Guidelines

The following tests are recommended in the diagnostic workup for AML:¹

• Complete blood count (CBC) with manual differential and routine chemistry profile (including liver function tests, serum creatinine, lactate dehydrogenase, and uric acid)
• Coagulation profile – prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen
• Bone marrow aspiration and biopsy, including classical cytogenetics, immunophenotyping, and molecular testing for c-KIT, FLT3 [ITD and TKD], NPM1, CEBPA, IDH1, IDH2, TP53 and other mutations
• Cytogenetic analyses (karyotype and FISH)
• HLA typing of patient and family for potential hematopoietic cell transplantation in the future
• Assessment of cardiac risk factors and myocardial function (by echocardiogram or multigated acquisition [MUGA] scan) if using an anthracycline or anthracenedione-based regimen
• CT of brain without contrast if CNS hemorrhage is suspected
• Brain MRI with contrast if leukemic meningitis is suspected
• PET/CT if clinical suspicion for extramedullary disease
• Lumbar puncture if neurologic symptoms are present

Treatment options for AML depend on patient age, fitness, and presence of comorbidities.

High-Intensity Treatment Options for Patients <60 years of age¹

Cytarabine + (idarubicin or daunorubicin)

Cytarabine + daunorubicin + cladribine

Cytarabine + daunorubicin + midostaurin for FLT3+ AML

Liposomal cytarabine + daunorubicin for treatment- or MDS-related AML

Cytarabine + daunorubicin + gemtuzumab for CD33+ AML

High-dose cytarabine (HiDAC) + (idarubicin or daunorubicin)

Fludarabine + high-dose cytarabine (HiDAC) + idarubicin + granulocyte colony-stimulating factor (G-CSF)

 

Subsequent Therapy After Standard Dose Cytarabine Induction or Re-induction for Patients <60 years of age¹

Induction Result	Therapy Options
Significant residual disease without a hypocellular marrow	Cytarabine + (idarubicin or daunorubicin)
	Cytarabine + daunorubicin + midostaurin for FLT3+ AML
	Liposomal daunorubicin and cytarabine for treatment- or MDS-related AML
Significant cytoreduction with low % residual blasts	Standard-dose cytarabine + (idarubicin or daunorubicin)
	Standard-dose cytarabine + daunorubicin + midostaurin
Hypoplasia	Wait for blood counts to return to normal

 

Post-Remission Therapy for Patients <60 years of age¹

Patient-Specific Factors	Therapy Options
Core binding factor (CBF) cytogenetic translocations without KIT mutation	HiDAC ± gemtuzumab ozogamicin for CD33+ AML
	Cytarabine + daunorubicin + gemtuzumab ozogamicin for CD33+ AML
Intermediate-risk cytogenetics and/or molecular abnormalities	Matched sibling or alternative donor hematopoietic stem cell transplantation (HSCT)
	HiDAC
	HiDAC + midostaurin for FLT3-mutated AML
	Cytarabine + daunorubicin + gemtuzumab ozogamicin for CD33+ AML
Treatment-related disease other than CBF and/or unfavorable cytogenetics and/or molecular abnormalities	Matched-sibling or alternative-donor HSCT
	HiDAC
	HiDAC + midostaurin for FLT3-mutated AML
	Liposomal daunorubicin and cytarabine for treatment- and MDS-related AML

 

Intensive Remission Induction Therapy for Patients >60 years of Age¹

Patient-Specific Factors	Therapy Options
Favorable- or intermediate-risk cytogenetics	Standard-dose cytarabine + daunorubicin + gemtuzumab ozogamacin for CD33+ AML
	Standard-dose cytarabine + (idarubicin or daunorubicin or mitoxantrone)
	Standard-dose cytarabine + daunorubicin + midostaurin for FLT3-mutated AML
Treatment- or MDS-related AML	Liposomal daunorubicin and cytarabine
Unfavorable-risk cytogenetics	Venetoclax + IV decitabine
	Venetoclax + SQ or IV azacitidine
	Venetoclax + SQ low-dose cytarabine
	Low-intensity azacitidine or decitabine
Other regimens for intermediate- or poor-risk disease	Standard-dose cytarabine + (idarubicin or daunorubicin or mitoxantrone)
	Standard-dose cytarabine + daunorubicin + gemtuzumab ozogamacin for CD33+ AML (intermediate risk)

 

