Acute myeloid leukemias (AML) are cancers of the hematopoieic tissue. In adults, this tissue is the bone marrow, located inside the bones and producing all blood cells, including red blood cells, white blood cells, lymphocytes and platelets.
means there are abnormal cancer cells in the peripheral blood. In acute leukemias, these cells, called blast cells or blasts, derive from the bone marrow hematopoietic tissue. In AML, the normal counterpart of these abnormal blasts produces white blood cells (including polymorphonuclear cells and monocytes) and platelets.
refers to the bone marrow, which is the tissue in the bones where all the blood cells are produced (not to be confused with the spinal cord which is part of the nervous system). The blasts accumulate in the bone marrow.
means that the disease appears rapidly. There are only days or weeks left between first symptoms and AML diagnosis, and the treatment should be initiated quickly after the diagnosis.
AML is a blood cancer, defined by the accumulation of these abnormal blast cells in the bone marrow and then in the blood. Normal hematopoiesis is impaired by these leukemic cells with a significant and rapid decrease in normal blood cell production, called bone marrow failure. As consequences, the patient suffers from anemia (a decrease in red blood cell number and hemoglobin level) with fatigue, paleness, headaches, dyspnea and palpitations; fever and infections (related to the decrease in polymorphonuclear white blood cells called neutropenia); and bleeding (epistaxis, gingival or cutaneous bleeding like hematomas) due to a low platelet count (thrombopenia). Leukemic blast accumulation might also be responsible for bone pain or lymph node, liver, spleen or gums enlargement. In rare cases, blast cells might also be present in the cerebrospinal fluid, located around the brain and the spinal cord, with neuropathies and meningitis.
AML is mostly an adult disease, with only 25% of cases before the age of 25 years and a median age of onset of 70 years. In the large majority of cases, there is no recognized cause for AML, except advanced age. Prior exposure to environmental toxics like benzene or radiations must be sought, as well as prior treatments with chemotherapy and/or radiotherapy for a previous cancer. AML could also evolve from a previously diagnosed abnormal bonne marrow status called myelodysplastic syndromes or myelodysplasia. AMLs are neither hereditary nor contagious.
AML diagnosis is based on morphological bone marrow examination through a microscope (myelogram). In Europe, the bone marrow is usually collected by aspiration of a small sample after introducing a needle in a bone (sternum or iliac crest) after local anesthesia. This aspiration allows not only the morphological examination of abnormal bone marrow blast cells, but also the analysis of their chromosomes and genes. Results are key elements for an optimal treatment choice and stratification. In parallel, differential peripheral blood count and examination (hemogram) are performed. If a neurologic localization of the disease is suspected, a microscopic examination of the cerebrospinal fluid by lumbar puncture might also be necessary.
AML is a heterogeneous disease, varying from one patient to another. Nonetheless, recurrent subsets have been identified on the basis of blast cell morphology, but mostly of recurrent chromosome abnormalities or gene mutations found in the leukemic blasts. As the risk of resistance to therapy or AML recurrence is variable from one subset to another, the precise characterization of which AML subtype is present in each individual patient is essential for an optimal treatment strategy. As explained above, this needs the analysis of AML karyotype (chromosome numbers and structures) and mutational profile (acquired gene anomalies or mutations).
The objective of the initial AML treatment is to reach and maintain a complete remission, defined as the morphological disappearance of the leukemic blasts associated with subnormal reconstitution of peripheral blood counts (essentially white blood cells and platelets). Standard treatment of a newly diagnosed AML relies on several courses of intensive chemotherapy:
The goal of the first induction course is to reach a complete remission as defined above. This first course of intensive chemotherapy is usually administered over a 7-day period. The duration of this first hospitalization may, nevertheless, reach 4 to 6 weeks, as this time is needed to wait for a normal bone marrow and peripheral blood reconstitution. Actually, intensive chemotherapy induces a transient but profound aplasia, which means absence of any bone marrow production with persistent anemia, thrombopenia and neutropenia requiring transfusions and lockdown. During this period, the patients must stay in the hospital in a single room and a protected environment, even if visits are still allowed. Once a stable complete remission has been obtained, the patients may return at home, even if we know now that a small amount of residual leukemic cells persists in the bone marrow. This minimal residual disease (MRD) cannot be seen by microscopy but may be quantified by sophisticated specific evaluation techniques. This is the reason why further treatments are absolutely needed in order to eradicate this MRD.
This treatment phase aims to maintain the complete remission and eradicate MRD in order to prevent AML recurrence. This needs to administer several additional courses of intensive chemotherapy leading to several rehospitalizations.
n patients with an AML subtype associated with a high risk of relapse, a transplantation of allogeneic hematopoietic stem cells (HSC) may be indicated. In these cases, transplantation takes place after one or several consolidation courses and is not followed by further intensive consolidation. This procedure can only be proposed to younger patients aged less than 60 to 70 years old and in good health condition, as older patients cannot not usually cope with transplant-related side effects.
HSCs are bone marrow cells which may give rise to all blood cell subsets. They could also be found in newborns cord blood units. Allogeneic HCS transplantation consists in the replacement of all patient’s HSCs by HCSs from a healthy related or unrelated donor. The donor could be a brother, a sister, a parent or a child, or an unrelated donor (or cord blood in some rare cases). Optimal donor’s choice is based on compatibility evaluations and technical preferences of the transplant team.
New targeted therapies have been developed and approved to treat some recurrent genetic AML subsets. These new drugs are usually administered orally in addition to chemotherapy during induction and consolidation cycles, and sometimes as prolonged maintenance therapy, including after allogeneic HSC transplantation. In some cases, it may also be indicated to add some injections of antibody-driven treatments (immunotherapy) to standard chemotherapy.
In older or frail patients, or in those with other diseases or comorbidities, frontline treatment is not as intensive as detailed above. Less intensive chemotherapies may be proposed. They do not induce severe aplasia and do not require prolonged hospitalizations. These less intensive treatments are associated with lower complete remission rates; they may nonetheless significantly prolong survival.
In patients experiencing AML relapse, a salvage treatment may often be proposed in order to induce a second remission. Its modalities depend on patients’ condition and relapse circumstances. Another chemotherapy of variable intensity or a targeted treatment may be administered, ideally followed by allogeneic HSC transplantation in second remission.
AML is a field of intense research for a better knowledge of leukemia genesis mechanisms and prognosis, as well as for developing new therapies or improving the results of already available treatments. Thus, it is often asked to patients with AML if they agree or not to participate in a clinical research protocol or trial. Such researches are subject to strict regulations. Patients must be clearly informed about the objectives and the procedures of the research and give their written consent or non-opposition, depending on the nature of the research.
After the end of the treatment phases, AML patients must be continuously followed for years. Regular visits to their hematologists are needed in order to eventually detect an AML recurrence or a late complication. Control hemograms are prescribed, initially relatively frequently, then in a spaced way.
AML is far of being a hopeless disease. Cure can be reached after several months of treatments and years of follow-up, as detailed above.