American Society of Hematology 2020 treatment guidelines for older adults with AML

The American Society of Hematology (ASH) has established new treatment guidelines for newly diagnosed (ND) or previously treated older adults with acute myeloid leukemia (AML), based on systematic reviews. The objective of these guidelines is to optimize treatment management for older patients with AML from diagnosis to post-remission and/or end-of-life therapy, however, it excludes the management of relapsed/refractory disease. The guidelines were prepared by a multidisciplinary panel of experts and patients and aimed to fulfil an unmet need for treatment recommendations specific to this vulnerable patient population. The inclusion criteria to describe eligible older patients with AML were defined as:

• ≥ 55 years of age.
• Newly diagnosed de novo, treatment-related, and secondary AML.
• Previous treatment with intensive or less intensive antileukemic treatment, depending on the critical question (see below).

Six critical questions were prioritized, as detailed below. The word ‘recommends’ was used for strong recommendations, while ‘suggests’ was used for conditional recommendations.¹

Prognosis in older patients with AML

The 5-year survival estimate for older adults with AML is between 5–8%, and these patients are more likely to have worse outcomes compared with younger patients, irrespective of treatment intensity. Age-related factors include worsening of organ function, greater comorbidity prevalence, a variation in performance status or disease-related factors, and shorter survival. For example, higher prevalence of adverse cytogenetic or molecular abnormalities may affect treatment and survival outcomes, namely, low remission rates, intolerance to treatment, and high rates of adverse events. Other factors contributing to poor outcome are the reluctancy to start therapy, and the inequality in accessing transplant for patients in remission.

The recommendations

1.      Decision to attempt antileukemic or best supportive treatment

Question: Should older adults with ND-AML who are candidates for antileukemic therapy receive antileukemic therapy instead of best supportive care only?

The ASH panel recommends pursuing antileukemic therapy instead of best supportive therapy in older adults who are candidates for both intensive and less intensive antileukemic therapy, based on the likelihood of lower risk of death with antileukemic therapy observed in studies. Intensive leukemic therapy (low-quality evidence) and less intensive leukemic therapy (moderate-quality evidence) have been associated with lower hazard ratios compared with best supportive care (HR, 0.36; 95% CI, 0.26–0.50; and HR, 0.74; 95% CI, 0.60–0.91, respectively). This recommendation also highly regards the belief that most patients would choose active treatment over supportive care, placing a high value on the perceived potential benefits of therapy. The panel acknowledges the potential adverse events from antileukemic therapy, such as febrile neutropenia and hospitalization, however, the quality of evidence is low, and the impact of this potential risk is considered small.

The treatment decision should be based on careful consideration of patient values, available resources, clinical context, and the risk/benefit balance with age or vulnerability.

2.      The level of intensity of antileukemic treatment: Intensive treatment vs less intensive treatment

Question: Should older adults with ND-AML considered candidates for antileukemic therapy receive intensive antileukemic therapy vs less-intensive antileukemic therapy?

The ASH panel suggests intensive antileukemic over less intensive therapy in older adults with ND-AML based on low-quality evidence of:

• A lower risk of death.
• Higher likelihood of receiving allogeneic hematopoietic stem cell transplantation (allo-HSCT).
• The lower likelihood of experiencing pneumonia.

The treatment decision should be based on disease assessment, patient-specific characteristics, and patient values. Evidence has shown that patients receiving intensive therapy may be at a greater risk of experiencing treatment-emergent adverse events and longer hospitalization. Addition of novel agents, such as adding venetoclax to hypomethylating agents, may increase the efficacy of less intensive regimens, which may change the panel’s conclusion in the future.

3.      Post-remission vs no additional therapy in patients who achieved remission following ≥ 1 cycle of intensive antileukemic therapy

Question: Should older adults with ND-AML who achieve remission after at least one cycle of intensive antileukemic therapy receive post-remission therapy vs no additional therapy?

The panel suggests the use of post-remission therapy over no additional therapy in patients who achieved remission following ≥ 1 cycle of intensive antileukemic therapy and who are not candidates for allo-HSCT. Evidence has shown that patients receiving consolidation therapy had:

• A lower risk of death.
• Longer survival.
• Lower risk of, and longer time to recurrence.
• Lower risk for febrile neutropenia.

Maintenance therapy with a hypomethylating agent may be considered instead of traditional consolidation therapy.

4.      Combination vs monotherapy for induction therapy and beyond

Question: Should older adults with AML, considered appropriate for antileukemic therapy but not for intensive antileukemic therapy, receive gemtuzumab ozogamicin, low-dose cytarabine, azacitidine, or 5-/10-day decitabine as monotherapy or in combination?

The panel suggests using either monotherapy with hypomethylating agents (azacitidine and decitabine) or low-dose cytarabine when making a decision for older adults with AML who are only eligible for less-intensive antileukemic therapy, but highlight a lack of evidence in this area.  For these patients, the panel also suggests using monotherapy instead of combination therapy with these agents. They highlight the inadequacy of evidence for greater benefit when a second agent is added, and the toxicity issues that may arise from combination therapy. However, a low dose cytarabine and glasdegib combination can be considered if this combination is preferred by patients.

5.      Duration of less intensive therapy

Question: Should older adults with AML who received less intensive antileukemic therapy and who achieved a response continue therapy indefinitely until progression/toxicity, or be given therapy for a finite number of cycles?

The panel suggests treating this patient population until progression or unacceptable toxicity, instead of defining a finite period. This is based on low-quality evidence of improved responses and survival outcomes with continuing treatment, however, there are no comparative trials in this area. The panel acknowledges the value of continuing treatment from a patient perspective.

6.      The role of transfusion support for patients no longer receiving antileukemic therapy or those receiving end-of-life care

Question: Should older adults with AML who are no longer receiving antileukemic therapy (including those receiving end-of-life or hospice care) receive red blood cell transfusions, platelet transfusions, or both vs no transfusion?

The panel suggests considering red blood cell and platelet transfusions over no transfusion, based on limited, indirect evidence of benefit in avoidance of bleeding events. However, the impact is considered to be very limited, and transfusion itself has been considered palliative care. Studies have shown that transfusion may be associated with improved health-related quality of life, including wellbeing scores, and fatigue. Another benefit of allowing transfusion is that it may make it easier to access hospice care for transfusion-dependent patients. In order to pursue or continue transfusion, it is deemed important to observe improvement in the wellbeing of patients, and to discuss any negative aspects of the transfusion procedure with patients.

Conclusion

The aim of these recommendations is to support treating clinicians in the decision-making process. Nevertheless, treatment decisions should take into consideration the individual needs and disease characteristics of the patient, as well as availability of treatment. These guidelines have been based on limited evidence of low or very low quality, demonstrating the need for high-quality evidence to establish stronger recommendations for the treatment of older adults with AML.