BCR Inhibitors Show Promise in Treating Chronic Lymphocytic Leukemia

Jennifer R. Brown, MD, PhD

Two novel, oral drugs that target the B-Cell receptor (BCR) signal transduction pathway could significantly change the way chronic lymphocytic leukemia (CLL) is treated, Jennifer R. Brown, MD, PhD, predicted during the 17th Annual International Congress on Hematologic Malignancies.

Idelalisib and ibrutinib are highly effective at reducing lymphadenopathy in CLL, with low toxicity, and should be considered extremely promising even though they cause initially marked increases in lymphocytosis, said Brown, who is director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute and assistant professor of Medicine at Harvard Medical School in Boston.

While lymphadenopathy starts decreasing rapidly within a couple of days of taking the medications, lymphocyte count simultaneously rises, peaking at 1 to 2 months. Then, the lymphocyte count drops, but how long that takes, and whether the count reaches normal levels, seems to vary depending on the drug and the patient, Brown said.

“By standard 2008 criteria, lymphocytosis would be considered progressive disease, or, at the very least, something that negatively affects response rate, and that influences some of the data with these drugs,” Brown said. “But lymphocytosis should not be considered progressive disease with these drugs, when all other disease parameters are improving.”

Brown added that combining idelalisib or ibrutinib with rituximab and/or bendamustine can largely mitigate the lymphocytosis in CLL patients.

Brown pointed out that the way idelalisib and ibrutinib work in CLL is unexpected.

While there are many kinases along the BCR pathway that constitute potential targets for smallmolecule inhibitors—including LYN, SYK, PI3K, BTK, and AKT—there is minimal evidence of somatic activating mutations in those genes.

Idelalisib

“Of 25 recurrent drivers in CLL in our most recent sequencing study [see sidebar], none are expected to activate a BCR signaling pathway, but we know that activated BCR signaling is seen in CLL,” Brown said. “So pathway stimulation comes from stimuli in the microenvironment, and in that setting, this pathway is a very effective target in CLL.”Idelalisib is a delta isoform-specific inhibitor of PI3 kinase.

A phase I study of the drug, mostly in heavily pretreated patients, looked at idelalisib monotherapy (J Clin Oncol 29: 2011 [suppl; abstr 6631]), while a subsequent phase Ib study in relapsed/refractory patients looked at idelalisib plus bendamustine and idelalisib plus rituximab (Blood [ASH Annual Meeting Abstracts] 2012 120: Abstract 191).

In terms of nodal response, the reduction of disease was comparable in all groups, Brown said. “Lymphocytosis was profound with the single agent, and largely resolved with rituximab or bendamustine in combination with idelalisib,” she said.

In a 24-month follow-up of the group that received idelalisib monotherapy, median progressionfree survival (PFS) was 16 months for those without a 17p deletion and 4 months for those with the deletion, Brown said.

In the phase Ib study, nodal and overall response rates (ORRs) were comparable between arms, and lymphocytosis was resolved in the combination arms, Brown said. In the idelalisib plus rituximab arm, nodal response was 90% and ORR was 79%; with idelalisib and bendamustine, nodal response and ORR were both 78%; and in the three-drug arm, nodal response and ORR were matched at 87%, Brown reported.

“PFS showed a bit of early drop-off, but the one-and two-year rates are comparable at about 63%,” she said.

Registration trials are ongoing, and include tests of rituximab with or without idelalisib; bendamustine and rituximab with or without idelalisib; and ofatumumab with or without idelalisib, Brown said.

Ibrutinib

Brown added that, across all studies, the most common adverse events with idelalisib were neutropenia, pneumonia, and transaminase elevation; the latter was resolved by temporarily stopping treatment.Ibrutinib is a potent inhibitor of Bruton’s tyrosine kinase that generated positive results in a recently updated phase II study, Brown said (Blood [ASH Annual Meeting Abstracts] 2012 120: Abstract 189).

In the study, 116 patients in three groups that ranged from low to high risk for disease progression were treated with ibrutinib monotherapy.

The lowest-risk group, composed of treatmentnaïve patients, demonstrated a 68% response rate, including a 10% complete remission rate, Brown said. Another 13% of that group had a partial response accompanied by lymphocytosis. Among relapsed/refractory patients, the response rate was 71%, including a 2% complete remission rate. An additional 18% of those patients experienced a partial response marked by lymphocytosis, Brown said.

“Deletion 17p patients and those with bulky disease had equally good response rates as patients without those features,” noted Brown, who called that result “exciting.”

She added that, of six patients in the study who had previously been treated with idelalisib, four responded to ibrutinib.

In a follow-up at 26 months, treatment-naïve patients had a median PFS of 96% and relapsed/ refractory patients had a PFS of 75%, Brown said.

Patients with deletions of 17p or 11q did not do quite as well, Brown said. Those with 17p deletions had a PFS of 57%; patients with 11q mutations had a PFS of 73%; and relapsed/refractory patients without those mutations had a PFS of 93%, Brown said. Mutational status of the immunoglobulin heavychain variable region (IgVH) gene in cancer cells had no effect on PFS.

In the follow-up, overall survival (OS) for treatment-naïve patients was 96%; for relapsed/ refractory patients with 17p deletion, 11q mutation, and neither mutation, respectively, OS was 70%, 85%, and 93%, Brown said. Again, IgVH status had no effect.

25 Recurrent Drivers in CLL

Mutations

SF3B1 TP53 NOTCH1 MYD88 ATM XPO1 CHD2 POT1 HIST1H1E NRAS

BCOR ZMYM3 RIPK1 SAMHD1 KRAS MED12 ITPKB DDX3X EGR2 FBXW7

sCNAs

del (13q)

trisomy12

del (11q)

del (17p)

del (8p)

sCNAs indicates somatic copy-number alterations.

Brown described ibrutinib as being well tolerated, with infections, most of them pneumonias, constituting the most common serious adverse events.

She noted that, in a 2-year follow-up to the study, ibrutinib improved hemoglobin and platelet counts in relapsed patients with cytopenias.

Brown said that lymphocytosis cropped up less among the study’s treatment-naïve patients than in relapsed patients. She added that lymphocytosis persisted longer in patients with mutated IgVH, half of whom had achieved normalization at follow-up, with a median time to resolution of over a year.

“While unmutated IgVH is normally thought of as higher risk, patients in that category normalized their lymphocytosis, in 85% of cases, in a median six months,” Brown said. “The reasons are not entirely clear.”

Registration trials of ibrutinib are in development, beginning with a phase III comparison of single-agent ibrutinib to ofatumumab, Brown said. Follow-on trials will test ibrutinib versus chlorambucil, as well as ibrutinib as a single agent in 17p deletion patients.