BTK Inhibitors, CAR T-Cell Therapies, and JAK Inhibitors Refine Hematologic Oncology Standards

Advances in targeted therapies have reshaped the field of hematologic cancer management, with BTK inhibitors taking center stage in the chronic lymphocytic leukemia (CLL) treatment arena, CAR T-cell therapies proving durable in large B-cell lymphoma (LBCL), and JAK inhibitors diversifying myelofibrosis management strategies, according to Aaron Gerds, MD, MS.

In an interview with OncLive®, Gerds discussed how the shift from chemotherapy to BTK inhibitors has helped optimize CLL management, noted real-world data that confirm the benefit of CAR T-cell therapies for patients with LBCL, and summarized the distinctions between available JAK inhibitors for patients with myelofibrosis.

He dove further into the roles of JAK inhibitors in myelofibrosis management in another part of the interview.

Gerds is an assistant professor in the Department of Medicine at the Case Western Reserve University School of Medicine in Cleveland, Ohio; the deputy associate director for clinical research and a member of the Developmental Therapeutics Program at Case Comprehensive Cancer Center; and a physician in the Department of Hematology and Medical Oncology at Cleveland Clinic.

OncLive: How have BTK inhibitors reshaped the CLL treatment paradigm?

Gerds: It's remarkable that even over my short career, we've pivoted from chemotherapy-based regimens to [almost] no chemotherapy at all. Chemotherapy is relatively extinct for patients receiving treatment for CLL, and BTK inhibition has been the centerpiece of a lot of that. We had ibrutinib [Imbruvica], but ibrutinib [was associated with] new toxicities.

Acalabrutinib [Calquence] took things a next step forward, where we see great, durable responses and better improvement in patients' quality of life and survival, but with less toxicity, so they can receive more therapy. Acalabrutinib and zanubrutinib [Brukinsa] represent a significant step forward for the field. It is remarkable that we are now using chemotherapy-free regimens standardly for patients with CLL.

What do real-world data show about the efficacy of CAR T-cell therapy in patients with LBCL?

Ten years ago, you wouldn't have imagined that CAR T cells would play such a predominant role in LBCL. They have changed the way we think about [the field], and the fact that there are a few FDA-approved CAR T-cell therapies is amazing.1-3 In the real-world setting, we are seeing outcomes similar to those seen in the original clinical trials that led to the approvals of these innovative cellular therapies for patients with LBCL. The caveat is that maybe [the real-world studies have not enrolled representative real-world populations]. All these real-world analyses were done at academic centers that did the trials because they have the infrastructure and the regulatory framework to deliver this standard-of-care option.

However, things outside of a clinical trial aren't always perfect. A patient may [have] more borderline [disease]. They may not have met the inclusion criteria for the study, so [real-world research] is an expansion into a more practical application of these therapies beyond the clinical trials.

The data outside the [CAR T-cell therapy] clinical trials reflect what we saw in those clinical trials. There are plenty of examples otherwise. For example, with ruxolitinib [Jakafi] for myelofibrosis, in the clinical trials, the median duration of therapy was over 3.2 years. However, in some real-world analyses of ruxolitinib given out in everyday practice, the median duration of therapy is sometimes as low as 6 months. That's a real separation between what we saw in clinical trials vs in real-world analyses. However, for CAR T-cell therapies, [these datasets are] closely aligned and say that [these therapies] benefit patients and have earned their spots in the treatment algorithms we use today.

Overall, where do JAK inhibitors fit into the polycythemia vera (PV) and myelofibrosis treatment paradigms?

There are currently 4 FDA-approved JAK inhibitors to treat patients with myelofibrosis, and one of those is also approved to treat patients with PV.4-7 You may ask why we need more JAK inhibitors if they all do the same thing. However, there are distinct differences between these JAK inhibitors that best position each of these agents in different populations of myelofibrosis.

Pacritinib [Vonjo] inhibits JAK2, spares JAK1, inhibits ACVR1, maybe helps anemia, inhibits IRAK1, and works on a myelodysplastic vein of myelofibrosis. You would use that in cytopenic myelofibrosis. Momelotinib [Ojjaara] has JAK1/JAK2 inhibition, but it also [inhibits] ACVR1. That may work best for anemic patients with myelofibrosis. With fedratinib [Inrebic], we have data in the second-line setting [showing this agent] can work after ruxolitinib. All 4 of these drugs are useful in our everyday treatment of patients with myelofibrosis.

On the horizon, there are more JAK inhibitors that are different. All the FDA-approved JAK inhibitors are type 1 JAK inhibitors. They inhibit the activated form of JAK2, whereas type 2 JAK inhibitors that are in development inhibit the inactive form, so they maybe have a different potency. There's a renewed interest in JAK2 V617F–specific JAK inhibitors that focus in on the mutant form of JAK2 and spare the wild-type form to get that differential effect compared with what we already have available. That's in addition to JAK2 degraders and other therapies along the same line that are in the same penumbra of JAK inhibition, but may not be exactly JAK inhibitors, therefore building on what we already have in an important way.

References

1. FDA approves axicabtagene ciloleucel for second-line treatment of large B-cell lymphoma. FDA. April 1, 2022. Accessed October 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-axicabtagene-ciloleucel-second-line-treatment-large-b-cell-lymphoma?utm_medium=email&utm_source=govdelivery
2. US FDA approves Bristol Myers Squibb’s CAR T cell therapy Breyanzi for relapsed or refractory large B-cell lymphoma after one prior therapy. News release. Bristol Myers Squibb. June 24, 2022. Accessed October 20, 2025. https://news.bms.com/news/details/2022/US-FDA-Approves-Bristol-Myers-Squibbs-CAR-T-Cell-Therapy-Breyanzifor-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx
3. FDA approves tisagenlecleucel for adults with relapsed or refractory large B-cell lymphoma. FDA. May 1, 2018. Accessed October 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-adults-relapsed-or-refractory-large-b-cell-lymphoma
4. FDA approves drug for adults with rare form of bone marrow disorder. FDA. Updated March 1, 2022. Accessed October 20, 2025. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-adults-rare-form-bone-marrow-disorder
5. Ojjaara (momelotinib) approved in the US as the first and only treatment indicated for myelofibrosis patients with anaemia. News release. GlaxoSmithKline. September 15, 2023. Accessed October 20, 2025. https://www.gsk.com/en-gb/media/press-releases/ojjaara-momelotinib-approved-in-the-us-as-the-first-and-only-treatment-indicated-for-myelofibrosis-patients-with-anaemia
6. Jakafi. Prescribing information. Incyte; 2023. Accessed October 20, 2025. https://www.jakafi.com/jakafi-prescribing-information
7. FDA approves fedratinib for myelofibrosis. FDA. August 16, 2019. Accessed October 20, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis