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mm_bma.jpg

Bone marrow aspirate
showing multiple myeloma

NEW YORK—Targeting the cell cycle with cyclin-dependent kinase (CDK) inhibitors may be an effective strategy to treat lymphoma and myeloma, according to a presentation at Lymphoma & Myeloma 2015

Palbociclib, an inhibitor of CDK4 and CDK6, received accelerated approval from the US Food and Drug Administration to treat advanced breast cancer.

Now, it is showing promise in mantle cell lymphoma (MCL) and multiple myeloma (MM) as well.

CDK family members are important regulators of cell-cycle progression. Dysregulation of CDK4 and CDK6 is one of the most common genomic aberrations in human cancer, including myeloma, lymphoma, leukemia, breast cancer, metastatic lung adenocarcinoma, and glioblastoma.

MCL, which accounts for 6% of non-Hodgkin lymphomas, has an overall poor prognosis, with most patients eventually becoming resistant to drugs. MCL expresses cyclin D1 as a consequence of the t(11;14) translocation and overexpresses CDK4.

“So this is a perfect disease for the development of targeting CDK4,” said Selina Chen-Kiang, PhD, of Weill Cornell Medical College in New York, New York, who presented this information at the meeting.

CDK4 and CDK6 signaling occur at the beginning of the cell cycle and bring the cell from the resting state into early G2.

“If we could control that,” Dr Chen-Kiang explained, “we reasoned that we could control the DNA replication and cell division” and increase tumor-specific cell death. 

Palbociclib (PD0332991; Ibrance), an orally bioavailable, selective CDK4/CDK6 inhibitor, induces early G1 arrest. It is reversible and low in toxicity, according to Dr Chen-Kiang.

Currently, it’s being tested in phase 1 trials in MCL with ibrutinib and in MM with lenalidomide-dexamethasone. Phase 1 trials have also been completed at Cornell with palbociclib as a single agent in MCL, with bortezomib in MCL, and with bortezomib-dexamethasone in MM.

Palbociclib in MCL

Investigators conducted a phase 1, single-agent study of palbociclib to determine whether it could be tolerated in humans.

“CDK4/CDK6 is expressed in every cell,” Dr Chen-Kiang noted, “and you are targeting 2 proteins that are needed for every cell.”

Seventeen patients received 125 mg of palbociclib per day for 21 of 28 days.

“And surprisingly,” Dr Chen-Kiang said, “it’s very well tolerated.”

The most common adverse events were neutropenia, fatigue, and diarrhea.

“And even more surprising,” she added “is that we actually had a complete response (CR) [and] 2 partial responses, in addition to 5 stable diseases.”

The investigators hypothesized that blocking the cell cycle in G1 creates an imbalance in gene expression.

They then conducted a trial of palbociclib plus bortezomib in 17 patients with recurrent MCL. Patients received palbociclib on days 1–12 and low-dose bortezomib on days 8, 11, 15, and 18.

The palbociclib dose ranged from 75 mg to 125 mg, and the bortezomib dose ranged from 1.0 mg/m2 to 1.3 mg/m2.

Eleven patients experienced a reduction in tumor volume, the majority at the 125-mg dose.

Using whole-exome and whole-transcriptome sequencing of serial biopsies, investigators determined that CDK4/CDK6 inhibition induces early G1 arrest in MCL cells in both responders and non-responders initially.

This may occur because the cell cycle is perfectly controlled, and there’s no mutation in CDK4 in any of the patients.

Investigators attempted to identify genes that could differentiate sensitivity from resistance to CDK4 targeting. They found that a very small number of genes display opposite regulation in prolonged early G1 arrest in responding versus non-responding patients.

These genes are involved in metabolism and redox homeostasis and include a gene called PIK3IP1, an inhibitor of PI3 kinase.

In earlier analyses, the investigators had discovered a relapse-specific C481S mutation at the ibrutinib binding site of Bruton’s tyrosine kinase (BTK) in MCL cells. The mutation occurred at progression following a durable response to ibrutinib.

The mutation is absent, however, in patients with transient ibrutinib responses or in primary resistance.

The team observed that early cell-cycle arrest by CDK4 inhibition reprograms MCL cells for killing by ibrutinib. This occurs through inhibition of BTK and AKT (protein kinase B).

So the investigators undertook to study palbociclib in combination with ibrutinib, “with extraordinary results,” Dr Chen-Kiang said.

The trial is ongoing and, at the moment, has a 60% CR rate with durable responses.

“We’re very happy with this,” Dr Chen-Kiang said.

Palbociclib in MM

In addition to the phase 1/2 study of palbociclib with bortezomib and dexamethasone, investigators are also pursuing palbociclib in combination with lenalidomide and dexamethasone, which Dr Chen-Kiang briefly elaborated upon.

Lenalidomide rarely produces a complete remission on its own, she explained, so the team decided to study palbociclib in combination with immunomodulatory drugs in MM (NCT02030483).

The strategy is to prime the cell cycle with palbociclib and then use lenalidomide and dexamethasone to increase efficacy.

Twenty patients have received this combination thus far, and investigators found that palbociclib enhances the activity of lenalidomide in the killing of primary bone marrow myeloma cells.

Lenalidomide reduces the MEIS2/CRBN ratio in these cells. The drug changes the ratio, reduces the blocker, and allows the CRBN to work. 

“The whole principle here is to control the gene coupling to the cell cycle and induce imbalance in gene expression,” Dr Chen-Kiang said. “And this weakens the tumor cells.”

Two-thirds of the samples respond to palboclib, she said, and those patients go on to be treated with lenalidomide or pomalidomide.

One third will not respond, but their in vivo clinical response and the ex vivo responders’ purified cells mimic one another.

“Now, this is very exciting to us,” she said.

The combination study with lenalidomide and dexamethasone is currently underway.

Palbociclib is being developed by Pfizer. end hematology article


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