Selina Chen-Kiang, PhD, professor of pathology and immunology, Weill Cornell Medicine, discusses challenges in the treatment of patients with mantle cell lymphoma (MCL).

There are foreseeable hurdles in the field, explains Chen-Kiang. Through past research, physicians know what is happening in tumor cells. Physicians know that they have to address a patient’s tumor and corresponding microenvironment, particularly the immune cells, because checkpoint action is very important for all cancers. The other aspect is understanding how to target tumor cells and spare normal cells. A patient’s metabolism is going to play an essential role, says Chen-Kiang.

Treatment progression is another important aspect of furthering treatment, says Chen-Kiang. By longitudinal sequencing, physicians know the difference during relapse versus the time that the patient is responding. Physicians have access to those tools and are designing salvage therapies for these patients.

However, some of these questions cannot be addressed in the immune-deficient mouse models, says Chen-Kiang. Nonetheless, she is confident that research will continue to push the field forward.

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Challenges in the Treatment of Patients With MCL

Selina Chen-Kiang, PhD, professor of pathology and immunology, Weill Cornell Medicine, discusses CDK4 inhibition with palbociclib (Ibrance) in mantle cell lymphoma (MCL).

The CDK4/6 inhibitor palbociclib has been shown to overcome ibrutinib (Imbruvica) resistance in primary human samples and MCL cell lines with the mutated BTKC481S protein. Targeting CDK4 is a rational approach in MCL, says Chen-Kiang, as dysregulation of CDK4 and cyclin D1 underlies unrestrained proliferation of MCL cells.

In a phase I clinical trial of 6 patients, palbociclib was administered to patients with MCL for 12 days, and bortezomib (Velcade) was given in prolonged early G1 arrest after synchronous S phase reentry. One patient progressed and 1 patient has been in complete remission for 6 years, suggesting that CDK4 inhibition reprograms MCL for therapy vulnerability. The follow-up clinical trial combined palbociclib together with ibrutinib. The combination looked durable with low toxicity, and induced impressive complete responses by preliminary analysis, says Chen-Kiang.

Selina Chen-Kiang, PhD, professor of pathology and immunology, Weill Cornell Medicine, discusses CDK4 inhibition with palbociclib (Ibrance) in mantle cell lymphoma.

CDK4 Inhibition With Palbociclib in MCL

Selina Chen-Kiang, PhD, professor of pathology and immunology, Weill Cornell Medicine, discusses the use of CDK 4/6 inhibitors in mantle cell lymphoma (MCL).

Chen-Kiang says that targeting tumor cells in lymphoid malignancies offers a unique advantage over solid tumors, as the cells can be purified in real time. Investigators are attempting to better target CDK 4 in patients with MCL with combination therapy. Chen-Kiang says that one of the big questions is differentiating who will respond to therapy with CDK 4/6 inhibitors and who will not.

The oral, specific CDK 4/6 inhibitor palbociclib (Ibrance) has already demonstrated cytotoxicity against the mutated BTKC481S protein. Studies have shown that adding palbociclib to ibrutinib could help deepen the response seen with ibrutinib through dual CDK 4/6 and BTK inhibition in MCL.

Selina Chen-Kiang, PhD, professor of pathology and immunology, Weill Cornell Medicine, discusses the use of CDK 4/6 inhibitors in mantle cell lymphoma. 

Selina Chen-Kiang, PhD

Articles

Challenges in the Treatment of Patients With MCL

CDK4 Inhibition With Palbociclib in MCL

CDK 4/6 Inhibitors in Mantle Cell Lymphoma