Second-Line Options in CLL: Progressing on Ibrutinib

William Wierda, MD, PhD:The expectation for ibrutinib in the frontline setting for this patient is very good. I would expect that the patient would have several years of disease control with ibrutinib. We know that a significant number of patients actually come off ibrutinib for intolerance and toxicities. If you have a patient who has that issue and has some toxicity or side effect from the ibrutinib and has to discontinue treatment, in particular, this patient—a young person with 17p deletion—and we’re looking at intolerance and alternatives because the patient is intolerant to ibrutinib, my recommendation would be to go to another BTK inhibitor. There is one that’s now available called acalabrutinib, which is approved for patients with mantle cell. It works by the same mechanism of action of ibrutinib. The toxicity profile is a little bit different, and it does represent a meaningful alternative for patients who are intolerant to ibrutinib.

A less common reason for coming off ibrutinib is progression of the disease and development of resistance. There are several treatment options for patients who develop resistance to ibrutinib. This patient didn’t have chemotherapy/chemoimmunotherapy exposure, and my expectation would be that when their disease progresses and they’ve become refractory or resistant to ibrutinib, they still have the high-risk feature of a 17p deletion. In those cases, regimens for relapsed disease would include venetoclax-based therapy or idelalisib-based therapy. Those are the 2 treatment modalities that have been shown to have activity in patients with 17p deletion in the relapsed setting. The preference in this case would be for venetoclax because there are data that also show that you can achieve durable remissions in patients who are ibrutinib failures with venetoclax as a salvage treatment—in particular, venetoclax monotherapy.

There was a recent clinical trial, referred to as the MURANO trial, that was a randomized trial looking at patients in the relapsed setting who were randomly assigned a treatment with venetoclax plus rituximab versus bendamustine and rituximab. That trial was very positive, showing improved outcomes for venetoclax plus rituximab. There were not very many patients on that trial who had been resistant to ibrutinib, but there are data from clinical trials that have treated patients who are ibrutinib resistant with venetoclax monotherapy and have shown clearly that there is activity with venetoclax in this setting.

There are also data that have been published looking at idelalisib in patients who have failed ibrutinib. The outcomes are poorer for those patients than one would expect with, for example, venetoclax. It hasn’t been studied in clinical trial. It has been more of a reported experience from a large data set of community and academic centers. For a patient who has been treated with ibrutinib either in the frontline setting or in the relapsed setting, who develops a resistance to ibrutinib and progressive disease, venetoclax would be the next option. My preference would be for venetoclax plus rituximab, based on the MURANO data. Idelalisib is an option, but the outcomes in this setting would be poorer.

For patients with relapsed disease, CD20 monotherapy is not very effective at long-term disease control. One could consider rituximab or obinutuzumab as options, but those would be very low on my list of options because of the limited activity and the expected short duration of activity in that setting. However, I would consider potentially using high-dose methylprednisolone with a CD20 antibody. There are data that support that regimen as a salvage regimen, and because you’re using high-dose methylprednisolone—non-chemotherapy treatment—it would be a reasonable option for patients with 17p deletion. The other possible option would be a lenalidomide-based treatment. We’ve done a lot of work with lenalidomide in the relapsed setting as well as in the frontline setting. There is activity and there’s activity in patients with 17p deletion CLL. There also is some toxicity with lenalidomide, so it can be a little more challenging to give because of the toxicity profile.

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