Table 2 Toxicities of new therapeutic drugs for AML

CPX-351 [34]

Common (≥ 25% incidence and ≥ 2% more common on CPX-351 arm): Hemorrhage (70% vs. 49%), rash (54% vs. 36%), constipation (40% vs. 38%), musculoskeletal pain (38% vs. 34%), abdominal pain (33% vs. 30%), cough (33% vs. 23%), headache (33% vs. 24%), arrhythmia (30% vs. 27%), and pneumonia (26% vs. 23%).

Prolonged thrombocytopenia (28% CPX-351 vs. 12% 7 + 3), prolonged neutropenia (17% vs. 3%)^a

During induction phase

Platelet recovery^b 35 vs. 29 days

Neutrophil recovery^b 36.5 vs. 29 days [35]

Supportive care: Monitor blood counts frequently until recovery. Administer platelet transfusions as needed.

Treat with anti-microbials per institutional standards

Serious:

1) Hemorrhage (> grade 3 12% vs 8%)

2) Cardiotoxicity

3) Hypersensitivity reactions

4) Copper overload

During the entire treatment period.

1) Supportive care: Monitor blood counts frequently until recovery. Administer transfusions as needed.

2) Check Echo at baseline and before consolidation.

3) Interrupt infusion immediately for hypersensitivity reactions. For mild symptoms, reinitiate the infusion at half the prior rate and consider premedication with antihistamines and/or steroids for subsequent doses. For moderate symptoms, do not reinitiate and premedicate prior to subsequent doses. For severe/life-threatening symptoms, permanently discontinue.

4) Caution in treating patients with Wilson’s disease or other copper-related metabolic disorders.

Enasidenib [36]

Common adverse reactions and laboratory abnormalities (≥ 30% all-grade; ≥ 5% grade ≥ 3): total bilirubin increased (81%; 15%), hypocalcemia (74%; 8%), nausea (50%; 5%), diarrhea (43%; 8%), hypokalemia (41%; 15%), vomiting (34%; 2%), decreased appetite (34%; 4%), tumor lysis syndrome (6%; 6%), differentiation syndrome (14%; 7%); non-infectious leukocytosis (12%; 6%).

During the entire treatment period.

If bilirubin > 3 times upper limit of normal (ULN) for ≥ 2 weeks with no other suspected etiology or elevation in transaminases, reduce dose to 50 mg daily. Resume at 100 mg daily if bilirubin resolves to less than 2 × ULN.

Serious:

1) Differentiation syndrome,

2) Non-infectious leukocytosis

1) Differentiation syndrome was seen from 10 days to 5 months after starting therapy

2) Non-infectious leukocytosis is typically seen in the first 2 cycles of treatment [37]

1) Steroids (Dexamethasone 10 mg BID) with taper and supportive care. Interrupt drug if intubation or ventilator support are required and/or kidney dysfunction persists > 48 h. Resume when adverse events are ≤ grade 2.

2) Initiate treatment with hydroxyurea and interrupt drug if leukocytosis does not improve. When WBC < 30 × 10⁹/L, resume drug.

Gemtuzumab ozogamicin [38,39,40]

Common (≥20%) monotherapy^c: fever (79%), infection (42%), increased AST (40%), bleeding (23%), nausea and vomiting (21%), constipation (21%), and mucositis (21%).

In combination with 7 + 3: prolonged thrombocytopenia (19% vs 7%), prolonged neutropenia (3% vs 0%)^a

During induction phase

Supportive care: Monitor blood counts frequently until recovery. Administer platelet transfusions as needed

If platelet or neutrophil count does not recover to greater than or equal to 100 Gi/L and 0.5 Gi/L respectively within 14 days following the planned start date of the consolidation cycle, discontinue drug.

Serious:

1) Hepatotoxicity including severe or fatal hepatic veno-occlusive disease (VOD) (5% ALFA trial GO arm—fatal in 50% of those afflicted)

2) Hemorrhage: grade 3–4 bleeding in 21% on ALFA trial GO arm, including fatal bleeding events (3%) (e.g., cerebral hematoma, intracranial hematoma, subdural hematoma)

3) Infusion related reactions (phase II studies reported one third of patients with a grade 3–4 infusion-related adverse event) [39]

1) Veno-occlusive disease occurred at a median time 9 days (range 2–298 days)

2) During the entire treatment period.

3) Infusion related reactions can occur during infusion and up to 24 h after, most commonly during the first infusion.

1) For total bilirubin > 2 × ULN or AST and/or ALT > 2.5 × ULN, hold drug until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT ≤ 2.5 × ULN. For VOD, institute supportive care and discontinue drug.

2) Dose delay or permanent discontinuation.

3) Premedicate with a corticosteroid (e.g., 1 mg/kg methylprednisolone), acetaminophen 650 mg, and diphenhydramine (50 mg). Patients should be monitored until 1 h after infusion. If reaction occurs, interrupt infusion and treat with same dose of steroid, acetaminophen and/or antihistamine. Permanently discontinue treatment if severe or life-threatening reaction.

