What are some of the most notable updates in the ASH 2020 Guidelines for treating newly diagnosed AML in older patients?

Dr DiNardo and Dr Maiti: The most notable take-home message from the ASH 2020 guidelines for AML in older patients is the recommendations for offering antileukemic therapy over best supportive care for patients who are candidates for such therapy. However, since that the VIALE-A and VIALE-C trial results were still maturing when these guidelines were developed, these important results could not be incorporated in these recommendations. Given the high-level evidence for venetoclax with hypomethylating agents, such combination regimens should be considered standard for patients who are eligible to receive such venetoclax-based regimens.

In a single center, phase 2 trial, venetoclax with 10-day decitabine had a manageable safety profile and high activity in patients with newly diagnosed AML. Have other hypomethylating agents been considered? If so, have any other treatments had comparable outcomes?


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Dr DiNardo and Dr Maiti: Currently venetoclax is approved for use in combination with azacitidine, decitabine, or low-dose cytarabine for [the] treatment of patients with newly diagnosed AML who are 75 years or older, or are ineligible for intensive therapies [due] to comorbidities. It is always challenging to compare results across trials given the differences in inclusion criteria, treatment settings, and reporting of results. Keeping those nuances in mind, the only data from a randomized clinical trial in this space is from the VIALE-A study, a double-blind multicenter trial comparing azacitidine with venetoclax vs azacitidine alone.2 In this trial venetoclax with azacitidine showed a composite complete remission (CRc) rate of 66% and a median overall survival of 14.7 months in older or unfit patients with AML including untreated secondary AML. The phase 1b/2 trial of venetoclax with HMA included 1 arm where venetoclax was combined with the 5-day regimen of decitabine, which offered a CRc rate of 71% in a similar population with median OS of 14.2 months.3 In comparison, our trial enrolled a relatively higher proportion of patients with adverse risk features, including patients with TP53-mutation and those with antecedent hematological disorders, including prior therapy for myelodysplastic syndrome. Among patients with newly diagnosed AML, our regimen of 10-day decitabine and venetoclax (DEC10-VEN) offered a CRc rate of 84%, with a CRc rate of 67% in patients with secondary AML who had not received prior therapy for antecedent hematological disorder (untreated secondary AML), and a CRc rate of 39% in patients with AML and prior therapy for an antecedent hematological disorder (treated secondary AML). The median OS in newly diagnosed AML was 18.1 months, in untreated secondary AML it was 7.8 months, and in treated secondary AML it was 6.0 months.

In contrast DEC10-VEN is the only regimen that has been prospectively evaluated for patients with relapsed or refractory (R/R) AML and in combination with FLT3 inhibitors for the high-risk FLT3-mutant AML.4

Of the newest therapies being used to treat older patients with AML, which treatments show the most promise?

Dr DiNardo and Dr Maiti: It is challenging to recommend a “one size fits all” approach given the biological heterogeneity of AML and personalized attention needed for each patient. Hence, patient selection is the key for optimizing outcomes and given the phase 3 data, azacitidine with venetoclax is an excellent option for patients with newly diagnosed AML who are 75 years or older, or are frail with [Eastern Cooperative Oncology Group] performance status of 2 or 3 or have cardiac or pulmonary comorbidities precluding intensive therapy. In contrast, given the high rates of morphologic response and negative measurable residual disease, DEC10-VEN is an attractive option for patients with newly diagnosed AML who are older than 60 years, or have comorbidities precluding intensive therapy. DEC10-VEN in combination with FLT3 inhibitors is also an important option to consider for patients with newly diagnosed or R/R FLT3-mutant AML.

DEC10-VEN is also an excellent option for older and younger patients with R/R AML and can serve as a bridge to stem cell transplantation. There are no standard treatment approaches for R/R AML who lack actionable mutations (eg, FLT3 or IDH1/2).

In contrast, low-dose cytarabine with venetoclax is another potential option for older or unfit patients who have received prior hypomethylating agent for antecedent myelodysplastic syndrome, and low-dose cytarabine with glasdegib is a potential option for older or unfit patients with secondary AML.

It is estimated that patients with R/R AML have less than a 10% overall survival at 3 years. What do you think is the most significant reason for this?

Dr DiNardo and Dr Maiti: R/R AML has been a long-standing therapeutic challenge for the leukemia community. One of the key reasons for dismal outcomes in R/R setting is the biological heterogeneity of AML. Other facets of this problem are the Darwinian evolution of resistant clones under the selection pressure of chemotherapy and targeted therapies, compounded by complex interplay of patient and treatment-related factors.

What are remaining challenges, and how are these currently approached in practice?

Dr DiNardo and Dr Maiti: Despite the recent advancements in the field of AML with venetoclax-based lower-intensity regimens and other promising targeted therapies, up to 20% to 50% patients do not benefit from these regimens due to primary refractory disease or relapse. Such patients have poor outcomes with median overall survival of 2 to 3 months. Several clinical trials are currently underway to improve outcomes in such patients.

What should be the focus of future investigation in treating older patients with AML?

Dr DiNardo and Dr Maiti: From a clinical perspective future investigation needs to focus on developing methods for optimizing patient selection for available therapies and accelerating the ongoing paradigm shift towards viewing subtypes of AML as distinct diseases. We also need to focus on improving our understanding of disease biology, response and resistance mechanism, and developing novel therapeutic approaches to treat AML.

References

  1. Sekeres MA, Guyatt G, Abel G, Alibhai S et al. American Society of Hematology 2020 guidelines for treating newly diagnosed acute myeloid leukemia in older adults. Blood Adv. Published online August 11, 2020. doi:10.1182/bloodadvances.2020001920
  2. DiNardo CD, Jonas BA, Pullarkat V, et al. Azacitidine and venetoclax in previously untreated acute myeloid leukemia. N Engl J Med. 2020;383(7):617-629. doi:10.1056/NEJMoa2012971
  3. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/blood-2018-08-868752
  4. Maiti A, DiNardo CD, Rausch CR, et al. Ten-day decitabine with venetoclax (DEC10-VEN) in acute myeloid leukemia: updated results of a phase II trial. Blood. 2019;134(Supplement_1):2637. doi:10.1182/blood-2019-127803