Differentiation (retinoic acid) syndrome
- Steven E Weinberger, MD
Steven E Weinberger, MD
- Adjunct Professor of Medicine
- University of Pennsylvania School of Medicine
- Executive Vice President and CEO Emeritus
- American College of Physicians
- Richard A Larson, MD
Richard A Larson, MD
- Editor-in-Chief — Hematology
- Section Editor — Leukemia
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
- Section Editor
- Kevin R Flaherty, MD, MS
Kevin R Flaherty, MD, MS
- Section Editor — Interstitial Lung Disease
- Associate Professor of Medicine
- University of Michigan Health System
- Deputy Editors
- Helen Hollingsworth, MD
Helen Hollingsworth, MD
- Deputy Editor — Pulmonary, Critical Care, and Sleep Medicine
- Associate Professor of Medicine
- Boston University School of Medicine
- Alan G Rosmarin, MD
Alan G Rosmarin, MD
- Deputy Editor — Hematology
- Professor of Medicine
- University of Massachusetts Medical School
The differentiation syndrome (previously called "retinoic acid syndrome") is a potentially fatal complication of induction chemotherapy in patients with acute promyelocytic leukemia (APL). It is characterized by fever, peripheral edema, pulmonary opacities, hypoxemia, respiratory distress, hypotension, renal and hepatic dysfunction, rash, and serositis resulting in pleural and pericardial effusions. It is a cytokine release syndrome, sometimes called "cytokine storm," and all of the pathophysiologic consequences result from the release of inflammatory cytokines from malignant promyelocytes, probably independent of their differentiation to segmented neutrophils and hyperleukocytosis.
The differentiation syndrome occurs in approximately 25 percent of patients with APL during induction therapy that includes all-trans retinoic acid (ATRA, also known as tretinoin) or arsenic trioxide (ATO), but it is also seen in untreated patients or after other cytotoxic therapies. Early recognition and aggressive management are essential.
The pathogenesis, clinical presentation, diagnosis, and treatment of differentiation syndrome will be discussed here. The pathogenesis, diagnosis, and treatment of APL are presented separately. (See "Clinical manifestations, pathologic features, and diagnosis of acute promyelocytic leukemia in adults" and "Initial treatment of acute promyelocytic leukemia in adults" and "Treatment of relapsed or refractory acute promyelocytic leukemia in adults".)
Differentiation syndrome occurs in approximately 25 percent of patients treated with all-trans retinoic acid (ATRA) or arsenic trioxide (ATO) as induction therapy for acute promyelocytic leukemia (APL). In addition, it also occurs in patients with relapsed or refractory APL who are treated with these agents. The risk of the syndrome is not a function of the dose of either of these agents, nor is it proportional to the WBC count. Differentiation syndrome is not observed when ATRA and/or ATO are used as consolidation or maintenance therapy for APL, nor does it complicate ATRA or ATO treatment of non-APL malignancies . This syndrome depends on the presence of malignant promyelocytes. For example, APL is the most common acute leukemia to present with non-infectious fever, and this is thought to be due to the release of cytokines even before treatment is initiated.
While the reported incidence rates of differentiation syndrome have ranged from 2 to 27 percent in patients treated with standard doses of ATRA and 30 percent in patients treated with ATO, this variation is at least partially due to the use of different diagnostic criteria among studies [1-4]. The incidence may be lower when ATRA is administered concurrently with induction chemotherapy or prophylactic glucocorticoids [1,5]. (See 'Prevention' below and "Initial treatment of acute promyelocytic leukemia in adults".)To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- 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 promyelocytic leukemia. The European APL Group. Blood 1998; 92:2712.
- Frankel SR, Eardley A, Lauwers G, et al. The "retinoic acid syndrome" in acute promyelocytic leukemia. Ann Intern Med 1992; 117:292.
- Jung JI, Choi JE, Hahn ST, et al. Radiologic features of all-trans-retinoic acid syndrome. AJR Am J Roentgenol 2002; 178:475.
- Camacho LH, Soignet SL, Chanel S, et al. Leukocytosis and the retinoic acid syndrome in patients with acute promyelocytic leukemia treated with arsenic trioxide. J Clin Oncol 2000; 18:2620.
- Sanz MA, Grimwade D, Tallman MS, et al. Management of acute promyelocytic leukemia: recommendations from an expert panel on behalf of the European LeukemiaNet. Blood 2009; 113:1875.
- Montesinos P, Bergua JM, Vellenga E, et al. Differentiation syndrome in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycline chemotherapy: characteristics, outcome, and prognostic factors. Blood 2009; 113:775.
- Tallman MS, Andersen JW, Schiffer CA, et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome. Blood 2000; 95:90.
- Vahdat L, Maslak P, Miller WH Jr, et al. Early mortality and the retinoic acid syndrome in acute promyelocytic leukemia: impact of leukocytosis, low-dose chemotherapy, PMN/RAR-alpha isoform, and CD13 expression in patients treated with all-trans retinoic acid. Blood 1994; 84:3843.
