All-Trans Retinoic Acid is a vitamin A derivative. It is indicated for the treatment of the following conditions:

Remission Induction for Acute Promyelocytic Leukemia (APL):

Induction of Remission:

• For patients with acute promyelocytic leukemia (APL), French-American-British classification M3 (including M3 variant), characterized by t(15;17) translocations and/or the PML/RARα gene presence.

Off-Label Uses in Adults:

• Consolidation Therapy for Acute Promyelocytic Leukemia
• Maintenance Therapy for Intermediate- and High-Risk Individuals with Acute Promyelocytic Leukemia

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All Trans-Retinoid Acid (Vesanoid, ATRA) Dose in Adults:

Note: APL induction with tretinoin should begin early. If cytogenetic analysis fails to confirm t(15;17) translocation or the presence of the PML/RARα fusion protein, discontinue treatment.

Treatment of Acute Promyelocytic Leukemia (APL): Oral

Remission Induction (Manufacturer’s Labeling):

• 45 mg/m²/day in two equally divided doses until documentation of complete remission (CR); discontinue treatment 30 days after CR (or after 90 days).

Additional Remission Induction Guidelines:

• 45 mg/m²/day for 90 days or until complete hematologic healing (Powell 2008; Sanz 2008/2010).
• 45 mg/m²/day in two equally divided doses until marrow blasts are ≤5% with no abnormal promyelocytes or for 85 days (Estey 2009; Ravandi 2006, 2009).

Consolidation Therapy:

• 45 mg/m²/day in two equally divided doses over 15 days (in conjunction with chemotherapy) (Lo-Coco 2010; Sanz 2010).
• 45 mg/m²/day for 14 days every four weeks for seven cycles (in addition to arsenic trioxide) (Ravandi 2009).

Maintenance Therapy for Intermediate- and High-Risk Patients (Off-Label):

• 45 mg/m²/day in two equally divided doses over 15 days (Adès 2008; Sanz 2004).
• 45 mg/m²/day for 7 days each week for 1 year (Powell 2010).

Concomitant Therapy:

• Significant drug interactions require dose/frequency adjustments or avoidance. For more information, consult the drug interactions database.

All-Trans Retinoic Acid Dose in Children:

Note: Frequency, number of doses, and timing of doses in cycles/phases and concomitant treatment may differ; consult individual protocols.

Dose for Acute Promyelocytic Leukemia (APL): Limited Data (Kutny 2017, Ortega 2005, Sanz 2019, Testi 2005)

Children and Adolescents:

Note: Daily doses should be rounded to the nearest 10 mg (i.e., if <5 mg, round down; if ≥5 mg, round up); the morning and evening doses may vary if necessary.

Remission Induction:

• Oral: 25 mg/m²/day in two divided doses on days 1-30 (in combination with idarubicin) (Kutny 2017). Initiate APL treatment with tretinoin as soon as possible. If cytogenetic analysis fails to confirm the presence of PML/RARα or t(15;17) translocation, discontinue use.

Consolidation 1:

• Oral: 25 mg/m²/day in two divided doses on days 1-14 of a 35-day cycle. Repeat once more (in combination with arsenic trioxide) (Kutny 2017).

Consolidation 2:

• Oral: 25 mg/m²/day in two doses on days 1-14 (in combination with IV cytarabine [higher dose], intrathecal cytarabine, and mitoxantrone) (Kutny 2017).

Consolidation 3:

• Oral: 25 mg/m²/day in two divided doses on days 1-14 (in combination with intrathecal cytarabine or idarubicin) (Kutny 2017).

Consolidation 4 (only for high-risk APL):

• Oral: 25 mg/m²/day in two divided doses on days 1-14 (in combination with IV cytarabine [high dose], intrathecal cytarabine, and idarubicin) (Kutny 2017).

Maintenance:

• Oral: 25 mg/m²/day in two divided doses on days 1-14 (in combination with oral methotrexate and mercaptopurine, as well as intrathecal cytarabine [first cycle only]) (Kutny 2017).

Concomitant Therapy:

• Significant drug interactions require dose/frequency adjustments or avoidance. For more information, consult the drug interactions database.

Toxicity Adjustment:

Note: Refer specifically to the protocol(s) for more information about the management of these and other drug-related toxicities.

Children and Adolescents:

APL Differentiation Syndrome:

• Take tretinoin and administer dexamethasone 0.25 mg/kg/dose IV or orally every 12 to 24 hours for 3 days. Stop taking tretinoin if signs/symptoms persist beyond 3 days. If symptoms recur or continue, resume tretinoin therapy (Kutny 2017).

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ATRA Pregnancy Risk Factor D

[US Boxed Warning] - There is a risk of a severely malformed baby if tretinoin pills are given during pregnancy.

After maternal use of standard doses of tretinoin during pregnancy, a neonate's serum was found to contain the drug at birth (Takitani 2005).

Other retinoids have been linked to major fetal abnormalities, spontaneous abortions, and some cases were even fatal.

