24 - ALL-TRANS RETINOIC ACID SYNDROME (ATRA): A CASE REPORT

Abstract Retinoic acid syndrome (RAS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid (ATRA). Incidence of RAS has been reported ranging from 2% to 30%. It has been suggested that patients with leukocytes >5 x109/L at presentation are at high risk for the development of RAS. The impact of RAS on long term outcome is still a matter of controversy. We analyze the incidence, prognostic factors and outcome of RAS in 733 patients with newly diagnosed APL enrolled in the PETHEMA LPA96 and LPA99 trials (175 and 558 patients, respectively). Induction therapy consisted of ATRA and idarubicin, followed by three consolidation courses of anthracycline monochemotherapy. In the LPA99 trial, ATRA was added in each cycle of consolidation, except for low-risk patients. In the LPA99 trial, all patients received RAS prophylaxis with oral prednisone (0.5 mg/kg). Temporary discontinuation of ATRA and treatment with intravenous dexamethasone were recommended at the first signs of suspected RAS, in both trials. Definite RAS was defined as the presence of at least four of the following criteria: unexplained fever, respiratory distress, radiological pulmonary infiltrates, pericardial/pleural effusion, hypotension, renal failure, and weight gain over 5 kg. Overall, 87 patients (12%) experienced RAS, after a median of 6 days of ATRA (range, 0 to 46). Forty-seven cases (54%) occurred from days 0 to 7, 4 (5%) from days 8 to 14, 32 (36%) from days 15 to 30, and 4 (5%) from days 31 to 46. The main clinical signs were pulmonary infiltrates (83%), fever (80%), weight gain (74%), pleural effusion (63%) and renal failure (49%). ATRA was discontinued in 63% of patients. RAS was associated with age >50 years (41% vs 29%, p=0.02), serum level of creatinine >1.4 mg/dl (9% vs 3%, p<0.01) and leukocytes at presentation >5x109/L (46% vs 32%, p=0.01). Leukocytes >5x109/L and creatinine >1.4 mg/dl remained as independent prognostic factors in multivariate analysis. The incidence of RAS was not statistically different between the LPA96 (without prednisone prophylaxis) and LPA99 trials (15% vs 11%, p=0.16). RAS was associated with induction death (26% vs 7%, p<0.01) and was the main cause of death in 10 patients (1.4%). Age >60 years, leukocytes >10x109/L, RAS, male gender and serum creatinine level >1.4 mg/dl at presentation were independent prognostic factors for induction death. Patients developing RAS had a higher cumulative incidence of relapse (CIR) in the LPA96 trial (40% vs 15%, p<0.01), but there were no significant differences in the LPA99 trial (12% vs 13%). In conclusion, we have observed a bimodal peak incidence of RAS during the induction phase, with the first peak from days 0 to 7 and the second peak from days 15 to 30. Patients with leukocytes >5x109/L and serum creatinine level >1.4 mg/dl are at high risk for development of RAS, which is an adverse prognostic factor for induction death. The negative impact of RAS on CIR among patients treated with the LPA96 trial was not observed in the LPA99, in which patients received additional doses of ATRA for consolidation therapy.

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Chemokine Induction by All-Trans Retinoic Acid in Acute Promyelocytic Leukemia - Triggering the Retinoic Acid Syndrome

Blood ◽

10.1182/blood.v112.11.2980.2980 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2980-2980

Author(s):

Maaike Luesink ◽

Jeroen Pennings ◽

Willemijn Wissink ◽

Peter Linssen ◽

Petra Muus ◽

...

Keyword(s):

Retinoic Acid ◽

Plasma Levels ◽

Promyelocytic Leukemia ◽

Inflammatory Cascade ◽

Trans Retinoic Acid ◽

All Trans Retinoic Acid ◽

Cc Chemokines ◽

Retinoic Acid Syndrome

Abstract The most important complication of all-trans retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) is the retinoic acid syndrome (RAS), a life-threatening hyper-inflammatory reaction with a distinct capillary leak syndrome and multi-organ failure. Once established, the syndrome has proven very difficult to manage. Early recognition in combination with prompt corticosteroid treatment significantly reduces the mortality rate of patients with this syndrome. Nonetheless, still 15% of the induction deaths in APL is caused by RAS. The pathogenic mechanism of the hyper-inflammatory cascade in RAS is not fully understood yet. Infiltration of differentiating APL cells in the lung is important in the development of RAS. In addition, differentiation of APL cells by ATRA is associated with increased expression and release of pro-inflammatory cytokines, chemokines and adhesion molecules in vitro and it has been hypothesized that this is important for the triggering of the hyper-inflammatory cascade in RAS. We investigated the effect of ATRA on the expression and secretion of chemokines in APL cells in vitro and in vivo. Using microarray, quantitative PCR and ELISA we demonstrated significant induction (up to 16000-fold) of 8 CC-chemokines (CCLs) in the NB4 APL cell line after differentiation induction with ATRA in vitro. To demonstrate the significance of chemokine induction by ATRA in vivo, we measured plasma levels of CCLs in 3 APL patients, treated with a combination of ATRA, idarubicine and prednisone according to the AIDA-2000/P protocol. One of these patients developed an obvious retinoic acid syndrome. During therapy we observed increased plasma levels of 3 CCLs in all three patients. Induction of 5 other CCLs (CCL3, CCL4, CCL7, CCL8, CL11) was only observed during RAS, suggesting that upregulation of these 5 CC-chemokines is specific for RAS. To investigate whether the plasma levels of CC-chemokines are functionally relevant, we measured chemo-attraction of peripheral blood leukocytes towards plasma of an APL patient who developed RAS using a transwell system. Plasma from this patient during RAS showed significant more chemo-attraction than plasma from the same patient before treatment with ATRA, idarubicine and prednisone. Subsequently we investigated whether the therapeutic effect of dexamethasone in RAS can be ascribed to downregulation of chemokine expression in APL cells. Despite dexamethasone, the induction of chemokine expression in NB4 cells by ATRA sustained. We conclude that ATRA causes massive secretion of chemokines by APL cells, which might trigger the hyper-inflammatory cascade in RAS by continuous attraction of APL cells and other inflammatory cells towards tissues like the lung. Dexamethasone does not abrogate the production of CC-chemokines by APL cells, but rather seems to inhibit the hyper-inflammatory cascade at the level of the effector cells and target tissues like the lung. This might explain why dexamethasone is not able to sufficiently reverse a retinoic acid syndrome once it has been established. The application of neutralizing CC-chemokine receptor antibodies or other antagonists might be an alternative route to treat an established retinoic acid syndrome.

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