Tretinoin

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Abstract
Tretinoin (all-trans retinoic acid), a vitamin A derivative, induces cellular differentiation in several haematological precursor cell lines and cells from patients with acute promyelocytic leukaemia. Drug treatment with tretinoin is associated with morphological and functional maturation of leukaemic promyelocytes and a progressive reduction in the occurrence of the characteristic t(15;17) chromosomal translocation. Recent therapeutic trials indicate that tretinoin induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. In newly diagnosed patients, remission induction treatment with tretinoin followed by intensive chemotherapy resulted in a significant reduction in relapse rate and prolongation of event-free and overall survival compared with chemotherapy alone in 1 comparative trial. Tretinoin alone does not totally eradicate the leukaemic clone and consolidation chemotherapy is recommended as follow-up. The use of reverse transcription polymerase chain reaction (RT-PCR) provides a sensitive and specific technique to assist in prediction and monitoring of a patient’s response to treatment and to help detect the presence of residual or recurrent disease. The use of tretinoin is potentially limited by the rapid and almost universal development of drug resistance and occurrence of the often severe retinoic acid syndrome. Useful strategies have been described to manage these effects but current and future efforts must be directed at elucidating the mechanisms involved and determining the optimum therapeutic management. In summary, results to date indicate that the combination of tretinoin and intensive chemotherapy is more effective than chemotherapy alone and appears to improve the prognosis of newly diagnosed patients with acute promyelocytic leukaemia. Further information on the relative efficacy of various induction and post-remission strategies in subsets of patients will help determine optimum use of this promising agent in the management of acute promyelocytic leukaemia. Acute promyelocytic leukaemia is characterised by a unique t(15;17) chromosomal translocation between the retinoic acid receptor-alpha (RAR-α) gene on chromosome 17 and a gene known as PML (promyelocyte leukaemia) on chromosome 15. The resultant PML/RAR-α fusion protein appears to be responsible for the failure of promyelocytes to differentiate and explains at a molecular level why only leukaemic cells that express this protein are sensitive to tretinoin. Thus, patients with variant cytogenetic abnormalities respond poorly to tretinoin. Tretinoin induces terminal differentiation in a number of haemopoietic precursor cell lines as well as in cells from patients with acute promyelocytic leukaemia. The exact mechanism of action of tretinoin remains to be fully elucidated, but drug exposure or treatment is associated with progressive morphological and functional maturation of leukaemic cells and the appearance of normal haemopoietic cells. In vitro sensitivity of acute promyelocytic leukaemia cells to tretinoin correlates well with the clinical response observed in patients during treatment with this agent. Additive or synergistic effects have been observed in vitro when tretinoin was combined with some putative differentiating agents, such as recombinant human interferon-α, but results require confirmation in vivo. The oral bioavailability of tretinoin is approximately 50% and, after single dose administration, plasma drug concentrations remain within the range required for in vitro differentiation of acute promyelocytic leukaemia cells for about 4 hours. Tretinoin is distributed rapidly and extensively to tissues but has not been detected in cerebrospinal fluid. Repeated dose administration results in a marked reduction in plasma drug concentration and area under the plasma concentration-time curve which is associated with relapse in treated patients. Tretinoin undergoes oxidative metabolism via the cytochrome P450 enzyme system in the liver, glucuronide conjugation and elimination in urine and bile. Tretinoin appears to undergo capacity-limited (saturable) elimination with a terminal elimination half-life of less than 1 hour. Results from 1 comparative and several noncomparative trials indicate that tretinoin (most commonly 45 mg/m2/day) induces remission in 64 to 100% of patients with acute promyelocytic leukaemia. The duration of drug treatment needed to induce remission has varied widely between 8 and 119 days. In newly diagnosed patients, tretinoin followed by intensive chemotherapy (daunorubicin and cytosine arabinoside) significantly reduced the 1-year relapse rate (13 vs 41%) and increased 2-year event-free (68 vs 23%) and overall survival (81 vs 51%) compared with the same chemotherapy regimen alone, despite similar rates of complete remission (91 vs 81%). In noncomparative studies, no significant differences in drug efficacy were evident on the basis of disease status, although definitive conclusions are precluded by limited patient enrolments. Although resistance to tretinoin in most patients with acute promyelocytic leukaemia and a t(15;17) translocation is initially very low, it appears to be acquired rapidly and almost universally during continuous drug treatment. Detection of the t(15;17) chromosomal translocation or the PML/RAR-α fusion protein correlates highly with the presence of disease and the occurrence of relapse. Induction of remission with tretinoin and/or chemotherapy is associated with progressive disappearance of these cytogenetic abnormalities, although reverse transcription polymerase chain reaction (RT-PCR) tests indicate that tretinoin alone is usually unable to totally eradicate the leukaemic clone. This finding is in keeping with clinical observations that remissions induced by tretinoin alone are generally brief in duration unless followed by consolidation chemotherapy or bone marrow transplant. There is no convincing evidence that tretinoin is useful for consolidation or maintenance therapy. Compared with standard antineoplastic chemotherapy, which is cytotoxic to normal haemopoietic and leukaemic cells, tretinoin induces remission in patients with acute promyelocytic leukaemia without causing bone marrow hypoplasia or exacerbation of the frequently occurring haemorrhagic syndrome. In fact, many trials have reported that bleeding complications associated with this disease resolve within 4 to 6 days of patients starting drug treatment. A potentially serious consequence of tretinoin therapy is the development of retinoic acid syndrome. This syndrome, which is characterised by fever, respiratory distress, interstitial pulmonary infiltrates, pleural effusions and weight gain, may occur in up to 25% of patients and can be fatal if not promptly recognised and treated. It has been successfully managed with high dose corticosteroids and/or addition of standard chemotherapy to tretinoin therapy, although additional data are needed to determine the efficacy and appropriate use of these strategies. In common with other retinoids, adverse events with tretinoin often involve the skin and mucous membranes. Dryness of the skin, nasal and/or other mucosal membranes and/or cheilitis occur in 24 to 65% of patients but respond to symptomatic treatment. Similarly, headaches, bone pain and arthralgias are frequently reported but are alleviated by analgesics. Children may be less tolerant of the adverse events associated with tretinoin, particularly those events related to the CNS (headache and pseudotumour cerebri). Increased levels of triglycerides, serum creatinine and/or hepatic enzymes are observed but do not usually necessitate interruption or withdrawal of tretinoin therapy. The recommended oral dose of tretinoin is 45 mg/m2/day in all patients with acute promyelocytic leukaemia, including children and the elderly. Treatment is continued for 30 to 90 days until complete remission has been achieved, at which time consolidation chemotherapy, such as daunorubicin and cytosine arabinoside, should be initiated. If significant elevation in white blood cell count is present or occurs within 15 days of treatment the addition of chemotherapy is recommended. High dose corticosteroids should be administered for at least 3 days to patients who develop symptoms of retinoic acid syndrome.
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