Low-intensity Remission Induction Therapy for Patients >60 years of Age ¹

Patient-Specific Factors	Therapy Options
AML without actionable mutations	Venetoclax + IV decitabine
	Venetoclax + SQ or IV azacitidine
	Venetoclax + SQ low-dose cytarabine
	Low-intensity azacitidine or decitabine
	Glasdegib
	Low-dose cytarabine
	Gemtuzumab ozogamicin for CD33+ AML
	Best supportive care (hydroxyurea, transfusion support)
IDH1 mutant	Ivosidenib
	Low-intensity azacitidine or decitabine
	Venetoclax-based therapy (as outlined above)
IDH2 mutant	Enasidenib
	Low-intensity azacitidine or decitabine
	Venetoclax-based therapy (as outlined above)
FLT3 mutant	Low-intensity azacitidine or decitabine + sorafenib for FLT3-ITD+ AML
	Venetoclax-based therapy (as outlined above)

 

Re-induction for Patient >60 Years After Standard-dose Cytarabine Induction¹

Induction Results	Therapy Options
Residual disease	Standard-dose cytarabine + (idarubicin or daunorubicin or mitoxantrone)
	Standard-dose cytarabine + daunorubicin + midostaurin for FLT3+ AML
	Liposomal daunorubicin and cytarabine for treatment- or MDS-related AML
	Intermediate-dose cytarabine-containing regimens
	Reduced-intensity allogeneic HSCT
	Await recovery
	Best supportive care
Hypoplasia	Await recovery

 

Post Remission Therapy for Patients >60 Years Previously Receiving Intensive Therapy¹

Induction Response	Therapy Options
Complete Response	Allogeneic HSCT
	Standard-dose cytarabine + (idarubicin or daunorubicin)
	Intermediate-dose cytarabine if good performance status, normal renal function, better-risk or normal karyotype with favorable molecular markers
	Intermediate-dose cytarabine + midostaurin
	Liposomal daunorubicin and cytarabine for treatment- or MDS-related AML
	Cytarabine + daunorubicin + gemtuzumab ozogamacin for CD33+ AML
	Maintenance therapy with azacitidine or decitabine
	Observation
Induction failure	Low-intensity azacitidine or decitabine
	Allogeneic HSCT
	Therapy for Relapsed/Refractory Disease (page AML-H: https://www.nccn.org/professionals/physician_gls/pdf/aml.pdf)
	Best supportive care

 

Post Remission Therapy for Patients >60 Years Previously Receiving Lower Intensity Therapy¹

Allogeneic HSCT

Continue azacitidine or decitabine until progression

Gemtuzumab ozogamicin for CD33+ AML

Continue ivosidenib for IDH1-mutated AML until progression

Continue enasidenib for IDH2-mutated AML until progression

Continue venetoclax + IV decitabine

Continue venetoclax + SQ or IV azacitidine

Continue venetoclax + SQ low-dose cytarabine

Continue glasdegib + low-dose cytarabine

Low-dose cytarabine

Gemtuzumab ozogamicin for CD33+ AML

Continue azacitidine or decitabine + sorafenib for FLT3-ITD+ AML

 

It is recommended that all AML patients receive supportive care that includes the following:¹

• Use of leukodepleted, irradiated blood if hemoglobin falls below 7-8 g/dL or if patient has symptomatic anemia
• Platelets for patients with platelets <10,000/mcL or with any signs of bleeding
• Tumor lysis prophylaxis (TLS): hydration with diuresis, and allopurinol or rasburicase. Independent risk factors for TLS are pretreatment serum lactate dehydrogenase levels above normal laboratory values, creatinine >1.4 mg/dL, uric acid >7.5 mg/dL, and white blood cell counts >25 x 10⁹/L
• Patients with impaired renal function or older than 60 years of age receiving cytarabine should be monitored for cerebellar toxicity. HiDAC should be discontinued if creatinine rises due to tumor lysis. Discontinue cytarabine permanently if cerebellar toxicity develops.
• The use of antibiotic prophylaxis should depend on the prevailing organisms and their drug resistance patterns.

Clinical Trial Data

In addition to chemotherapeutic agents, several targeted therapies may be used in select AML patients.

Venetoclax

Oral BH3-mimetic drug that triggers apoptosis by antagonizing the anti-apoptotic protein BCL-2.

