Treatment for Acute Myeloid Leukemia (AML) is a multifaceted and highly individualized process, designed to eradicate cancer cells and prevent the disease from recurring. The treatment typically unfolds in two main phases: remission induction and postremission therapy.

During the induction phase, chemotherapy is administered intensively, often using a combination of drugs such as cytarabine and an anthracycline (like daunorubicin or idarubicin) in a regimen known as the “7 + 3 protocol,” where cytarabine is given continuously for 7 days and the anthracycline is administered over the first 3 days. This phase aims to eliminate leukemia cells from the blood and bone marrow, achieving remission.

Following induction, the postremission or consolidation phase involves additional cycles of chemotherapy, sometimes including high-dose cytarabine, to eliminate any remaining cancer cells and reduce the risk of relapse. For some patients, particularly those with specific genetic mutations, targeted therapies such as midostaurin or gemtuzumab ozogamicin may be incorporated.

Supportive care for acute myeloid leukemia, including antibiotics, antifungals, and growth factors, is also integral to managing side effects and complications. In certain cases, maintenance therapy may be recommended to prolong remission, and for those who cannot undergo intensive treatment, less intensive chemotherapy or palliative care may be considered.

Most patients under the age of 75 are eligible for intensive combination therapy with chemotherapy to achieve complete remission. Intensive treatment requires a central venous catheter for efficient administration and frequent blood sampling. Transfusions are often necessary during the months-long treatment period, especially at the beginning. Any infections should be well-controlled before starting chemotherapy to minimize complications.

What medicine is used to treat AML?

Patients with acute myeloid leukemia need to be well-hydrated and in optimal condition prior to treatment. To prevent tumor lysis syndrome and urate nephropathy, daily allopurinol (300 mg) should be initiated before chemotherapy. In cases of high blood blast counts with uric acid elevation and kidney impairment, rasburicase may be required. Occasionally, leukapheresis is considered to reduce tumor burden before chemotherapy. For patients with very high blast counts in the blood (over 10×10⁹/L), high doses of hydroxyurea (2-8 g/day) can be used during diagnostic workup and preparation to reduce tumor lysis risks.

Initial treatment for younger patients who can tolerate intensive chemotherapy typically begins with induction therapy, combining cytarabine (Ara-C) with an anthracycline drug such as daunorubicin, idarubicin, or mitoxantrone. National guidelines recommend specific dosing protocols for these drugs, with variations depending on the country.

Side effects are severe, including profound bone marrow suppression, requiring multiple blood and platelet transfusions and intensive antibiotic therapy to manage febrile infections.

Complete remission, seen in 75% of patients under 60 and slightly over 50% of older patients, is crucial for symptom relief and the possibility of cure. For patients with specific genetic mutations, additional targeted therapies such as midostaurin or gemtuzumab ozogamicin may enhance treatment efficacy.

Initial AML treatment for younger patients – candidates for intensive chemotherapy

Induction therapy for acute myeloid leukemia includes:

• Cytarabine (Ara-C) (brand names Cytosar, DepoCyt, or generic Cytarabine),
• Combined with an anthracycline drug, typically one of the following:
  • Daunorubicin (Cerubidine),
  • Idarubicin (Idamycin), or
  • Mitoxantrone (Novantrone).

Dosage

According to national guidelines for diagnosing and treating AML, the first two treatment cycles usually involve:

• Daunorubicin infusion at 60 mg/m² on days 1 through 3, and
• Ara-C at 1 g/m² twice daily for five days.

In most countries and acute myeloid leukemia treatment protocols worldwide, Ara-C is given at a lower dose of 200 mg/m²/day as a continuous infusion over 7–10 days. The rationale for the Swedish protocol’s higher dosing is specified in their national guidelines.

Effects and side effects

This treatment of AML causes severe bone marrow suppression, requiring multiple transfusions of red blood cells and platelets. Most patients develop febrile infections requiring intensive antibiotic therapy. Blood cell recovery typically begins 3–4 weeks after treatment, first seen in rising platelet and white blood cell levels, particularly among patients who achieve complete remission (normalization of bone marrow function).

Complete acute myeloid leukemia remission is achieved after one or two cycles in about three-quarters of younger patients (under 60 years old) and slightly over half of older patients. Treatment success is assessed through a follow-up bone marrow aspiration after blood count recovery, around day 28.

Achieving complete remission is essential as it renders patients symptom-free, eliminates the need for transfusions, and improves the resolution of infections.

Complete remission is also necessary for the potential to achieve a cure.

For patients who do not achieve complete remission after one or two treatments, it may be appropriate to transition to palliative care. Intensified or modified induction therapy, or stem cell transplantation, may be considered for some patients. In other cases, low-intensity treatments may become the focus.

Supplementary treatment for AML with specific genetic mutations

For patients under 70 years of age with an ITD (internal tandem duplication) or other specific mutations in the FLT3 gene, it is recommended to add the multikinase inhibitor midostaurin (Rydapt) from days 8–21 following induction therapy and consolidation therapy.