- Jeddi R, Kacem K, Ben Neji H, et al. Predictive factors of all-trans-retinoic acid related complications during induction therapy for acute promyelocytic leukemia. Hematology 2008; 13:142.
- Jeddi R, Ghédira H, Mnif S, et al. High body mass index is an independent predictor of differentiation syndrome in patients with acute promyelocytic leukemia. Leuk Res 2010; 34:545.
- Gallagher RE, Willman CL, Slack JL, et al. Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study. Blood 1997; 90:1656.
- Santos FL, Dore AI, Lima AS, et al. [Hematological features and expression profile of myeloid antigens of acute promyelocytic leukemia patients: analysis of prognostic factors for development of the retinoic acid syndrome]. Rev Assoc Med Bras (1992) 2004; 50:286.
- Fenaux P, Castaigne S, Chomienne C, et al. All trans retinoic acid treatment for patients with acute promyelocytic leukemia. Leukemia 1992; 6 Suppl 1:64.
- Breccia M, Mazzarella L, Bagnardi V, et al. Increased BMI correlates with higher risk of disease relapse and differentiation syndrome in patients with acute promyelocytic leukemia treated with the AIDA protocols. Blood 2012; 119:49.
- Luesink M, Jansen JH. Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia. Br J Haematol 2010; 151:209.
- Che-Pin Lin, Huang MJ, Chang IY, et al. Retinoic acid syndrome induced by arsenic trioxide in treating recurrent all-trans retinoic acid resistant acute promyelocytic leukemia. Leuk Lymphoma 2000; 38:195.
- Luesink M, Pennings JL, Wissink WM, et al. Chemokine induction by all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia: triggering the differentiation syndrome. Blood 2009; 114:5512.
- Margolin KA, Rayner AA, Hawkins MJ, et al. Interleukin-2 and lymphokine-activated killer cell therapy of solid tumors: analysis of toxicity and management guidelines. J Clin Oncol 1989; 7:486.
- Gordon M, Jakubowski A, Frankel S, et al. Neutrophil (PMN) function in patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) (abstract). Proc Annu Meet Am Soc Clin Oncol 1991; 10:A761.
- Frankel SR, Eardley A, Heller G, et al. All-trans retinoic acid for acute promyelocytic leukemia. Results of the New York Study. Ann Intern Med 1994; 120:278.
- Hickstein DD, Hickey MJ, Collins SJ. Transcriptional regulation of the leukocyte adherence protein beta subunit during human myeloid cell differentiation. J Biol Chem 1988; 263:13863.
- Nicolls MR, Terada LS, Tuder RM, et al. Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the retinoic acid syndrome. Am J Respir Crit Care Med 1998; 158:1302.
- Larson RS, Brown DC, Sklar LA. Retinoic acid induces aggregation of the acute promyelocytic leukemia cell line NB-4 by utilization of LFA-1 and ICAM-2. Blood 1997; 90:2747.
- Flombaum CD, Isaacs M, Reich L, et al. Acute renal failure associated with the retinoic acid syndrome in acute promyelocytic leukemia. Am J Kidney Dis 1996; 27:134.
- Breccia M, Latagliata R, Carmosino I, et al. Clinical and biological features of acute promyelocytic leukemia patients developing retinoic acid syndrome during induction treatment with all-trans retinoic acid and idarubicin. Haematologica 2008; 93:1918.
- Raanani P, Segal E, Levi I, et al. Diffuse alveolar hemorrhage in acute promyelocytic leukemia patients treated with ATRA--a manifestation of the basic disease or the treatment. Leuk Lymphoma 2000; 37:605.
- Cox NH, O'Brien HA. Sweet's syndrome associated with trans-retinoic acid treatment in acute promyelocytic leukaemia. Clin Exp Dermatol 1994; 19:51.
- Park CJ, Bae YD, Choi JY, et al. Sweet's syndrome during the treatment of acute promyelocytic leukemia with all-trans retinoic acid. Korean J Intern Med 2001; 16:218.
- Breccia M, Avvisati G, Latagliata R, et al. Occurrence of thrombotic events in acute promyelocytic leukemia correlates with consistent immunophenotypic and molecular features. Leukemia 2007; 21:79.
- Tallman MS, Brenner B, Serna Jde L, et al. Meeting report. Acute promyelocytic leukemia-associated coagulopathy, 21 January 2004, London, United Kingdom. Leuk Res 2005; 29:347.
- Mitrovic M, Suvajdzic N, Elezovic I, et al. Thrombotic events in acute promyelocytic leukemia. Thromb Res 2015; 135:588.
- Patatanian E, Thompson DF. Retinoic acid syndrome: a review. J Clin Pharm Ther 2008; 33:331.