Gilteritinib [41]

Common (≥ 25%): transaminase increased (51%), myalgia/arthralgia (50%), fatigue/malaise (44%), fever (41%), mucositis (41%), edema (40%), rash (36%), non-infectious diarrhea (35%), dyspnea (35%), nausea (30%),, cough (28%), constipation (28%), and eye disorders (25%).

Common grade 3–4 laboratory abnormalities ≥ 5%: hypophosphatemia (14%), increased ALT (13%), hyponatremia (12%), AST increased (10%), hypocalcemia (6%), increased CK (6%), and triglycerides increased (6%)

During the entire treatment period.

Assess blood counts and chemistries including creatinine phosphokinase at baseline, at least weekly for the first month, every other week for the second month, and once monthly for the duration of therapy.

Any nonhematologic toxicity grade 3 of over, hold drug until toxicity resolves or improves to Grade 1 and resume at a dose of 80 mg.

Serious:

1) Differentiation syndrome (3%)

2) QT prolongation > 500 ms (1%), increase from baseline QTc > 60 ms (7%)

3) Posterior Reversible Encephalopathy Syndrome (1%)

4) Pancreatitis (4%)

1) Differentiation syndrome was seen from 2 to 75 days after starting therapy.

2)–4) During the entire treatment period.

1) Steroids (Dexamethasone 10 mg BID) with taper and supportive care. Interrupt drug if severe signs/symptoms persist > 48 h. Resume when adverse events are ≤ grade 2.

2) Assess EKGs prior to initiation of treatment with gilteritinib, on days 8 and 15 of cycle 1, and prior to the start of the next two subsequent cycles.

If QTc interval > 500 ms, interrupt drug and resume at 80 mg when QTc interval returns to within 30 ms of baseline or ≤ 480 ms.

3) Discontinue drug.

4) Hold drug until pancreatitis is resolved. Then resume at a dose of 80 mg.

Glasdegib [42]

Common adverse reactions and laboratory abnormalities (≥ 20% and ≥ 2% more common on glasdegib + LDAC arm): creatinine increased (96% vs. 80%), hyponatremia (54% vs. 41%), hypomagnesemia (33% vs. 23%), febrile neutropenia (31% vs. 22%), thrombocytopenia (30% vs. 27%), fatigue (36% vs. 32%), edema (30% vs. 20%), musculoskeletal pain (30% vs. 17%), nausea (29% vs. 12%), AST increased (28% vs. 23%), decreased appetite (21% vs. 7%), dysgeusia (21% vs. 2%), mucositis (21% vs. 12%), constipation (20% vs. 12%), and rash (20% vs. 7%).

Within the first 90 days of therapy. Muscle spasms and decreased appetite worsened after the first 90 days of therapy in some patients.

Monitor blood counts, electrolytes, renal, and hepatic function prior to initiation and at least once monthly for the first month. Monitor electrolytes and renal function once monthly for the duration of therapy. Check creatine kinase at baseline and as clinically indicated.

Dose modifications: For grade 3 non-hematologic toxicity, hold glasdegib and/or LDAC until toxicity resolves or improves to Grade 1 and resume same dose of glasdegib or reduce to 50 mg. Discontinue glasdegib and LDAC for grade 4 nonhematologic toxicity.

Serious:

1) QT prolongation > 500 ms (5%), increase from baseline QTc > 60 ms (4%)

2) Strongly embryotoxic, fetotoxic, and teratogenic

During the entire treatment period

1) Assess EKGs at baseline, after one week, and then once monthly for the next 2 months; repeat if abnormal. Avoid concomitant use with other QTc prolonging drugs. Avoid use of strong CYP3A4 inhibitors. If QTc interval > 500 ms, interrupt glasdegib and resume at 50 mg when QTc interval returns to within 30 ms of baseline or ≤ 480 ms. Permanently stop drug if there are signs or symptoms of life-threatening arrhythmia.

2) Must use contraception for females and males for at least 30 days after last dose. Pregnancy test must be done prior to initiating drug in women of reproductive potential.

Ivosidenib [61]

Common adverse reactions and laboratory abnormalities (≥ 25%)^d: anemia (60%), hyponatremia (39%), fatigue (39%), hypomagnesemia (38%), leukocytosis (38%), arthralgia (36%), diarrhea (34%), dyspnea (33%), edema (32%), uric acid increased (32%), hypokalemia (31%), increased AST (27%), increased alkaline phosphatase (27%), nausea (31%), mucositis (28%), QT prolongation (26%), rash (26%), hypophosphatemia (25%)

During the entire treatment period.

Monitor blood counts and chemistries at baseline, at least weekly for the first month, once every other week for the second month, and once monthly for the duration of therapy. Monitor creatine phosphokinase weekly for the first month of therapy.

Any non-hematologic toxicity grade ≥ 3, stop drug until resolves to grade 2 or lower. Resume drug at 250 mg once daily and can increase to 500 mg once daily if toxicities resolve to grade 1 or lower. If grade 3 or higher toxicity recurs, discontinue drug.