For patients with Core-Binding Factor (CBF) acute myeloid leukemia, such as t(8;21) or inv(16)/t(16;16), the addition of gemtuzumab ozogamicin (Mylotarg) is recommended. This is a toxin-conjugated antibody targeting CD33, a protein expressed on most AML cells and mature normal granulocytes, but not on normal stem cells.

Upon binding to the antibody, the toxin is internalized and activated, causing a strong cytotoxic effect lasting a few seconds. Because Mylotarg should be administered on day 1 of chemotherapy, rapid diagnostics using FISH (fluorescent in situ hybridization) for CBF abnormalities should be performed on diagnostic samples when applicable.

Treatment of acute promyelocytic leukemia (APL)

AML of the acute promyelocytic leukemia (APL) type (classified as “AML M3”) is characterized by a translocation between chromosomes 15 and 17 in leukemia cells. This translocation forms the PML::RARA hybrid gene, leading to overexpression of the retinoic acid receptor.

This type of acute myeloid leukemia is associated with a particularly high risk of coagulation disorders and significantly increased early mortality due to bleeding complications. Despite these risks, APL is the most favorable form of AML, as treatment often leads to complete remission and relapses can frequently be avoided.

APL typically affects younger individuals and can usually—but not always—be identified through bone marrow microscopy and flow cytometry. Definitive diagnosis is confirmed through chromosome analysis (e.g., FISH) and molecular analysis (RT-PCR).

Prompt recognition of APL is crucial because early treatment with all-trans-retinoic acid (ATRA) (Vesanoid, a licensed preparation) significantly reduces bleeding complications and provides a high likelihood of complete remission.

Immediate vigilance for APL symptoms is vital. In suspected cases, urgent FISH analysis for t(15;17) should be ordered, and ATRA should be initiated alongside intensified supportive care for bleeding while awaiting a definitive diagnosis.

ATRA treatment initially causes an increase, rather than a decrease, in white blood cell counts due to differentiation of immature myeloid cells, which increases the risk of differentiation syndrome (formerly known as retinoic acid syndrome).

Differentiation syndrome is a potentially serious complication affecting primarily the lungs and skin and requires prompt treatment with steroids and/or chemotherapy. Suspected APL should always prompt immediate consultation with a regional hematology center.

Since 2018, national guidelines recommend treatment with ATRA in combination with arsenic trioxide (ATO) (Trisenox), following a long-term regimen including induction and repeated maintenance treatments. ATO is administered via short intravenous infusions, with electrolyte levels and an EKG monitored due to the risk of cardiac arrhythmias.

Once blood counts and general health improve (usually within four weeks), outpatient continuation of treatment is possible. For high/intermediate-risk APL (white blood cell count >10 at diagnosis, less common), a small dose of an anthracycline, often idarubicin (Idamycin), is added initially.

Continued treatment

Patients who have achieved complete remission should undergo an additional 1–3 cycles of intensive chemotherapy, following a slightly modified protocol compared to the initial therapy.

These treatments should be administered as soon as the patient recovers from the previous cycle, typically at intervals of about one month. Monitoring for minimal residual disease (MRD) through flow cytometric analysis of bone marrow is recommended after the second treatment cycle and at the end of therapy in cases of intermediate- and standard-risk acute myeloid leukemia. Persistent disease markers increase the risk of relapse, in which case allogeneic stem cell transplantation may be considered. Molecular MRD analysis is also possible for specific genetic subtypes, particularly core-binding factor (CBF) leukemia and AML with NPM1 mutations.

Maintenance chemotherapy, commonly used in acute lymphoblastic leukemia (ALL), has not shown convincing benefits in AML. However, a combination of low-dose interleukin-2 (Proleukin) and histamine (Ceplene), administered as subcutaneous injections twice daily for three weeks in repeated treatment cycles over 18 months, has been shown in a large comparative study to prolong relapse-free survival, especially in monocytic AML (FAB M5).

Maintenance therapy with FLT3 inhibitors may be appropriate for certain patients with FLT3-ITD mutations. Maintenance treatment with azacitidine or decitabine, administered orally or parenterally, has been studied but is not included as a standard recommendation in current national guidelines.

Stem cell transplantation

Stem cell transplantation offers the most significant reduction in relapse risk. There are two types:

1. Allogeneic Transplantation: Stem cells are donated by another person.
2. Autologous Transplantation: Stem cells are harvested from the patient themselves.

Allogeneic stem cell transplantation

• Should be considered for patients with acute myeloid leukemia with intermediate or high genetic risk, under approximately 70 years old, and in good physical condition. This approach reduces the relapse risk by approximately 50%.
• Note that the ELN 2022 guidelines provide updated risk classifications, which, along with MRD analysis results, may modify the indications for allogeneic transplantation.

Donor matching

• A donor with the same tissue type (HLA type) is required, typically sought among siblings, who have a 25% chance of being a match.
• Alternatively, donors can be identified through international registries, which now include over 20 million individuals. However, locating a donor through these registries can take several months.
• In urgent cases where an HLA-matched donor cannot be found, transplantation with a haploidentical donor (a partial match) can be considered. A haploidentical donor shares one matching HLA chromosome, making parents and children of the patient always haploidentical.
• An international study led by Sweden aims to prospectively compare haploidentical donor transplants with matched registry donor transplants.