- Kelaidi C, Chevret S, De Botton S, et al. Improved outcome of acute promyelocytic leukemia with high WBC counts over the last 15 years: the European APL Group experience. J Clin Oncol 2009; 27:2668.
- Tallman MS, Altman JK. How I treat acute promyelocytic leukemia. Blood 2009; 114:5126.
- Frankfurt O, Tallman MS. Strategies for the treatment of acute promyelocytic leukemia. J Natl Compr Canc Netw 2006; 4:37.
- National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).
- Cortes JE, Kantarjian H, O'Brien S, et al. All-trans retinoic acid followed by chemotherapy for salvage of refractory or relapsed acute promyelocytic leukemia. Cancer 1994; 73:2946.
- Tallman MS, Nabhan C, Feusner JH, Rowe JM. Acute promyelocytic leukemia: evolving therapeutic strategies. Blood 2002; 99:759.
- Smith-Whitley K, Lange B. Fatal all-trans retinoic acid pneumonitis. Ann Intern Med 1993; 118:472.
- Yokokura M, Hatake K, Komatsu N, et al. Toxicity of tretinoin in acute promyelocytic leukaemia. Lancet 1994; 343:361.
- Sanz MA, Martín G, González M, et al. Risk-adapted treatment of acute promyelocytic leukemia with all-trans-retinoic acid and anthracycline monochemotherapy: a multicenter study by the PETHEMA group. Blood 2004; 103:1237.
- Lo-Coco F, Avvisati G, Vignetti M, et al. Front-line treatment of acute promyelocytic leukemia with AIDA induction followed by risk-adapted consolidation for adults younger than 61 years: results of the AIDA-2000 trial of the GIMEMA Group. Blood 2010; 116:3171.
- Iland HJ, Bradstock K, Supple SG, et al. All-trans-retinoic acid, idarubicin, and IV arsenic trioxide as initial therapy in acute promyelocytic leukemia (APML4). Blood 2012; 120:1570.
- Sanz MA, Montesinos P, Rayón C, et al. Risk-adapted treatment of acute promyelocytic leukemia based on all-trans retinoic acid and anthracycline with addition of cytarabine in consolidation therapy for high-risk patients: further improvements in treatment outcome. Blood 2010; 115:5137.
- Rego EM, Kim HT, Ruiz-Argüelles GJ, et al. Improving acute promyelocytic leukemia (APL) outcome in developing countries through networking, results of the International Consortium on APL. Blood 2013; 121:1935.
- Lo-Coco F, Avvisati G, Vignetti M, et al. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med 2013; 369:111.
- Ravandi F, Estey E, Jones D, et al. Effective treatment of acute promyelocytic leukemia with all-trans-retinoic acid, arsenic trioxide, and gemtuzumab ozogamicin. J Clin Oncol 2009; 27:504.
- Adès L, Chevret S, Raffoux E, et al. Is cytarabine useful in the treatment of acute promyelocytic leukemia? Results of a randomized trial from the European Acute Promyelocytic Leukemia Group. J Clin Oncol 2006; 24:5703.
- Burnett AK, Hills RK, Grimwade D, et al. Inclusion of chemotherapy in addition to anthracycline in the treatment of acute promyelocytic leukaemia does not improve outcomes: results of the MRC AML15 trial. Leukemia 2013; 27:843.
- Lengfelder E, Haferlach C, Saussele S, et al. High dose ara-C in the treatment of newly diagnosed acute promyelocytic leukemia: long-term results of the German AMLCG. Leukemia 2009; 23:2248.
- Asou N, Kishimoto Y, Kiyoi H, et al. A randomized study with or without intensified maintenance chemotherapy in patients with acute promyelocytic leukemia who have become negative for PML-RARalpha transcript after consolidation therapy: the Japan Adult Leukemia Study Group (JALSG) APL97 study. Blood 2007; 110:59.
- Powell BL, Moser B, Stock W, et al. Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia: North American Leukemia Intergroup Study C9710. Blood 2010; 116:3751.
- Mathews V, George B, Chendamarai E, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol 2010; 28:3866.
- Hu J, Liu YF, Wu CF, et al. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A 2009; 106:3342.
- Wiley JS, Firkin FC. Reduction of pulmonary toxicity by prednisolone prophylaxis during all-trans retinoic acid treatment of acute promyelocytic leukemia. Australian Leukaemia Study Group. Leukemia 1995; 9:774.
- Sanz MA, Montesinos P. How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia. Blood 2014; 123:2777.
- CLINICAL PRESENTATION
- Symptoms and signs
- - Chest radiographs
- - Computed tomography
- Bronchoscopy and bronchoalveolar lavage
- Lung biopsy
- DIFFERENTIAL DIAGNOSIS
- Lung infection
- Heart failure
- General approach
- Differentiation agents
- Supportive care
- Other modalities
- SUMMARY AND RECOMMENDATIONS