• In a phase 1b dose-escalation and expansion study, 145 treatment-naïve AML patients aged 65 or older and ineligible for intensive chemotherapy were treated with venetoclax plus decitabine or azacitidine. Median OS was 17.5 months and 67% of patients achieved complete remission (CR) or complete remission with incomplete count recovery (CRi). The CR+CRi rate was 73% for patients in the venetoclax 400-mg arm. The median duration of CR+CRi was 11.3 months for all patients. Patients with poor risk cytogenetics and patients >75 years had CR+CRi rates of 60% and 65%, respectively.²
• In an open-label, phase 1b/2 trial of venetoclax plus low-dose cytarabine in treatment-naïve, elderly AML patients unfit for intensive chemotherapy, 62% of patients achieved CR+CRi with a median duration of 14.9 months. Best responses were 26% CR, 36% CRi, and 2% PR. Median OS was 11.4 months (95% CI, 5.7-15.7 months) for all patients and 18.4 months for patients that achieved CR/CRi (95% CI, 13.5 months to not reached). The observed 12-month OS was 46% (95% CI, 33-58%).³
• In a phase I/II study of venetoclax plus low-dose cytarabine in treatment-naïve AML patients >65 years, 75% of patients achieved an objective response (CR+CRi+PR), with 70% experiencing a CR+CRi. The 12-month OS was 74.7% (95% CI, 49.4-88.6) for all patients and 86.7% for responders (95% CI, 56.4-96.5).⁴
• A phase II study evaluated the efficacy and safety of venetoclax monotherapy in patients with high-risk relapsed/refractory AML or those who were unfit for intensive chemotherapy. The patient cohort in this study consisted of older patients and included many patients with high-risk features including multiple prior therapies, antecedent hematologic disorders, and adverse cytogenetic features. The overall response rate was 19%, with an additional 19% demonstrating some antileukemic activity. All objective responses were achieved within 4 weeks of therapy initiation.⁵
• Venetoclax was granted accelerated approval for use in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients aged ≥ 75 years or who have comorbidities that preclude the use of intensive induction chemotherapy.^6,7  Phase III studies VIALE-A (NCT02993523) and VIALE-C (NCT03069352), are evaluating venetoclax in combination with azacitidine or low-dose cytarabine with overall survival as the primary endpoint and are intended as the confirmatory trials.⁷
• VIALE-A and VIALE-C (NCT03069352) have reported differing results—initial reports from the VIALE-C suggest that the study did not demonstrate statistically significant improvement with a combination of low-dose cytarabine for the primary endpoint of overall survival (OS) (Hazard Ratio [HR]=0.75, [95% CI 0.52 – 1.07], p=0.11), while VIALE-A study demonstrated statistically significant improvement in the primary endpoints of overall survival (OS) and composite complete remission rate (CR + CRi) in combination azacitidine.

Midostaurin

Multitargeted kinase inhibitor that inhibits FLT3 receptor signaling and cell proliferation, and induces apoptosis in leukemic cells expressing ITD and TKD mutant FLT3 receptors or overexpressing wild-type FLT3 and PDGF receptors.

• In a phase III trial of 717 newly diagnosed AML patients with FLT3 mutations, subjects received daunorubicin and cytarabine for induction and high-dose cytarabine for consolidation plus either midostaurin or placebo. Patients receiving midostaurin had significantly longer overall survival (HR for death, 0.78; one-sided P=0.009) and event-free survival (HR for event or death, 0.78; one-sided p=0.002) compared to placebo. The benefit of midostaurin was similar for all FLT3 subtypes, including ITD high, ITD low, and TKD mutations.⁸
• In the phase III RATIFY (CALGB10603) trial, treatment-naïve AML patients between 18 and 60 years of age with FLT3 mutations were randomized to receive either midostaurin or placebo in addition to cytarabine and daunorubicin for induction or high-dose cytarabine for consolidation. Patients were treated with midostaurin monotherapy after completion of consolidation for 12 months. Midostaurin significantly improved median overall survival (74.7 vs 26.0 months; HR, 0.77; p=0.007) and median event-free survival (8.0 vs 3.0 months; HR, 0.80; P=0.0044).⁹

Gemtuzumab ozogamicin

Immunoconjugate between CD33 and calicheamicin that binds to CD33 on the surface of leukemic cells, where it is subsequently internalized. Calicheamicin is released in the cell, binding to DNA and resulting in double strand breaks and cell death.

