A Promising New Agent's Road to Approval in CLL Raises Questions, Stirs Controversy 

Get Permission

Based on the ASH meeting presentations, the 26-month progression-free survival rate in the relapsed/refractory patients is 75%, and in treatment-naive patients, it’s 96%. That kind of durability is part of what’s generating the excitement about ibrutinib.

—Susan M. O’Brien, MD

Early trial results in single-agent therapy with the oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib have produced excellent responses in patients with chronic lymphocytic leukemia (CLL). Moreover, ibrutinib is extremely well tolerated, allowing patients to remain on trial and receive the drug’s full benefit. These encouraging responses and solid safety profile have left many in the oncology community anxious for results from phase III studies of the drug in patients with CLL.

In an interview with The ASCO Post, leukemia expert Susan M. O’Brien, MD, Ashbel Smith Professor at The University of Texas MD Anderson Cancer Center, explained ibrutinib’s clinical allure. Dr. O’Brien, who is a principal investigator in RESONATE, an active phase III trial of single-agent ibrutinib vs ofatumumab (Arzerra) in CLL, also offered her candid opinion about the trial design of the ongoing study, which is causing concern among clinicians and patients. (See Dr. O’Brien’s commentary here.)

Mechanism of Action

In the simplest terms, how does ibrutinib work?

The clinical idea behind ibrutinib is that if you ligate the B-cell receptor on either a normal or malignant B cell, it provides a very strong survival and proliferation signal to the cell. One might then assume that interrupting that survival signal in a malignancy should cause a favorable effect on the disease. That’s the agent’s promise in a nutshell.

Phase II Trial

This is such a challenging disease setting; could you discuss some of the early data of ibrutinib in CLL?

The exciting ibrutinib data in CLL presented at the American Society of Hematology (ASH) Annual Meeting and several other conferences are from a phase II trial in two different patient populations: treatment-naive patients aged 65 years and older, and patients with relapsed or refractory disease.1

The study opened with relapsed or refractory patients. However, once the investigators saw how well the drug was tolerated, that led to the enrollment of older, treatment-naive patients, the rationale being that although chemoimmunotherapy is the standard of care in CLL, toxicities such as myelosuppression and infection are more problematic in this older population. Therefore, it’s prudent to give them an investigational agent, if the toxicity is tolerable.

The data in the older, treatment-naive patients looked better, which is not surprising in previously untreated patients. But on short-term follow-up, the relapsed/refractory data are actually more clinically impressive, simply because of the heavily pretreated disease in these patients. For example, they had received a median of four prior regimens, and they often had very severe baseline cytopenias. Quite frankly, these cytopenic patients rarely get enrolled in clinical trials, but they tolerated ibrutinib, which is one of the very encouraging properties of this drug.

Pattern of Response

What have we learned so far about ibrutinib’s “personality”?

Ibrutinib and other drugs that target these B-cell tumors have a very interesting response pattern. When we first give ibrutinib to a patient, there’s a dramatic shrinkage in the lymph nodes, but at the same time, the lymphocyte count goes up. In fact, some patients were taken off the phase I study early on, because the rise in lymphocytes was interpreted as disease progression.

But something more complicated was happening: True, the lymphocyte count went up, but a week later, the nodes had shrunk demonstrably. This unique pattern of response began to be recognized and addressed. The good news is that CLL patients can walk around with very high lymphocyte counts without being symptomatic, probably because the cells are so small and soft that they pass through the vasculature without creating the hyperviscosity we see in other diseases. And over time, those high lymphocyte numbers come down.

Interpreting the Data

Please describe the drug’s response data so far?

Using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for response in CLL, a partial remission indicates not only a 50% reduction in tumor bulk in the lymph nodes, liver, and spleen, but also a 50% reduction in the lymphocyte count. At about 3 months into therapy, some patients with an 80% reduction in their lymph nodes were not qualifying as a partial remission because their baseline lymphocyte counts were actually higher than the 50% cutoff.

This is important because when you look at responses over time, the response profile changes with longer follow-up, which has been made clear by presentations at the ASCO Annual Meetings. So, in effect, this changed the established terminology. In other words, you may now see a patient who achieves a partial remission with lymphocytosis or a partial remission with nodal responses. These terms were not part of the original IWCLL criteria, but they are now fairly well recognized to indicate patients who have dramatic lymph node shrinkage, and yet, because of their lymphocyte count, they are not qualifying as having a partial remission.

The latest ASH data in relapsed/refractory patients are impressive. If you add the different responses—71% had a partial remission using standard IWCLL criteria, and 18% had the newer classification of partial remission with lymphocytosis—89% of these patients on trial had at least 50% shrinkage in their tumor bulk, which is very impressive.

Further Considerations

Would you discuss the drug’s safety profile?

Ibrutinib is not myelosuppressive, so we don’t see an increased rate of infection, which is the biggest complication in treating CLL. Some infections are seen since these patients are already immunocompromised by the disease itself and prior treatment. Moreover, the side effects of ibrutinib are almost negligible; the most common is diarrhea, which is self-limiting. In fact, I have never seen a patient come off study because of diarrhea. This is probably the easiest hematologic drug for patients to handle that I’ve ever seen.

And last, the durability is another plus. Sure, it’s nice to have a 70% response rate in a refractory population, but if it only lasts 3 months, the value is limited. Based on the ASH meeting presentations, the 26-month progression-free survival rate in the relapsed/refractory patients is 75%, and in treatment-naive patients, it’s 96%. That kind of durability is part of what’s generating the excitement about ibrutinib. ■ 

Disclosure:Dr. O’Brien receives research support from Pharmacyclics.


1. Byrd JC, Furman RR, Coutre S, et al: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve and relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia patients including patients with high-risk disease: New and updated results of 116 patients in a phase Ib/II study. 2012 ASH Annual Meeting. Abstract 189. Presented December 9, 2012.

Related Articles

SIDEBAR: Three Breakthrough Therapy Designations for Ibrutinib from the FDA

In February 2013, FDA granted Breakthrough Therapy Designations for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma and as a monotherapy for the treatment of patients with Waldenström’s macroglobulinemia, both of which are also B-cell...