Burney, I A

Islam, M U

Khursheed, M

English

eCommons@AKU

eCommons@AKUSection of Internal Medicine Department of MedicineFebruary 1998Retinoic acid syndrome: a potentially fatal sideeffect of retinoic acid therapyI A. BurneyAga Khan UniversityM U. IslamAga Khan UniversityM KhursheedAga Khan UniversityFollow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_med_intern_medRecommended CitationBurney, I. A., Islam, M. U., Khursheed, M. (1998). Retinoic acid syndrome: a potentially fatal side effect of retinoic acid therapy.Journal of Pakistan Medical Association, 48(2), 54-55.Available at: https://ecommons.aku.edu/pakistan_fhs_mc_med_intern_med/91Retinoic Acid Syndrome: A Potentially Fatal Side Effect ofRetinoic Acid TherapyPages with reference to book, From 54 To 55 Ikram A. Burney ( Departments of Medicine, The Aga Khan University Hospital, Karachi. ) M. Umar Islam ( Radiology, The Aga Khan University Hospital, Karachi. ) M. Khursheed ( Pathology, The Aga Khan University Hospital, Karachi. ) The management of acute promyelocytic leukemia (APL) has changed over the past few years1-2. Thediscoveiy of specific molecular abnormality (PML/RAR-cz gene product) has raised considerableinterest in the management of the disorder with All trans- retinoic acid (ATRA)3-5. The compound isnow being increasingly used for the remission-induction in APL. However, the drug is not free of sideeffects. We report a potentially fatal side effect of the drug in two patients.Case 1A 23 year old lady presented with pancytopenia and was diagnosed to have APL. The patient also hadright basal consolidation at presentation. She was started on ATRA, at a dose 45 mg/rn2 in two divideddoses. It was planned that ATRA would be administered for a total of 90 days. She also receivedantibiotic therapy consisting of Cloxacillin, Amikacin and Ceftazidime. On the 5th day of therapy, thepatient became acutely dyspnoeic and restless. On examination, the respiratory rate was 32/mm., BP140/80mm Hg, Pulse 160/min, temperature 37°C. Auscultation of the chest revealed decreased breathsounds on the left side. The chest x-ray showed infiltrates throughout the right lung with completeopacification of the left hemithorax. Arterial blood gasses showed severe arterial hypoxemia. Becauseof the continuously decreasing 02 saturation, the patient was intubated and ventilated. A chest tube waspassed on the left side which drained 650 ml of hemorrhagic fluid. A subsequent CBC revealed a totalleucocyte count of 28,400/uL. Dexamethasone 10 mg b.i.d. parenterally, was initiated immediately.Subsequently, Cytosine Arabinoside ma dose of 100 mg/m2 was administered for five days andDaunorubicin inadose of45 mg/m2 for two days. Overthe next several days, clinical as well as theradiological picture improved. About 3 weeks after the acute episode, the chest x-ray showed completeresolution of bilateral infiltrates and pleural effusion. The chest tube was removed and the patient wassubsequently extubated. The patient returned to the ward, where a bone marrow aspirate showed her tobe in complete remission.Case 2A 37 year old lady presented with history of menorrhagia and easy bruisability and was found to bepancytopenic. Her full blood count revealed a hemoglobin of 8.4 g/dl total leucocyte count 0.9x10 /Land platelet count 18x10 /L. The liver and renal function tests were within nonnal limits. The bonemarrow aspirate acute promyelocytic leukemia according to the FAB criteria. The patient was startedon remission - induction treatment with ATRA 45 mg/m2 daily intwo divided doses. On the 6th thy oftreatment, the white cell count increased to 19,000/uL and remained at this level over the next couple ofdays. The patient became febrile and developed a hematorna on the right upper arm, which was painful,warm, tender and resulted in limitation of movements at the elbow joint. Antibiotics were started butthe fevercontinued. Blood cultures remained negative. On the 8th day of treatment with ATRA, shedeveloped another hematoma in her right calf followed by one in left calf. Peripheral blood smearshowed persistent leukocytosis with left shifted neutmpbils. The fever continued to spike despite theuse of antibiotics. On the 21st day of treatment with ATRA, the patient suddenly became dyspnoeic andtachypnoeic. The respiratory rate was found to be 42/min. Auscultation of the chest revealed bilateralcrepitations and there was severe hypoxemia. Chest x-ray showed bilateral fluffy infiltrates.Dexamethasone 10 mg was injected immediately and an endotracheal tube passed. She also developedoligurea and systemic hypotension and eventually succumbed to persistent severe hypoxemia.Discussion Acute promyelocytic leukemia (APL) comprises 10% of all cases of acute myeloid leukemia6. Thedisease is characterized by increased bleeding tendency, primarily due to disseminated intravascularcoagulation (DIC), which may occur in upto 80% cases of