Therapeutic Options for High-Risk CLL

Matthew S. Davids, MD, MMSc:The iLLUMINATE study is another exciting dataset that was recently presented and then published. This is a randomized phase III study of ibrutinib with the CD20 antibody obinutuzumab, versus the chlorambucil/obinutuzumab regimen for frontline CLL [chronic lymphocytic leukemia].

What was interesting about this study is that it was fairly enriched for higher-risk CLL patients, in particular, those with deletion 17p, deletion 11q, and also unmutatedIgHV. So as expected, the ibrutinib/obinutuzumab arm looked significantly superior to the chlorambucil/obinutuzumab arm with a marked progression-free survival [PFS] benefit.

But what I thought was particularly interesting about the iLLUMINATE study is that the patients with the higher-risk markers, especially those 11q patients, and 17p patients tended to do better than we might expect for patients on ibrutinib monotherapy.

Overall in the study there was about a 40% rate of complete remission, which is higher than we might expect with ibrutinib as monotherapy. So we think about the iLLUMINATE regimen for our patients who have higher-risk disease, maybe those in whom we want to try to get a faster or deeper response. I think a limitation of the iLLUMINATE dataset is that the ibrutinib/obinutuzumab was still designed as a continuous therapy. Six months of the combination, but then continuous ibrutinib thereafter.

It’s still not completely clear to me whether in the long term the addition of the antibody is going to make a difference. It’s something that we’ve explored now with rituximab and ibrutinib and there’s been no benefit to adding the rituximab. I would say the jury is still out on whether obinutuzumab adds significantly to ibrutinib. And I’m optimistic about that based on some of the early data, but we’re just going to need longer-term follow-up to know.

I think 17p remains an unmet need for CLL patients. We have some exciting data coming along with using venetoclax with obinutuzumab in the frontline setting. This was explored in the CLL14 study, which randomized patients to venetoclax/obinutuzumab versus chlorambucil/obinutuzumab. And we heard in the fall from a press release that this is a positive study showing a significant benefit in PFS with a venetoclax-based regimen.

We haven’t yet seen the data from the study presented or published, but we anticipate seeing it soon. And what’s nice about this study is that it’s certainly active for those 17p patients, but also it’s designed as a time limited 1-year regimen. And so once this does receive approval, it will become interesting to see how this discussion goes in the frontline setting, both for 17p patients, and even for non-17p patients.

It’s good to have these options. We’ll have ibrutinib still as a great option for frontline therapy. But we’ll also have venetoclax with obinutuzumab. I think it’s going to be an interesting discussion with patients to see if they prefer a single oral agent that’s got long-term follow-up and very good efficacy, versus the time-limited regimen of venetoclax with obinutuzumab, which does require some infusions but has the promise of being time-limited, and therefore, patients wouldn’t need to stay on continuous therapy.

Transcript edited for clarity.

Case:A 74-Year-Old Male WithIgVH-Unmutated CLL

• A 74-year-old male presented to PCP with complaints of extreme fatigue, weakness, and weight loss of ~15lbs over the last 3 months.
• PMH: Mild hypertension managed by statin
• PE: BP 135/85, enlarged lymph nodes (~6cm), palpable spleen approx. 7cm below costal margin
• Laboratory findings:
  • WBC; 100 X 10⁹/L
  • Lymphocytes; 82 X 10⁹/L
  • Hb; 15.1 g/dL
  • Platelets; 125 X 10⁹/L
  • ANC; 1,800/mm³
  • LDH 250 u/L
• β2M, 4.3 mg/L
• FISH; normal
• Molecular analysis;IgVH-,TP53wild-type
• ECOG PS 1
• Rai Stage II