Ibrutinib's Role in Frontline Management of CLL

William G. Wierda, MD, PhD:Standard treatments for frontline, particularly for patients over 65, have changed, and that is based on new data that have become available as recently as December with the ASH [American Society of Hematology] 2018 Annual Meeting & Exposition results. The 2 options prior to ASH were ibrutinib-based therapy and chemoimmunotherapy, chemoimmunotherapy being chlorambucil plus obinutuzumab or bendamustine plus rituximab [BR] if patients can tolerate a bit more intensive myelosuppressive regimen. With the iLLUMINATE trial, we know that there’s an improvement in progression-free survival with ibrutinib-based therapy over chlorambucil plus obinutuzumab.

There was another trial presented at ASH that looked at BR or bendamustine plus rituximab versus ibrutinib-based therapy. That trial was an Alliance trial, and that trial showed also improvement in progression-free survival with ibrutinib-based therapy in the frontline setting. But I think people are still using, or up till now have been using, chemoimmunotherapy. And it has been an option for these patients, either chlorambucil plus obinutuzumab or bendamustine plus rituximab.

And the approach for that strategy is to treat patients, get patients in remission, get them a period off treatment in remission, and then re-treat if they need it subsequently when their disease relapses and progresses. And as I mentioned, standards are changing with the recent trial data that we’ve had available, and that’s driven for patients over 65 mostly by the iLLUMINATE study and by the Alliance study.

In terms of our standards of care and what we’ve been doing at The University of Texas MD Anderson Cancer Center and what my approach is and has been, we have done a lot of work with chemoimmunotherapy. And we developed the FCR [fludarabine, cyclophosphamide, and rituximab] regimen, so for years we had been using chemoimmunotherapy. And our long-term follow-up with our chemoimmunotherapy results have directed us to using chemoimmunotherapy really for patients who are likely to benefit most with chemoimmunotherapy. Those are patients who get very deep remissions for long periods of time and those who potentially may be cured with chemoimmunotherapy. That’s really related to the FCR treatment and related to the younger, fit population.

We have been using ibrutinib-based therapy for most of our patients, based on those results and also observations and experience that we have with BTK [Bruton tyrosine kinase] inhibitor—based therapy. So we have transitioned into a period of having BTK-based therapy available for all patients over 65. We don’t use chemoimmunotherapy for those patients as frontline treatment, and then for the younger patients who have an unmutatedVgene, ibrutinib-based therapy and clinical trials with ibrutinib-based therapy have been our standard of care for several years now.

Of these randomized clinical trials, some have evaluated the addition of the CD20 antibody to ibrutinib-based therapy. We at MD Anderson have reported our results previously on a trial of ibrutinib plus or minus rituximab. Most of those patients were previously treated, but there were some untreated patients enrolled in that study. That was a large 200-patient study and has been reported by Jan Burger from MD Anderson. That trial showed no benefit with the addition of rituximab to ibrutinib for the population of patients who were enrolled in that study. The Alliance study that was reported at ASH this past December was a 3-arm randomized trial, ibrutinib versus ibrutinib plus rituximab versus bendamustine plus rituximab. And in that trial, the ibrutinib arms outperformed bendamustine and rituximab. And if you look at the outcomes, particularly progression-free survival between the ibrutinib monotherapy versus ibrutinib plus rituximab, there was no difference. Those curves are superimposed. My opinion, and I think the general opinion of experts who work in this area, is that a CD20 antibody doesn’t really add much to ibrutinib-based therapy, either in the frontline setting or in the relapsed setting.

Transcript edited for clarity.

An Elderly Woman With CLL

• A 78-year—old female presented with symptoms of fatigue and loss of appetite for the past six months
• PMH: recurrent bronchitis during past 12 months, treated with antibiotics
• PE: vital signs WNL, right cervical lymphadenopathy, spleen palpable 5 cm below costal margin, otherwise well-appearing
• Laboratory findings:
  • WBC, 53,000; 76% lymphocytes
  • Hb; 10.4 g/dL
  • Platelets; 150 X 10⁹/L
  • ANC; 180/mm³
• Flow cytometry; CD5+, CD19+, CD23+
• Cytogenetics, FISH: trisomy 12; IgVH mutated
• β2M, 3.6 mg/L
• BM biopsy; diffuse infiltration by CLL
• Diagnosis; chronic lymphocytic leukemia
• The patient was treated with ibrutinib and achieved a complete response to therapy after 4 months