Older adults or adults with significant comorbid conditions

Hypomethylating agents (azacitidine and decitabine).

Low-dose cytarabine.

Venetoclax plus hypomethylating agents or low-dose cytarabine.

Glasdegib plus low-dose cytarabine.

Ivosidenib with or without azacitidine.

Enasidenib.

Intrathecal cytarabine or methotrexate may be used to treat CNS leukemia, if present.

Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older patients, particularly in the United States. Although approval of the drugs by the FDA is for an MDS indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19]

Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older patients, particularly in the United States. Although approval of the drugs by the FDA is for an MDS indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19]

Azacitidine: An international phase III trial (NCT01074047) randomly assigned patients with AML who were 65 years or older to receive either azacitidine or conventional regimens (7 + 3 induction, low-dose cytarabine, or best supportive care alone).[20]

Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older patients, particularly in the United States. Although approval of the drugs by the FDA is for an MDS indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19] › Azacitidine: An international phase III trial (NCT01074047) randomly assigned patients with AML who were 65 years or older to receive either azacitidine or conventional regimens (7 + 3 induction, low-dose cytarabine, or best supportive care alone).[20]

Azacitidine led to a median OS of 10.4 months (95% CI, 8.0−12.7) as compared with 6.5 months (95% CI, 5.0−8.6) with conventional regimens (HR, 0.85; 95% CI, 0.69−1.03; P = .1009).[20][Level of evidence A1]

Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older patients, particularly in the United States. Although approval of the drugs by the FDA is for an MDS indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19]

Decitabine: One phase III trial randomly assigned 485 patients with AML who were older than 65 years to receive either decitabine (n = 242) or their preferred choice (n = 243) of either supportive care (n = 28) or low-dose cytarabine (n = 215).[21]Compared with treatment for 5 consecutive days, treatment for 10 consecutive days may lead to higher response rates, particularly in those with TP53 variants and/or unfavorable cytogenetic features.[22][Level of evidence C3]

Hypomethylating agents: The hypomethylating agents azacitidine and decitabine are used commonly in this population of older patients, particularly in the United States. Although approval of the drugs by the FDA is for an MDS indication, the registration studies leading to approval included patients with 20% to 30% myeloblasts, or what would now be considered oligoblastic AML.[18,19] › Decitabine: One phase III trial randomly assigned 485 patients with AML who were older than 65 years to receive either decitabine (n = 242) or their preferred choice (n = 243) of either supportive care (n = 28) or low-dose cytarabine (n = 215).[21]Compared with treatment for 5 consecutive days, treatment for 10 consecutive days may lead to higher response rates, particularly in those with TP53 variants and/or unfavorable cytogenetic features.[22][Level of evidence C3]

Although rates of CR + CRp (CR with incomplete platelet recovery) were more than double in the decitabine arm (17.8%) compared with the treatment-choice arm (7.8%) (P = .001), median OS was not significantly improved for patients receiving decitabine (7.7 months) compared with the treatment of choice (5.0 months) (HR for death for decitabine, 0.85; 95% CI, .69–1.04; P = .11).

Low-dose cytarabine: Older adults who decline intensive remission-induction therapy or are considered ineligible for intensive remission-induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks.[23]

Low-dose cytarabine: Older adults who decline intensive remission-induction therapy or are considered ineligible for intensive remission-induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks.[23]

The CR rate using this regimen was 18% compared with 1% for patients treated with hydroxyurea (P = .006).

Low-dose cytarabine: Older adults who decline intensive remission-induction therapy or are considered ineligible for intensive remission-induction therapy may derive benefit from low-dose cytarabine, administered twice daily for 10 days in cycles repeated every 4 to 6 weeks.[23]

Survival with low-dose cytarabine was better than was survival with hydroxyurea (OR, 0.60; 95% CI, 0.44–0.81; P = .009).[23][Level of evidence A1]

Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies.

Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies.

The first study (NCT02203773) was a nonrandomized, open-label, phase Ib clinical trial of venetoclax in combination with azacitidine or decitabine.[24]

Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies. › The first study (NCT02203773) was a nonrandomized, open-label, phase Ib clinical trial of venetoclax in combination with azacitidine or decitabine.[24]

In this study, 35 (61%; 95% CI, 47.6%−74.0%) of 57 patients had CR or CR with incomplete hematologic recovery (CRi). The median duration of response for all patients with a response (CR + CRi + partial remission [PR]) was 8.4 months (range, 4.7−11.7; n = 36).

Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies.

The second study (NCT02287233) was a phase I/IIb study of venetoclax in combination with low-dose cytarabine in 82 patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder such as MDS.[25]

Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies. › The second study (NCT02287233) was a phase I/IIb study of venetoclax in combination with low-dose cytarabine in 82 patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder such as MDS.[25]

In the 82 patients enrolled in the study, the CR/CRi rate was 54% (95% CI, 42%−65%), with a median duration of remission of 8.1 months (95% CI, 5.3−14.9 months). The median OS for all patients, irrespective of response, was 10.1 months (95% CI, 5.7−14.2 months).

