Acute myeloid leukemia (AML) is the most common acute leukemia among adults in the US accounting for about 1.1% of all new cancers and about 1.8% of all cancer-related deaths. The overall incidence and mortality rate of AML has been stable during the last decade. AML more commonly affects older age individuals with highest incidences observed in individuals aged between 65 to 74 years. The incidence rate of AML is slightly higher in males than in females.
AML Treatment Overview
The treatment for AML is one of the most complex and intensive cancer therapy programs. The treatment of AML depends on many factors, including but not limited to, the type of disease, patient’s age, WBC count, immunophenotypic/cytogenetic abnormality involved, CNS involvement, and response to induction therapy.
AML treatment generally includes the following phases:
The main aim of induction therapy is to achieve remission, that is, depletion of leukemia cells from the blood and bone marrow. However, this does not mean a cure as some leukemia cells may still exist that are undetectable by conventional diagnostic techniques. Thus, further treatment is usually recommended.
Induction treatment usually depends upon the type of AML, age and performance status of the patient. For a healthy individual, induction treatment usually includes multiagent chemotherapy with or without a targeted agent depending upon the type of AML.
The treatment for AML may also include CNS treatment with intrathecal chemotherapy if the leukemia cells have spread to the CNS. Patients also generally require supportive treatment with blood product transfusion, antibiotics, antifungals, and drugs that raise blood cell count.
The main aim of consolidation treatment is to wipe out any remaining leukemia cells in the body after induction treatment. Consolidation treatment for otherwise healthy young patient usually includes chemotherapy with or without a targeted drug depending upon the type of AML.
Allogenic or autologous stem cell transplant (SCT) may be considered in high risk and some intermediate risk patients who are good candidates for the same. Older patients with poor performance status usually receive low-intensity therapy based upon the risk-benefit analysis.
The main aim of maintenance treatment is to avoid disease recurrence after induction and consolidation therapy. The maintenance treatment is not recommended for all types of AML but usually given to patients with APML.
Treatment of AML in patients younger than 60 years and good performance status
For patients with age less than 60 years and who are otherwise healthy (without accompanying comorbidities), the preferred induction treatment regimen include cytarabine + anthracycline.
Human leukocyte antigen (HLA) typing and allogenic stem cell transplant is recommended to be performed in high risk and some intermediate risk patients who are the good candidate for it. A bone marrow aspirate or biopsy should be performed 14 to 21 days after the start of induction therapy to assess the response.
If patient achieves a CR after induction therapy, consolidation treatment is started. The preferred consolidation treatment regimen mainly includes HiDAC (high dose Ara-C).
Treatment of AML in patients older than 60 years or poor performance status
For patients with age more than 60 years OR who are not overall healthy (have accompanying comorbidities), the preferred induction treatment regimen includes lower-intensity therapy with hypomethylating drugs 5-azacitidine or decitabine, or low-dose cytarabine.
For patients who are the candidate for intensive induction therapy, standard-dose cytarabine and anthracycline can be employed. A bone marrow aspirate or biopsy should be performed 14 to 21 days after the start of induction therapy to assess the response.
If patient achieves a CR after induction therapy, consolidation treatment is started. Non-myeloablative or reduced-intensity (RIC) SCT can be a good option for selected patients who are good candidates for it.
Treatment for Acute Promyelocytic Leukemia (APML)
The translocation of the PML gene on chromosome 15 to the RARA gene on chromosome 17 [t(15;17] producing a PML-RARA fusion gene is the characteristic feature of APL. Patient with APL may have fatal coagulopathy and it is recommended to start treatment even before confirmation of the disease with cytogenetic testing.
After consolidation therapy, bone marrow samples from patients are assessed for MRD using PCR technique. Some patients may receive maintenance therapy with ATRA with or without 6-mercaptopurine and methotrexate for around 1 to 2 years. A periodic monitoring of MRD with PCR technique is recommended for up to 2 years.
Treatment for APL is frequently associated with differentiation syndrome (constellation of symptoms and physiologic abnormalities, including fluid retention, dyspnea, episodic hypotension, pulmonary infiltrates, and pulmonary or pericardial effusions) which should be managed with prophylactic corticosteroid treatment.
Coagulopathy, another common complication encountered in patients with APL, should be managed by transfusion support to maintain platelet counts >/=50,000/microliters, by fibrinogen replacement with cryoprecipitate and frozen plasma to maintain a fibrinogen level of 150 mg/dL, and by the maintenance of prothrombin time and partial thromboplastin time close to normal.
Role of Chemotherapy
Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells. Chemotherapy may be employed in combination with targeted drugs for the management of AML having certain genetic abnormalities for which targeted drugs are available. It may also be injected directly in the CSF for CNS prophylaxis/treatment.