• In a study of 1,115 previously untreated older patients with AML or high-risk myelodysplastic syndrome, subjects were randomized to receive daunorubicin/cytarabine or daunorubicin/clofarabine with or without gemtuzumab ozogamicin (GO). The overall response rate was 69% with no difference between either treatment arm. The 3-year cumulative incidence of relapse was significantly lower with GO (68% vs 76%; HR, 0.78; 95% CI, 0.66-0.93; P=0.007), and the 3-year survival rate was significantly improved (25% vs 20%; HR, 0.87; 95% CI, 0.76-1.00; P=0.05).¹⁰
• A meta-analysis of 5 trials investigating the efficacy of gemtuzumab ozogamicin (GO) found a decreased risk of relapse at 5 years with GO therapy, irrespective of patient age (30.7% vs 34.6%; HR, 0.90; 95% CI, 0.82-0.98; P=0.01). The survival benefit was larger in patients with favorable cytogenetics (55.2 vs 76.3%; HR, 0.47; 95% CI, 0.31-0.73; P=0.0005), but patients with intermediate-risk also saw improvement (34.1% vs 39.4%; HR, 0.84; 95% CI, 0.75-0.95; P=0.007). Patients with unfavorable cytogenetics or adverse karyotype did not benefit from GO therapy.¹¹
• In the open-label MRC AML15 trial, 1,113 previously untreated younger patients received gemtuzumab ozogamicin (GO) in combination with one of three possible induction regimens: daunorubicin and cytarabine; cytarabine, daunorubicin, and etoposide; or fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin. Patients receiving GO had a complete response of 86%, and 42% survived 5 years. The overall response rate of patients not receiving GO was 83%, with a 40% 5-year survival rate. Neither difference was statistically significant. There were no differences in overall response rate, refractory disease, or 30-day all-cause mortality between patients receiving or not receiving GO. The addition of GO improved 5-year survival by 10% (from 46% to 56%) in 70% of patients, who were identified by an internally validated prognostic score. Patients in the GO treatment group required more units of platelets after course 1 (mean, 18.9 vs 13.7 units; P<0.001) and more days of antibiotics (mean, 20.4 vs 19.0 days; P=0.02) than patients who did not receive GO.¹²
• In the phase III EORTC-GIMEMA AML-19 trial, 237 patients >60 years and ineligible to receive intensive chemotherapy were randomized to receive either gemtuzumab ozogamicin (GO) monotherapy or best supportive care (BSC). Median OS was longer in the GO group (4.9 vs 3.6 months; HR, 0.69; 95% CI, 0.53-0.90; P=0.005) and the 1-year OS rate was 24.3% for GO and 9.7% for BSC. CR+CRi was achieved in 27% of GO recipients. Patients with high CD33 expression status, favorable or intermediate cytogenetic risk profiles, and women saw larger benefit with GO therapy.¹³

Enasidenib

Small molecule inhibitor that targets mutant versions of isocitrate dehydrogenase 2 (IDH2), leading to the induction of myeloid differentiation.

• A phase I/II trial of enasidenib in 176 patients with relapsed/refractory AML found an overall response rate of 40.3% and a median response duration of 5.8 months with enasidenib. Median OS was 9.3 months for all patients and 19.7 months for the 19.3% of patients who attained complete remission. The most common treatment-related adverse events were indirect hyperbilirubinemia (38%) and nausea (23%). Grade 3 or 4 adverse events occurred in 41% of patients, and the most frequent were indirect hyperbilirubinemia (12%) and IDH-inhibitor-associated differentiation syndrome (6%).¹⁴
• In a study of enasidenib monotherapy in treatment-naïve AML patients greater than 60 years of age with IDH2 mutations, median OS was 10.4 months (95% CI, 5.7-15.1) and median event-free survival was 11.3 months. Median OS for responding patients (n=14) was 19.8 months and for non-responders was 5.4 months. ORR was 37.8% (95% CI 22.5-55.2) with seven patients (19%) attaining CR. The most frequent adverse events were fatigue (43%), nausea (41%), decreased appetite (41%), and hyperbilirubinemia (30%).¹⁵

Ivosidenib

Small molecule inhibitor that targets mutant versions of isocitrate dehydrogenase 1 (IDH1), leading to the induction of myeloid differentiation.

