ASH 2018: Dr. Anthony Mato on a new Triple Combination of Novel Drugs for CLL and Richter’s Transformation

The annual meeting of American Society of Hematology (ASH) 2018 is where new research is presented.

Dr. Anthony Mato of Memorial Sloan Kettering is a top CLL researcher studying the safety and efficacy of three powerful novel drugs never before combined to treat relapsed/refractory (r/r) chronic lymphocytic leukemia and Richter’s Transformation (RT).

Let me start by explaining the two groups he was studying to assess if this new combo could help were some of the toughest patients to get into durable remissions:

1. The CLL cohort had failed multiple prior therapies, including ibrutinib in most cases.
2. RT is notoriously tough to treat and tends to be very aggressive with a poor prognosis. It refers to when the CLL “transform” to a more aggressive blood cancer, most often a diffuse large B cell lymphoma. For more background on Richter’s Transformation or Richter’s Syndrome as it sometimes called see this article by Dr. Wiestner.

Next let’s provide some background on the three drugs that he is combining.

1. Ublituximab (TG-1101 or UTX) is a monoclonal antibody (mAb) directed at a surface protein named CD20 that is found on all B lymphocytes including CLL cells. It is a form of an intravenous (IV) “passive immune therapy” similar to rituximab or obinutuzumab. This class of drugs have proven to add a significant benefit to many but not all CLL therapies.
2. Umbralisib (UMB) is an oral PI3K-δ inhibitor similar to idelalisib that targets the B- cell receptor (BCR) by blocking a different pathway than ibrutinib. The BCR inhibitors such as ibrutinib have revolutionized the treatment of CLL.
3. Pembrolizumab (pembro) is another type of antibody (you can tell it’s a mAb because its name ends in mab) that removes the brakes on the immune system that CLL and other cancers seem to impose for their own survival advantage. While pembro radically improved the outcomes for some patients with melanoma and certain types of lung cancer, it has proven ineffective in (r/r) CLL when used on its own, but has shown promise in RT. See this abstract in the journal Blood for more details.

Take Aways:

• The hope was that by adding pembro to turn back on the immune system, we could improve outcomes. We know CLL tends to make the immune systems, specifically the T cells less effective.
• Side effects were manageable and as expected with the individual drugs. They were not increased by the combination
• Response rate in the CLL patients was 89% with 9 out of 10 are still on the treatment at more than one year.
• Only 5 patients with Richter’s were studied, but two had durable complete remission, one appears to be responding but it is too soon to know for sure, and for two the disease progressed.
• The trial is being continued and modified to address the unmet needs of those with RT and r/r CLL especially those that have failed the novel targeted therapies.

Conclusions:

The future of CLL therapies, especially for the hard to treat patients, is trending towards powerful combinations. Reengaging the immune systems is the smart rationale behind this trial and also this one at the NIH for high risk and r/r chronic lymphocytic leukemia.

Please enjoy my brief interview with Dr. Mato from ASH 2018 on this important unmet need in CLL:

You can read the actual ASH abstract here.

Thanks

Brian Koffman MD, Chief Medical Officer and Executive VP, CLL Society