Sorafenib plus intensive chemotherapy in newly diagnosed FLT3-ITD AML: a randomized, placebo-controlled study by the ALLG

Author(s): Sun Loo1,2,3; Andrew W. Roberts1,2,3; Natasha S. Anstee2,3; Glen A. Kennedy4; Simon He5; Anthony P. Schwarer6; Anoop K. Enjeti7,8; James D’Rozario9; Paula Marlton10; Ian A. Bilmon11; John Taper12; Gavin Cull13; Campbell Tiley14; Emma Verner15; Uwe Hahn16; Devendra K. Hiwase17; Harry J. Iland18,19; Nick Murphy20; Sundra Ramanathan21; John Reynolds22; Doen Ming Ong22; Ing Soo Tiong1,22; Meaghan Wall23; Michael Murray24; Tristan Rawling25; Joanna Leadbetter26; Leesa Rowley27; Maya Latimer9; Sam Yuen7; Stephen B. Ting6; Chun Yew Fong5; Kirk Morris4; Ashish Bajel1; John F. Seymour1; Mark J. Levis28; Andrew H. Wei1,2,3,22
Source: Blood (2023) 142 (23): 1960–1971
Original Article
Professional photo of Maem Hussein, MD

Dr. Maen Hussein's Thoughts

Sorafenib did not help in newly diagnosed AML (with FLT-ITD) patients as maintenance therapy. MRD testing can also predict survival outcome.

ABSTRACT

Sorafenib maintenance improves outcomes after hematopoietic cell transplant (HCT) for patients with FMS-like tyrosine kinase 3–internal tandem duplication (FLT3-ITD) acute myeloid leukemia (AML). Although promising outcomes have been reported for sorafenib plus intensive chemotherapy, randomized data are limited. This placebo-controlled, phase 2 study (ACTRN12611001112954) randomized 102 patients (aged 18-65 years) 2:1 to sorafenib vs placebo (days 4-10) combined with intensive induction: idarubicin 12 mg/m2 on days 1 to 3 plus either cytarabine 1.5 g/m2 twice daily on days 1, 3, 5, and 7 (18-55 years) or 100 mg/m2 on days 1 to 7 (56-65 years), followed by consolidation and maintenance therapy for 12 months (post-HCT excluded) in newly diagnosed patients with FLT3-ITD AML. Four patients were excluded in a modified intention-to-treat final analysis (3 not commencing therapy and 1 was FLT3-ITD negative). Rates of complete remission (CR)/CR with incomplete hematologic recovery were high in both arms (sorafenib, 78%/9%; placebo, 70%/24%). With 49.1-months median follow-up, the primary end point of event-free survival (EFS) was not improved by sorafenib (2-year EFS 47.9% vs 45.4%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.51-1.51; P = .61). Two-year overall survival (OS) was 67% in the sorafenib arm and 58% in the placebo arm (HR, 0.76; 95% CI, 0.42-1.39). For patients who received HCT in first remission, the 2-year OS rates were 84% and 67% in the sorafenib and placebo arms, respectively (HR, 0.45; 95% CI, 0.18-1.12; P = .08). In exploratory analyses, FLT3-ITD measurable residual disease (MRD) negative status (<0.001%) after induction was associated with improved 2-year OS (83% vs 60%; HR, 0.4; 95% CI, 0.17-0.93; P = .028). In conclusion, routine use of pretransplant sorafenib plus chemotherapy in unselected patients with FLT3-ITD AML is not supported by this study.