Exposure to retinoids can cause birth defects such as facial dysmorphia and cleft palate. Other possible defects include eye abnormalities, central nervous system abnormalities, cardiovascular system abnormalities, musculoskeletal system abnormalities, and parathyroid hormone deficiency.

All exposed fetuses are at risk.

The use of APL in humans is very limited. Most cases were treated after the first trimester (Valappil 2007).

A pregnant woman with APL should not use tretinoin in her first trimester. Instead, it is best to avoid tretinoin in the second or third trimester. Fetal monitoring and cardiac monitoring are important (Sanz 2009).

Use of All-Trans Retinoic Acid During Breastfeeding:

It is unknown if breast milk contains tretinoin. Breastfeeding should be stopped before treatment begins.

All-Trans Retinoic Acid Dose in Kidney and Liver Disease:

The manufacturer's labeling does not contain any dosage adjustments (hasn't been studied) for patients with kidney or liver disease.

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Side Effects of All-Trans Retinoic Acid:

Unless otherwise stated, the following adverse drug reactions and incidences are based on product labeling. Most patients will experience drug-related toxicities, including headaches, fever, weakness, fatigue, and nausea. These are rarely permanent or irreversible and usually do not require therapy interruption.

Common Side Effects of All-Trans Retinoic Acid Include:

Cardiovascular:

• Peripheral edema
• Chest discomfort
• Edema
• Cardiac arrhythmia
• Flushing
• Hypotension
• Hypertension
• Localized phlebitis

Central Nervous System:

• Headache
• Malaise
• Shivering
• Pain
• Dizziness
• Anxiety
• Paresthesia
• Depression
• Insomnia
• Confusion

Dermatologic:

• Xeroderma
• Skin rash
• Diaphoresis
• Pruritus
• Alopecia
• Skin changes

Endocrine and Metabolic:

• Hypercholesterolemia
• Hypertriglyceridemia
• Weight loss

Gastrointestinal:

• Dry mucous membranes
• Nausea
• Vomiting
• Gastrointestinal hemorrhage
• Abdominal pain
• Mucositis
• Diarrhea
• Anorexia
• Constipation
• Dyspepsia
• Abdominal distention

Hematologic:

• Hemorrhage
• Leukocytosis
• Disseminated intravascular coagulation

Hepatic:

• Increased liver enzymes

Infection:

• Infection

Neuromuscular & Skeletal:

• Ostealgia
• APL differentiation syndrome
• Myalgia

Ophthalmic:

• Eye disease
• Visual disturbance

Otic:

• Otalgia

Renal:

• Renal insufficiency

Respiratory:

• Upper respiratory complaints
• Dyspnea
• Respiratory insufficiency
• Pleural effusion
• Pneumonia
• Rales
• Wheezing

Miscellaneous:

• Fever

Less Common Side Effects of All-Trans Retinoic Acid Include:

Cardiovascular:

• Cardiac failure
• Facial edema
• Cardiomegaly
• Cardiomyopathy
• Cerebrovascular accident
• Heart murmur
• Ischemia
• Myocardial infarction
• Myocarditis
• Pericarditis

Central Nervous System:

• Agitation
• Cerebral hemorrhage
• Flank pain
• Intracranial hypertension
• Hallucination
• Abnormal gait
• Agnosia
• Aphasia
• Asterixis
• Ataxia
• Brain disease
• Cerebral edema
• Central nervous system depression
• Coma
• Dementia
• Drowsiness
• Dysarthria
• Facial paralysis
• Forgetfulness
• Hemiplegia
• Hyporeflexia
• Hypothermia
• Perception loss
• Seizure
• Speech disturbance

Dermatologic:

• Cellulitis
• Pallor

Endocrine and Metabolic:

• Fluid balance disturbance
• Acidosis

Gastrointestinal:

• Gastrointestinal ulcer

Genitourinary:

• Dysuria
• Benign prostatic hypertrophy
• Urinary frequency

Hematologic:

• Lymphatic disease

Hepatic:

• Hepatosplenomegaly
• Ascites
• Hepatitis

Local:

• Local inflammation

Neuromuscular & Skeletal:

• Weakness in the lower extremities
• Myelopathy
• Tremor

Ophthalmic:

• Declined visual acuity
• Reduced pupillary reflex
• Visual field defect

Otic:

• Hearing loss

Renal:

• Acute renal failure
• Renal tubular necrosis

Respiratory:

• Lower respiratory symptoms and signs
• Pulmonary blood infiltrates
• Asthma
• Laryngeal edema
• Pulmonary hypertension

All-Trans Retinoic Acid Contraindications:

Contraindications Include:

• Hypersensitivity to tretinoin, parabens, retinoids, or any other component of the formulation

Warnings/Precautions

• APL Differentiation Syndrome:

[US Boxed Warning] About 25% of APL patients treated with tretinoin have developed APL differentiation syndrome, also known as retinoic acid-APL (RA-APL) syndrome. It is characterized by fever, dyspnea, and weight gain.

This syndrome can be associated with impaired myocardial contractility or episodic hypotension.

It can be observed with or without concomitant leukocytosis.