Venetoclax plus hypomethylating agents or low-dose cytarabine: The FDA approved venetoclax, an inhibitor of the anti-apoptotic protein BCL2, in combination with low-dose cytarabine or a hypomethylating agent for the treatment of AML in patients aged 75 years or older, and those who cannot undergo 7 + 3 induction chemotherapy because of comorbidities. Approval was granted based on the results of two studies. › The second study (NCT02287233) was a phase I/IIb study of venetoclax in combination with low-dose cytarabine in 82 patients with newly diagnosed AML, including patients with previous exposure to a hypomethylating agent for an antecedent hematologic disorder such as MDS.[25]

The most common adverse events with venetoclax combinations are gastrointestinal symptoms and myelosuppression, which may require delays between cycles, growth factor support, or decreased duration of venetoclax administration per cycle. Additionally, appropriate prophylactic measures are typically taken to prevent tumor lysis syndrome.[25][Level of evidence C3]

Glasdegib plus low-dose cytarabine: Glasdegib, an oral inhibitor of the hedgehog pathway, combined with low-dose cytarabine was compared with low-dose cytarabine alone in a randomized, phase II open-label study that included 116 patients with AML who were aged 75 years or older or who had severe comorbid conditions (cardiac disease, renal impairment, or Eastern Cooperative Oncology Group performance status 2).[26] Similar to venetoclax, the FDA approved glasdegib in combination with low-dose cytarabine for the treatment of AML in patients aged 75 years or older or who are unable to receive intensive induction chemotherapy.

Glasdegib plus low-dose cytarabine: Glasdegib, an oral inhibitor of the hedgehog pathway, combined with low-dose cytarabine was compared with low-dose cytarabine alone in a randomized, phase II open-label study that included 116 patients with AML who were aged 75 years or older or who had severe comorbid conditions (cardiac disease, renal impairment, or Eastern Cooperative Oncology Group performance status 2).[26] Similar to venetoclax, the FDA approved glasdegib in combination with low-dose cytarabine for the treatment of AML in patients aged 75 years or older or who are unable to receive intensive induction chemotherapy.

Of the 78 patients with AML who received glasdegib plus low-dose cytarabine, 24% (n = 19) of patients had a CR or CRi compared with 5% (2 of 38) of patients who received low-dose cytarabine alone. The median OS was 8.3 months (80%; CI, 6.6–9.5) for patients who received glasdegib/low-dose cytarabine and 4.3 months (80%; CI, 2.9–4.9) for patients who received low-dose cytarabine alone in patients with AML (HR, 0.46; 80% CI, 0.35–0.62; P = .0002).[26][Level of evidence A1]

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

Differentiation syndrome was reported in 6 patients (18%), but did not require treatment discontinuation.

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

The rate of CR plus CRi was 42.4% (95% CI, 25.5%−60.8%), with a median duration of response that was not reached (lower bound of the 95% CI was 4.6 months).

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

For all 34 patients on the study, the median OS was 12.6 months (95% CI, 4.5−25.7).[27][Level of evidence C3]

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

At a median follow-up of 12.4 months, the primary end point of EFS was improved in patients who received azacitidine and ivosidenib, compared with patients who received azacitidine and placebo (HR, 0.33; 95% CI, 0.16–0.69).

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

The median OS was 24 months for patients who received azacitidine and ivosidenib and 7.9 months for patients who received azacitidine and placebo (HR for death, 0.44; 95% CI, 0.27–0.73).

Ivosidenib: For older or frail patients with AML and IDH1 variants, the IDH1 inhibitor ivosidenib is an option. The FDA approved ivosidenib alone or in combination with azacitidine for the treatment of AML that has a susceptible IDH1 variant (detected by an FDA-approved diagnostic test) in adults aged 75 years or older with newly diagnosed AML or who have comorbidities that preclude the use of intensive induction chemotherapy. Within the context of a phase I study, 34 patients with newly diagnosed IDH1-altered AML who were not candidates for intensive induction chemotherapy were treated with single-agent ivosidenib.[27]The combination of azacitidine and ivosidenib was evaluated in a double-blind, randomized, placebo-controlled, phase III trial in patients with newly diagnosed AML who were not eligible for intensive induction chemotherapy. The intention-to-treat analysis included 72 patients treated with azacitidine and ivosidenib and 74 patients treated with azacitidine and placebo. A supplemental new drug application for ivosidenib in combination with azacitidine for patients with untreated IDH1-altered AML is under priority review with the FDA.[28]

Differentiation syndrome occurred in 14% of patients who received azacitidine and ivosidenib and 8% of patients who received azacitidine and placebo. The incidence of bleeding events was 41% with azacitidine and ivosidenib and 29% with azacitidine and placebo. Infection of any grade was seen in 28% of patients who received azacitidine and ivosidenib and 49% of patients who received azacitidine and placebo. For more information about differentiation syndrome, see the Treatment of Newly Diagnosed Acute Promyelocytic Leukemia section.[28][Level of evidence A1]

Enasidenib: For patients with AML and IDH2 variants, the IDH2 inhibitor enasidenib is an option for older or frail patients. Although it does not have approval in this setting, enasidenib monotherapy was evaluated in a phase I/II trial in patients with newly diagnosed AML who were not eligible for standard chemotherapy.[29]

Enasidenib: For patients with AML and IDH2 variants, the IDH2 inhibitor enasidenib is an option for older or frail patients. Although it does not have approval in this setting, enasidenib monotherapy was evaluated in a phase I/II trial in patients with newly diagnosed AML who were not eligible for standard chemotherapy.[29]

Of the 39 patients enrolled, seven (18%) had CR, one (3%) had CRi, and two (5%) had a PR.

Enasidenib: For patients with AML and IDH2 variants, the IDH2 inhibitor enasidenib is an option for older or frail patients. Although it does not have approval in this setting, enasidenib monotherapy was evaluated in a phase I/II trial in patients with newly diagnosed AML who were not eligible for standard chemotherapy.[29]

Median OS for all patients was 11.3 months (95% CI, 5.7−15.1), and was not reached for patients who had a response.[29][Level of evidence C3]