Process and risks

• After allogeneic stem cell transplantation, the patient’s blood production will rely on the donor’s stem cells. The new immune system may attack residual leukemia stem cells, reducing relapse risk through the graft-versus-leukemia effect.
• However, this treatment carries significant risks, primarily immune complications and temporary vulnerability to infections. These risks are most common within the first six months following the transplant. An individualized assessment of the patient’s suitability for this procedure is essential.

Autologous stem cell transplantation

• An alternative to allogeneic transplantation, this procedure involves harvesting hematopoietic stem cells from the patient during remission and freezing them. This allows for more intensive cytotoxic treatment, as blood cell production can later be restored using the frozen stem cells. The treatment relies on a short-term enhanced cytotoxic effect.
• While it can reduce the risk of relapse, the effect is not as significant as with allogeneic transplantation, which also benefits from immune control through the graft-versus-leukemia effect.
• Treatment-related complications are less severe compared to allogeneic transplantation.
• A successful stem cell harvest is required for autologous transplantation, achievable in slightly more than half of AML patients in remission.
• It is mainly considered for patients with low to intermediate genetic risk and no detectable residual leukemia cells as determined by measurable residual disease (MRD) analysis.

Treatment of older patients and certain genetic subtypes

Older patients (over 75 years) or those with significant comorbidities are usually not eligible for intensive cytotoxic chemotherapy. Some opt for purely palliative care, while others may receive low-intensity treatment based on hypomethylating agents.

• Azacitidine (Vidaza): Approved for acute myeloid leukemia, myelodysplastic syndromes (MDS), and chronic myelomonocytic leukemia (CMML).
  • Administered subcutaneously for 7 consecutive days monthly.
• Decitabine (Dacogen): Approved for AML in patients over 65 years.
  • Given as a 5-day intravenous bolus monthly.

Both drugs are less acutely toxic than intensive chemotherapy and are now available in oral formulations in the U.S., although not formally approved in some countries. Effects are often slow to manifest, with low remission rates, but registration studies have shown extended survival compared to palliative care.

These treatments are appropriate for:

• Patients over 75–80 years who seek active therapy.
• Patients over 70 years with significant comorbidities.
• Acute Myeloid Leukemia with an unfavorable genetic profile, such as TP53 mutations, del(5q), or complex karyotypes, which respond poorly to standard intensive therapy.

Combination with venetoclax

• The VIALE-A study (2020) showed that adding venetoclax (Venclexta) to hypomethylating agents improves outcomes compared to hypomethylating treatment alone.
• Venetoclax, a BCL-2 inhibitor inducing apoptosis, is widely used for lymphoproliferative disorders like chronic lymphocytic leukemia. It is taken orally daily over varying periods.
• In 2022, the combination of venetoclax + azacitidine was approved for acute myeloid leukemia in patients ineligible for intensive therapy and is now included in U.S. treatment guidelines.
  • It often provides rapid results, with a high rate of complete remission or leukemia-free bone marrow within four weeks. However, there is a significant risk of bone marrow suppression.
  • If disease control is achieved, monthly treatments continue indefinitely.

Due to its complexity, this therapy requires experienced clinicians. Genetic subgroups respond differently to this combination.

Numerous trials are ongoing for triplet therapies that add new drugs to azacitidine + venetoclax combinations.

Treatment for relapsed and refractory AML

Patients generally cannot be cured of AML relapse with chemotherapy alone.

• Late relapses: Remission may be achieved with the same treatment initially used.
• Early relapses: Prognosis is poorer.

Considerations for Cytotoxic Agents:

• Anthracycline-based chemotherapy carries cumulative cardiac toxicity.
• Idarubicin (Zavedos), mitoxantrone (Novantrone), and amsacrine (Amekrin) have less cardiac impact.
• Prolonging anthracycline infusion time reduces cardiac toxicity and is recommended in national guidelines.

Key Takeaways

1. Treatment is aggressive and typically involves multiple phases: AML requires intensive chemotherapy to eliminate leukemia cells and achieve remission. This usually involves an initial induction phase followed by consolidation therapy, sometimes including a stem cell transplant. The intensity and duration of treatment depend on factors like the patient’s age, overall health, and the specific subtype of acute myeloid leukemia.

2. Targeted therapies and other treatment options are expanding: Beyond traditional chemotherapy, newer targeted therapies are becoming increasingly important in acute myeloid leukemia treatment. These therapies focus on specific genetic mutations or proteins within the leukemia cells, offering more personalized and potentially less toxic treatment options. Immunotherapies, which harness the body’s immune system to fight cancer, are also emerging as promising additions to the AML treatment arsenal.

3. Supportive care is essential for managing side effects: AML treatment can cause significant side effects, including low blood counts, nausea, vomiting, and infections. Supportive care measures, such as blood transfusions, antibiotics, and growth factors, play a vital role in managing these side effects and improving patients’ quality of life during and after treatment.