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A Patient Overview of Therapy Options

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This content was current as of the date it was released. In science and medicine, information is constantly changing and may become out-of-date as new data emerge.

This content was originally written in 2018 also partially updated in 2022.

Mark Hoffman Patient

I am on a trial of Imbruvica and Venetoclax and doing well so far. I got to MRD negative (minimal or measurable residual disease) in my bone marrow after 15 months. This is very good since I am 17P deleted, Trisomy 12, and unmutated. As a result, I am always looking at future options- if needed. Fortunately, there are a lot of new emerging treatments. Note: I am not an expert, and this is just my opinion and my research.

Here is some terminology to start. Technically, all drugs are chemotherapy, derived from the term “chemical” therapy. However, the word that chemotherapy has become most associated with is cytotoxic (cell-killing) chemotherapy (i.e., fludarabine/ cyclophosphamide taken with the immunotherapy antibody rituximab (FCR), bendamustine/rituximab (BR), cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)). The problem with cytotoxic chemotherapy is it can damage one’s bone marrow and immune system while simultaneously killing cancer. This has short-term and possible long-term effects.

In my opinion, with so many new options available, it is best to use at least one or a combination of the drug types below, especially with the promise of combinations, such as the one that I am on, which can bring people to MRD negative in the bone marrow after 15 months. The goal of the combination treatments is to get to MRD negative and to be able to discontinue therapy for an extended time. The argument is that ongoing treatment with the targeted drug ibrutinib may not be accurate anymore when you add in Venetoclax. Bob Dylan once wrote: “The times they are a changing…”

Below are some of the new CLL treatments I have discovered:

Targeted therapy works primarily by blocking key pathways the CLL cells depend on to survive. CLL cells rely on the host body to support and send signals to stay alive. Outside of the body, CLL cells die in a day or two in the lab.

Immunotherapy works by enhancing the immune system. Combining non-cytotoxic drugs with synergies in killing CLL cells without increasing toxicity is another active area of research.

It is incredible how many new drugs are being developed!!! This is a partial list of what I discovered with my research as a motivated patient. This is not meant as a comprehensive list of approved CLL drugs or those in the pipeline to treat chronic lymphocytic leukemia.

Targeted Therapy

BTK Inhibitors

Ibrutinib (Imbruvica, PCI-32765) – the first BTK inhibitor. Brian Koffman was on one of the earliest trials with ibrutinib.

Acalabrutinib (Calquence, ACP-196) – now approved 2nd Generation BTK inhibitor that may have a different side effect profile than ibrutinib. See https://cllsociety.org/2017/10/acalabrutinib-fda-accelerated-approval/

Pirtobrutinib (Loxo-305)   – Potent selective and reversible Bruton’s tyrosine kinase (BTK) inhibitor with equivalent potency against wild-type and cysteine-481 (C481) mutated BTK. This should work for those who become resistant due to ibrutinib due to a mutation at its binding site – C481S

Zanubrutinib (BGB-3111) – See: https://cllsociety.org/2018/03/ash-2017-tam-bgb-3111-zanubrutinib-cll/

Nemtabrutinib (MK-1026, ARQ-531) is like other BTK inhibitors that do not require the intact C481S to work. https://www.clinicaltrials.gov/ct2/show/NCT03162536

PI3 Kinase inhibitors

Idelalisib (Zydelig) -more specifically, it blocks P110δSee https://cllsociety.org/2018/03/things-to-know-about-idelalisib/

Umbralisib (TGR-1202)  in trial with Ublituximab. See https://cllsociety.org/2018/05/ash-2017-dr-matthew-davids-on-umbralisib-cll/

Duvelisib (IPI-145) (In trial) Dual inhibitor of PI3Kδ and PI3KƔ. See https://cllsociety.org/2018/04/fda-priority-review-duvelisib/

BCL-2 Blocker

Venetoclax (Venclexta, ABT199) – I am on a trial of Venetoclax and Ibrutinib. It is called the CAPTIVATE trial. https://clinicaltrials.gov/ct2/show/NCT02910583, Venetoclax is an approved therapy in CLL/SLL.

CDK Inhibitor

Fadraciclib (CYC065)– CDK 2/9 Inhibitor that targets the various phases of cell cycle control, being studied with Venetoclax to target anti-apoptotic proteins. See https://ashpublications.org/blood/article/134/Supplement_1/1761/427511/A-Phase-I-Study-Combining-CDK2-9-Inhibitor-CYC065

Antibodies

Cirmtuzumab (UC-961) – ROR1 AntibodySee https://cllsociety.org/2017/09/cirmtuzumab-whats-ror-ing/

Daratumumab– CD38 target. In Trials with Daratumumab and Imbruvica. See https://clinicaltrials.gov/ct2/show/NCT03447808

Ublituximab – CD20 Antibody. See https://cllsociety.org/2017/02/news-on-ublituximab/

Cellular Therapies

CAR (chimeric antigen receptor) 

CAR-T with CD19 as a target – See https://cllsociety.org/car-t-and-other-cellular-therapies/

CAR-T with ROR1 as a targetSee https://clinicaltrials.gov/ct2/show/NCT02706392

CAR-NKSee https://cllsociety.org/2017/07/car-nk-cellular-therapy-cll/

Mark is now 57 yrs. old and lives in San Diego with his wife and three children. He was diagnosed with CLL in December of 2015. He enjoys biking, backpacking, and other outdoor activities.

Initially published in 2018 by Mark Hoffman and updated by Dr. Brian Koffman in 2022

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