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.
“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.
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.”