Incidence, Clinical Features, and Outcome of AllTrans-Retinoic Acid Syndrome in 413 Cases of Newly Diagnosed Acute Promyelocytic Leukemia

Abstract

All trans-retinoic acid (ATRA) syndrome is a life-threatening complication of uncertain pathogenesis that can occur during the treatment of acute promyelocytic leukemia (APL) by ATRA. Since its initial description, however, no large series of ATRA syndrome has been reported in detail. We analyzed cases of ATRA syndrome observed in an ongoing European trial of treatment of newly diagnosed APL. In this trial, patients 65 years of age or less with an initial white blood cell count (WBC) less than 5,000/μL were initially randomized between ATRA followed by chemotherapy (CT) (ATRA→CT group) or ATRA with CT started on day 3; patients with WBC greater than 5,000/μL received ATRA and CT from day 1; patients aged 66 to 75 received ATRA→CT. In patients with initial WBC less than 5,000/μL and allocated to ATRA→CT, CT was rapidly added if WBC was greater than 6,000, 10,000, 15,000/μL by days 5, 10, and 15 of ATRA treatment. A total of 64 (15%) of the 413 patients included in this trial experienced ATRA syndrome during induction treatment. Clinical signs developed after a median of 7 days (range, 0 to 35 days). In two of them, they were in fact present before the onset of ATRA. In 11 patients, they occurred upon recovery from the phase of aplasia due to the addition of CT. Respiratory distress (89% of the patients), fever (81%), pulmonary infiltrates (81%), weight gain (50%), pleural effusion (47%), renal failure (39%), pericardial effusion (19%), cardiac failure (17%), and hypotension (12%) were the main clinical signs, and 63 of the 64 patients had at least three of them. Thirteen patients required mechanical ventilation and two dialysis. A total of 60 patients received CT in addition to ATRA as per protocol or based on increasing WBC; 58 also received high dose dexamethasone (DXM); ATRA was stopped when clinical signs developed in 30 patients. A total of 55 patients (86%) who experienced ATRA syndrome achieved complete remission (CR), as compared with 94% of patients who had no ATRA syndrome (P= .07) and nine (14%) died of ATRA syndrome (5 cases), sepsis (2 cases), leukemic resistance (1 patient), and central nervous system (CNS) bleeding (1 patient). None of the patients who achieved CR and received ATRA for maintenance had ATRA syndrome recurrence. No significant predictive factors of ATRA syndrome, including pretreatment WBC, could be found. Kaplan Meier estimates of relapse, event-free survival (EFS), and survival at 2 years were 32% ± 10%, 63% ± 8%, and 68% ± 7% in patients who had ATRA syndrome as compared with 15% ± 3%, 77% ± 2%, and 80% ± 2% in patients who had no ATRA syndrome (P= .05, P = .003, and P = .03), respectively. In a stepwise Cox model that also included pretreatment prognostic variables, ATRA syndrome remained predictive for EFS and survival. In conclusion, in this multicenter trial where CT was rapidly added to ATRA in case of high or increasing WBC counts and DXM generally also used at the earliest clinical sign, the incidence of ATRA syndrome was 15%, but ATRA syndrome was responsible for death in only 1.2% of the total number of patients treated. However, occurrence of ATRA syndrome was associated with lower EFS and survival. © 1998 by The American Society of Hematology.

Phosphatidylinositol 3‐kinases are involved in the all‐trans retinoic acid‐induced upregulation of CD38 antigen on human haematopoietic cells

“…The second potential use of selective PI3-K inhibitors might be in the prevention of RAS during ATRA treatment. The CD38 overexpression in ATRA-treated APL cells can be considered pathological and may contribute to the development of retinoic acid syndrome, a fatal condition often associated with this treatment (De Botton et al, 1998). The pathophysiology of this syndrome is still poorly understood, but one proposed mechanism might involve CD38, whose aberrant expression on treated leukaemia cells might enhance their propensity to interact with platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) on the surface of lung endothelial cells (Deaglio et al, 2000;Mehta, 2000).…”

“…Moreover, CD38 overexpression in ATRA-treated APL cells could be involved in the onset of retinoic acid syndrome (RAS), the most dangerous side-effect of ATRA treatment (Deaglio et al, 2000;Mehta, 2000). RAS, with an incidence of about 15% (range, 6% to 27%) (Kanamaru et al, 1995;Tallman et al, 1997;De Botton et al, 1998), is marked by acute respiratory distress and pulmonary oedema (Gruson et al, 1998). The adhesion of blast cells to lung endothelial cells might be involved in the pathophysiology of this syndrome through an interaction between CD38 and CD31.…”

Intercellular adhesion molecule‐1 in extravasation of normal mononuclear and leukaemia cells

“…The feared and sometimes fatal complication of RA therapy is the RA syndrome (Frankel et al, 1992), which is characterized by leucocytosis, fever and pulmonary infiltrations. It has been shown that APL patients with the RA syndrome have a shorter event-free survival as well as overall survival than APL patients without the syndrome (De Botton et al, 1998), indicating the importance of defining the mechanisms responsible for initiating this syndrome. We recently found that RA induces plasmin formation on the NB4 cell surface and also increases the expression of urokinase receptor, which can mediate cell adhesion and migration (Tapiovaara et al, 1994;Mustjoki et al, 1998).…”

Differentiation syndrome in acute promyelocytic leukaemia

“…There are no universally accepted diagnostic criteria for APL DS, which contributes to a wide variety of incidences of APL DS reported in different studies, ranging from 2% to 48% (Vahdat et al, 1994;Wiley & Firkin, 1995;De Botton et al, 1998;Tallman et al, 2000;Montesinos et al, 2009). An example of this are two studies presented by the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA).…”

“…Differentiation syndrome (DS), also formerly known as retinoic acid syndrome, can occur when patients with acute promyelocytic leukaemia (APL) are treated with the differentiating agents all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) (Frankel et al, 1992;Montesinos et al, 2009). APL DS is a common complication in the treatment of APL with a reported incidence ranging from 2% to 48% (Vahdat et al, 1994;Wiley & Firkin, 1995;De Botton et al, 1998;Tallman et al, 2000;Montesinos et al, 2009). This wide variation in the incidence of DS is explained by the application of different diagnostic criteria as well as the use of varied induction therapy regimens and prophylactic strategies in the treatment of APL.…”