• A phase I dose-escalation and dose-expansion study of ivosidenib monotherapy in 258 patients with IDH1-mutated AML found a CR+CRi rate of 30.4% (95% CI, 22.5-39.3) and an ORR of 41.6% (95% CI, 32.9-50.8). Of the 179 patients with relapsed or refractory AML, 98.9% experienced an adverse event. The most commonly reported AEs were diarrhea (30.7%), leukocytosis (29.6%), febrile neutropenia (28.5%), nausea (27.9%), fatigue (25.7%), dyspnea (24.6%), prolongation of the QT interval (24.6%), peripheral edema (21.8%), anemia (21.8%), pyrexia (21.2%), and cough (20.7%). Grade 3 or higher AEs included prolongation of the QT interval (7.8%), IDH differentiation syndrome (3.9%), anemia (2.2%), thrombocytopenia (3.4%), and leukocytosis (1.7%).¹⁶
• An ongoing, open-label phase 1b/2 is assessing the efficacy of ivosidenib in combination with subcutaneous azacitidine in treatment-naïve patients with IDH1 mutations who were ineligible for intensive chemotherapy. Interim results have shown an ORR of 78% (n=18/23) with 44% of patients attaining CR. Serious treatment-emergent AEs occurring in more than 2 patients receiving ivosidenib plus azacitidine were febrile neutropenia (8 patients) and IDH differentiation syndrome (3 patients).¹⁷
• Ivosidenib plus azacitidine is also under further investigation in the ongoing, placebo-controlled, phase 3 AGILE study (NCT03173248).¹⁷

Glasdegib

Inhibits Hedgehog pathway signaling and disrupts the regulation of cancer stem-cell survival.

• In a study of 132 previously untreated AML or high-risk MDS patients ineligible for intensive chemotherapy, subjects were randomized to receive either low-dose cytarabine (LDAC) plus glasdegib or low-dose cytarabine alone. Median OS was longer for LDAC/glasdegib than for LDAC alone (8.3 vs 4.9 months; HR, 0.511; 80% CI, 0.386-0.675; one-sided log rank P-value, 0.002 stratified by cytogenetic risk). CR rates were higher for LDAC/glasdegib than LDAC monotherapy (15% vs 2.3%, P=0.0142). Median OS was longer for LDAC/glasdegib versus LDAC alone for both good- and intermediate-risk patients (12.2 vs 6.0 months; HR, 0.464; p=0.003) and poor-risk patients (4.4 vs 2.3 months; HR, 0.575; P=0.04). Adverse events occurring in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%), alopecia (10.7%), cytopenias, gastrointestinal toxicities, and febrile neutropenia.¹⁸
• In a phase II trial of 69 patients with previously untreated AML or high-risk myelodysplastic syndrome, patients received glasdegib in combination with cytarabine and daunorubicin. Investigator-reported CR was reported in 46.4% (80% CI, 38.7-54.1) of patients, with a 40% CR rate in patients over 55 years of age and a rate of 88.9% in patients under 55 years. Median OS was 14.9 months (80% CI, 13.4-19.3), with a 12-month survival probability of 66% (80% CI, 58.5-73.4). The most common treatment-related adverse events (TRAE) were diarrhea and nausea, and the most frequent grade >3 TRAE were febrile neutropenia and anemia.¹⁹
• Glasdegib is currently being studied in combination with standard induction therapy in fit patients, or with azacitidine in unfit patients (ClinicalTrials.gov identifier: NCT03416179).

Gilteritinib

Selective dual FLT3 (to a lesser extent to FLT3-TKD than -ITD) and AXL inhibitor (AXL also promotes proliferation and survival of AML cells)

• Gilteritinib has demonstrated a composite CR (cCR) of 30% as single agent in 252 R/R AML patients (with a cCR rate of 41% and a CR rate of 11% in 169 FLT3 ITD and TKD mutant patients). The response rates for patients with only FLT3-ITD and those with FLT3-ITD and FLT3D835 mutations were identical. The most common non-hematologic adverse events were diarrhea and hepatic enzyme elevation.^20,21
• The phase 3 ADMIRAL trial assessing oral gilteritinib 120 mg per day versus salvage chemotherapy in adult R/R FLT3-mutated AML patients demonstrated a cCR of 21% with a duration of 4.6 months and 54.3% at a median duration of remission of 11 months. Patients who achieved a cCR had a median time to response of 3.6 months.^21,22 
• Gilteritinib is being studied as upfront treatment versus midostaurin in combination with intensive chemotherapy and as maintenance therapy following induction/consolidation treatment in first remission (NCT03836209, NCT04027309, NCT02236013)

 

