Retinoic acid syndrome

Tretinoin, also referred to ATRA, which stands for all-trans-retinoic acid, is a retinoic acid that is not cytotoxic but promotes the maturation of early promyelocytic cells and is specific to the t(15 17) cytogenetic marker. The time to peak concentrations is 1 to 2 hours after an oral dose. The elimination half-life is 21 to 51 minutes.32 These maroon-and-gold capsules are dosed at 45 mg/m2 per day divided into two doses. The most significant side effect is the retinoic acid syndrome, which may occur anywhere from the first couple of days of therapy until the end of therapy and consists of symptoms of... 

Tretinoin -naturally occurring retinoid -retinoic acid syndrome -fever -chest pain -hypoxia -pulmonary infiltrates -pleural/pericardial effusions -nausea and vomiting -mucocutaneous effects -arthralgias -headaches -increased triglycerides -xerostomia, exfoliation, chelitis... 

In acute promyelocytic leukemia arsenic trioxide can cause a syndrome similar to the retinoic acid syndrome (15), with fever, skin rash, edema, pleural effusion, pericardial effusion, and acute respiratory failure. 

Che-Pin Lin, Huang MJ, Chang lY, Lin WY, Sheu YT. Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia. Leuk Lymphoma 2000 38(l-2) 195-8. 

Nicolls MR, Terada LS, Tuder RM, Prindiville SA, Schwarz MI. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. Am J Respir Crit Care Med 1998 158(4) 1302-5. 

Fatal adverse effects have been reported in patients given tretinoin for acute promyelocytic leukemia (5). Of 82 patients with acute promyelocytic leukemia, 35 developed leukocytosis and 22 had fatal adverse effects (15 with the retinoic acid syndrome and 7 with intracranial bleeding). Leukocytosis was a risk factor for fatal adverse effects. The authors suggested that the combination of tretinoin with low-dose harringtonine can reduce the incidence of leukocytosis-related intracranial bleeding and glucocorticoids can reduce mortality from the retinoic acid syndrome. 

In another study of 413 patients with acute promyelocytic leukemia treated with tretinoin plus daunorubicin, the retinoic acid syndrome occurred in 64 cases, of which 5 were fatal (6). 

In a retrospective study, 22 children taking tretinoin (median age 9.3 years, range 1.8-16.3) for a median of 38 (6-138) days were compared with 22 taking conventional therapy (median age 12.3 years, range 3.2-16.7) (25). Overall, 12 of 22 patients had sjrmptoms associated with tretinoin (Table 2). Three developed the retinoic acid syndrome. 

Of 69 patients with acute promyelocytic leukemia treated with tretinoin for 5 years, 15 developed retinoic acid syndrome (28). The following features were found on chest radiographs an increased cardio-thoracic ratio, an increased pedicle width, pulmonary congestion in 13, pleural effusion in 11, ground-glass opacities, septal lines, and peribronchial cuffing in 9,... 

A syndrome similar to that of the retinoic acid syndrome occurred after 10 days of tretinoin therapy in a patient with a relapse of acute myeloblastic leukemia (31). 

A 32-year-old woman with acute promyelocytic leukemia developed severe retinoic acid syndrome after 3 days, with respiratory failure, fever, and bilateral lung infiltrates. Withdrawal of tretinoin and treatment with dexamethasone and antibiotics rapidly ameliorated the syndrome, and on day 10 tretinoin was restarted. However, routine echocardiography showed a 3 cm pedunculated mass in the right ventricle. There was consistent and stable reduction of the mass after 1 year of oral anticoagulant therapy. 

Although the retinoic acid syndrome involves the lungs, pulmonary hemorrhage has only rarely been reported. Two patients with acute promyelocytic leukemia developed severe lung hemorrhage during the first 3 weeks of treatment with tretinoin, shortly after the administration of chemotherapy (40). 

