Expert Discusses Optimal Care for Relapsed/Refractory CLL

Jennifer Woyach, MD

Following the emergence of several new treatment options for relapsed/refractory chronic lymphocytic leukemia (CLL) in recent years, researchers and clinicians are now focusing on the optimal use of these novel agents.

Jennifer Woyach, MD, offered her expert insight into the practical clinical use of these treatments at the PER meeting, Medical Crossfire: Redefining Treatment Paradigms in the Management of Chronic Lymphocytic Leukemia.

Second-Line Therapy

Woyach, an associate professor, division of hematology, department of internal medicine, The Ohio State University, discussed using the FDA-approved agents ibrutinib (Imbruvica), idelalisib (Zydelig), and venetoclax (Venclexta) in a hypothetical patient scenario, and highlighted emerging targets and treatments in relapsed/refractory CLL.Woyach detailed a hypothetical patient with CLL whose first-line treatment was the chemotherapy regimen of fludarabine, cyclophosphamide, and rituximab (FCR). After 7 years, the patient now has progressive disease with progressive symptomatic adenopathy and splenomegaly. The individual is otherwise healthy and highly active. FISH testing shows trisomy 12 but no other abnormalities.

The available treatment options are to repeat chemoimmunotherapy, use an anti-CD20 antibody, or use kinase inhibitor therapy.

“Far and away, I believe that the kinase inhibitors are the best option at this point,” Woyach said. She then detailed the available data for the use of the tyrosine kinase inhibitors (TKIs) ibrutinib and idelalisib.

In the initial single-agent phase I study of idelalisib, 54 patients with relapsed/refractory CLL were treated with varying doses of the the PI3K inhibitor.¹ The overall response rate (ORR) was 72%, comprised of all partial responses. It is “very unlikely to reach a complete response with idelalisib,” Woyach said.

The median progression free survival (PFS) was 31.9 months among the 28 patients who received idelalisib at ≥150 mg twice daily. In the group of 26 patients treated with idelalisib at <150 mg twice daily, the median PFS was 6.6 months. The median overall survival (OS) was not reached.

The phase III Study 116 trial led to the FDA approval of idelalisib in July 2014 for use in combination with rituximab (Rituxan) in patients with high-risk relapsed or refractory CLL.² Study 116 randomized 220 previously treated patients with relapsed or refractory CLL in a 1:1 ratio to receive idelalisib plus rituximab (n = 110) or rituximab and placebo (n = 110).

The ORR for the idelalisib combination was 81% versus 13% in the control arm. The 1-year OS rate was 92% versus 80%, respectively. The median PFS was not yet reached in the idelalisib combination arm compared with 5.5 months in patients who received rituximab alone (HR, 0.15; P <.001).

Switching to ibrutinib, Woyach discussed the phase III RESONATE study, which both confirmed the accelerated FDA approval of the BTK inhibitor as a treatment for patients with CLL who have received at least 1 previous therapy, and expanded the approval to include the treatment of patients with a 17p deletion (del[17p]).³

The RESONATE trial randomized 391 patients to single-agent therapy with ibrutinib (n = 195) or ofatumumab (Arzerra; n = 196). Ibrutinib reduced the risk of progression or death by 78% versus ofatumumab (HR, 0.22; P <.0001). The median PFS was 8.08 months with ofatumumab and was not reached with ibrutinib. Ibrutinib also reduced the risk of death by 57% (HR, 0.43; log-rank P = .0049).

Based on the currently available evidence for the 2 agents, Woyach said the best choice for second-line therapy for the hypothetical patient would be ibrutinib. However, she noted that there are cases in which idelalisib may be preferred.

“There are patients who don’t tolerate ibrutinib or who have contraindications to the drug—people who have had bleeding in the past or who are on warfarin. For those patients, idelalisib plus rituximab is a good option.”

Woyach also stressed that the optimal choice is far from settled, and clinicians must consider options beyond TKIs.

“We have not cured CLL in the relapsed setting. There are still a number of open questions. So a clinical trial of either a completely novel agent or a kinase inhibitor therapy—based combination is really an alternative that should be explored with patients who are interested.”

She also stressed that clinicians should not forget about the potential for transplant.

Progression After Ibrutinib/Idelalisib

“I always consider a transplant workup in these patients who are eligible for transplant at the time when I am starting them on ibrutinib or whatever inhibitor you’re choosing, so [if the treatment] doesn’t work after a period of time, you are still able potentially to transplant that patient as long as you have a salvage regimen in mind.”Woyach said the BLC-2 inhibitor venetoclax has emerged as a “standard option for patients who progress after [second-line] ibrutinib or idelalisib.”

Venetoclax received an accelerated approval from the FDA in April 2016 for the treatment of patients with del(17p) CLL who have received at least 1 prior therapy. The approval was based on the phase II M13-982 study, in which single-agent venetoclax induced an ORR of 79% in 107 patients with relapsed/refractory del(17p) CLL.⁴ The rate of complete response (CR)/CR with incomplete marrow recovery was 8%. The 12-months OS and PFS rates were 87% and 72%, respectively.

Woyach said one thing that distinguishes venetoclax from the TKIs is that the drug reduces bone marrow infiltration. “There are a number of patients who are achieving complete responses—even MRD-negative complete responses&mdash;with even very low doses of venetoclax.”

She added that patients with a complete response have a “superior progression-free survival compared to patients who had a partial response. This is similar to what we see with chemoimmunotherapy, where we know that the depth of remission correlates with the duration of remission and is different than the kinase inhibitors where we haven’t seen yet that those patients who have a deeper response are going to do better over time.”

Looking beyond venetoclax, Woyach said, “There are other salvage regimens currently in use for high-risk CLL.”

One is high dose methylprednisolone plus rituximab. The regimen works in patients with del(17p), but is highly toxic and usually does not produce that long of a remission duration. The other is lenalidomide plus rituximab, which Woyach described as “slower acting, relatively well tolerated, and has the potential for restoring some of the immune function in CLL.”

Next Steps for Relapsed/Refractory CLL

Commenting on these regimens, Woyach said, “Whether or not these are really appropriate for many patients at this time, I think is an open question.”Woyach noted that there are other targets and treatments in CLL moving through clinical trials or moving into clinical trials besides BTK, PI3K, and BCL2 inhibitors. These included other targets in the BCR pathway (eg, Syk, PKC beta), XPO1, CD19, BRD4, and HSP90.

“Checkpoint molecules have been extremely effective in solid tumors and in lymphomas, and I think looking at them in CLL, both alone and in combination, is going to be of great interest in the future,” added Woyach, “And everybody has heard of CAR T-cell therapy in CLL, which is still under active investigation and is potentially a curative strategy for these patients, pending more data.”

She concluded by listing key phase III studies that could expand the treatment options for relapsed/refractory CLL. These included the ACE-CL-006 trial comparing acalabrutinib with ibrutinib (NCT02477696), the UTX-IB-301 trial comparing ublituximab plus ibrutinib versus ibrutinib alone (NCT02301156), and the DUO trial comparing duvelisib with ofatumumab (NCT02004522).

References

1. Brown JR, Byrd JC, Coutre SE, et al. Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia. Blood. 2014;123(22):3390-3397.
2. Furman RR, Sharman JP, Coutre SE et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007.
3. Byrd JC, Brown JR, O'Brien S, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223.
4. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-778.