From OncoLog, April 2014, Vol. 59, No. 4
New Kinase Inhibitors Hold Promise for Chronic Lymphocytic Leukemia, Other B-Cell Malignancies
By Joe MunchNew targeted therapies against chronic lymphocytic leukemia (CLL) are eliciting overall response rates similar to those achieved using standard chemoimmunotherapy but with fewer toxic effects.
BCR pathway inhibitors
The main advantage of BCR pathway inhibitors over standard treatments for CLL is that the targeted drugs do not induce the classic, sometimes life-threatening side effects of cytotoxic chemotherapy.
“One of the biggest issues in treating CLL is that up until now, most of the therapies we had caused myelosuppression,” said Susan O’Brien, M.D., a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center. “In a CLL patient who has an elevated white blood cell count, we want the white count to come down, but we don’t want the nonspecific effects of lowering the platelets or hemoglobin, which could cause the patient to need a transfusion.”
Because BCR pathway inhibitors do not cause myelosuppression, they also carry a lower risk of infection than do cytotoxic chemotherapy drugs. These qualities make the targeted agents ideally suited for CLL patients whose advanced age or comorbidities preclude traditional chemotherapy. Numerous clinical trials are now investigating BCR pathway inhibitors alone or in combination with other agents in these and other populations.
BCR pathway inhibitors target CLL cells more specifically than do cytotoxic agents. The inhibitors work by disabling enzymes in the BCR signaling pathway, which are aberrantly activated in CLL, to render the pathway nonfunctional. For example, ibrutinib inhibits Bruton tyrosine kinase, and idelalisib inhibits phosphoinositide 3-kinase δ; both enzymes are critical to BCR signaling. As a result of this interrupted signaling, CLL cells lose not only their ability to proliferate and survive but also their ability to home in on, invade, and remain in the lymph nodes, which would otherwise serve as havens for further CLL growth. Deprived of these abilities, the bulk of CLL cells in the lymph nodes are dislodged into the peripheral blood.
The rapid redistribution of the cells causes transient lymphocytosis; in early trials of BCR pathway inhibitors, this was mistakenly viewed as a reason to stop treatment. “The patient’s lymphocyte count will go up initially. But this should not be interpreted as a sign of progressive disease, and the patient should not be taken off the drug for that reason,” Dr. O’Brien said.
Of the BCR pathway inhibitors, idelalisib and ibrutinib have generated the most excitement, as both drugs have advanced to phase III studies against multiple B-cell malignancies.
Trials of idelalisib against relapsed CLL or treatment-refractory indolent non-Hodgkin lymphoma have had encouraging results, and applications for the drug’s use in patients with these conditions are pending approval by the U.S. Food and Drug Administration (FDA).
Ibrutinib, approved by the FDA in November 2013 for the treatment of mantle cell lymphoma in patients who have received at least one prior therapy, made headlines again in February when it was approved for the treatment of CLL in patients who have received at least one prior therapy. And a recent phase Ib/II study demonstrating ibrutinib’s safety and efficacy in treatment-naïve patients older than 65 years who had CLL or small lymphocytic lymphoma is likely a harbinger of the approval of the drug for use in additional populations of patients with B-cell malignancies.
The 17p chromosomal deletion is a negative prognostic factor that almost invariably portends suboptimal responses to chemoimmunotherapy. In contrast, ibrutinib has elicited relatively good responses in patients who have the 17p deletion and is likely to have a role as frontline therapy for the 5%–10% of CLL patients who have this deletion at diagnosis.
“In patients with relapsed, refractory disease who have the 17p deletion, the median progression-free survival duration with ibrutinib is about 2 years,” Dr. O’Brien said. “That is better than any published median progression-free survival duration—which is typically 1 year—for patients with the 17p deletion receiving frontline chemotherapy,” Dr. O’Brien said. “Right now, I would not hesitate to treat a patient with the 17p deletion up front with ibrutinib because I know such patients don’t do well with cytotoxic chemotherapy.”
