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ASH 2020: Dr. Bill Wierda on CAR-T liso-cel combined with ibrutinib for chronic lymphocytic leukemia (CLL)

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Following the American Society of Hematology Annual Meeting and Exhibition (ASH 2020) through the magic of ZOOM, I interviewed many of the top CLL researchers and presenters from the virtual meeting including Dr. Bill Wierda from MD Anderson Cancer Center in Houston, Texas who gave two of the six prestigious oral clinical CLL presentations at ASH including this one on CAR-T or Chimeric Antigen Receptor T cell therapy, arguably the most exciting CLL abstract of 2020.

During the first few minutes of my interview Dr. Wierda provides a succinct and cogent explanation of how CAR-Ts are made and why there is so much enthusiasm about this treatment for chronic lymphocytic leukemia. If you are new to CAR-T therapy, please take a look at our CAR-T comic and our CAR-T section of the website for a fun way to get up to pace on this emerging cellular therapy.

Take-Aways

  • CAR-T therapies have been studied at multiple single sites such as U. Penn in Philadelphia, Fred Hutch in Seattle and the NIH in Bethesda, with significant success using CAR-T cells directed against a surface marker, CD19 that is found on both CLL cells, a type of malignant B cell, and on normal B cells.
  • The TRANSCEND study is the first multicenter trial sponsored by a pharmaceutical company (BMS) using the same CAR-T product in all sites, namely liso-cel or JCAR017 that is also directed against CD19.
  • The trial has two arms, the arm with ibrutinib that is discussed here and one without ibrutinib Dr. Siddiqi discusses in another of our ASH 2020 interviews.
  • Ibrutinib is well known for its targeted ability to inhibit the enzyme BTK (Bruton’s Tyrosine Kinase). This is how it blocks critical signaling in CLL cells, thus controlling the cancer. Ibrutinib’s astonishing success has led to a revolution in how CLL is treated.
  • But ibrutinib also has “off target” effects, many directed at T cells, that turn out to be helpful in improving outcomes with CAR-T therapy.
  • Prior studies from single institutions had shown that ibrutinib, when added to CAR-T therapies for CLL, both improved responses and lowered toxicity.
  • This study was designed to confirm those results across multiple centers and also to prove the feasibility of using one product, liso-cel, at all these different centers, hopefully leading to its approval for use in CLL patients.
  • The trial Study Evaluating Safety and Efficacy of JCAR017 in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) is still open and enrolling.
  • Only 19 patients were treated at the time of the data cut, which is a small number.
  • The study was directed at patients who were running low on options. Inclusion criteria were:
    • Subjects with CLL or SLL and high-risk features who have failed at least 2 lines of prior therapy.
    • Subjects with CLL or SLL and standard-risk features who have failed at least 3 lines of prior therapy.
  • Patients had a median of 4 (range, 2‒11) prior therapies. All patients had been unresponsive or relapsed with prior ibrutinib. This was tough group to treat, as expectations for significant success would be low.
  • Safely and Adverse Events:
    • Thankfully there were no new safety issues or side effects seen when liso-cel and ibrutinib were used together.
    • 14 patients had cytokine release syndrome (CRS) and 6 had neurological events.
    • There were no deaths.
  • Efficacy:
    • Over half the patients had a complete response (CR).
  • More importantly, of the 19 patients evaluable for minimal residual disease (MRD), 17 (89%) achieved undetectable MRD (uMRD) in blood via flow cytometry and 15 (79%) in BM by next-generation sequencing (both sensitivity of ≤10-4). Achieving uMRD has been associated with long remissions post CAR-T. (I am an example of this, now almost three years post-CAR-T.)
    • Though follow-up has been short, remissions do seem durable.

Conclusion:

These are extraordinary results for these very difficult to treat CLL patients. More CAR-T trials that are now open or opening soon with different drugs are listed here on ClinicalTrials.gov.

Maybe most importantly, once CAR-T drugs such as liso-cel are approved in these worse of the worse cases, they could be moved up the line as an earlier possible “one and done” treatment for CLL with fewer side effects and even better outcomes when used in a less beaten-up group of patients.

Here is my ASH 2020 Zoom interview with Dr. Wierda:

Here is the ASH abstract: Transcend CLL 004: Phase 1 Cohort of Lisocabtagene Maraleucel (liso-cel) in Combination with Ibrutinib for Patients with Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)

Thanks for reading.

Stay strong.  We are all in this together.

Brian

Brian Koffman MDCM (retired) MS Ed
Co-Founder, Executive VP and Chief Medical Officer
CLL Society, Inc.

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