Therapy Related Acute Leukaemia With Mitoxantrone: 4 Years On, What Is the Risk and Can It Be Limited?

Abstract

Background Therapy related acute leukaemia (TRAL) is a concern for neurologists and patients when considering treatment with Mitoxantrone for Multiple Sclerosis (MS). In 2008 we performed a literature review to determine the risk of TRAL, the associated mortality and potential relationship to total dose exposure. 1 Four years on, there have inevitably been numerous further reports of TRAL associated with mitoxantrone therapy for MS, and we have therefore re-reviewed the literature to attempt to establish a definitive risk and stratify this according to dose. Methods A literature search was undertaken for relevant articles to identify all reported cases of TRAL in MS and data extracted from cases reporting individual exposure (dose or mg/m 2 ) and timing of TRAL. We also identified all case series of >50 patients, reporting follow-up and complications of treatment with Mitoxantrone in MS and combined this with the 250 cases from the Walton Centre, Liverpool treated since 1997. Results Case series including 12,511 patients were identified; mean dose of Mitoxantrone was 90.1 mg/m 2 (range 12-242 mg/m 2 ). TRAL was diagnosed in 0.72%; with a number needed to harm of 139.2 patients. In 142 TRAL cases sufficient data was available to inform analysis of exposure. Onset was a median of 22 months following treatment (range 1-64). APL was the most common leukaemia subtype (58.0%) and AML second most frequent (35.1%). Thirty-seven of 124 TRAL

Topoisomerase II and leukemia

“…Unfortunately, the use of mitoxantrone in multiple sclerosis regimens correlates with the appearance of t(15;17) t‐APLs in patient populations. Overall, multiple sclerosis patients account for ∼16% of t‐APLs . The chromosomal breakpoints mapped in multiple sclerosis patients are identical to those observed in mitoxantrone‐treated cancer patients and are centered on the topoisomerase II–mediated cleavage hotspot in the PML gene .…”

Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 1 Historical and established therapies

“…A safety review of mitoxantrone [161] reported an estimated rate of reduced left ventricular ejection fraction of 12% (mostly reversible on treatment cessation) and 2% risk of delayed congestive cardiac failure. The published overall risk of acute leukaemia ranges over 0.1-4.2% [162,163] and a meta-analysis published in abstract form quotes an overall risk of 0.72%, with a mortality rate of 30% [164]. Because of these risks mitoxantrone is now rarely used, but in patients with aggressive disease who have failed to respond to all other treatments mitoxantrone remains an option.…”