Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: CHEPLAPHARM Arzneimittel GmbH, Bahnhofstr. 1a, 17498 Mesekenhagen, Germany
Pharmacotherapeutic group: Cytostatic-differentiating agent
ATC code: L01XX14
Tretinoin is a natural metabolite of retinol and belongs to the class of retinoids, comprising natural and synthetic analogs.
According to the FAB (French-American-British) classification of haematological disease, acute promyelocytic leukaemia (APL) is classified as M3 and M3v form of acute myeloid leukemia (AML).The mechanism of action of tretinoin in APL is not entirely known, and may be linked to specific binding of tretinoin to a nuclear retinoic acid receptor (RAR) given that the nuclear receptor alpha of retinoic acid (RARa) is altered in APL patients by fusion with a protein called PML. Pharmacological doses of tretinoin induce proteolytic degradation of the PML/RARa chimeric protein, hallmark of APL. Transcriptome analyses suggest that tretinoin may clear PML/RARa from promoters, thereby restoring the wild-type RARa function and releasing the differentiation block.
In vitro studies with tretinoin have demonstrated induction of differentiation and inhibition of cell proliferation in transformed hemopoietic cell lines, including human myeloid leukaemia cell lines.
In patients suffering from acute promyelocytic leukaemia (APL), tretinoin in combination with cytotoxic chemotherapy or with arsenic trioxide inhibits proliferation and induces the differentiation of promyelocytic blasts. With such combination treatment approach high rates of complete remission and low relapse rates can be achieved.
The combination of tretinoin with anthracycline chemotherapeutics has been investigated in various clinical trials with children, adults, and elderly APL patients. One of the internationally established and accepted treatment regimens is the AIDA2000 protocol. In this regimen, newly diagnosed patients were treated for induction therapy with 45 mg/m²/day tretinoin until complete remission, for a maximum of 45 days. This was followed by 3 courses of consolidation therapy with a treatment for 15 days with an equal dose in each course. During maintenance therapy, tretinoin was administered every 3 months for 15 days for 2 years. According to their relapse risk, patients received a different regimen of chemotherapy. Using this treatment approach, a 6-year overall survival of 87.4%, and a 6-year disease-free survival of 85.6% was achieved. These data are in line with other larger clinical trials (LPA99 and LPA2005, APL2000, AMLCG2009) with complete remission rates of ≥90%, overall survival of 82 to 94%, and disease-free survival (DFS) of 82 to 90%.
The combination of tretinoin with arsenic trioxide has been investigated in the APL0406 clinical trial. In this prospective, randomized, multicentre, open-label, phase III non-inferiority trial, 276 newly diagnosed patients (adults between 18 and 71 years of age) with non-high risk APL were randomly assigned to receive tretinoin/arsenic trioxide (ATO) or tretinoin/chemotherapy. Complete remission was achieved in 100% in the tretinoin/arsenic trioxide arm and 97% in the tretinoin/chemotherapy arm, respectively. After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the tretinoin/arsenic trioxide versus tretinoin/chemotherapy arms were 97.3% vs. 80%, 1.9% vs. 13.9%, and 99.2% vs. 92.6%, respectively (P<0.001, P=0.0013, and P=0.0073, respectively). Concerning the safety profiles of treatment regimen, for patients receiving tretinoin/arsenic trioxide, adverse effects mainly consisted of frequent increase of liver enzymes, QTc prolongation, and hyperleukocytosis. In almost all patients, this toxicity was reversible and manageable with temporary drug interruption and dose adjustments as per protocol recommendations, including the addition of hydroxyurea.
In children, the treatment combining tretinoin with chemotherapy gives comparable results as with adults. For example, compared to data from adults in the APL93 trial 576 patients with 31 newly diagnosed children (5%) were investigated and no difference between adults and children was seen for complete remission rate, 5-year relapse rate, event free survival, and overall survival, but significantly better survival was seen in children after adjustment on white blood cell counts and incidence of microgranular M3 variant of APL.
In terms of toxicity and compared to adults, a higher frequency of pseudotumor cerebri has been observed in children and adolescents. The incidence decreases with the use of lower dose of tretinoin.
There are only limited data concerning the use of tretinoin in combination with arsenic trioxide in the paediatric population.
APL is less frequently diagnosed in the elderly (patients above 60 years). Elderly patients seem at least as responsive to therapy as younger patients but rates of response and survival are lower in this age setting owing to a higher incidence of early deaths and deaths in remission when conventional treatment with tretinoin and chemotherapy is used. The higher rate of early deaths in this cohort is due to greater comorbidities compared to those of younger patients.
There are only limited data concerning the use of tretinoin in combination with arsenic trioxide in the elderly population.
Tretinoin is an endogenous metabolite of vitamin A and is normally present in plasma.
After oral administration, tretinoin is absorbed by the digestive tract, and maximum plasma concentrations in healthy volunteers are attained after 3 hours.
There is a large inter-patient and intra-patient variation in plasma levels of tretinoin.
Tretinoin is extensively bound to plasma proteins. Following peak levels, plasma concentrations decline with a mean elimination half-life of 0.7 hours. Plasma concentrations return to endogenous levels following a single 40 mg dose after 7 to 12 hours. No accumulation is seen after multiple doses and tretinoin is not retained in body tissues.
During continuous administration a marked decrease in plasma concentration can occur, possibly due to cytochrome P450 enzyme induction which increases clearance and decreases bioavailability after oral doses.
Renal excretion of metabolites formed by oxidation and glucuronidation is a major route (60%) of elimination, while 30% is excreted in the faeces. Tretinoin (all-trans retinoic acid) is isomerised to 13-cis retinoic acid and oxidized to 4-oxo-metabolites. These metabolites have longer half-lives than tretinoin and may show some accumulation.
The requirement for dosage adjustment in patients with kidney or liver dysfunction has not been investigated. As a precautionary measure, the dose will be decreased to 25 mg/m²/day (see section 4.2).
Oral administration of tretinoin to animals indicated that the compound had very low acute toxicity in all species investigated.
In animal experimental tests it was shown that in all investigated species the acute toxicity of tretinoin administered orally is low. After a longer period of administration rats exhibit a dose- and time-dependent bone matrix dissolution, a decrease in erythrocyte count and toxic alterations in kidney and testes.
Dogs mainly exhibited disorders concerning spermatogenesis and hyperplasia of the bone marrow.
The major metabolites of tretinoin (4-oxo-tretinoin, isotretinoin and 4-oxo-isotretinoin) are less effective than tretinoin in inducing differentiation of human leukaemic cells (HL-60).
Sub-chronic and chronic toxicity studies in rats indicated that the no effect oral dose was at or below 1 mg/kg/day; in dogs, 30 mg/kg/day was associated with toxic effects including weight loss, dermatological and testicular changes.
Reproduction studies in animals have demonstrated the teratogenic activity of tretinoin.
No evidence of mutagenicity has been found.
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