Author Affiliations

1Department of Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne, VIC, Australasian; 2Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australasian; 3University of Melbourne, Parkville, VIC, Australasian; 4Royal Brisbane and Women’s Hospital, Herston, QLD, Australasian; 5Department of Clinical Haematology, Austin Health, Heidelberg, VIC, Australasian; 6Department of Haematology, Box Hill Hospital, Box Hill, VIC, Australasian; 7Calvary Mater Newcastle Hospital, Waratah, NSW, Australasian; 8University of Newcastle, Callaghan, NSW, Australasian; 9Canberra Hospital, Garran, ACT, Australasian; 10Princess Alexandra Hospital and University of Queensland, Woolloongabba, QLD, Australasian; 11Department of Haematology, Westmead Hospital, Westmead, NSW, Australasian; 12Nepean Hospital Cancer Care Centre, Kingswood, NSW, Australasian; 13Sir Charles Gairdner Hospital, University of Western Australia, Crawley, WA, Australasian; 14Gosford Hospital, Gosford, NSW, Australasian; 15Concord Repatriation General Hospital, Concord, NSW, Australasian; 16Department of Haematology, The Queen Elizabeth Hospital, Adelaide, SA, Australasian; 17Department of Haematology, Royal Adelaide Hospital, Adelaide, SA, Australasian; 18Institute of Haematology, Royal Prince Alfred Hospital, Camperdown, NSW, Australasian; 19University of Sydney, Camperdown, NSW, Australasian; 20Royal Hobart Hospital, Hobart, TS, Australasian; 21St George Hospital, Kogarah, NSW, Australasian; 22Department of Haematology, The Alfred Hospital and Monash University, Melbourne, VIC, Australasian; 23Murdoch Children’s Research Institute, Melbourne, VIC, Australasian; 24Sydney Pharmacy School, Faculty of Medicine and Health, University of Sydney, Camperdown, NSW, Australasian; 25University of Technology Sydney, Sydney, NSW, Australasian; 26WriteSource Medical Pty Ltd, Lane Cove, NSW, Australasian; 27Australasian Leukaemia and Lymphoma Group, Richmond, VIC, Australasian; 28Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MDAustralasian

Leave a Comment

Your email address will not be published. Required fields are marked *

Related Articles

Orca-T vs allogeneic hematopoietic stem cell transplantation (Precision-T): a multicenter, randomized phase 3 trial Open Access

This is an impressive advance in allo transplant, Orca-T cutting moderate–severe cGVHD dramatically (≈13% vs 44%) and nearly doubling cGVHD-free survival at 1 year (78% vs 38%) while also lowering NRM and serious infections is hard to ignore. Overall survival (OS) isn’t statistically different yet, but the combination of better disease control, less toxicity, and preserved immune reconstitution makes this feel like a meaningful step toward safer, more “engineered” transplants rather than just better immunosuppression.

Read More »

Asciminib demonstrates superior efficacy and safety in newly diagnosed chronic myeloid leukemia in the ASC4FIRST trial Open Access

This is starting to look like a real frontline disruptor in chronic myeloid leukemia (CML), asciminib showing a pretty striking ~22% absolute improvement in MMR at 96 weeks vs investigator-selected TKIs (and nearly 30% over imatinib) with a cleaner tolerability profile makes a strong case for moving beyond ATP-competitive tyrosine kinase inhibitors (TKIs) upfront. The efficacy signal is consistent across depths of response and durability looks excellent, with fewer discontinuations, overall survival (OS) will take time, but this feels very competitive as a new standard option.

Read More »

Fixed-Duration versus Continuous Treatment for Chronic Lymphocytic Leukemia

CLL17 shows that fixed‑duration venetoclax–obinutuzumab or venetoclax–ibrutinib is noninferior to continuous ibrutinib upfront, with 3‑year PFS ≈80% across all arms. The big difference is depth of response, undetectable MRD was 73% with venetoclax–obinutuzumab, 47% with venetoclax–ibrutinib, and 0% with ibrutinib. Toxicities tracked with mechanism (more cytopenias/infusion reactions with ven‑obinutuzumab, more cardiac events with ibrutinib). Overall, this strongly supports time‑limited therapy as a frontline standard for many chronic lymphocytic leukemia (CLL) patients.

Read More »

BRUIN CLL-313: Randomized Phase III Trial of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma

Pirtobrutinib demonstrated superiority over bendamustine rituximab in IRC assessed progression free survival (PFS) in treatment naïve CLL/SLL, with a 24 month PFS rate of 93.4% versus 70.7%. Overall survival trends favored pirtobrutinib, despite the study design allowing for crossover. Who would have thought this was coming????

Read More »
Load More