Top Discoveries in Chronic Lymphocytic Leukemia at ASH 2018

With respect to the treatment of chronic lymphocytic leukemia (CLL), 2018 was notable for an improved understanding of ibrutinib-based therapies. The increased focus on ibrutinib was evident at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition, held December 1–4 in San Diego.

“Definitely in CLL, ibrutinib made a huge splash at ASH and cemented a very promising role for ibrutinib front-line therapy. It could also be beneficial in select patients with diffuse large B-cell lymphoma when added to R-CHOP [rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone],” said Brad S. Kahl, MD, a professor in the Department of medicine, Oncology Division, at the Washington University School of Medicine, in an interview with Cancer Network. “[Ibrutinib] didn’t have to beat stiff competition until now. It finally was shown to beat stiff competition [from other agents] in the treatment of CLL.”

Kahl noted the importance of three phase III ibrutinib trials of interest, also presented at ASH, which he said “showed similar findings.”

In the first trial (LBA-4), Shanafelt and colleagues presented results from a US intergroup trial comparing fludarabine, cyclophosphamide, and rituximab (FCR) immunochemotherapy with ibrutinib-rituximab in young, fit CLL patients in need of first-line treatment.  

“The trial took patients up to age 70, which is getting a little old for FCR in my opinion,” said Kahl. “I try to limit FCR to patients under the age of 60, and, occasionally, I go to 65. The regimen becomes prohibitively toxic when administered to older patients. But the results of the trial were striking. Ibrutinib was superior to the FCR regimen for progression-free survival [PFS] at 2 years and 3 years, and the difference is pretty significant,” he said. There was also an overall survival benefit for the ibrutinib-rituximab arm, although the number of events was very low in both treatment groups.

Looking forward, Kahl is interested in reviewing results from the trial once it is stratified by immunoglobulin heavy-chain gene mutation status.

“We know from prior work that patients who have ‘mutated’ IgVH genes do fairly well with immunochemotherapy, whereas patients who have unmutated versions of the disease do less well with immunochemotherapy.,” he said. “The PFS advantage for ibrutinib starts to shrink when you limit the analysis to the mutated patients. So, if you have a young patient with mutated disease, it’s still reasonable to discuss FCR therapy, but patients with unmutated disease can expect a substantially longer remission duration with ibrutinib therapy.”

Kahl also noted that, unlike ibrutinib, which is continuously administered, the use of FCR provides a therapeutic break, which generally improves quality of life.

“The benefit of ibrutinib in mutated patients is so small that it would be reasonable to continue to use FCR in those patients,” he said. “It’s a conversation you have to have with the patient. The advantage of FCR or any immunochemotherapy strategy is that it’s time-limited treatment. You do your treatment for 6 months and you’re done-you get to have a therapeutic break. Whereas with ibrutinib, you start on therapy and stay on therapy, and you don’t get a therapeutic break.”

On a related note, Kahl noted that the combination of ibrutinib and FCR in CLL is currently being studied at Dana-Farber Cancer Institute, where the study is in its early stages.

In the second ibrutinib trial (abstract 6), Woyach and colleagues compared bendamustine plus rituximab vs ibrutinib compared with a combination of ibrutinib plus rituximab to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy in CLL patients with regard to PFS. One key difference between the Woyach et al and Shanafelt et al trials was that in the Woyach trial, patients were all aged 65 years or older. In older patients, FCR is typically too toxic.

“The two ibrutinib-based arms did beat bendamustine plus rituximab for PFS, if you look at the proportion of patients in remission at 2 or 3 years,” said Kahl. Interestingly, the addition of rituximab to ibrutinib did not improve performance of ibrutinib. “It was somewhat unexpected. Pretty much our entire careers, whenever we add rituximab, it makes [outcomes] better,” he said. “This is one of the first examples that adding rituximab did not make it better.”

Kahl also brought up that in the Woyach et al trial, bendamustine plus rituximab performed almost as well as ibrutinib in patients with IgVH-mutated disease. Consequently, he would still consider bendamustine plus rituximab in patients aged 65 years and older with mutated disease as a perfectly reasonable option.

In the third ibrutinib trial (abstract 691), Moreno and colleagues randomized CLL patients in a 1:1 ratio to receive ibrutinib plus obinutuzumab or chlorambucil plus obinutuzumab, with the primary endpoint being PFS. Patients in the study were either aged 65 years or older or were younger than 65 years with coexisting conditions.

“Ibrutinib-based treatment performed far better than chlorambucil-based treatment. But should you add in the obinutuzumab to the regimen? That’s an unknown right now,” said Kahl. “I’m skeptical that obinutuzumab materially improves the results over what would be seen with ibrutinib alone.”

On a final note, at ASH 2018, a study was presented in which ibrutinib was tested in patients with treatment-naïve non-germinal center B-cell-like (GCB) diffuse large B-cell lymphoma (abstract 784). In a phase III trial, Younes et al randomized patients in a 1:1 ratio to R-CHOP with either ibrutinib or placebo.

Although the trial was negative, the results were mixed, said Kahl. In patients 65 years and older, unexpected toxicity occurred in those taking ibrutinib and R-CHOP, resulting in decreased R-CHOP exposure, which possibly led to worse clinical benefit/risk profile vs patients in the placebo R-CHOP arm. However, in patients younger than 65 years, the addition of ibrutinib demonstrated a clinical improvement in PFS and other survival measures, as well as acceptable toxicity.

“The trial begs the question, “Is ibrutinib therapy advantageous if used in the right type of patient who can handle added toxicities? It leaves the field in a bit of predicament regarding what to do with this data, and it will be interesting to see if ibrutinib gets regulatory approval in a subset of [DLBCL] patients, whether people will use it off label, and whether insurance would pay for it off label,” Kahl said.