LEUKEMIA: ACUTE PROMYELOCYTIC

LEUKEMIA: ACUTE PROMYELOCYTIC

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Arsenic Trioxide

(Soignet SL, et al.

J Clin Oncol.

2001;19:3852-60)

N = 40

Induction Therapy

Arsenic Trioxide 0.15 mg/kg IV over 2 hours daily; cumulative, maximum of 60 doses

Consolidation Therapy

Arsenic Trioxide 0.15 mg/kg IV over 2 hours daily, weekdays only, or a combination of

both; cumulative maximum of 25 doses

Neutropenia 8%

Leukocytosis 50%

Coagulopathy

Clinical 48%

Subclinical 35%

APL Syndrome 25%

Abdominal pain

(Grade IV) 8%

Dyspnea (Grade IV) 10% Headache (Grade IV) 3%

Insomnia (Grade IV) 3%

Hypokalemia

(Grade IV) 13%

Hyperglycemia

(Grade IV) 13%

Neuropathy (Grade III) 3%

level 3

40% of patients had

at least 1 EKG with

QT prolongation

Acute renal insufficiency

occurred in 3 patients;

1 patient required

dialysis

Monitor the patient for

signs and symptoms

of the APL differentia-

tion syndrome (ATRA-

syndrome)

Baseline EKG should be

performed

Monitor the Qtc interval

and institute corrective

measures if the Qtc

interval is > 500 msec

Monitor the patients for

signs and symptoms

of arsenic toxicity;

recommended

antidotes include

dimercaprol and

penicillamine

LEUKEMIA: ACUTE PROMYELOCYTIC (continued ) : Page 2

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Cytarabine

Daunorubicin

(Tallman MS, et al.

N Engl J Med.

1997;337:1021-28)

N = 174

Induction

Cytarabine 100 mg/m²/d IV continuous

infusion days 1-7

Daunorubicin 45 mg/m²/d IV days 1-3

Consolidation

First cycle―identical to induction

Second cycle (postremission)―

Cytarabine 2000 mg/m² IV over 1 hour

every 12 hours days 1-4

Daunorubicin 45 mg/m² IV days 1, 2

Maintenance therapy―randomized

ATRA 45 mg/m²/d PO in divided doses

every 12 hours for 1 year or

to observation

Induction Therapy

Severe = S

Life-Threatening = LT

Lethal = L

Infection

S = 38%, LT = 8%, L = 6%

Hepatic S =13%, LT = 9%

Hemorrhage

S = 6%, LT = 4%, L = 7%

Pulmonary

S = 2%, LT = 2%, L = 1%

Stomatitis S = 5%, LT = 1%

Cardiac S = 9%

Nausea S = 9%

Diarrhea s= 10%, LT = 1%

Dematologic

S = 5%, LT = 1%

Neurologic S = 7%, LT = 1%

Maintenance Therapy

(n = 94)

Infection 7.4%

Life-Threatening

Toxicity 36%

Neurotoxicity 11.7%

Hepatotoxicity 5.3%

Days 1-3―

level 4

Days 4-7―

level 2

12.4% toxic deaths

during induction

14.9% withdrawal for

toxic effects in ATRA

maintenance

LEUKEMIA: ACUTE PROMYELOCYTIC (continued ) : Page 3

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Tretinoin (ATRA)

(Tallman MS, et al.

N Engl J Med.

1997;337:1021-28)

N = 172

Infection

ATRA 45 mg/m²/d PO in divided doses

every 12 hours days 1-90 (maximum or

until complete remission)

Consolidation

First cycle―identical to Induction

Second cycle (postremission)―

Cytarabine 2000 mg/m² IV over 1 hour

every 12 hours days 1-4

Daunorubicin 45 mg/m² IV days 1, 2

Maintenance therapy―randomized

ATRA 45 mg/m²/d PO in divided doses

every 12 hours for 1 year or

to observation

Induction Therapy

Severe = S

Life-Threatening = LT

Lethal = L

infection

S = 20%, LT = 3%, L = 1%

Hepatic

S = 13%, LT = 6%, L = 1%

Hemorrhage

S = 2%, LT = 6%, L = 6%

Pulmonary

S = 7%, LT = 11%, L = 2%

Stomatitis

S = 5%, LT = 2%, L = 1%

Cardac

S = 7%, LT = 3%, L = 1%

Nausea S = 6%

Diarrhea S = 3%, LT = 1%

Dermatologic

S = 2%, LT = 1%

Neurologic S = 9%, LT = 1%

Thrombosis L = 1%

Maintenance Therapy

(n = 94)

Infection 7.4%

Life-Threatening

Toxicity 36%

Neurotoxicity 11.7%

Hepatotoxicity 5.3%

Induction

level 3

Consolidation

Days 1, 2―

level 5

Days 3, 4―

level 4

12.4% toxic deaths

during induction

14.9% withdrawal for

toxic effects in ATRA

maintenance

LEUKEMIA: ACUTE PROMYELOCYTIC (continued ) : Page 4

Regimen/Number

Of Patients

Drug Dose and Route

Leukopenia/

Neutropenia

Toxicity

Anemia

Toxicity

Other

Grade III-IV Toxicities

Emetogenic

Potential

Consequences of

Adverse Event(s)

Tretinoin (ATRA)

Idarubicin

Mitoxantrone

Methotrexate

Mercaptopurine

(Sanz MA, et al. Blood.

1999;94:3015-21)

N = 123

Induction

Tretinoin 45 mg/m²/d PO every 12 hours

daily for 90 days maximum or until

complete remission

Idarubicin 12 mg/m² IV days 2, 4, 6, 8

Consolidation #1

Idarubicin 5mg/m²/d IV days 1-4

Consolidation #2

Mitoxantrone 10 mg/m²/d IV days 1-5

Consolidation #3

Idarubicin 12 mg/m² IV day 1

Maintenance Therapy

Tretinoin 45 mg/m²/d days 1-15

(repeat every 3 months)

Methotrexate 15 mg/m² IM every week

Mercaptopurine 90 mg/m² PO daily

Maintenance therapy for 2 years

Granulocytopenia

Median day to

recovery―24

Granulocytopenia

Consolidation

#1: 28%

Consolidation

#2: 94%

Consolidation

#3: 17%

Hepatic 5%

Pulmonary 16%

Renal 1%

Cardiac 6%

Neurologic 2%

Dermatologic 2%

Diarrhea 3%

Oral 14%

ATRA Syndrome

6% (definite)

20% (indeterminate)

Induction

Days 2, 4,

6, 8―

level 3

Consolidation

Days 1-4―

level 3

Consolidation

Days 1-5―

level 3

Consolidation

Day 1―

Induction toxicities

(not graded):

Fever 93%

Bacteremia 22%

Hemorrhage 67%

Thrombocytopenia

(19 days to recovery

50,000/mm³)

12 deaths in induction