Blood 1998 Oct 15;92(8):2712-8

Incidence, clinical features, and outcome of all trans-retinoic acid
syndrome in 413 cases of newly diagnosed acute promyelocytic leukemia.
The European APL Group.

De Botton S, Dombret H, Sanz M, Miguel JS, Caillot D, Zittoun R, Gardembas M, Stamatoulas A, Conde E,
Guerci A, Gardin C, Geiser K, Makhoul DC, Reman O, de la Serna J, Lefrere F, Chomienne C, Chastang C,
Degos L, Fenaux P

Service d'Hematologie of the Centre Hospitalier Universitaire (CHU) of Lille, France.

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/microL 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/microL
received ATRA and CT from day 1; patients aged 66 to 75 received ATRA-->CT. In patients with initial WBC less
than 5, 000/microL and allocated to ATRA-->CT, CT was rapidly added if WBC was greater than 6,000, 10,000,
15,000/microL 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. Copyright 1998 by The American Society of Hematology.
 

Am J Respir Crit Care Med 1998 Oct;158(4):1302-5
Diffuse alveolar hemorrhage with underlying pulmonary capillaritis in the
retinoic acid syndrome.
Nicolls MR, Terada LS, Tuder RM, Prindiville SA, Schwarz MI
Division of Pulmonary Sciences and Critical Care Medicine, Department of Pathology, University of Colorado Health
Sciences Center, Denver, Colorado, USA.

All-trans-retinoic acid (ATRA) can induce a clinical remission in patients with acute promyelocytic leukemia. An
adverse condition called "retinoic acid syndrome" limits this therapy. It is characterized by fever and respiratory
distress, along with weight gain, pleural or pericardial effusions, peripheral edema, thromboembolic events, and
intermittent hypotension. The lung disease has been previously ascribed to an infiltration of leukemic or maturing
myeloid cells into lung parenchyma, which is sometimes associated with pleural effusions and diffuse alveolar
hemorrhage. We report a case of retinoic acid syndrome in an 18-yr-old woman who developed diffuse alveolar
hemorrhage while being treated with ATRA for acute promyelocytic leukemia. An open lung biopsy revealed
pulmonary capillaritis.
PMID: 9769296, UI: 98443331