A prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia

Abstract

SummaryThis prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre-, mid-and post-each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 lg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13Á8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19-130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment-related deaths occurred in the deferasirox arm (P = 0Á25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/ consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

Deferasirox nephrotoxicity—the knowns and unknowns

“…In 22 published, randomized clinical trials that included a total of 2,119 deferasirox-treated patients, the overall incidence of nephrotoxicity defined as an increase in sCr levels was 22% (n = 471; Figure 2a and Supplementary Table 2 online). 2,9,12,[22][23][24]43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] Similarly, in 16 published clinical practice studies that included a total of 1,373 patients, sCr levels increased in 18% of participants (n = 242; Figure 2b and Supplementary Table 3 online). 37,38,40,60-72 However, in clinical trials and in clinical practice reports, the incidence of nephrotoxicity is higher when defined by a >33% increase in sCr levels over baseline (36% and 28.5%, respectively) than when defined by an increase in sCr levels above the ULN (7.2% and 6.3%, respectively; Figure 2).…”

“…42 This finding is expected because the liver metabolizes and secretes the drug. In published randomized clinical trials 2,9,12,[22][23][24]43,[45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] and clinical practice studies, 37,38,40,60-72 incidence of increased sCr levels has been shown to vary by age (panels a-f) and dose of deferasirox (panels g-l). a,g | Data from randomized controlled trials that defined nephrotoxicity as sCr levels >ULN.…”

Bone marrow iron score as an indicator for secondary iron overload in acute myeloid leukemia patients

“…Hemoglobin levels are often not sufficiently high to perform phlebotomies, while drug interactions or adverse events could hamper the use of iron chelation therapy (ICT). 8 ICT in AML patients has to be the subject of further study and should at least show a clear benefit on clinical outcomes like survival with an acceptable toxicity profile. Alternatively, more restrictive RBCT strategies may help prevent secondary iron overload.…”

“…Treatment of secondary iron overload in AML patients remains, however, challenging. Hemoglobin levels are often not sufficiently high to perform phlebotomies, while drug interactions or adverse events could hamper the use of iron chelation therapy (ICT) . ICT in AML patients has to be the subject of further study and should at least show a clear benefit on clinical outcomes like survival with an acceptable toxicity profile.…”

“…Despite increasing evidence for iron toxicity, monitoring and management of secondary iron overload in patients with hematological malignancies are still not common practice . This may be partly due to the imprecision of serum markers for monitoring iron overload, the invasiveness of accurate diagnostics, and the possible drawbacks of iron chelation therapy (ICT) . A further contributing factor could be the lack of uniform guidelines on monitoring and treatment of iron overload …”