Selection and management of older patients with acute myeloid leukemia treated with glasdegib plus low-dose cytarabine: expert panel review

Figures & data

Figure 1. Agents approved for treatment of newly diagnosed patients with AML ineligible for intensive chemotherapy. AML: acute myeloid leukemia; IC: intensive chemotherapy; IDH: isocitrate dehydrogenase; LDAC: low-dose cytarabine.

Table 1. Summary of agents approved for treatment of patients with AML ineligible for intensive chemotherapy.

Product	Mechanism of action	FDA approval status in AML	Approved dosage	EMA approval status in AML	Approved dosage
Azacitidine [30,31]	Hypomethylating agent	Indicated for MDS, including refractory anemia with excess blasts in transformation (i.e. 20–30% blasts), which is now classified as AML per contemporary classification systems	75 mg/m^2 SC or IV daily for 7 days (28-day cycle). Increase to 100 mg/m^2 after 2 cycles if no beneficial effect or toxicity observed	Indicated for intermediate-II and high-risk MDS according to the IPSS, AML with 20–30% blasts and multilineage dysplasia, according to WHO classification, and AML with >30% marrow blasts according to WHO classification	75 mg/m^2 SC or IV daily for 7 days (28-day cycle)
Cytarabine [2,32]	Nucleoside metabolic inhibitor	Indicated in combination with other approved anticancer drugs for induction in acute non-lymphocytic leukemia of adults and children	100–200 mg/m^2/day cytarabine by continuous IV for 7 days	Historical use	100–200 mg/m^2/day cytarabine by continuous IV for 7 days
Decitabine [33,34]	Hypomethylating agent	Indicated for adult patients with MDS, including previously treated and untreated, de novo and secondary MDS of all French/American/British subtypes and intermediate-I, intermediate-II, and high-risk IPSS groups	4-week cycle: 20 mg/m^2 IV over 60 min for 5 days 6-week cycle: 15 mg/m^2 continuous IV over 3 h, repeated every 8 h, for 3 days	Patients with newly diagnosed de novo or secondary AML, according to WHO classification, who are not candidates for standard induction chemotherapy	20 mg/m^2 IV over 60 min for 5 days (4-week cycle)
Glasdegib [35,36]	SMO inhibitor	In combination with LDAC for adult patients with AML aged ≥75 or who have comorbidities that preclude use of intensive induction chemotherapy	100 mg/day PO	Initial authorization in combination with LDAC for newly diagnosed de novo or secondary AML in adult patients who are not candidates for standard induction chemotherapy	To be confirmed
Ivosidenib [37,38]	IDH1 inhibitor	Indicated for treatment of AML with a susceptible IDH1 mutation in adult patients with newly diagnosed AML who are aged ≥75 or who have comorbidities that preclude use of intensive induction chemotherapy, or adult patients with R/R AML	500 mg/day PO	Granted orphan designation for treatment of AML	Not applicable
Venetoclax [39]	BCL-2 inhibitor	In combination with azacitidine or decitabine or LDAC for newly diagnosed AML in adults who are aged ≥75, or who have comorbidities that preclude use of intensive induction chemotherapy	100 mg (day 1), 200 mg (day 2), 400 mg (day 3), 400 mg (days 4+; in combination with azacitidine or decitabine) or 600 mg (days 4+; in combination with low-dose cytarabine)	Not yet approved for AML	Not applicable

AML: acute myeloid leukemia; APL: acute promyelocytic leukemia; EMA: European Medicines Agency; FDA: US Food and Drug Administration; IDH: isocitrate dehydrogenase; IPSS: International Prognostic Scoring System; IV: intravenously; LDAC: low-dose cytarabine; MDS: myelodysplastic syndrome; PO: orally; R/R: relapsed or refractory; SC: subcutaneously; SMO: smoothened; WHO: World Health Organization.

Details correct as of 10 July 2020.

Table 2. Summary of eligibility criteria in key clinical trials in patients with AML who are ineligible for intensive treatment.

