Not only ibrutinib attracts attention

For patients with refractory or relapsed chronic lymphocytic leukemia, several agents are currently under investigation that show promising results. At the EHA Congress in Milan, the main focus was on the kinase inhibitor ibrutinib and the BCL-2 inhibitor ABT-199. Both show high response rates with a controllable safety profile.

(ag) In chronic lymphocytic leukemia (CLL), the process of apoptosis does not proceed normally. CLL cells overexpress the so-called BCL-2 protein. BCL-2 is again anti-apoptotic. Thus, overexpression in cancer cells promotes tumor growth and inhibition of BCL-2 drives cells into apoptosis. BH3 mimetics inhibit in principle all anti-apoptotic BCL proteins expressing BH3. This leads to apoptosis, but also in cells that one actually wants to spare (platelets, via BCL-XL). Therefore, the selective inhibitor ABT-199 was developed to target only BCL-2-expressing cancer cells. Consequently, it is a selective, potent BCL-2 inhibitor that is being investigated as monotherapy in refractory or relapsed CLL, among other indications. The preliminary results of one such phase I trial, which is still ongoing, were presented by Prof. John Seymour, MD, Melbourne, at this year’s EHA Congress in Milan.

Primarily, the focus was on safety and pharmacokinetic data. Furthermore, the maximum tolerable dose and the recommended dose for phase II studies should be found. Preliminary efficacy data were a secondary objective of the study.

By April, 105 patients had been enrolled. On median, they had received four prior therapies. 78 of them were evaluable, achieving very high response rates: The overall response rate was approximately 77, and the complete response rate was approximately 23%. This is remarkable in such a heavily pretreated population, according to Prof. Seymour; moreover, the efficacy was independent of 17p status. Compared with ibrutinib, ABT-199 appears to lead to much faster destruction of cancer cells, even in high-risk CLL patients, Prof. Seymour said.
Preliminary analysis in eleven of the 18 patients with complete response found no evidence of residual disease at all in six and minor evidence in four. An omission of minimal residual disease was found even in high-risk subgroups with a del(17p) chromosomal abnormality, a non-mutated immunoglobulin-rich chain gene (IGHV), and in patients whose disease is refractory to fludarabine.

They also calculated a progression-free survival rate of 59% in patients treated with at least 400 mg ABT-199 for two years.

Increased risk of tumor lysis syndrome?

Tumor lysis syndrome (TLS) is a very rapid decay of tumor tissue, which can cause severe metabolic disturbances due to the increased number of metabolites in the blood. Therefore, Prof. Seymour’s team undertook dose escalation of ABT-199 under close monitoring (20 mg at week 1 to 400 mg at week 5).

Seven patients (7%) developed TLS before the dose-escalation regimen, but there were no cases after the new regimen was introduced. 400 mg is currently established and being studied as the safest extension dose.

According to Prof. Seymour, the long-term safety profile is very good, with only a few patients discontinuing the medication due to toxicities after the first few weeks. In April, they counted a total of 37 discontinuations, 22 due to disease progression, 12 due to adverse events, two due to the possibility of transplantation, and one due to the need for warfarin treatment. The most common side effects included nausea, diarrhea, fatigue, and anemia.
In the future, such drugs could also be combined with other molecules or antibodies to further improve results, the expert said. Phase II and III trials testing ABT-199 also in combination with anti-CD20 antibodies and standard chemotherapy are ongoing.

And what is the status of ibrutinib?

There is also news on the Bruton tyrosine kinase inhibitor ibrutinib, which blocks the B-cell receptor signaling pathway via the kinase switch site. A multicenter international phase III study (RESONATE) evaluated monotherapy versus the anti-CD-20 antibody ofatumumab in patients with refractory or relapsed CLL or small lymphocytic lymphoma (SLL). 391 patients in whom one or more prior therapies had been ineffective were randomized to either the ibrutinib (420 mg/d until progression) or ofatumumab (300/2000 mg over 12 doses) groups. Peter Hillmen, MD, Leeds, presented the results at the EHA Congress. The primary endpoint was progression-free survival, and secondary endpoints were overall survival, response rate, and safety.

The ibrutinib group included 195 people (median with three prior therapies), and the ofatumumab group included 196 people (median with two prior therapies).
Patients were on study for a median of 9.4 months, with ibrutinib significantly prolonging progression-free survival compared to ofatumumab. This translated into a 78.5 percent risk reduction for progressive disease or death in the ibrutinib group.
Overall survival also significantly prolonged with the kinase inhibitor (both arms failed to reach the median, p=0.0049), representing a 56.6% risk reduction.
The overall response rate was significantly higher with ibrutinib (42.6 vs. 4.1%, p<0.0001).
Patients with del(17p) also benefited in progression-free and overall survival and in terms of response.
Ibrutinib caused diarrhea and nausea more frequently compared with ofatumumab. Atrial fibrillation and bleeding events were also more frequent with ibrutinib. Overall, however, adverse events leading to treatment discontinuation were about equally frequent in the two arms.

The safety profile is comparable to that already known [1], is well managed, and rarely leads to dose reductions or discontinuations, the speaker said. 86.2% in the ibrutinib group continued therapy and 57 patients switched to this agent after experiencing progression in the ofatumumab group. In conclusion, ibrutinib showed significant benefit as a single agent for patients with refractory or relapsed CLL/SLL, regardless of del(17p) status, Dr. Hillmen concluded.

Source: EHA Congress 2014, June 12-15, 2014, Milan

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