According to Dr. Burger, ibrutinib and idelalisib both represent excellent options for the treatment of CLL. Whether patients receive one or the other may ultimately depend on the patients’ ability to tolerate the side effects of the drugs or whether other agents are being given concurrently. For example, ibrutinib, which can increase the risk of bleeding, may not be ideal for patients taking certain anticoagulants, such as warfarin.
“Only time will tell whether one drug is a little better than the other in patient subgroups,” Dr. Burger said. “We have followed up patients treated with these drugs for only 3–3.5 years. That’s a relatively short time for follow-up.”
Long-term data may hold answers
Without sufficient long-term follow-up data, some vexing questions about the use and action of BCR pathway inhibitors remain. Chief among these is the issue of why patients treated in a frontline therapy setting, where one might expect to see a more robust treatment response, overwhelmingly have partial rather than complete responses. However, responses to BCR pathway inhibitors are very slow to occur; given that these patients have been followed for only a short time, additional complete responses may yet be observed.
“I think some patients who have partial responses to these drugs as frontline therapy will eventually transition to a complete response. How many will actually become complete responders is very hard to know because we don’t have long-term follow-up data yet,” Dr. O’Brien said.
The lack of long-term follow-up data also clouds researchers’ understanding of the side effects of BCR pathway inhibitors.
“Once larger populations get treated, then there could be safety issues that did not come up in the earlier clinical trials,” Dr. Burger said. “Kinase inhibitors can have cardiovascular side effects. That relationship may still emerge in the case of BCR pathway inhibitors, and that’s something we need to be cautious about.”
Additional long-term data may also provide insight into CLL cells’ development of resistance to BCR pathway inhibitors. This resistance is not yet common but remains a prime concern.
“These agents target one pathway, which is clearly an important pathway, but malignant cells rarely have only one abnormal pathway,” Dr. O’Brien said. “Targeting one pathway may not be enough.”
Given their success as single-agent therapies, their good tolerability, and the fact that they are oral agents, BCR pathway inhibitors such as ibrutinib and idelalisib are being given with other agents against CLL in the hopes of eliciting even better treatment responses.
The findings of ongoing phase II trials of combinations of the targeted therapies and cytotoxic chemotherapy are promising, although combining these therapies sacrifices the BCR pathway inhibitors’ advantage of not causing myelosuppression.
A more promising approach may be to combine the inhibitors with monoclonal antibodies to treat CLL. For example, Dr. Burger recently completed a pilot study of ibrutinib plus rituximab—the monoclonal antibody that has had a major impact on survival in CLL—in which 38 of 40 patients (95%) had a complete or partial response. The only patients who did not respond exited the study early owing to side effects or treatment complications.
“I have one patient for whom eight or nine lines of therapy had failed; he really didn’t have any options left. I enrolled him in the ibrutinib-rituximab trial, and 2 years into this treatment, he’s doing fine and traveling throughout Europe,” Dr. Burger said. “These patients who didn’t have other options wouldn’t be here with us without this treatment. And there’s quite a large number of these patients.”
As in the case of patients treated with single-agent ibrutinib, most patients receiving the ibrutinib-rituximab combination had partial responses; only about 10% of patients had complete remissions. However, Dr. Burger said that the patients’ CLL did respond faster than is typically seen in patients who receive ibrutinib alone, and this may translate into longer progression-free survival. The combination is now being compared with rituximab alone in a trial enrolling 208 CLL patients at MD Anderson.
Dr. Burger is optimistic about the future of BCR pathway inhibitors and other targeted drugs for CLL treatment. “Patients have been waiting for drugs like these. The feedback that I get from the patients I enroll in the studies of these drugs is extremely positive,” Dr. Burger said. “Moving forward, we’re going to use them more often and more broadly. I’m hopeful that these more targeted approaches will offer more benefit than side effects for a large majority of patients.”
“I think what people like to envision for CLL is non-cytotoxic therapy,” Dr. O’Brien said. “These new agents are going to raise a lot of interesting questions about potential combinations that in the long run may get us away from the use of cytotoxic chemotherapy entirely.”
Burger JA. Inhibiting B-cell receptor signaling pathways in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2012;7:26–33.
For more information, contact Dr. Jan Burger at 713-563-1487 or Dr. Susan O’Brien at 713-792-7543.