Study design	Treatments	Age	Diagnosis	ECOG PS and cytogenetic risk	Other
Patients ineligible for IC
BRIGHT MDS&AML 1003: Open-label, multicenter phase 2 study [40]	Patients were randomized 2:1 to: glasdegib 100 mg QD + LDAC 20 mg BID (N = 88) or LDAC 20 mg BID alone (N = 44)	≥55	Newly diagnosed Previously untreated AML or high-risk MDS	See other Known cytogenetic profile	Considered not suitable for IC, ≥1 of the following criteria: Age: ≥75 Serum creatinine: >1.3 mg/dL Severe cardiac disease ECOG PS = 2 ECOG PS = 0 or 1+ ≥1 other criteria listed above
Open-label, multicenter, multinational phase 1B/2 study [41]	82 patients received venetoclax 600 mg QD + LDAC 20 mg/m^2/day	≥60	Previously untreated AML Patients with secondary AML or prior treatment with HMAs for MDS were permitted	ECOG PS = 0–2 if aged ≥75 ECOG PS = 0–3 if aged 60–74 (if ECOG PS = 0–1, another comorbidity was required)	Ineligible for IC due to comorbidity or other factors Life expectancy >12 weeks White blood cells: ≤25 × 10^9/L Cardiovascular disability status of NYHA class ≤ II
Multicenter, phase 1B dose-escalation and expansion study [42]	145 patients received venetoclax at 400, 800, or 1200 mg/day + decitabine 20 mg/m^2 or azacitidine 75 mg/m^2	≥65	Previously untreated AML	ECOG PS = 0–2	Adequate renal and hepatic function White blood cell count of ≤25 × 10^9/L Ineligible for standard induction chemotherapy due to comorbidities, such as: Age: >75 Cardiac disease Prior anthracycline use Secondary AML High probability of treatment-related mortality
Prospective randomized study [43]	Patients were randomized to LDAC 20 mg BID (N = 103) or hydroxyurea (N = 99)	≥60	De novo or secondary AML or high-risk MDS	Not specified	No specific criteria used to define patients considered not fit for intensive treatment, except: Patients aged <70 should have a documented comorbidity that precluded chemotherapy Patients who entered the non-intensive approach were significantly older, had a poorer performance score, had more secondary disease, and had more heart disease and documented comorbid conditions
EORTC-GIMEMA AML-19: Open-label, phase 3 study [44]	Patients were randomized 1:1 to a single induction course of GO (6 mg/m^2 on day 1 and 3 mg/m^2 on day 8; N = 118) or best supportive care (N = 119)	>75	Previously untreated AML (de novo or secondary to myelodysplasia) and who were deemed ineligible for IC	See other	Age: 61–75 with a WHO performance score >2 or who were unwilling to receive standard chemotherapy Serum creatinine and liver function test results (bilirubin and transaminases): ≤1.5 × ULN White blood cell count: <30 × 10^9/L
Phase 1 multicenter, open-label, dose-escalation and dose-expansion study [45]	258 patients received ivosidenib 500 mg/day	≥18	R/R IDH1-mutated AML	ECOG PS = 0–2	Included a cohort of patients who were ≥75 or who had comorbidities that precluded the use of IC based on ≥1 of the following criteria: ECOG PS ≥2 Severe cardiac or pulmonary disease hepatic impairment with bilirubin >1.5 × ULN Creatinine clearance <45 mL/min
Multicenter, open-label, single-arm study [46]	39 patients received enasidenib 50–650 mg/day	≥18	Previously untreated IDH2-mutated AML	ECOG PS = 0–2	Not candidates for standard AML treatments
Older patients
Multicenter, randomized, open-label, phase 3 study [47]	Patients were randomized 1:1 to: decitabine 20 mg/m^2/day (N = 242) or treatment choice (N = 243; supportive care or cytarabine 20 mg/m^2/day)	≥65	Previously untreated de novo or secondary AML	ECOG PS = 0–2 Poor- or intermediate-risk cytogenetics	>30% bone marrow blasts White blood cell count: ≤15/mm Not considered eligible for HSCT
Multicenter, randomized, open-label, phase 3 study [48]	Patients were randomized 1:1 to azacitidine 75 mg/m^2/day (N = 241) or conventional care regimens (N = 247; standard induction chemotherapy, LDAC, or supportive care only)	≥65	De novo or secondary AML	ECOG PS = 0–2 Poor- or intermediate-risk cytogenetics	White blood cell count: ≤40,000/mm Bilirubin: ≤1.5 × ULN AST/ALT: ≤2.5 × ULN Creatinine clearance: ≥40 mL/min Life expectancy ≥12 weeks Exclusion criteria included: unstable angina or NYHA class III/IV congestive heart failure, inaspirable bone marrow, comorbidities, or organ dysfunction

