Abstract
Background: Pseudotumor cerebri associated with all-trans-retinoic acid (ATRA) treatment in acute promyelocytic leukemia (APL) have been frequently described in pediatric patients. However, the incidence, outcome and risk factors of pseudotumor cerebri in APL are not well-known. We analyze the incidence and risk factors of this complication in a large series of patients with newly diagnosed APL enrolled in three consecutive trials of the PETHEMA Group (LPA96, LPA99 and LPA2005).
Mehods: AIDA regimen (ATRA 45 mg/m2/d [25mg/m2/d in patients younger than 20] until CR and idarubicin 12 mg/m2/d on days 2, 4, 6 and 8) was given as induction therapy. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy: idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3). Since November 1999 (LPA99 trial), for patients with intermediate or high risk of relapse (Sanz et al, Blood 2000), consolidation was slightly intensified by increasing idarubicin doses in courses #1 and #3, and by simultaneously administering 25 mg/m2 ATRA together with chemotherapy in all three courses. Since July 2005, consolidation therapy in the ongoing LPA 2005 trial included the following modifications:
the administration of ATRA for all patients; for low- and intermediate-risk patients, mitoxantrone has been reduced from five to three days in the second course; and for high-risk patients, cytarabine has been added to idarubicin in the first and third course.
Maintenance therapy consisted of 50 mg/m2/d mercaptopurine orally, 15 mg/m2/week methotrexate intramuscularly, and 25 mg/m2/d ATRA for 15 days every three months. Diagnosis of pseudotumor cerebri was made in the presence of signs and symptoms of intracranial hypertension without clinical or radiological evidence of infective or space occupying lesions.
Results: Of 1034 patients enrolled between November 1996 and July 2008, 32 (3%) experienced pseudotumor cerebri. Headaches without pseudotumor were present in 252 patients (25%). Thirty cases of pseudotumor occurred during induction therapy and 2 cases manifested only during consolidation. In all, 9 of 32 patients (28%) had recurrent pseudotumor cerebri after reinitiating ATRA. All these side effects were transient, reversible, and never a cause of death. CR rates were 96% and 90% in patients with and without pseudotumor cerebri, respectively (p=0.32). The incidence of pseudotumor cerebri among patients younger than 18 years, 18–25 years, 25–50 years and older than 50 years was 13%, 7%, 2% and 0.3%, respectively (p<0.0001). There was a trend toward a correlation between fibrinogen <170 mg/dL and worse general state (ECOG>1) at presentation and development of pseudotumor cerebri (p=0.08 and p=0.06, respectively). We did not found any significant association between pseudotumor cerebri and WBC, platelets, relapse risk-score, hemoglobin, creatinine, PETHEMA trial, gender, morphological subtype, PML/RARA isoform, FLT3 mutations, and surface antigens (CD2, CD11b, CD13, CD15, CD34, CD56, and CD117).
Conclusion: This study shows an overall incidence of pseudotumor cerebri of 3% among APL patients treated with ATRA and anthracycline-based regimens, with higher incidences in children and young adults (13% and 7%, respectively). No other prognostic factors could be demonstrated. The development of pseudotumor cerebri was not associated with a worse induction outcome. Side effects were reversible and transient, but roughly a third of patients had recurrent pseudotumor cerebri after reinitiating ATRA
Alterations in tretinoin pharmacokinetics following administration of liposomal all-trans retinoic acid
