Acute Myeloid Leukemia (AML)
Treatment Options & Assessment of Response

Updated: September 2010

The goals of therapy and the likelihood of success vary greatly in AML according to disease and patient characteristics. Thus, the treatment varies depending on the ‘Risk Categories’ described under Diagnosis as well as patient age and co-morbidities. For the purpose of clinical trials and Consensus Guidelines such as those developed by the National Comprehensive Cancer Network (NCCN) (www.nccn.org) in the USA treatment strategies are usually stratified by age with those patients over age 60 years at diagnosis treated with a somewhat different strategy than younger patients. This approach is also followed by the Leukemia/BMT Program.

The Leukemia/BMT Program participates in a variety of Phase 1 through Phase 3 clinical trials for which AML patients in different categories may be eligible. Clinical trial availability is listed under ‘Research’ on the Leukemia/BMT website. Below are the current treatment guidelines for patients not treated on such trials.

AML < age 60, low co-morbidity

A.  Induction chemotherapy

The first goal of therapy is achievement of ‘complete remission’ (CR) which is defined as less than 5% blasts in a post treatment marrow with an absolute neutrophil count >1.0X10⁹/L, platelets ≥ 100X10⁹/L and absence of transfusion requirements. Recommended remission induction chemotherapy includes cytarabine and an anthracycline. The Leukemia/BMT Program currently uses conventional ‘7+3’ chemotherapy which includes cytarabine 100 mg/m²/d by continuous IV infusion for 7 days and daunorubicin 60 mg/m²/d for 3 days. A repeat bone marrow is done on ~ day 14 after the start of therapy to assess cytoreduction (see 'Treatment Algorithms'). If significant residual leukemic blasts are present a second cycle of the same therapy is started immediately. A repeat marrow is done on count recovery or by day 30 if count recovery has not occurred. The probability of achieving CR with 1 or 2 cycles of 7+3 is ~70%. If CR is documented the patient proceeds to consolidation therapy as determined by their prognostic risk assessment. If CR is not obtained the patient receives salvage chemotherapy. The current standard salvage regimen in this circumstance in etoposide (2.4 g/m² by CIVI over 34h) and cyclophosphamide (2 g/m²/d on days 3-5). The probability of achieving CR with this therapy is ~50%. Thus, the overall probability of AML patients <60 yrs at diagnosis achieving CR is ~80%. Patients who fail to achieve CR after salvage chemotherapy are offered participation in a Phase I or II clinical trial, if available. If a trial is not available or the patient declines participation they receive palliative/best supportive care.

B. Post remission therapy

The goal of post remission therapy is the prevention of relapse. If such therapy is not given >80% of AML patients will relapse within a few months of achieving CR. There are 2 broad categories of post remission therapy; chemotherapy consolidation or stem cell transplantation, usually using cells from a healthy donor. Chemotherapy consolidation is well-tolerated but has a high risk of relapse particularly in patient with AML with poor risk prognostic features. The relapse risk is lower with donor stem cell transplantation but the risk of treatment related death is high, varying between 20 and >40% depending on the type of donor and the degree of matching between the donor and recipient as well as patient-specific risk factors. Thus, the risk must be weighed against the benefit for post remission strategies.

Patients with good risk prognostic features as defined under ‘Diagnosis’ receive consolidation chemotherapy with 3 cycles of high-dose cytarabine at a dose of 3 gm/m²/d for 6 days. The probability of cure for such patients is ≥ 60%, thus the risk of donor stem cell transplantation in CR1 is difficult to justify.

Patients with intermediate risk features receive myeloablative sibling donor stem cell transplant if a fully-matched sibling donor is available. In the absence of a matched sibling donor 3 cycles of high-dose cytarabine are administered.

Patients with poor risk features receive a myeloablative matched sibling or volunteer unrelated donor stem cell transplant if a donor can be identified because the probability of cure with chemotherapy alone is <20%. If no suitably matched donor is available, 3 cycles of high dose cytarabine are administered.

The probability of long-term disease free survival with related and unrelated donor stem cell transplant performed in CR1 is 50% and 40%, respectively. Donor stem cell transplantation appears to overcome some of the negative prognosis associated with poor risk AML.

C. Therapy of relapsed disease

AML patients frequently develop relapsed disease after the completion of all planned therapy. There is no standard ‘best’ therapy in this situation and the prognosis is poor. Currently, the Leukemia/BMT program offers clinical trial participation to all such patients if such a trial is available. If the patient declines participation or a suitable trial is not available the patient receives intermediate dose cytarabine (1.5 gm/m ²/d by CIVI for 3 days) or a combination cytarabine/anthracycline regimen. The probability of achieving a second CR is ~30% overall but varies with the length of CR1 (longer CR1 predicts greater likelihood of CR2). If CR2 is obtained the patient would receive related or unrelated donor stem cell transplantation if a matched donor could be identified. The risk of treatment-related complications and relapse post transplantation are higher when a donor transplant is done beyond CR1. In selected cases (typically where CR1 was long and the leukemia had other good risk features) an autologous stem cell transplant may be performed. If CR2 is not obtained the patient would receive palliative/supportive care.

