Idarubicin-based 7+3 induction with supportive care is safe and effective for acute myeloid leukaemia, according to new Aussie research.
An Australian study has found idarubicin-based 7+3 induction treatment for acute myeloid leukaemia is safe and effective, especially with the addition of midostaurin for fms-like tyrosine kinase 3 (FLT3) mutations.
“The application of [the Australasian Leukaemia & Lymphoma Group] consensus recommendations featuring the inclusion of PBS-reimbursed midostaurin was associated with acceptable safety and efficacy in our cohort of 58 patients with newly diagnosed AML, benchmarking favourably against published trial and registry data,” Professor Jake Shortt, haematologist at Monash Haematology in Victoria, and colleagues wrote.
In 2018, the Australasian Leukaemia & Lymphoma Group updated the 7+3 chemotherapy treatment approach following the PBS listing of midostaurin for FLT3-mutated acute myeloid leukaemia.
Around one in three new AML cases has FLT3 mutations, and these patients have worse prognosis with conventional chemotherapy, Professor Shortt and colleagues said.
Reported remission and induction mortality rates varied widely in the literature, they said, “with up to one in seven younger patients dying due to treatment failure or associated complications in ‘real-world’ series (and worse outcomes in patients aged >60)”.
To assess the success of the ALLG approach in a real-world setting, the researchers analysed cure and safety data from 58 patients receiving front-line AML treatment in hospital over the last five years since the consensus approach was published.
They found that 88% of patients on the 7+3 treatment plan achieved remission, and one person died from induction mortality.
“Idarubicin-based 7+3 induction with contemporary supportive care yields good safety and [complete remission] rates, including in midostaurin-treated FLT3-mutated patients,” Professor Shortt wrote.
At around two years follow-up, median overall survival was 17.6 months for adverse-risk patients, whereas a median was not reached for non-adverse-risk patients – meaning more than 50% were alive at that time.
Complete remission was achieved in 89% of FLT3-mutated patients, event-free survival in 65% of patients and overall survival in 68% of patients – comparable figures to wild-type patients.
“Safety across 58 induction and 139 consolidation cycles was acceptable, with a single death and a 21% ICU admission rate (95% CI: 11%–33%) during induction,” the authors said.
“FLT3-mutant AML had excellent [complete remission] rates and long-term survival comparable to the RATIFY trial comparator cohort attained with substitution of daunorubicin with idarubicin.
“In contrast, patients with adverse [European LeukaemiaNet] ELN risk AML fared poorly, requiring new approaches including consideration for VEN-AZA [venetoclax-azacitidine]-based induction.”
Only 76% of adverse-risk AML patients achieved complete remission, and event-free survival was a median nine months. Around half of the adverse-risk patients successfully underwent allograft and there were high rates of relapse and mortality from refractory disease.
“Recognising that midostaurin approval would set a template for future AML trials utilising standard 7+3 induction, the ALLG AML scientific working party suggested adopting a RATIFY-like approach for AML induction in 2018,” the authors wrote.
“This represented a pivot from previous ALLG protocols, which incorporated escalated cytarabine doses in induction and using anthracyclines in consolidation. The recommendation also adopted a ‘double induction strategy’, where non-adverse ELN risk patients not in [complete remission] after the first 7+3 would receive a second 7+3 cycle rather than immediate intensification.
“Today, with the approval of additional novel agents for front-line AML management (e.g., venetoclax, gemtuzumabozogamicin, CPX-35115), the ALLG consensus approach has evolved into a ‘living treatment considerations document’ available to members online (www.allg.org.au).
“Other features of the Australian treatment landscape distinct to the RATIFY protocol 12 include: (i) substitution of daunorubicin with idarubicin as the anthracycline due to the higher local daunorubicin cost, (ii) routine use of mould-spectrum azole anti-fungal prophylaxis concurrent to midostaurin (where there is a major cytochrome P450 interaction) and (iii) extension of the upper age limit for intensive induction with midostaurin to patients >59 years old.”
