Clinical trialPhase 3Leukaemia

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial

Lancet Haematol · 2023202 patients (100 sorafenib, 102 no maintenance)

Xuan L, Wang Y, Yang K, Shao R, Huang F, Fan Z, et al. Lancet Haematol. 2023. 10:e600-e611

Study type: Clinical trial
Study name: Xuan 2023
Phase: Phase 3
Design: Post-hoc analysis of five-year follow-up of a randomised (1:1), open-label, multicentre trial at 7 hospitals in China
Sample size: 202 patients (100 sorafenib, 102 no maintenance)
Source: Lancet Haematol · 2023
Trial registration: NCT02474290

In plain words

In acute myeloid leukaemia with the FLT3-ITD mutation, the risk of the disease coming back is high even after a bone marrow (stem cell) transplant. In this study, taking sorafenib tablets after the transplant cut the risk of relapse over five years from about 36% to 15%, and five years after the transplant 72% of patients were alive compared with 56% in the group without sorafenib, with no increase in transplant complications.

Key results

72.0% vs 55.9%

Five-year overall survival

HR 0.55 (0.34 to 0.88); P=0.011

15.0% vs 36.3%

Cumulative incidence of relapse

HR 0.33 (0.18 to 0.60); P=0.0003

70.0% vs 49.0%

Leukaemia-free survival

HR 0.47; P=0.0007

15.0% vs 14.7%

Non-relapse mortality

Difference not significant

Drugs in this study:Sorafenib (Nexavar)

Dose and schedule cards

Sorafenib maintenance after allogeneic transplantation

FLT3-ITD AML after allogeneic transplantation, in composite complete remission before and after transplantation, aged 18 to 60 years, ECOG 0–2, with haematologic recovery by Day 60 after transplantationCycle length: ContinuousOn the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Drug	Dose	Route	Schedule
Sorafenib	400 mg twice daily (adjusted within 200 to 800 mg per day according to toxicity)	Oral	Start between Day 30 and Day 60 after transplantation

Cycle length: Continuous
Duration: Until Day 180 after transplantation

This use (after transplantation) is not in the sorafenib FDA label and is based on a Chinese phase 3 trial; at five-year follow-up it was not associated with an increase in non-relapse mortality or chronic GVHD.

On the page “Leukaemia” · Regimens and dosing in newly diagnosed AML (induction, consolidation and maintenance)

Sorafenib maintenance after allogeneic transplant

FLT3-ITD AML after allogeneic transplant, in composite complete remission before and after transplant, age 18 to 60, ECOG 0 to 2, with haematological recovery by day 60Cycle length: ContinuousOn the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

FLT3-ITD AML after allogeneic transplant, in composite complete remission before and after transplant, age 18 to 60, ECOG 0 to 2, with haematological recovery by day 60

Drug	Dose	Route	Schedule
Sorafenib	400 mg twice a day (within a range of 200 to 800 mg a day for toxicity)	Oral	Start on day 30 to 60 after transplant

Cycle length: Continuous
Duration: Until day 180 after transplant (per trial registration)

In the phase 3 trial, grade 3 and 4 adverse events in the first 210 days (infection, acute and chronic GVHD) were similar in both groups, and haematological toxicity was more common with sorafenib (15% vs 7%); at 5-year follow-up, non-relapse mortality and chronic GVHD did not increase. The dose and duration come from the trial registration.

On the page “Acute myeloid leukaemia (AML): 2022 classification, ELN genetic risk and treatment” · Lower-intensity treatment, maintenance and post-transplant treatment

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Sorafenib maintenance

Sorafenib 400 mg orally twice daily, starting 30 to 60 days after allogeneic transplantation and continuing to day 180 after transplantation; the dose was adjusted within 200 to 800 mg per day for toxicity or suspected resistance.

2No maintenance (control group)

No maintenance therapy.

Source of the regimen details: Abstract of the paper (400 mg twice daily from day 30 to 60 after transplantation) and ClinicalTrials.gov NCT02474290 (use from day 30 to 180 after transplantation; dose adjustment range 200 to 800 mg per day)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients aged 18 to 60 years with FLT3-ITD acute myeloid leukaemia undergoing allogeneic haematopoietic stem cell transplantation, with ECOG performance status 0 to 2, in composite complete remission before and after transplantation and with haematopoietic recovery within 60 days of transplantation.

Endpoints

Primary outcome (previously reported): cumulative incidence of relapse at one year. Five-year outcomes in this analysis: overall survival, cumulative incidence of relapse, non-relapse mortality, leukaemia-free survival, GVHD-free relapse-free survival (GRFS), cumulative incidence of chronic GVHD and late effects.

Safety and side effects

The five-year cumulative incidence of chronic GVHD did not differ significantly (54.0% versus 51.0%), and no notable difference in late effects was seen. No treatment-related deaths occurred.

Clinical significance and place in guidelines

This five-year follow-up confirmed the overall survival benefit of sorafenib maintenance after allogeneic transplantation in FLT3-ITD acute myeloid leukaemia and, together with the randomised SORMAIN trial, supports the use of this strategy in clinical practice.

Limitations

The trial was open-label and limited to patients aged 18 to 60 years in China; this follow-up report is a post-hoc analysis. Most patients had not received newer FLT3 inhibitors before transplantation.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.