7 + 3: cytarabine 100 mg/m² IV for 7 days by continuous infusion, and daunorubicin 60 mg/m² for 3 days; ALT: alanine transaminase; AML: acute myeloid leukemia; AST: aspartate transaminase; BID: twice daily; CMML: chronic myelomonocytic leukemia; ECOG PS: Eastern Cooperative Oncology Group performance status; GFR: glomerular filtration rate; GO: gemtuzumab ozogamicin; HMA: hypomethylating agent; HSCT: hematopoietic stem cell transplant; IC: intensive chemotherapy; IDH: isocitrate dehydrogenase; IV: intravenous; LDAC: low-dose cytarabine; LVEF: left ventricular ejection fraction; MDS: myelodysplastic syndromes; NYHA: New York Heart Association; QD: once daily; QTcF: QT interval corrected for heart rate using Fridericia’s formula; R/R: relapsed or refractory; ULN: upper limit of normal; WHO: World Health Organization.

Table 3. Summary of baseline characteristics in key clinical trials in patients with AML who are ineligible for intensive treatment.

Treatment	Median (range) age, years	ECOG PS	Cytogenetic risk	AML diagnosis	Prior treatment details	Mutations
Patients ineligible for IC
Glasdegib 100 mg QD + LDAC 20 mg BID or LDAC 20 mg BID alone [40]	Glasdegib + LDAC: 77 (63–92) LDAC alone: 75 (58–83)	For glasdegib + LDAC and LDAC alone, respectively: 0: 12.5% and 6.8% 1: 33.0% and 40.9% 2: 53.4% and 52.3% Not reported: 1.1% and 0%	For glasdegib + LDAC and LDAC alone, respectively: Good/intermediate risk: 59.1% and 56.8% Poor risk: 40.9% and 43.2%	For glasdegib + LDAC and LDAC alone, respectively: AML: 88.6% and 86.4% MDS: 11.4% and 13.6%	Prior therapy with MDS drug for glasdegib + LDAC and LDAC alone, respectively: Azacitidine: 14.8% and 18.2% Decitabine: 2.3% and 2.3%	Genes mutated in ≥10% of patients for glasdegib + LDAC and LDAC alone, respectively: CEBPA: 13.8% and 12.0% DNMT3A: 25.9% and 24.0% IDH1: 13.8% and 8.0% IDH2: 19.0% and 16.0% RUNX1: 43.1% and 24.0% TET2: 24.1% and 36.0%
Venetoclax 600 mg QD + LDAC 20 mg/m^2/day [41]	74 (63–90)	0: 15% 1: 56% 2: 28% 3: 1%	Intermediate risk: 60% Poor risk: 32% No mitosis: 8%	De novo: 51% Secondary: 49%	Prior HMA treatment: 29%	TP53: 14% FLT3: 23% IDH1/2: 25% NPM1: 13%
Venetoclax at 400, 800, or 1200 mg/day + decitabine 20 mg/m^2 or azacitidine 75 mg/m^2 [42]	74 (65–86)	0: 22% 1: 62% 2: 16%	Intermediate risk: 51% Poor risk: 49%	De novo: 75% Secondary: 25%	Prior hydroxyurea: 12%	FLT3: 12% IDH1/IDH2: 24% NPM1: 16% TP53: 25%
LDAC 20 mg BID or hydroxyurea [43]	Age ≥75: LDAC: 49% Hydroxyurea: 48%	Performance score for LDAC and hydroxyurea, respectively: 0: 28% and 26% 1: 43% and 44% 2: 19% and 16% 3: 12% each 4: 1% each	For LDAC and hydroxyurea, respectively: Favorable risk: 2% and 1% Intermediate risk: 54% and 52% Adverse risk: 17% and 24% Unknown: 30% and 22%	For LDAC and hydroxyurea, respectively: De novo: 61% and 60% Secondary: 28% and 25% MDS: 14% and 14%	N/A	N/A
GO (6 mg/m^2 or best supportive care [44]	GO: 77 (62–88) Best supportive care: 77 (66–88)	WHO performance score for GO and best supportive care, respectively: 0–1: 64.4% and 64.7% 2: 28.8% and 27.7% >2: 6.8% and 7.6%	For GO and best supportive care, respectively: Favorable/intermediate risk: 50.0% and 37.8% Adverse risk: 28.0% and 26.9% Unknown risk: 22.0% and 35.3%	For GO and best supportive care, respectively: De novo: 66.9% and 71.4% Secondary: 33.1% and 28.6%	N/A	For GO and best supportive care, respectively: CD33 <20: 8.5% and 11.8% CD33 20–80: 49.1% and 48.7% CD33 >80: 40.7% and 39.5% Unknown: 1.7% and 0%
