The addition of anti-CD20 monoclonal antibodies, such as rituximab to chemotherapy drugs, has substantially improved progression-free survival and overall survival in patients with chronic lymphocytic leukemia (CLL). Nearly ten years ago, chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR), was established as the standard first-line therapy for younger fit patients with CLL. FCR has been particularly effective in patients with immunoglobulin heavy-chain variable region (IGHV) mutated CLL, but it does have substantial toxic side effects.
Ibrutinib is a newer targeted therapy that inhibits Bruton’s tyrosine kinase, a key B-cell signaling protein. Ibrutinib was shown to be more effective than the standard chemotherapy drug chlorambucil in phase 3 clinical trials. It has never been tested against FCR, which is considered the gold-standard treatment.
At the annual meeting of the American Society of Hematology (ASH) 2019, our own Dr. Brian Koffman interviewed Dr. Neil Kay, a Professor of Medicine and a hematologist at Mayo Clinic. They discussed the new 5-year follow-up results from the ECOG 1912 a.k.a. E1912 trial.
The E1912 trial is a phase 3, randomized, open label trial, comparing the efficacy of combination ibrutinib and rituximab with standard chemoimmunotherapy. (FCR in patients 70 years of age or younger with previously untreated CLL).
- Patients received either 1) ibrutinib and rituximab for six cycles, followed by ibrutinib until disease progression, or 2) six cycles of chemoimmunotherapy with FCR.
- Patients with chromosome 17p13 deletion were excluded because they are known to respond poorly to FCR. It would be unethical to randomize them to treatment.
- Previous results at 3 years of follow-up showed that combination ibrutinib and rituximab resulted in progression-free survival and overall survival that were superior to FCR.
- The overall survival results are controversial because the trial has not been going on very long. Thus, there have not been very many deaths. Longer-term follow-up is needed to see if this finding is real.
- With an additional year of follow-up, the combination of ibrutinib and rituximab continues to provide superior progression-free survival compared to FCR for younger patients with previously untreated CLL.
- While combination ibrutinib and rituximab results in superior outcomes for IGHV unmutated patients, there were no differences between treatments for IGHV mutated patients.
In the past, FCR would have been the clear treatment recommendation for a younger, fit patient with CLL. However, this new data suggests that combination ibrutinib and rituximab should at least be part of the conversation when discussing treatment options. It is a longer and more complicated conversation when weighing the risks and benefits of these different treatments, but it is one worth having.
Please enjoy this interview with Dr. Kay from December 2019 at ASH in Orlando, FL.
You can read the ASH abstract here: Ibrutinib and Rituximab Provides Superior Clinical Outcome Compared to FCR in Younger Patients with Chronic Lymphocytic Leukemia (CLL): Extended Follow-up from the E1912 Trial
You can also read their previous paper here: Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia
Take care of yourself first.
Ann Liu, PhD