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.

Relationship between obesity and clinical outcome in adults with acute myeloid leukemia: A pooled analysis from fourCALGB(alliance) clinical trials

“…Obese APL patients might have an inherent increased risk of developing life‐threatening complications. There is mounting evidence that obese APL patients might have higher risk of differentiation syndrome, a systemic inflammatory response seen in patients with APL treated with ATRA or ATO characterized by the development of pulmonary infiltrates and hypoxia . A recent Italian study has shown that obese APL patients have seven times higher odds of differentiation syndrome than normal weight patients after adjusting for age, sex, white blood cell count, hemoglobin level, platelet counts, PML‐RAR subtype, and FAB variant .…”

Advances in understanding the pulmonary infiltration in acute promyelocytic leukaemia

“…DS is a life‐threatening complication, characterized by respiratory distress, unexplained fever, weight gain, interstitial pulmonary infiltrates, pleural or pericardial effusions, hypotension and acute renal failure, as described by Frankel et al (1992). DS can be associated with the development of hyperleucocytosis, pulmonary oedema, generalized oedema, headache and bone pain (Frankel et al , 1992; de Botton et al , 1998; Tallman et al , 2000; Dore et al , 2007; Breccia et al , 2008; Montesinos et al , 2008). The most common manifestations are respiratory distress, pulmonary infiltrates and fever, which occur in about 80% of patients (Table I) (Frankel et al , 1992; de Botton et al , 1998; Tallman et al , 2000; Dore et al , 2007; Breccia et al , 2008; Montesinos et al , 2008).…”

“…DS can be associated with the development of hyperleucocytosis, pulmonary oedema, generalized oedema, headache and bone pain (Frankel et al , 1992; de Botton et al , 1998; Tallman et al , 2000; Dore et al , 2007; Breccia et al , 2008; Montesinos et al , 2008). The most common manifestations are respiratory distress, pulmonary infiltrates and fever, which occur in about 80% of patients (Table I) (Frankel et al , 1992; de Botton et al , 1998; Tallman et al , 2000; Dore et al , 2007; Breccia et al , 2008; Montesinos et al , 2008). The diagnosis of DS is made on clinical grounds and has proven to be difficult, because none of the symptoms is pathognomonic for the syndrome and can be due to concurrent medical problems, such as bacteraemia, sepsis, pneumonia, pulmonary haemorrhage, or congestive heart failure.…”

“… *(Frankel et al , 1992), †(Tallman et al , 2000), ‡(de Botton et al , 1998), §(Montesinos et al , 2008), ¶(Breccia et al , 2008), **(Dore et al , 2007). …”

“…Variation in the incidence of DS between studies could be the result of differences in induction therapy and prophylactic approaches. The incidence of DS may be lower when ATRA is administered concurrently with induction chemotherapy or prophylactic corticosteroids (Asou et al , 1998; de Botton et al , 1998; Montesinos et al , 2008). However, difficulties in distinguishing the syndrome from other medical problems and the use of different diagnostic criteria for DS may also explain variation in the incidence of DS.…”