An Analysis of the Incidence, Risk Factors and Prognosis of Acute Promyelocytic Leukemia Following Mitoxantrone Therapy in Patients Affected by Multiple Sclerosis.

Background. Mitoxantrone is an anthracenedione derivative with cytostatic and immunomodulatory activity, which is licensed for worsening multiple sclerosis (MS), an autoimmune central nervous system disease. The occurrence of acute promyelocytic leukaemia (APL) following mitoxantrone therapy in MS has been sporadically reported, but its actual incidence and clinical outcome need further definition

Aims and Methods. Among 1050 patients with a diagnosis of MS followed at our Institution since 1985, the clinical records of those receiving mitoxantrone were reviewed, in order to clarify the incidence of secondary APL as well as its clinical characteristics and outcome.

Results. Since 1990, 98 patients affected by MS were treated with mitoxantrone, in most cases as third-line treatment after corticosteroids and interferon therapy. Four patients (M/F: 1/4) developed APL. Median age at presentation was 57.5 year (range 47–59), significantly higher than that of unselected MS patients. APL developed a median of 55.5 months (range 3766 mo) after the first course of mitoxantrone. The median total dose of mitoxantrone was 149 mg (range 35–234 mg), delivered over a median of 7 courses (3–13). The cumulative number of years of follow-up after the start of mitoxantrone was 690. Therefore the risk of developing APL in this cohort was 5.8‰. All but one patients were classified as low-risk APL according to the GIMEMA/PETHEMA scoring system, the fourth being intermediate-risk. Morphology was FAB M3v in 1 case, and classic in the remaining. Typical chromosomal translocation t(15;17) was observed in all patients as well as PML/RAR-α molecular rearrangement, of bcr1 type in all. Flt-3 mutation was always absent. Given the treatment-related pathogenesis of APL, a modification of the AIDA2000 treatment program was used, with a reduced dose of idarubicin during induction in 2 patients. The second consolidation course with mitoxantrone was avoided by repeating the first course twice. Complete hematologic and cytogenetic remission was obtained after induction in all patients. Two patients are receiving consolidation. Molecular response was documented after consolidation in the other two patients. Both of them relapsed. The first had molecular relapse after 4 months; he was treated with ATRA and Ara-C and obtained a second molecular remission, lasting 50+ months. The second patient showed a morphological relapse after 5 months. She was treated with arsenic trioxide obtaining a second complete morphologic and molecular remission, but relapsed 1 month after autologous peripheral stem cell transplantation given for consolidation. She is currently on reinduction therapy with arsenic trioxide, 26 months after diagnosis.

Conclusions. APL is a rare hematological disease, but its incidence among mitoxantrone-treated MS patients is significantly increased, like in patients with malignant diseases treated with mitoxantrone. Age is a major risk factor for the development of mitoxantrone-related APL. Analysis of further potential risk-factor is ongoing. The clinical outcome of this subset of patients seems worse than in de-novo APL. The use of anthracyclines as part of the treatment program needs further evaluation.