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21st June 2022

First results from the FLAIR Trial

First results from the FLAIR trial

These results were presented at the American Society of Haematology conference in December 2021

This document is a plain English summary of the two presentations.

Links to the summaries presented at the conference are at the end of the document

For people having their first treatment for CLL, ibrutinib with rituximab is better than chemotherapy (fludarabine, cyclophosphamide and rituximab, FCR):

Results of the FLAIR trial

Why was the research needed?

For people having their first treatment for chronic lymphocytic leukaemia (CLL), the chemotherapy that works best is the combination of fludarabine, cyclophosphamide and rituximab (called FCR). Ibrutinib is a relatively new targeted cancer drug (compared to chemotherapy), which previous studies suggested would work well for treatment of CLL.

What were the main questions studied?

The trial studied whether ibrutinib with rituximab (another targeted drug called a monoclonal antibody) is better than FCR for people having their first treatment for CLL. Results from this part of the trial were presented at the conference in December 2021 and are summarised here.

The FLAIR trial is also studying whether taking ibrutinib alone is better than taking ibrutinib with venetoclax (another new targeted cancer drug). Results from this part of the trial will be published later.

Who took part in the trial?

Participants joined this part of the study between September 2014 and July 2018. 771 adults (younger than 76 years) having their first treatment for CLL took part at 113 hospitals in the UK. Results presented here use data collected up to May 2021. At that time participants had been in the study for, on average, 4 years 5 months.

Of those who took part, three quarters were men, and a third were older than 65 years. Most participants (94%) were tested for the Immunoglobulin Variable Heavy chain gene (IgVH). For half (53%) this was unmutated (meaning they are higher risk than if IgVH was mutated). Participants were similar in the two treatment groups.

What happened during the study?

For everyone who took part, their doctor considered both study treatments were appropriate. As FLAIR was a randomised trial, the decision about which treatment each person received was decided by chance, rather like tossing a coin. This process is called randomisation. A computer chose which treatment each participant received. Neither they nor their doctor were able to choose.

What treatments did the participants receive?

386 participants had ibrutinib with rituximab (IR), and 385 had FCR. Ibrutinib was given as 3 capsules taken at the same time each day, for up to 6 years, with rituximab given as a drip into the vein once every four weeks for the first 6 months.

FCR was given as tablets of fludarabine and cyclophosphamide taken for 5 days every 4 weeks. Each 4 week treatment is called a cycle. On the first day of each cycle rituximab was given as a drip into the vein. FCR was given for 6 cycles.

What side effects and other problems did the participants have?

Overall, half the participants had serious side effects, and this was similar in both groups (53% on IR; 54% on FCR).

There were some differences between the treatment groups in the type of side effects. People in the IR group had fewer infections than those in the FCR group (27% for IR; 34% for FCR), and fewer blood and lymphatic complications (11% on IR; 20% on FCR). However, those in the IR group had more heart and blood pressure problems (8% on IR; 1% on FCR). Ten people died after a cardiac arrest (their heart stopped beating), 8 were on IR and 2 on FCR. Of the 8 deaths in the IR group, 7 were participants known to have high blood pressure or heart disease. Of the 2 deaths in the FCR group, neither were known to have high blood pressure or heart disease. Safety monitoring in the trial suggested that taking one group of drugs for high blood pressure (called ‘ACE inhibitors’) at the same time as ibrutinib may increase the risk of a fatal cardiac arrest.

Seven people developed a second blood cancer (either myelodysplastic syndrome or acute myeloid leukaemia), 1 on IR and 6 on FCR.

What were the results of the trial?

Participants in the IR group had better Progression-Free Survival (PFS) than those in the FCR group. PFS is the time between joining the trial and either CLL getting worse or death. After 4 years, in the IR group 87% (337/386) were alive and their CLL had not got worse, compared with 77% (295/385) in the FCR group. Those in the FCR group had a 56% higher risk of either their CLL getting worse or dying, than those in the IR group.

There was no clear difference in overall survival between the two treatment groups. To date, in the IR group 7.8% have died (30/386) compared with 7.5% (29/385) in the FCR group. Cause of death for those on IR was CLL (3 deaths), Richter’s transformation (1 death), COVID-19 (3 deaths) and heart attack (8 deaths). For FCR, cause of death was CLL (4 deaths), Richter’s transformation (3 deaths), second blood cancer (3 deaths), COVID-19 (3 deaths) and heart attack (2 deaths).

Some participants needed a second treatment for their CLL; of those in the IR group 5% (21/386) had a second treatment, compared with 15% (59/383) in the FCR group. Of the 59 who had a second treatment in the FCR group, for 52 participants (88%) this included a targeted cancer drug. In FLAIR, those in the FCR group lived for longer than those who took part in earlier similar trials of FCR (done between 2009 and 2012). These earlier trials had been done before targeted cancer drugs were available. In FLAIR, 94% of people were alive 4 years after they started FCR, compared to 84% in the earlier trials.

How has this study helped people with CLL?

This study found that for people having their first treatment for CLL, IR was better than FCR for increasing the time to either first progression or death. There was no difference between the groups in time to death, which was probably because targeted cancer drugs are now available for those whose CLL comes back after FCR treatment.

For people on ibrutinib who need treatment for high blood pressure, ACE inhibitors should only be used with caution.

Who were the researchers who did this study?

The trial team was led by Professor Peter Hillmen and supported by the Leeds Institute of Clinical Trials Research.

Summaries of the conference presentations are available here:

https://ash.confex.com/ash/2021/webprogram/Paper152319.html

https://ash.confex.com/ash/2021/webprogram/Paper152167.html

Trial registration number: ISRCTN01844152