Serious:

1) Differentiation syndrome (19% R/R patients; 13% grade ≥ 3, 25% newly-diagnosed patients; 11% grade ≥ 3)

2) QT prolongation > 500 msec (9%), increase from baseline QTc > 60 msec (14%)

3) Leukocytosis (8% grade ≥ 3 R/R patients, 7% grade ≥ 3 newly-diagnosed patients)

4) Guillain-Barré syndrome (< 1%)

1) Differentiation syndrome occurred as early as 1 day and up to 3 months after drug initiation.

2)-4) During the entire treatment period.

1) Steroids (Dexamethasone 10 mg BID) with taper and hemodynamic monitoring for at least 3 days. Interrupt drug if severe signs and/or symptoms persist > 48 h after steroid initiation. Resume when adverse events are ≤ grade 2.

2) Monitor ECGs at least once weekly for the first 3 weeks of therapy and then at least once monthly for the duration of therapy. If QTc interval > 500 ms, stop drug and resume at 250 mg when QTc interval returns to within 30 ms of baseline or ≤ 480 ms. Monitor EKG weekly for 2 weeks following resolution and consider re-escalating to 500 mg daily. Permanently stop drug if there are signs or symptoms of life-threatening arrhythmia.

Avoid concomitant use with other QTc prolonging drugs. Avoid use of strong or moderate CYP3A4 inhibitors. Dose reduce ivosidenib to 250 mg daily if co-administration of a strong CYP3A4 inhibitor is unavoidable.

3) For WBC > 25 × 10⁹/L or absolute increase of > 15 × 10⁹/L from baseline, initiate treatment with hydroxyurea and/or leukapheresis and interrupt drug if leukocytosis does not improve. When leukocytosis resolves, resume ivosidenib.

4) Supportive care and discontinue drug permanently.

Midostaurin [28]

Common adverse events and laboratory abnormalities (≥ 25% and ≥ 2% more common on midostaurin arm): febrile neutropenia (83% vs. 81%), nausea (83% vs. 70%), ALT increased (71% vs. 69%), hypocalcemia (74% vs. 70%), mucositis (66% vs. 62%), vomiting (61% vs. 53%), headache (46% vs. 38%), petechiae (36% vs. 27%), musculoskeletal pain (33% vs. 31%), and epistaxis (28% vs. 24%).

Throughout the treatment period.

Supportive care: Monitor blood counts frequently and give antibiotics as clinically indicated until recovery.

Any nonhematologic toxicity ≥ grade 3, interrupt Midostaurin until event has resolved to ≤ Grade 2, then resume at a dose of 50 mg twice daily. If tolerated, can increase to 100 mg twice daily.

Serious:

Pulmonary toxicity (interstitial lung disease or pneumonitis, with some reported fatal cases)

Throughout the treatment period.

Discontinue midostaurin in patients with signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology. Start steroids (Dexamethasone 10 mg BID) with taper, hemodynamic monitoring and supportive care until symptom resolution [43].

Venetoclax [44]

Common (≥ 30%)^e:

nausea, diarrhea, thrombocytopenia, constipation, neutropenia, febrile neutropenia, fatigue, vomiting, peripheral edema, pyrexia, pneumonia, dyspnea, hemorrhage, anemia, rash, abdominal pain, sepsis, back pain, myalgia, dizziness, cough, oropharyngeal pain, and hypotension.

Common nonhematologic laboratory abnormalities (≥ 30%)^e: hyperglycemia, hypocalcemia, hypoalbuminemia, hypokalemia, hyponatremia, hypophosphatemia, hyperbilirubinemia, hypomagnesemia, creatinine increased, bicarbonate decreased

Throughout the treatment period.

Supportive care: Monitor blood counts frequently and give antibiotics as clinically indicated until count recovery.

If grade 4 neutropenia or thrombocytopenia:

- Prior to remission: supportive care; transfuse blood products and administer prophylactic or treatment with antibiotics as indicated.

- First occurrence after achieving remission and lasting at least 7 days: delay subsequent treatment cycle. Administer G-CSF if clinically indicated for neutropenia. Once toxicity grade 1 or 2, resume treatment at same dose in combination with HMA or LDAC.

- Subsequent occurrences in cycles after remission and lasting 7 days or longer: delay subsequent treatment cycle. Administer G-CSF if clinically indicated for neutropenia. Once toxicity grade 1 or 2, resume treatment at same dose and reduce duration by 7 days for each subsequent cycle.

Serious:

1) Tumor Lysis Syndrome

2) Neutropenia (96–100% experienced grade ≥ 3)

1) At initiation and during the ramp-up phase

2) Throughout the treatment period.

1) Prior to the first dose, premedicate with anti-hyperuricemic agents and ensure adequate hydration; continue during the ramp-up phase. All patients should have white blood cell count < 25 × 10⁹/L prior to initiation of drug. May have to cytoreduce prior to treatment. Monitor blood chemistries for TLS at pre-dose, 6 to 8 h after each new dose during ramp-up and 24 h after reaching final dose.

Can consider increased laboratory monitoring and reduced starting dose for patients at higher risk of TLS.

2) See above.