Ivosidenib 500 mg/day [45]	Primary population: 67 (18–87) R/R AML population: 67 (18–87)	N/A	For the primary and R/R AML populations, respectively: Favorable risk: 0% each Intermediate risk: 53% and 59% Poor risk: 30% and 28% Unknown/missing: 17% and 13%	For the primary and R/R AML populations, respectively: Primary AML: 66% and 67% Secondary AML: 34% and 33%	Prior therapy and response to prior therapy for the primary and R/R AML populations, respectively: IC: 74% and 71% Non-IC: 66% and 64% Investigational therapy: 30% and 31% Relapse after transplantation: 29% and 24% Second or later relapse: 16% and 15% Disease that was refractory to initial induction Reinduction therapy: 69% and 59% Relapse within 1 year after initial therapy: 10% and 9%	For the primary and R/R AML populations, respectively: FLT3: 8% and 6% NPM1: 20% and 26% CEBPA: 3% and 2%
Enasidenib 50–650 mg/day [46]	77 (58–87)	0: 31% 1: 46% 2: 23%	Intermediate risk: 49% Poor risk: 26% Missing: 23%	Myelodysplasia-related changes: 36% Recurrent genetic abnormalities: 5% Therapy-related myeloid neoplasms: 5% Not otherwise specified: 51% Missing: 3%	N/A	IDH2 mutant allele: R140: 67% R172: 31% Other/missing: 3% Genes mutated in ≥10% of patients: SRSF2: 53% ASXL1: 50% STAG2: 35% RUNX1: 29% DNMT3A: 24% TET2: 15% NRAS: 12%
Older patients
Decitabine 20 mg/m^2/day or treatment choice (supportive care or cytarabine 20 mg/m^2/day) [47]	Decitabine: 73 (64–89) Treatment choice: 73 (64–91)	For decitabine and treatment choice, respectively: 0 or 1: 76.0% and 75.3% 2: 24.0% and 24.7%	For decitabine and treatment choice, respectively: Intermediate risk: 63.1% and 63.6% Poor risk: 36.1% and 36.0%	For decitabine and treatment choice, respectively: De novo: 64.0% and 64.6% Secondary: 36.0% and 34.6%	N/A	N/A
Azacitidine 75 mg/m^2/day or conventional care regimens (standard induction chemotherapy, LDAC, or supportive care only) [48]	Azacitidine: 75 (64–91) Conventional care regimens: 75 (65–89)	For azacitidine and conventional care regimens, respectively: 0 or 1: 77.2% and 76.8% 2: 22.8% and 23.2%	For azacitidine and conventional care regimens, respectively: Intermediate risk: 64.3% and 64.5% Poor risk: 35.3% and 34.4%	For azacitidine and conventional care regimens, respectively: AML, not otherwise specified: 63.5% and 57.9% AML with myelodysplasia-related changes: 31.1% and 33.6% AML with therapy-related myeloid neoplasms: 3.3% and 4.9% AML with recurrent genetic abnormalities: 2.1% and 3.6%	N/A	N/A

7 + 3: cytarabine 100 mg/m² IV for 7 days by continuous infusion, and daunorubicin 60 mg/m² for 3 days; AML: acute myeloid leukemia; BID: twice daily; CMML: chronic myelomonocytic leukemia; ECOG PS: Eastern Cooperative Oncology Group performance status; GO: gemtuzumab ozogamicin; HMA: hypomethylating agent; HSCT: hematopoietic stem cell transplant; IC: intensive chemotherapy; LDAC: low-dose cytarabine; MDS: myelodysplastic syndromes; N/A: not available; QD: once daily; R/R: relapsed or refractory; SD: standard deviation; WHO: World Health Organization.

