Ibrutinib works amazingly well for most CLL patient by blocking BTK (Bruton’s tyrosine kinase), an enzyme that is overactive in CLL cells. BTK tells CLL cells to stay alive and to hang out in the safety of the lymph nodes. Ibrutinib blocks that pathway causing cells to leave the nodes and eventually to die.
This article from by Nahla A M Hamed , PhD from Alexandria University, Egypt reviews the latest literature on ibrutinib resistance, an increasingly important issue for a small subset of CLL patients, namely those such as me who have been treated with ibrutinib after they have relapsed from other therapies and who also have deletion 17p or non-functioning TP53 or a complex karyotype.
Remember that for those who get ibrutinib as their first treatment or those who do not have the poor markers listed above, resistance is very rare.
This article is for those few where ibrutinib stops working.
Key Take Aways:
- Transformation of the CLL to a different more aggressive cancer called Richter’s Syndrome (or Richter’s Transformation) usually occurs early, in the first two years or less and often has a poor prognosis.
- Progressive CLL, on the other hand, tends to occur later and the incidence increases over time.
- Most, but not all, of those who progress with CLL have a mutation in the BTK pathway that either prevents ibrutinib from binding to block BTK or have a gain of function mutation that turns the BTK pathway on again.
- For those with progressive CLL, there is a 70% response rate to venetoclax.
- Idelalisib and several other drugs in development are other worthy options.
- These experimental options either:
- Work downstream from or work differently than ibrutinib to turn off the survival signals again. These include the SYK inhibitor, entospletinib and possibly HSP90 inhibitors, HDAC inhibitors, and XPO1 inhibitors.
- Bind differently (reversibly) to the BTK receptor and so are not affected by the usual mutations in the binding sites. These include GDC-0853, ARQ- 531, and SNS-062
- Though not mentioned in the article, CAR-T is also being used with success in clinical trials.
For those interested in getting into more details, this article reviews and references the latest thinking and research about this challenging group of patients
Brian Koffman, MD 4/18/17