Highlights from iwCLL International Workshop on CLL, Edinburgh, Scotland

iwCLL is a biannual meeting which focuses only on CLL and offers the 1,400 hematologists in attendance access to the top CLL experts’ overview on where CLL management is today and where the research is going.

What it doesn’t offer is much new research. The doctors tend to publish that at the annual ASH Conference and Exhibition which occurs every December, this year in Orlando. ASH is about 20X bigger and generally recognized as the most important hematology meeting in the world.

Still there were several nuggets worth mining from the biannual meeting. And absolutely every moment of this meeting is focused on CLL.

In no particular order, here are a few takeaways from the faculty:

• The E1912 Trial (ECOG) and Alliance Trial continue to show the superiority of ibrutinib based therapy over FCR and BR as frontline therapy.
• There appears to be no benefit to adding rituximab to ibrutinib.
• Mutations in the BTK binding site and downstream at PCLɣ2 explain much but not all the resistance to ibrutinib.
• Some patients CLL “flares” when they stop ibrutinib.
• The venetoclax and obinutuzumab combo is a very worthy option as frontline therapy with the advantage of deep responses and a fixed duration of therapy.
• Patients who reduce the CLL level to < 1% with venetoclax and then stop are likely to enjoy at least a 2-year remission. However, most patients with >1% disease at the end of treatment will relapse quickly.
• Continuing venetoclax longer may not help those patients who have not reached a deep remission MRD. Tracking suggests the resistant clone has often been slowly growing for months while still on venetoclax.
• Resistance mechanisms to venetoclax are starting to be better understood and include:
  • Changes in the binding site so that the venetoclax can no longer inhibit BCL-2.
  • Upregulation of other anti-apoptotic proteins including MCL-1.
  • Others that were less well characterized.
• Research is generally moving towards fixed duration non-chemo cocktails and using U-MRD as an informational tool as to when to stop, but this approach is still in the trial phase as is not ready to be recommended for adoption in the broad community.
• Ibrutinib and venetoclax has been and is being evaluated in several trials, including in the upcoming German CLL17 where it will be compared to venetoclax and obinutuzumab.
• Clonal evolution now can be studied at the single cell level.
• U-MRD should not be seen as a yes or no answer, but rather as on a continuum. It is possible to be U-MRD+ and have long term stable disease.
• All patients should have their IgVH mutation, TP53 and FISH testing done before treatment.
• IgVH subsets, especially subset 2, and Notch1 status may also be important to assess in trials, but again, it is too early to recommend these in the community.
• Notch1 mutations predict poor response to rituximab and ofatumumab, but perhaps not obinutuzumab.
• CAR-T therapy is likely to be more effective and less toxic when it is used sooner for CLL patients.
• CAR-NK has had some promising early results in CLL.
• In contrast to all the progress being made in 1^st world countries, in some 3^rd world countries, it is difficult to get even a CBC, let alone any advanced testing or novel agents and there is a grave shortage of hematologists.