Table 4. Summary of results from patients ineligible for IC in BRIGHT MDS&AML 1003 (including unpublished data) [40,50–52].

Parameter	Glasdegib plus LDAC	LDAC alone
BRIGHT MDS&AML 1003 population – data from [40], except where indicated	(N = 88)	(N = 44)
Patient characteristics, %
Age >75	60.2	54.5
Comorbidities (unpublished data)
Severe cardiac disease	65.9	47.7
Serum creatinine >1.3 mg/dL	21.6	11.4
Concomitant medications (unpublished data)
Most common, n
Allopurinol	54	27
Paracetamol	45	17
Furosemide	43	19
CYP3A4 inhibitors, n
Ciprofloxacin/ciprofloxacin hydrochloride	31	9
Fluconazole^a	24	14
Voriconazole	15	3
Posaconazole	13	3
Diltiazem/diltiazem hydrochloride	4	0
Itraconazole	3	3
Clarithromycin	2	3
Ketoconazole	1	0
Amiodarone/amiodarone hydrochloride	1	2
Verapamil/verapamil hydrochloride	1	1
Erythromycin	1	0
CYP3A4 inducers, n
Dexamethasone/dexamethasone sodium phosphate	7	0
Carbamazepine	1	0
Phenytoin	1	0
Drugs with QT-prolongation potential^b, n
Ondansetron/ondansetron hydrochloride	42	12
Levofloxacin	41	15
Median (range) treatment cycles	3 (1–35)	2 (1–9)
OS, months, median (80% CI)	8.8 (6.9–9.9)	4.9 (3.5–6.0)
Complete remission, %	17.0	2.3
Common all-causality AEs associated with SMO inhibitors, %
Alopecia	<20	<20
Dysgeusia	25.0	2.4
Fatigue	31.0	19.5
Gastrointestinal disorders
Nausea	35.7	12.2
Decreased appetite	33.3	12.2
Diarrhea	27.4	22.0
Constipation	25.0	14.6
Vomiting	21.4	9.8
Hematological toxicities
Anemia	45.2	41.5
Febrile neutropenia	35.7	24.4
Thrombocytopenia	31.0	26.8
Musculoskeletal disorders
Muscle spasms	22.6	4.9
Musculoskeletal pain^c	≥20	≥20
Rash^c	≥20	≥20
QTcF >500 ms	6.0	11.8
BRIGHT AML 1003 population – data from [50–52] and unpublished data	(N = 78)	(N = 38)
Survival probability at 1 year, %	39.4	8.4
Survival probability at 2 years, %	19.0	2.8
Complete remission, %	19.2	2.6
Median (range) time to complete remission, days	59 (33–919)	170^d
Achieved transfusion independence, %	29.3	5.6
Median duration, days	212	144
Median time to ANC ≥1000/µL, days	27	13
Median (range) time to first recovery, days	27 (7–114)	13 (8–70)
Median time to ANC ≥500/µL, days	16	11
Median (range) time to first recovery, days	16 (3–143)	11 (8–119)
Median time to platelets ≥1,00,000/µL, days	30	26
Median (range) time to first recovery, days	30 (6–171)	26 (2–56)
Median time to platelets ≥50,000/µL, days	26	24
Median (range) time to first recovery, days	26 (4–141)	24 (2–119)

AE: adverse event; ANC: absolute neutrophil count; CI: confidence interval; CYP: cytochrome P450; IC: intensive chemotherapy; LDAC: low-dose cytarabine; OS: overall survival; QTcF: QT interval corrected for heart rate using Fridericia’s formula; SMO: smoothened.

a One grade 3 AE of prolonged QT interval was considered related to fluconazole.

b Five patients (two receiving a concomitant QT-prolonging medication) had QTcF >480 ms and/or increase >60 ms from baseline, but no event was accompanied by serious arrhythmias.

c From glasdegib product label [35].

d Only one patient achieved complete remission; therefore, no range available.

Table 5. Summary of considerations for glasdegib use.