AML ≥ age 60, low co-morbidity

A.  Induction chemotherapy

Outcomes are generally poor with elderly AML patients and have not changed for ~30 years. Thus, it is appropriate to consider entry into clinical trials at diagnosis for such patients. If an appropriate clinical trial is not available or the patient declines participation conventional therapy can be offered. The Leukemia/BMT Program currently uses conventional ‘7+3’ chemotherapy as described above for younger AML patients. A repeat bone marrow is done on ~ day 14 after the start of therapy to assess cytoreduction. If significant residual leukemic blasts are present a second cycle of the same therapy is started immediately if the patient’s general condition allows this to be done safely. The probability of achieving CR with 1 or 2 cycles of 7+3 is ~50%, i.e., lower than the remission rate achieved for younger patients. If CR is documented the patient proceeds to consolidation therapy as determined by their prognostic risk assessment. If CR is not obtained and the patient is a potential stem cell transplantation candidate the patient may receive salvage chemotherapy as described for younger patients. Reduced intensity conditioning regimens are typically used for patients in this age group. However, it is the minority of older patients who are stem cell candidates due to lack of a suitable donor or comorbid issues. Patients who fail to achieve CR are offered participation in a Phase I or II clinical trial, if available. If a trial is not available or the patient declines participation they receive palliative/best supportive care.

B.  Post remission therapy

The goal of post remission therapy is the prevention of relapse. Unfortunately, this is an elusive goal as ~90% of elderly AML patients who achieve CR1 will eventually relapse. Thus, the benefit of any post remission therapy must be carefully weighed against the risk of morbidity and occasional mortality associated with the treatment.  Chemotherapy consolidation is generally offered to elderly AML patients who achieve CR1 and who tolerate induction therapy well. Outside of a clinical trial protocol this now consists of 2 additional cycles of 7+3 chemotherapy similar to that used for induction. A subgroup of the ‘fit’ elderly may be suitable candidates for donor stem cell transplantation. Cytogenetic and molecular genetic risk assessment is performed as for younger patients and those with intermediate or high risk features may be offered a sibling or unrelated donor transplant, usually with reduced intensity conditioning.  

C.  Therapy of relapsed disease

The duration of CR1 for most elderly AML patients is less than one year. Since second remissions are typically more difficult to achieve and, when achieved, are much shorter than the first, re-induction therapy is rarely offered to elderly AML patients. Selected patients may be appropriate candidates for Phase I/II clinical trials, if available. Most patients receive palliative/best supportive care. The rare patient may be a stem cell transplantation candidate. In this case re-induction chemotherapy would be given to attempt achievement of a second CR. However, every effort should be made to undertake stem cell transplantation in CR1 for those patients for whom this therapy is appropriate as the risk increases and the likely benefit decreases when transplants are performed for more advanced disease.

AML ≥ 60 years with high co-morbidity or ≥ 70 years

Patients ≥70years of age or with serious co-moribidity should rarely be offered standard induction chemotherapy and should usually be treated with palliative/best supportive care (transfusions, hydrea) and ‘closer to home’ if living outside the lower BC mainland.

Patients wishing more active treatment may be eligible for Phase I/II trials of novel agents. Occasional patients who wish chemotherapy and for whom no trials are available/appropriate may be offered low dose cytarabine according to the following criteria:

• Newly-diagnosed AML by WHO criteria
• Patient preference for ‘more aggressive’ therapy as compared to oral hydrea and transfusion support
• Good or intermediate risk cytogenetics by MRC criteria
• Able to administer s.c. Ara-C at home and pick-up medication from BCCA pharmacy
• Patients who have poor risk cytogenetics, a poor performance status (ECOG >2) or who are unable to self-administer s.c. cytarabine are not offered this therapy

Patients receive a maximum of 4 cycles of low dose cytarabine (20mg bid s.c. X 10d every 4 – 6 wks). Treatment stops regardless of response after 4 cycles. Treatment stops earlier if CR is achieved after fewer cycles or prohibitive toxicity develops defined as:

• ↓ ANC with sepsis requiring IV antibiotics and/or hospital admission or

• ↓ platelet count with platelet refractoriness and/or bleeding

The probability of achieving CR with low dose cytarabine is ~20% in this patient group.  These remissions rarely last more than a few months.  The rare patient who achieves a CR with duration > 12 mos may be eligible for retreatment on relapse.

The information contained in these guidelines is a statement of consensus of Leukemia/BMT Program of BC professionals regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these documents is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. Use of these guidelines and documents is at your own risk and is subject to the Leukemia/BMT Program of BC’s terms of use available at Terms of Use.