Extramedullary relapse of acute promyelocytic leukemia, which is rare after chemotherapy alone, was more common after tretinoin, but it is not clear whether it truly increases the risk of extramedullary recurrence and what the risk factors are. In a retrospective analysis of the incidence of extramedullary relapse in patients after prior treatment with tretinoin and in patients previously treated with chemotherapy alone (68) three of the 13 patients who received tretinoin had extramedullary involvement compared with none of the 11 patients previously treated with chemotherapy alone (RR = 2.1 Cl = 1.34, 3.29). The retinoic acid syndrome during prior induction treatment was significantly associated with extramedullary relapse (three of five patients with the retinoic acid syndrome versus none of eight without the syndrome (RR = 5.0 Cl = 1.4,17)). Thus, tretinoin may predispose patients with acute promyelocytic leukemia to extramedullary involvement at relapse and the retinoic acid syndrome is a risk factor. 

During tretinoin therapy, some patients with retinoic acid syndrome or with a hypercoagulable state develop acute renal insufficiency, usually accompanied by dysfunction of other organs. A patient with acute promyelo-cytic leukemia developed renal insufficiency alone during tretinoin treatment (86). 

Amano Y, Tajika K, Mizuki T, Amano M, Dan K, Kumazaki T. All-trans retinoic acid syndrome chest CT assessment. Eur Radiol 2001 11(8) 1516-17. 

Jung JI, Choi JE, Hahn ST, Min CK, Kim CC, Park SH. Radiologic features of all-trans-retinoic acid syndrome. Am J Roentgenol 2002 178(2) 475-80. 

Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Rowe JM, Francois C, Larson RS, Wiernik PH. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 2000 95(l) 90-5. 

Lehmann S, Paul C. The retinoic acid syndrome in non-M3 acute myeloid leukaemia a case report. Br J Haematol 2000 108(l) 198-9. 

Ko BS, Tang JL, Chen YC, Yao M, Wang CH, Shen MC, Tien HF. Extramedullary relapse after all-trans retinoic acid treatment in acute promyelocytic leukemia—the occurrence of retinoic acid syndrome is a risk factor. Leukemia 1999 13(9) 1406-8. 

Astudillo L, Loche F, Reynish W, Rigal-Huguet F, Lamant L, Pris J. Sweet s syndrome associated with retinoic acid syndrome in a patient with promyelocytic leukemia. Ann Hematol 2002 81(2) 111-14. 

Headache xerosis pruritus retinoic acid syndrome (fever, dyspnea, pulmonary infiltrates, pleural effusions, peripheral edema, hypotension) arthralgias myalgias Fever chills malaise rash pruritus hyperpigmentation... 

Retinoic acid syndrome must be treated promptly with corticosteroids weight gain secondary to fluid retention may be dose limiting... 

While being devoid of myelosuppressive effects, tretinoin therapy is associated with headache, skin and mucous membrane reactions, bone pain, nausea, and the retinoic acid syndrome. When tretinoin is started, rapid onset of differentiation of promyelocytes occurs, which can lead to leukocytosis and/or retinoic acid syndrome. The retinoic acid syndrome (fever, respiratory distress, interstitial pulmonary infiltrates, pleural effusions, and weight gain) is now referred to as the APL differentiation syndrome or APL hyperleukocytosis syndrome, because it has been associated with other treatment modalities in the management of APL. Among tretinoin-treated patients, this syndrome has been fatal in 5% to 29% of cases. A combination of chemotherapy with tretinoin induction decreases the incidence of retinoic acid syndrome, and rapid initiation of dex-amethasone 10 mg (0.2 mg/kg per dose in children) twice daily for 3 days upon development of symptoms decreases associated mortality. 

Frankel, S. R., Eardley, A, Lauwers, G., Weiss, M., and Warrell, R P (1992) The retinoic acid syndrome in acute promyelocytic leukemia Am. Intern. Medicine 117,292-296... 

Transretinoic acid has dramatically changed the management of acute promye-locytic leukemia. It allows the maturation of leukemic cells and induces remission. It is typically used in association with daunombicin and cytosine arabinoside. The retinoic acid syndrome occurs in 25% of patients and consists of a capillary leak syndrome with noncardiogenic pulmonary edema (14). Diffuse alveolar hemorrhage is also a well-documented complication. 

De Botton S, Dombret H, Sanz M, et al. Incidence, clinical features, and outcome of all trans-retinoic acid syndrome in 413 cases of newly diagnosed acute promyelo-cytic leukemia. The European APL Group. Blood 1998 92 2712-2718. 

---