Consideration	Use of glasdegib
Baseline risk factors
Age	Can be used in patients ≥75
Cytogenetic risk	Can be used in patients of all ELN risk groups
Ineligible for IC	Can be used in patients who have comorbidities that preclude use of intensive induction chemotherapy
Secondary AML	Can be used in patients with secondary AML
Mutations	Can be used in patients with AML who do not present with therapy-targeted mutations
Comorbidities
General comorbidities	Can be used in patients who have comorbidities that preclude use of intensive induction chemotherapy
Cardiac disease	Can be used in patients with severe cardiac disease
Renal impairment	No glasdegib dose adjustment required for mild, moderate, or severe renal impairment
Hepatic impairment	No glasdegib dose adjustment required for mild, moderate, or severe hepatic impairment
Cytopenias	Can be considered for patients with the possibility of prolonged cytopenias, who may be frail, who experienced toxicities with venetoclax, or who are ineligible for venetoclax treatment
Gastrointestinal comorbidities	Evaluate for the potential to increase the risk of gastrointestinal AEs, and ensure that any prophylactic or supportive care therapies are initiated
Musculoskeletal comorbidities	Evaluate for the potential to increase the risk of musculoskeletal AEs, and ensure that any prophylactic or supportive care therapies are initiated
Concomitant medications
Strong CYP3A inhibitors, e.g. azole antifungals, macrolide antibiotics, protease inhibitors	If coadministration is necessary, monitor patients for increased risk of AEs
Strong CYP3A inducers, e.g. bosentan, carbamazepine, dexamethasone, phenytoin, rifampin	Avoid coadministration
QTc-prolonging agents, e.g. antiarrythmics, antimalarials, macrolide antibiotics	Consider alternative therapies, if possible If coadministration is necessary, monitor patients for increased risk of QTc prolongation
Proton pump inhibitors, e.g. omeprazole, lansoprazole, pantoprazole, rabeprazole	No restrictions on the use of proton pump inhibitors with glasdegib

AE: adverse event; AML: acute myeloid leukemia; CYP: cytochrome P450; ELN: European LeukemiaNet; IC: intensive chemotherapy; QTc: QT interval corrected for heart rate.

Figure 2. The most common adverse events associated with glasdegib.

Table 6. Summary of the management of the most common AEs associated with glasdegib [35,81–84].