Some cases of progressive hypoxemia required mechanical ventilation and intubation. Multiorgan failure has led to fatalities.

The majority of cases occur within the first month of treatment. However, some cases have been reported after the first dose.

Although high-dose steroids administered at the first suspicion of a problem have been shown to decrease morbidity and death, management has yet to be determined.

No matter what the leukocyte count is, immediately begin corticosteroid treatment with dexamethasone 10 mg IV every 12 hours for 3 to 5 days or until symptoms resolve.

Many patients don't need to stop taking tretinoin during treatment for the APL differentiation syndrome.

• Cardiovascular Effects:

Patients without MI or thrombosis risk factors have reported venous thrombosis and MI. The first month of treatment is when there is a greater risk of thrombosis (arterial or venous). Be careful when using antifibrinolytic drugs; concomitant use can cause thrombotic complications (rarely).

• CNS Effects:

Can cause headaches, dizziness, and malaise. Patients should be cautious about driving or operating machinery that requires mental alertness.

• Leukocytosis: [US Boxed Warning]

Approximately 40% of patients will develop rapidly developing leukocytosis during treatment.

Patients with high WBC (>5,000/mm³) at diagnosis are at greater risk for an increase in WBC.

A higher chance of developing life-threatening complications is associated with rapid leukocytosis.

If you notice signs and symptoms of APL differentiation syndrome, start treatment immediately with high-dose corticosteroids.

Patients with a WBC >5,000/mm³ or a rapid WBC rise in patients leukopenic at the start of treatment may receive chemotherapy. This could reduce the incidence of APL differentiation syndrome.

Add full-dose chemotherapy (including anthracycline, if necessary) to tretinoin treatment on day 1 or 2 for patients with a WBC >5,000/mm³, immediately increase chemotherapy for patients with a WBC >5,000/mm³. If the WBC counts reach ≥6,000/mm³ or ≥10,000/mm³ at day 10, or ≥15,000/mm³ at day 28,

• Lipid Effects:

Up to 60% of patients experienced hypercholesterolemia or hypertriglyceridemia, which were reversible upon completion of treatment.

• Liver Function Abnormalities:

During treatment, 50%-60% of patients have elevated liver function tests.

If liver function tests show a significant increase in the normal range, it is worth considering a temporary withdrawal from tretinoin.

Most abnormalities in liver function tests will disappear without treatment interruptions or after completion of therapy.

• Pseudotumor Cerebri:

Pseudotumor cerebri (benign intracranial hypertension) has been linked to retinoids, especially in children.

Risk may be increased by concurrent use of other drugs that have this effect (e.g., tetracyclines).

Early symptoms and signs include headache, nausea, vomiting, or intracranial noises.

• APL:

Tretinoin should be started early for APL. If pending cytogenetic analyses do not confirm APL by the t(15;17) translocation or the presence of the PML/RARα fusion protein (caused due to translocations of the promyelocytic [PML] gene on chromosome 15, and the retinoic acid receptor alpha [RARα] gene on chromosome 17), discontinue treatment.

Monitoring Parameters:

Bone marrow cytology is required to confirm the t(15;17) translocation or the presence/absence of the PML/RARα fusion proteins (do NOT withhold treatment initiation); monitor CBC with differential, coagulation profile, and liver function test results frequently; closely monitor for signs of APL differentiation syndrome (e.g., monitor volume status and temperature; respiration).

The American Society of Clinical Oncology hepatitis B vaccine screening and management provisional clinical opinion (ASCO [Hwang 2020]) recommends HBV testing with hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc), total IgG or IgG and antibody to hepatitis B surface antigen (anti-HBs) before starting (or continuing) systemic anticancer treatment. Do not delay screening/results. A risk assessment is required to detect chronic or past HBV infections. This will determine the antiviral prophylaxis needs, monitoring, and follow-up.

How Do You Administer All-Trans Retinoic Acid?

Take the capsules orally with a meal.

Sublingual administration of tretinoin can also be done by sucking the contents under the tongue (Kueh 1999).

When tretinoin was administered via a feeding tube, low plasma concentrations were reported. However, patient-specific impaired absorption (e.g., soybean oil) could have contributed to the problem (Takitani 2004).

Mechanism of Action of All-Trans Retinoic Acid:

Tretinoin may bind to one or more nuclear receptors. It decreases proliferation and induces differentiation in APL cells. Initially, it produces maturation and repopulation of peripheral blood and the marrow with normal hematopoietic cells to achieve complete remission.

Note: Reported pediatric values are similar to adults (Smith 1992; Takitani 2004)

Absorption: Well absorbed

Protein Binding: >95%, mainly to albumin

Metabolism: Hepatic via CYP; primary metabolite: 4-oxo-all-trans-retinoic acid; displays auto-metabolism

Half-life Elimination: Terminal Parent Drug: 0.5 to 2 hours

Time to Peak, Saline: 1 to 2 hours

Excretion: Urine (63%); feces (30%)

International Brands of All-Trans Retinoic Acid:

• Vesanoid
• Reticap-5