Acute leukemia is a cancer characterized by the rapid growth of abnormal blood cells in the bone marrow and blood. These cancers are categorized based on the type of blood cell they affect. A rare and complex form known as Mixed Phenotype Acute Leukemia (MPAL) presents a unique challenge because it does not fit into standard classifications. It represents only about 1-3% of all acute leukemia cases and is notable for the ambiguous nature of its cancerous cells.
Defining Mixed Phenotype Acute Leukemia
Leukemias are classified based on the origin of the cancerous cells. Blood cells originate from stem cells in the bone marrow, which develop along two primary lineages: myeloid and lymphoid. Myeloid stem cells mature into red blood cells, platelets, and certain white blood cells, while lymphoid stem cells become lymphocytes. Acute Myeloid Leukemia (AML) arises from the myeloid line, and Acute Lymphoblastic Leukemia (ALL) from the lymphoid line.
A leukemia cell’s “phenotype” refers to its observable characteristics, particularly the protein markers on its surface. These markers are identified by antibodies and indicate the cell’s lineage. In most leukemias, the cancer cells, or “blasts,” uniformly display markers of either the myeloid or lymphoid lineage. This clear distinction guides diagnosis and treatment.
In MPAL, the leukemic blasts simultaneously show markers from more than one lineage. This can happen in two ways. In biphenotypic leukemia, a single population of cancer cells expresses both myeloid and lymphoid markers. In bilineal leukemia, the patient has two separate populations of blast cells—one myeloid and the other lymphoid.
Signs and Symptoms
The signs and symptoms of MPAL are consistent with other forms of acute leukemia. These symptoms arise because rapidly multiplying leukemia cells crowd out healthy cells in the bone marrow. This disruption of normal blood cell production leads to shortages of red blood cells, healthy white blood cells, and platelets.
A deficiency in red blood cells, a condition known as anemia, causes persistent fatigue, pale skin, and shortness of breath. The lack of sufficient healthy white blood cells compromises the immune system. This makes individuals more susceptible to frequent or severe infections that may be accompanied by fevers.
A low platelet count is another consequence of bone marrow failure. Platelets are small cell fragments necessary for blood clotting. When their numbers are insufficient, patients may bruise easily or experience prolonged bleeding from minor cuts, bleeding gums, or nosebleeds. Tiny, pinpoint red spots on the skin, known as petechiae, may also appear, along with bone or joint pain.
The Diagnostic Process
Diagnosing MPAL is a multi-step process that moves from general tests to specialized analyses. The investigation often starts when a person presents with symptoms like fatigue or easy bruising, prompting a physician to order a complete blood count (CBC). This test measures blood cell levels and may reveal abnormalities suggestive of leukemia, such as a high white blood cell count with many immature blast cells.
If the CBC is abnormal, the next step is a bone marrow aspiration and biopsy. During this procedure, a needle is used to remove a small sample of bone marrow fluid and tissue. Pathologists examine the marrow under a microscope to confirm the presence of leukemia cells and assess their characteristics, which is where the definitive diagnosis is made.
The most important test for identifying MPAL is flow cytometry. This technology analyzes the specific protein markers on the surface of the leukemia cells. A sample of the bone marrow is treated with fluorescently tagged antibodies that bind to specific markers. The cells are then passed through a laser, and the machine detects the fluorescent signals to create a detailed profile of the markers present. In MPAL, flow cytometry reveals the presence of both myeloid and lymphoid markers, confirming the mixed lineage.
Further testing involves cytogenetic and molecular analysis. Cytogenetics examines the chromosomes of the cancer cells for abnormalities, such as translocations where parts of different chromosomes swap places. Molecular tests look for mutations in specific genes. Certain genetic findings are common in MPAL, including the Philadelphia chromosome or rearrangements in the KMT2A gene. These genetic details help predict the disease’s behavior and guide treatment decisions.
Therapeutic Strategies
Treating MPAL is complex due to its dual characteristics. With no single standard of care, oncologists choose between several chemotherapy strategies based on the leukemia’s features and genetic abnormalities. The primary approaches use chemotherapy regimens designed for either ALL or AML, or a hybrid schedule combining elements from both.
The choice of chemotherapy depends on which lineage appears more dominant. If the blasts have more lymphoid features, an ALL-like protocol may be selected, while an AML-type regimen might be preferred if myeloid characteristics are prominent. Research has not definitively proven one approach to be superior for all MPAL cases.
Targeted therapies attack cancer cells with specific genetic mutations while largely sparing healthy cells. A prime example is the use of tyrosine kinase inhibitors (TKIs) for patients whose leukemia cells carry the Philadelphia chromosome. TKIs block the overactive protein that drives cancer growth, leading to better outcomes when combined with chemotherapy.
For many patients, an allogeneic stem cell transplant is considered for a long-term cure. This procedure replaces the patient’s diseased bone marrow with healthy stem cells from a matched donor after high-dose chemotherapy. A transplant is performed after initial chemotherapy has induced remission and offers the best chance of preventing the disease from returning.
Prognosis and Survival Factors
The prognosis for individuals with MPAL is more challenging compared to standard cases of ALL or AML. This is due to the rarity of the disease, the lack of a standardized treatment protocol, and the cancer’s biological complexity. However, outcomes depend on individual factors.
A patient’s prognosis is influenced by several elements. The age and overall health at diagnosis are important, as younger and healthier patients are better able to tolerate intensive treatments like chemotherapy and stem cell transplantation. The specific genetic subtype of the MPAL also plays a part, as the presence of the Philadelphia chromosome can now be targeted with specific drugs, altering the outlook.
A strong indicator of the long-term outcome is the patient’s response to the initial phase of chemotherapy, called induction therapy. Achieving a complete remission, meaning no detectable leukemia in the bone marrow after this treatment, is a positive sign. Ongoing research into the genetic drivers of MPAL is expected to lead to more refined diagnostics and novel therapies, improving the outlook.