Optimizing Targeted Therapy in IgVH-Unmutated CLL - Episode 6

Shifting the Treatment Paradigm of CLL

William Wierda, MD, PhD:Chemotherapy has been around for a long time. Chemotherapy has evolved into chemoimmunotherapy, which has been a very, very highly effective way of managing the disease. It doesn’t work as well for patients who have 17p deletion but is very effective in patients who don’t have a 17p deletion. It’s effective in terms of getting these deep remissions and giving patients the opportunity to have a treatment-free period. As I mentioned, the group of patients whom it’s most effective for and we’re still most enthusiastic about is patients who are younger and fit and who have a mutated immunoglobulin heavy chain variable gene because those are the patients we think may be cured with chemoimmunotherapy-based treatment.

There has been a revolution of treatments and options in patients with CLL, and management of CLL has really changed over the recent years. Previously, our main option was chemotherapy/ chemoimmunotherapy, and we would manage patients with repeated cycles and treatment courses with various options of chemoimmunotherapy, usually in an escalating fashion. We might start with something that has lower intensity and work our way up as patients develop resistance. However, in recent years, in the past 5 or so years, we’ve had these small molecule inhibitors developed, and clearly, they have changed how we manage patients with CLL. They’ve also fundamentally changed the outcomes for patients with CLL, where survival has very much improved with the new small molecule inhibitors. There are some challenges with them; they do have some toxicities and some limitations. One limitation I mentioned was patients. Although they’re very effective at controlling the disease, patients generally are committed to treatment when they go on the inhibitors. We don’t usually stop them. They have made fundamental advances in management for patients with CLL by virtue of how well they control and prevent progression of the disease and extend patient survival.

Our most recent work and what I’m most excited about right now is combining these agents; for example, combining a BTK inhibitor with a BCL2 inhibitor like venetoclax. We’ve done a clinical trial with ibrutinib plus venetoclax and are able to achieve a very high complete remission rate and a very high MRD-negative rate. Where we weren’t previously having discussions about getting patients off treatment, we’re now able to have discussions about these deep remissions that can be achieved in a reasonable amount of time, discontinuation of treatment, and a period of observation and remission.

It’s not only the small molecule inhibitor combinations that we’re very excited about. There are also new treatment modalities that are currently being developed, one of which is the CAR T-cell therapy. We’re very excited about the prospect of that strategy, in terms of achieving remissions and potentially curing patients. I think there’s a lot of work still to do with the CAR T cells because of the toxicity profile with that modality. However, there are definitely a number of other strategies that are in development and that we’re working with in clinical trials that are equally exciting and will potentially represent additional advances in treatment. I’m very optimistic that in the next 3 to 5 years, we’ll be able to cure many patients with CLL.

Transcript edited for clarity.

A 58-Year Old Female with IgVH-Unmutetd CLL

  • A 58-year-old female with incidentally noted lymphocytosis on routine
  • PMH: hypercholesterolemia managed on simvistatin, mild osteoarthritis
  • PE: 1.0-cm cervical node, no palpable spleen or liver
  • PS, ECOG 0
  • Laboratory findings:
    • WBC; 45 X 109/L, 85% lymphocytes
    • Lymphocytes; 86.2 X 109/L
    • Hb; 13.9 g/dL
    • Platelets; 274 X 109/L
    • ANC; 1,950/mm3
    • LDH 160 U/L
  • Flow cytometry; CD5+, CD19+, CD20+(dim), CD23+, slg+ (dim), ZAP70+
  • Cytogenetics by FISH; del(17p), trisomy 12, IgVH unmutated
  • β2M, 3.6 mg/L
  • BM biopsy; 70% lymphocytes, diffuse pattern
  • Diagnosis; chronic lymphocytic leukemia
  • Observed for over 2 years, then developed progressive sever fatigue and night sweats
  • The patient was treated with ibrutinib and achieved a complete response to therapy after 2 months