We all know that blocking the B cell receptor (BCR) has revolutionized the management of chronic lymphocytic leukemia.
This has mostly been done with ibrutinib that blocks the BCR by inhibiting its signaling through blocking BTK.
But before there was ibrutinib there was another drug, CAL-101 that later became idelalisib that is also incredibly effective on blocking BCR and thus in controlling CLL.
Idelalisib and the recently approved duvelisib are PI3K inhibitors, both approved for treating CLL, both very effective. Both block PI3K and therefore block the pro-survival signals that our CLL cells get from the B-cell receptor (BCR).
The problem has been the side effects, especially the diarrhea. But with proper education and management, this can almost always be managed and at least with duvelisib usually responds to holding the drug (a safe thing to do) and maybe some simple over the counter anti-diarrheal medications. Diarrhea that occurs later, about 7 months after starting the medications may need more aggressive therapy, but again can almost always be managed.
Dr. John Pagel is a well- respected CLL researcher from the Swedish Hospital in Seattle with a breadth of experience with multiple PI3K inhibitors.
I interviewed Dr. Pagel at ASH 2018 on some of the research he helped with on two new PI3K inhibitors and I have included two related trials on duvelisib that were presented at the ASH conference.
- Similar to ibrutinib, the oral PI3K inhibitors have a demonstrated ability to control CLL, even in patients with bad prognostic makers such as deletion 17p.
- There are potentially dangerous side effects that one needs to anticipate and treat appropriately.
- The best place for these drugs right now is probably for those patients who have failed a BTK inhibitor such as ibrutinib.
- In the future, they may be used in a more front line setting in combination with other drugs.
- One study reported at ASH 2018 was of Umbralisib (TGR-1202), an experimental PI3K inhibitor used in combination with Ublituximab (TG-1101- an anti-CD20 monoclonal antibody similar to rituximab) and pembrolizumab (a checkpoint inhibitor that takes the brakes off the immune system and has been successful in difficult to treat several solid cancers) in patients with relapsed/refractory CLL and Richter’s Transformation (RT)
- In the 9 CLL patients on this triplet therapy, 8 responded including 3 of the 4 that were refractory to a BTK inhibitor.
- 2 of 4 RT patients had durable complete responses.
- ME-401 is another experimental oral PI3K that is being used in an innovative dosing schedule (after a run in of 2 months, patients take ME-401 for only one week out of each month) in the hope of reducing side effects.
- Only 1 of 18 patients progressed when switched to the intermittent schedule and most of the adverse events occurred within 60 days of the change to the intermittent dosing.
- In “The Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL: Updated Results from the DUO Crossover Extension Study”, duvelisib, an approved oral, first-in-class dual inhibitor of PI3K-δ,-γ had an overall response rate (ORR) of 77% and saw 80% of patents with deletion 17p respond with relapsed refractory CLL who had progressed on ofatumumab.
- In the “Characterization of the Long-Term Efficacy and Safety of Duvelisib Monotherapy in Patients with Relapsed/Refractory CLL/SLL on Treatment for > 2 Years across 4 Clinical Studies”, 45 pts with relapsed/ refractory CLL/SLL have been on duvelisib >2 years, with a median of 31 months on treatment. ORR for these long-term pts was 89%. A majority (60%) of the long-term pts remain on treatment.
I purposely pulled several studies on PI3K inhibitors presented at ASH 2018, because I don’t want patients or clinicians to forget just how helpful these drugs can be, admittedly with significant toxicities that need to be properly managed.
Here is my interview with Dr. Pagel at ASH 2018:
For those like me who want to read all the details and see the data, what follows are the links to the four referenced abstracts.
Here is the Phase I/II Study of Umbralisib (TGR-1202) in Combination with Ublituximab (TG-1101) and Pembrolizumab in Patients with Relapsed/Refractory CLL and Richter’s Transformation abstract.
Here is the ME-101 abstract that Dr. Pagel references.
Click here to read this abstract: The Efficacy and Safety of Duvelisib Following Disease Progression on Ofatumumab in Patients with Relapsed/Refractory CLL or SLL: Updated Results from the DUO Crossover Extension Study.
The long-term efficacy data on duvelisib can be found here.
These four articles are my effort to start a rehabilitation of this class of drugs for CLL and other cancers. I don’t mean to be dismissive of the potentially life-threatening adverse events that can occur, but if patients and doctors are aware and prepared, these molecules have an important role to play in helping patients who relapse on or who can’t tolerate ibrutinib.
We are all in this together