Chemotherapy drugs used in treatemnt of AML are-
Role of Targeted Therapy
Targeted drug delivery refers to the preferential or specific delivery of chemotherapy drug to the cancer cells sparing the normal cells. This helps in increased efficacy with decreased side-effects of the chemotherapy drug.
Gemtuzumab Ozogamicin (GO)
It is an antibody-drug conjugate (ADC) that consists of a monoclonal antibody (a man-made immune protein) linked to a chemotherapeutic drug. The drug targets the CD33 protein, a protein commonly found on AML cells of most patients. The antibody helps in the targeted action of the chemotherapy drug on the leukemia cells.
It is approved for the treatment of adult patients with newly diagnosed CD33-positive AML or relapsed/refractory CD33-positive AML. GO has also been approved to be included in the induction phase treatment in patients with with core binding factor (CBF) positive AML that expresses CD33. It can also be employed as a single agent treatment for patients who cannot tolerate standard chemotherapy.
CPX-351 is a liposomal (a tiny fatlike particle) formulation of two chemotherapeutic agents– cytarabine and daunorubicin mixed in a molar ratio of 5:1 approved by the US FDA for the treatment of AML with myelodysplasia-related changes (AML-MRC). It is preferentially taken up by leukemia cells, which leads to increased efficacy and decreased side-effects.
It is a multi-targeted tyrosine kinase inhibitor that blocks Fms-related tyrosine kinase 3 (FLT3) and several other proteins found in AML cells. It is approved in combination with standard chemotherapy for the treatment of patients with newly diagnosed AML with FLT3 mutated gene.
It is another multi-kinase inhibitor with FLT3 inhibitor activity, which has been investigated and has shown a beneficial effect in combination with standard chemotherapy drugs for FLT3 mutated AML patients.
Other FLT3 inhibitors, such as Quizartinib, Crenolanib, and Gilteritinib, have also shown a beneficial effect when combined with standard chemotherapeutic agents for the treatment of patients with AML and FLT3 mutation.
It is an IDH2 inhibitor, approved for the treatment of adult patients with relapsed or refractory AML and an IDH2 mutation.
It is an IDH1 inhibitor, approved for the treatment of adult patients with relapsed or refractory AML and an IDH1 mutation. The NCCN guidelines recommend ivosidenib or enasidenib as the frontline therapy for patients who cannot receive intensive chemotherapy with IDH1 or IDH2 mutated AML, respectively.
All-trans-retinoic acid (ATRA)
It is a form of vitamin A, which brings about conformational changes in PML-RARA. This causes the differentiation in immature myeloid cells by removing the differentiation block. Common side effects include headache, fever, dry skin and mouth, skin rash, swollen feet, sores in the mouth or throat, itching, and irritation in eyes.
Arsenic trioxide (ATO)
It’s exact mechanism of action is unknown. It is postulated to have differentiation and cytotoxic effects that help in reducing the myeloid blasts.
Role of Stem Cell Transplant (SCT)
SCT is considered as the standard of care for high risk and some intermediate risk patients who are a good candidate for the same. Following are major types of stem cell transplant techniques used for the treatment of AML:
In this technique, the patient’s own stem cells are first collected from the bone marrow tissue or peripheral blood (preferred nowadays). Then, the patient receives high-dose chemotherapy with or without radiation therapy to kill the leukemia The collected stem cells are re-administered to the patient which slowly replenish the blood cells in the patient’s body.
In this technique, healthy stem cells to be administered to the patient after high dose chemotherapy are obtained from another person known as the donor. It is very important that donor is a close blood relative (preferably a sibling) so that donor HLA closely matches with that of the patient.
Non-myeloablative transplant (RIC or mini-transplant)
In case of older individuals or individuals who cannot tolerate a standard allogeneic transplant procedure, a non-myeloablative transplant can be employed. In this technique, a relatively lower dose of chemotherapy/radiotherapy is used to partially kill the cells in the bone marrow. Then, the patient is infused with stem cells from a donor and newly generated immune cells identify and kill any remaining leukemia cells due to the graft versus leukemia effect. Chances of fatal complication due to graft-versus-host disease still exist.
It is very important to assess the benefits of each treatment option versus the possible risks and side effects before making a treatment decision. Sometimes patient’s choice and health condition are also important to make a treatment choice.
Response Assessment after Starting Treatment
A complete response means absence of leukemia cells in the blood and <5% blasts in bone marrow. Any sign or symptom of the disease like spleen/liver enlargement should return to normal.
When complete response cannot be achieved after induction treatment, the disease is termed as a refractory disease. Second-line of treatment is usually employed in such cases.
When leukemia cells are detected in blood or any other body part (including CNS) or >5% blasts in bone marrow, after complete remission, it is known as relapsed disease.
Minimal Residual Disease (MRD)
When leukemia cells are undetectable with conventional diagnostic technique after treatment but detectable with a more sensitive technique such as PCR, or flow cytometry, it is known as MRD. Patients with MRD after treatment are more likely to have disease relapse.