 0 (low risk) — No enlargement of lymph tissues, and other blood cells (RBCs and platelets) are normal.
• Stage 1 (intermediate risk) — Lymph nodes are enlarged, but the spleen and liver are not. RBCs and platelet counts are near normal.
• Stage 2 (intermediate risk) — Enlarged spleen, but the lymph nodes and liver may or may not be enlarged, and RBCs and platelets are near normal.
• Stage 3 (high risk) — The lymph nodes, spleen, and liver may or may not be enlarged, but RBCs are low (anemia). Platelets are near normal.
• Stage 4 (high risk) — The lymph nodes, spleen, and liver may be enlarged. The RBCs might be low or near normal, but the platelets are low (thrombocytopenia).

Binet Classification of CLL

Another staging system for CLL is the Binet staging system. The Binet staging system is more commonly used in Europe. This system is based on the number of enlarged lymph tissue areas (lymph nodes or liver) and the number of red blood cells and platelets in the blood and bone marrow.

• Stage A — RBC and platelet counts are normal, and fewer than three lymph areas are enlarged.
• Stage B — Three or more lymph areas are enlarged, but RBCs and platelets are normal.
• Stage C — Any number of lymph areas can be enlarged, and RBCs or platelets are low.

The American Society of Clinical Oncology notes that Binet stage A corresponds to Rai stages 0, 1, and 2, and is low or intermediate risk. Binet stage B corresponds to Rai stages 1 and 2 and is intermediate risk. Binet stage C corresponds to Rai stages 3 and 4 and is high risk.

Chronic Myeloid Leukemia (CML) Phases

The American Cancer Society, based on WHO guidelines, describes three phases of CML that can help predict outlook: chronic, accelerated, and blast. CML stages can change, and different doctors might have slightly different definitions. The American Cancer Society suggests talking with your oncologist if you are unsure how they classify CML. CML phases are based on the number of blasts (immature white blood cells) in the blood and bone marrow.

In the chronic phase, leukemia symptoms are mild and fewer than 10 percent of cells in the blood and bone marrow are blast cells.

If one of the following conditions is present, CML is considered to be in the accelerated phase:

• Between 15 percent to 30 percent of blood or bone marrow cells are blasts.
• A type of white blood cell called basophils make up more than 20 percent of blood cells.
• Very low platelet counts (thrombocytopenia) are present.
• Genetic changes have occurred in leukemia cells.
• At least 30 percent of the blood is made of a combination of blasts and promyelocytes.

In the acute phase, bone marrow or blood cells contain more than 20 percent blast cells, and leukemia symptoms are present. This is also called the blastic phase. When this condition is accompanied by an enlarged spleen, fever, and tiredness, it is called blast crisis.

Staging Challenges

Staging of leukemia can be difficult due to the variability of this disease. There are many genetic changes or abnormalities within each type of leukemia. However, understanding how a cancer behaves is important to determine an effective treatment plan. As technology advances, researchers can better understand the different stages and phases of leukemia to provide more treatment options and improve the outlook for people with leukemia.