APL7. Although chemotherapy is highlyeffective in inducing remissions, it may also exacerbate the DIC by rapidly releasing cytoplasmicgranules from the malignant promyelocytes8. The incidence of fatal hemorrhage during the course ofinitial treatment is more than 30 percent8. The identification of a non- random chrornosomalabnormality resolves within the first 48 hours of the treatment. The treatment is generally welltolerated, except for modest degree of thy skin, cheilosis, nasal stuffness and itching13. However, inabout a quarter of patients, the side effects may assume life threatening proportions. These side effectshave beenreported to occur between the second day and the third week of the treatment and consist offever, respiratory distress, radiographic pulmonary infiltrates and pleural and pericardial effusions.Collectively, these have beentenned togetheras the retinoic acid syndrome9,10,14. The pathophysiologyof the syndrome, is unclear, but clinically it resembles the capillary leak syndrome observed in patientstreated with cytokines10,15. It is postulated that the syndrome may be a consequence of the fusiontranscript activity on the intracellular adhesion molecules10. As the leukemic cells differentiate, theymigrate to the pulmonary capillary bed, express the adhesion molecules, liberate vasoactive cytokines,which result in capillary leak and consequent clinical abnormalities. Similar changes occur in thecapillary bed of kidney, liver, skin and lymph nodes10,16. Multi-organ failure ensues and if thesyndrome is not recognized early and treated promptly, it may be rapidly fatal. The syndrome isdifficult to manage once established; however, dexamethasone 10mg i/v every 12 hours has beenshown to halt the proçress of rapidly evolving cellularevents in a number of patients 14. The patientsmay require drainage of pleural effusion and mechanical ventilation may be necessary till theresolutionof symptoms as was the case in our first patient.Acknowledgement We are thankful to Mr. Qureshi for typing the manuscript.References 1. Huang, M, Yu-Chen,Y., Shu-Rong, C. eta!. Use ofall-trans retinoic acid in the treatment of acutepromyelocytic leukemia. Blood, 1 988;72:567-572.2. Warrell, R.P.,Frankel, SR., Miller, W.H. etal. Differentiation therapy for acute promyelocyticleukemia with tretinoin (all- trans-retinoic acid). N. EngI. J. Med., 1991;324:1385-87.3. dc-The, H., Chomienne, C., Lannote, M. et a!. The t (15; 17) translocation of acute promyelocyticleukemia fuses the retinoic acid receptor a gene to a novel transcribed locus. Nature, 1990;347:558-561.4. Avvisati, 0., Petti, MC. and Mandelli, F What is the best treatment for acute promyclocyticleukemia? Lcuk. Lymphoma, 1993;2:29-35.5. Frankel, S.R., Eardley, A,,Heller, 0. et al. All trans retinoic acid for acute promyelocytic leukemia.Results of the New York Study. Ann. Intern. Med., 1994; 120:278-286.6. Stone, R.M. and Mayer, R.J. The unique aspects of acute promyelocytic leukemia. 3. Clin. Oncol.,1990;8:1913-1921.7. Tallman, M.S. and Kwaan, H.C. Reaaaesaing the hemostatic disorder associated with acutepromyelocytic leukemia. Blood, l992;79:543- 553.8. Rodghiero, F, Avvisati, 0., Caataman, G. et al. Early deaths and anti-hemorrhagic treatments in acutepromyelocytic leukemia: A GIMEMA retrospective study in 268 consecutive patients. Blood,1990;75:2112-2117.9. Rowley, J.D., Golomb, H.M. and Dougherty, C. 15/17 Translocation: A consistent chromosomalchange in acute promyelocytic leukemia. Lancet, 1977;1:549-550.10. Warrell, R.P., dc-The, H., Wang, l.Y. et al. Acute promyelocytic leukemia. N. EngI. J. Med.,1993;329:177-189.11. Huang, ME., Ye, Y.C., Chen, S.R. et al. Use of all trans retinoic acid in the treatment ofacutepromyelocytic leukemia. Blood, 1 988;72:567-572.12. Warrell, R.P., Frankel, SR. Miller, W.H. et al. Differentiation therapy of acute promyelocyticleukemia with tretinoin (all-trans-retinoic acid). N. EngI. 3. Med., 1991 ;324:1385-1 393.13. Eardley, A.M., Heller, 0. and Warrell, R.P. Morbidity and costs of remission induction therapy withall-trans retinoic acid compared with standard chemotherapy in acute promyelocytic leukemia.Leukemia, 1 994;8 :934-939.14. Frankel, SR., Eardley, A., Lauwers, G. et al. The ‘retinoic acid syndrome’ in acute promyclocyticleukemia. Ann. Intern. Med., 1992;117:292-296.15. Margolin, K.A., Rayner, A.A., Hawkins, M.J. et al. Interleukin-2 and lymphokine-activated killercell therapy of solid tumours: Analysis of toxicity and management guidelines. J. Clin. Oncol.,1989;7:486-498.16. Grignani, F., Fagioti, M., Atcalay, M. et al. Acute promyelocytic leukemia: From genetics totreatment. Blood, I 994;83: 10-25.

Retinoic acid syndrome: a potentially fatal side effect of retinoic acid therapy

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Retinoic acid syndrome: a potentially fatal side effect of retinoic acid therapy

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