Adverse event	AE severity	Examples of suggested AE management strategies
Alopecia	Grade 0 and general prophylaxis	Advise patients on the possibility of alopecia, and reassure them that hair typically begins to regrow upon cessation of treatment Educate patients with respect to sun protection and the avoidance of certain chemicals/irritants in order to support hair and scalp health Assess patients for comorbidities or underlying nutrient deficiencies that may contribute to alopecia May consider prophylactic treatment with minoxidil or oral dihydrotestosterone inhibitors
	Grade 1–2	May consider treatment with minoxidil or oral dihydrotestosterone inhibitors For eyelashes, may consider treatment with bimatoprost Suggest the use of a wig/hairpiece or to shave remaining hair
Dysgeusia	Grade 0 and general prophylaxis	Nutritional and dietary assessment prior to initiating treatment Educate patients on dietary strategies such as smaller and more frequent meals, use of stronger seasoning and flavor enhancers, and to increase chewing time Address any potential issues regarding oral hygiene, postnasal drip, or oral infections
	Grade 1–2	Periodic monitoring of zinc levels and supplementation of zinc Provide nutritional support If fluid intake is poor, assess renal function
	Grade ≥3	Employ management strategies listed for grade 1–2 AEs Consider glasdegib interruptions or dose modifications as advised in the product label for non-hematologic AEs
Fatigue	Grade 0 and general prophylaxis	Assess patients for other symptoms, sleep disturbances, nutritional deficiencies, comorbidities, or concomitant medications that may contribute to fatigue Advise patients to maintain regular physical activity
	Grade 1–2	Provide access to well-being and mindfulness programs Consider rehabilitation and psychology consultations Cognitive behavioral therapies or treatment with psychostimulants Assess for anemia, and treat if positive
	Grade ≥3	Employ management strategies listed for grade 1–2 AEs Consider glasdegib interruptions or dose modifications as advised in the product label for non-hematologic AEs
Gastrointestinal toxicities, e.g. nausea, vomiting, decreased appetite, diarrhea, and constipation	Grade 0 and general prophylaxis	Patient education on potential symptoms Take medication at nighttime or with food Eat small meals Remain hydrated and minimize caffeine intake Include ginger in the diet Avoid fatty, fried, or sweet foods Avoid pungent odors
	Grade 1–2	Treatment with antiemetics, e.g. antidopaminergic (metoclopramide or domperidone), serotonin receptor antagonist (ondansetron), antihistamine (dimenhydrinate), phenothiazine, or steroid medications Treatment with antidiarrheal medications, e.g. loperamide and trimebutine Treatment with stool softeners for constipation Oral fluid replenishment in cases of vomiting and/or diarrhea
	Grade ≥3	Employ management strategies listed for grade 1–2 AEs Consider glasdegib interruptions or dose modifications as advised in the product label for non-hematologic AEs
Hematologic toxicities	Grade 0 and general prophylaxis	Assess complete blood counts prior to treatment initiation and at least weekly for the first month of treatment Assess patients for comorbidities or concomitant medications that may contribute to hematologic toxicities Patient education on symptom monitoring, e.g. bruising easily, unexpected bleeding, blood in urine or stools
	Platelets <10 × 10^9/L for >42 days in the absence of disease	Permanently discontinue glasdegib treatment
	Neutrophil count <0.5 × 10^9/L for >42 days in the absence of disease	Permanently discontinue glasdegib treatment
Muscle spasms and musculoskeletal pain	Grade 0 and general prophylaxis	Obtain serum creatine kinase levels prior to initiating treatment and, where necessary, during treatment, e.g. if muscle symptoms are reported Advise the patient to maintain adequate hydration and provide education on passive stretching/gentle physical activity
	Grade 1–2	Examples of non-pharmacologic management include: massage; heat therapy, e.g. thermal compresses; tonic water or sports drinks as part of fluid intake; transcutaneous electrical nerve stimulation Examples of pharmacologic management include: electrolyte replacement; calcium channel blockers, e.g. amlodipine; muscle relaxants, e.g. cyclobenzaprine In the case of abdominal symptoms: calcium channel blockers or antimuscarinic agents
	Grade ≥3	Employ management strategies listed for grade 1–2 AEs Consider glasdegib interruptions or dose modifications as advised in the product label for non-hematologic AEs
QTc prolongation	Grade 0 and general prophylaxis	Assess electrolyte levels and supplement as clinically indicated Assess patients for comorbidities or concomitant medications that may contribute to QTc prolongation Monitor ECGs prior to initiation of treatment, for 1 week after treatment initiation, then once monthly for the next 2 months
	QTc interval 480–500 ms	Review and adjust concomitant medications Assess and correct electrolyte abnormalities Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation to ≤480 ms
	QTc interval >500 ms	Review and adjust concomitant medications Assess and correct electrolyte abnormalities Interrupt glasdegib treatment, and resume glasdegib treatment at a reduced dose of 50 mg QD when QTc interval returns to within 30 ms of baseline or ≤480 ms Monitor ECGs at least weekly for 2 weeks following resolution of QTc prolongation Consider re-escalating to glasdegib 100 mg/day if an alternative etiology for the QTc prolongation is identified
	QTc interval prolongation with life-threatening arrhythmia	Permanently discontinue glasdegib treatment
Rash	Grade 0 and general prophylaxis	Patient education on behavioral changes, e.g. avoiding prolonged exposure to hot water and baths, using sunscreen regularly, and avoiding tight clothes
	Grade 1–2	Consider supportive care therapies, such as hypoallergenic moisturizing creams and topical therapy in the form of steroids, antiseptics, antibiotics, and/or antihistamines Consider support from a dermatologist
	Grade ≥3	Employ management strategies listed for grade 1–2 AEs Consider glasdegib interruptions or dose modifications as advised in the product label for non-hematologic AEs
Weight loss	Grade 0 and general prophylaxis	Nutritional and dietary assessment prior to starting treatment Assess patients for risk factors, comorbidities or underlying nutrient deficiencies that may contribute to weight loss
	Grade 1–2	Provide nutritional or dietary support Treatment with supplements, corticosteroids (excluding dexamethasone), or appetite stimulants, e.g. megestrol acetate or dronabinol
	Grade ≥3	Employ management strategies listed for grade 1–2 AEs Consider glasdegib interruptions or dose modifications as advised in the product label for non-hematologic AEs

AE: adverse event; ECG: electrocardiogram; QD: once daily; QTc: QT interval corrected for heart rate.

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