References

1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology. Acute Myeloid Leukemia. Version 3.2020. www.nccn.org/professionals/physician_gls/pdf/aml.pdf. Accessed June 3, 2020.
2. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naïve, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17.
3. Wei A, Strickland SA, Roboz GJ, et al. Phase 1/2 study of venetoclax with low-dose cytarabine in treatment-naïve, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes. Blood. 2017;130:890.
4. Wei A, Strickland SA, Roboz GJ, et al. Safety and efficacy of venetoclax plus low-dose cytarabine in treatment-naïve patients aged >65 years with acute myeloid leukemia. Blood. 2016;128(22):102.
5. Konopleva M, Pollyea DA, Potluri J, et al. Efficacy and biological correlates of response in a phase II study of venetoclax monotherapy in patients with acute myelogenous leukemia. Cancer Discov. 2016;6(10):1106-1117.
6. US Food and Drug Administration. FDA approves venetoclax in combination for AML in adults. https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm626499.htm. Accessed March 20, 2019.
7. Stenger M [The ASCO Post].Venetoclax in combination regimens for older patients with AML or those with comorbidities precluding intensive induction. http://www.ascopost.com/issues/december-25-2018/venetoclax-in-combination-regimens-for-older-patients-with-aml-or-those-with-comorbidities-precluding-intensive-induction/. Accessed March 20, 2019.
8. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464.
9. Stone RM, Mandrekar S, Sanford BL, et al. The multi-kinase inhibitor midostaurin (M) prolongs survival compared to placebo (P) in combination with daunorubicin (D)/cytarabine (C) induction (ind), high-dose C consolidation (consol), and as maintenance (maint) therapy in newly diagnosed acute myeloid leukemia (AML) patients (pts) age 18-60 with FLT3 mutations (muts): an international prospective randomized (rand) p-controlled double-blind trial (CALGB 10603/RATIFY [Alliance]). Blood. 2015;126(23):6.
10. Burnett AK, Russell NH, Hills RK, et al. Addition of gemtuzumab ozogamicin to induction chemotherapy improves survival in older patients with acute myeloid leukemia. J Clin Oncol. 2012;30(32):3924-3931.
11. Hills RK, Castaigne S, Appelbaum FR, et al. The addition of gemtuzumab ozogamicin to induction chemotherapy in acute myeloid leukaemia: an individual patient data meta-analysis of randomized trials in adults. Lancet Oncol. 2014;15(9):986-996.
12. Burnett AK, Hills RK, Milligan D, et al. Identification of patients with acute myeloblastic leukemia who benefit from the addition of gemtuzumab ozogamicin: Results of the MRC AML15 trial. J Clin Oncol. 2011;29:369-377.
13. Amadori S, Suciu S, Sellesleg D, et al. Gemtuzumab ozogamicin versus best supportive care in older patients with newly diagnosed acute myeloid leukemia unsuitable for intensive chemotherapy: Results of the randomized phase III EORTC-GIMEMA AML-19 trial. J Clin Oncol. 2016;34:972-979.
14. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
15. Pollyea DA, Tallman MS, De Botton S, et al. Enasidenib monotherapy is effective and well-tolerated in patients with previously untreated mutant – IDH2 (m IDH2) acute myeloid leukemia (AML). Blood. 2017;130:638.
16. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398.
17. DiNardo CD, Stein AS, Stein EM, et al. Mutant IDH (mIDH) inhibitors, ivosidenib or enasidenib, with azacitidine (AZA) in patients with acute myeloid leukemia (AML). [abstract 7042 poster]. J Clin Oncol. 2018;36(15 suppl).
18. Cortes JE, Heidel FH, Heuser M, et al. A phase 2 randomized study of low-dose Ara-C with or without glasdegib (PF-04449913) in untreated patients with acute myeloid leukemia or high-risk myelodysplastic syndrome. Blood. 2016;128:99.
19. Cortes JE, Smith BD, Wang ES, et al. Glasdegib in combination with cytarabine and daunorubicin in patients with AML or high-risk MDS: phase 2 study results. Am J Hematol. 2018;93:1301-1310.
20. Perl AE, Altman JK, Cortes J, et al. Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukemia: A multicentre, first-in-human, open-label, phase 1–2 study. Lancet Oncol. 2017;18:1061–1075.
21. Bohl SR, Bullinger L, Rücker FG. New targeted agents in acute myeloid leukemia: new hope on the rise. Int J Mol Sci. 2019;20(8):1983.
22. Perl AE, Cortes JE, Strickland SA, et al. An open-label, randomized phase 3 study of gilteritinib versus salvage chemotherapy in relapsed or refractory FLT3 mutation-positive acute myeloid leukemia. J Clin Oncol. 2017;35:TPS7067.