Considerations of Ibrutinib for IgHV-Unmutated CLL

Matthew S. Davids, MD, MMSc:For this patient we know that he does not have deletion 17p orTP53dysfunction. Therefore, this is a patient whereIgHVmutation status becomes very important in helping to identify the optimal treatment regimen. We know that this patient has unmutatedIgHV, and so historically with chemoimmunotherapy regimens, although we could expect an initial response, we would think that the durability of that response would be less than for some of the novel agent based approaches.

Until very recently we did not have any convincing clinical trial evidence to support this approach. We had some phase III data from a study called RESONATE-2, which showed the superiority of ibrutinib as a monotherapy over chlorambucil as a monotherapy for these patients. Unfortunately, chlorambucil is probably not the best comparator because we’re not using that drug as a single agent very commonly now CLL [chronic lymphocytic leukemia].

It was really only very recently that we had data presented and then published that informed the decision for this patient from a phase III trial. And that was the Alliance [North American Intergroup] randomized trial that was presented at the ASH [American Society of Hematology] meeting and later published in theNew England Journal of Medicineby [Jennifer] Woyach [,MD,] and colleagues. This is a very important study because it randomized previously untreated older patients with CLL to either ibrutinib, ibrutinib with rituximab, or the traditional bendamustine/rituximab chemoimmunotherapy.

For this patient with unmutatedIgHV, how can we interpret the data from this study? What the study showed was that there was a significant improvement in the progression-free survival [PFS] of both of the ibrutinib arms over the bendamustine and rituximab arm. And interestingly there was absolutely no difference in PFS between the two ibrutinib arms. Meaning that the rituximab did not add any significant benefit from an efficacy perspective to ibrutinib, and certainly was associated with some additional toxicities such as infusion reactions.

As we look at the different subsets of patients on this trial, those who tended to benefit the most actually were patients with unmutatedIgHV, and that’s where the PFS difference was most significant. The ibrutinib-based regimens did not lead to an overall survival benefit [OS] over bendamustine and rituximab. This is most likely due to the fact that the study allowed for a crossover. And so most of the patients who progressed after bendamustine and rituximab were able to then go on to receive ibrutinib.

In terms of interpreting the Alliance study for this particular patient, I think there’s a couple of different ways that we could think about it. My personal preference is that for patients with unmutatedIgHV, based on the strong progression-free survival benefit, if they’re a good candidate for ibrutinib otherwise, meaning that they don’t have significant cardiovascular risks or are not on anticoagulation, then I think ibrutinib monotherapy is a good way to start. And that’s probably what I would recommend for a patient like this.

The argument could also be made though that there’s no overall survival benefit to starting with ibrutinib, and therefore, it could be a reasonable case to start with bendamustine and rituximab, knowing that the remission would be relatively short, but the patient would be likely to respond well to ibrutinib in the relapsed setting.

So I think either approach is reasonable. If I had a patient who maybe had more cardiovascular risk factors than this patient, for example, recent MI [myocardial infarction], on anticoagulation already for atrial fibrillation, those sorts of things, that might be a patient even the unmutatedIgHVsetting where I’d be thinking about bendamustine and rituximab as a nice option, to try to reserve the ibrutinib for a time where I really need it, knowing that there are some significant cardiovascular risks with ibrutinib. On the other hand, for this patient with some mild hypertension and no other significant cardiac risk factors, I do think ibrutinib would be a very reasonable option.

Age, fitness, and comorbidities all factor into the treatment decision for patients with non-17p deleted CLL. In particular, we consider the age to be important in deciding whether to give chemoimmunotherapy, particularly for those patients who have mutatedIgHV. So far I’ve mainly been talking about the Alliance trial, which was the randomized study of ibrutinib versus chemoimmunotherapy for older patients. But also at this year’s [2018] ASH meeting was an important study from the ECOG[-ACRIN Cancer Research] Group, ECOG 1912, which randomized patients to ibrutinib with rituximab versus FCR [fludarabine/cyclophosphamide/rituximab] chemoimmunotherapy. And these were all CLL patients under the age of 70.

In the ECOG study there was also a significant benefit from a PFS perspective of the ibrutinib regimen, and interestingly there was also an overall survival benefit starting with the ibrutinib-rituximab regimen over FCR when looking at the entire study population. But interestingly when focusing on theIgHVmutated group, there’s not yet a significant improvement in PFS or OS. Given the fact that we have long-term data with FCR that suggests a plateau with a functional cure for about half of patients with mutatedIgHV, I think it’s still preferred to use FCR for that young, fit patient population who have mutatedIgHV.But this ECOG study does provide good evidence that it’s good to start with ibrutinib for patients with unmutatedIgHV, even in the younger population. Certainly other comorbidities will factor in. We’ve talked about some of the cardiovascular risk factors, and that does always make me think twice about using ibrutinib, particularly in the older population.

One of the other things that emerged from the Alliance study was that patients in the ibrutinib arm did have a slightly higher risk of sudden death. It was not statistically significant when compared with bendamustine and rituximab, but it makes me think that if I have a patient who has significant cardiac risk factors, I should be thinking twice about using ibrutinib. It doesn’t mean that I can’t use it, it’s more of a relative contraindication, but I think it’s a factor that people need to consider.

Transcript edited for clarity.

Case:A 74-Year-Old Male WithIgVH-Unmutated CLL

• A 74-year-old male presented to PCP with complaints of extreme fatigue, weakness, and weight loss of ~15lbs over the last 3 months.
• PMH: Mild hypertension managed by statin
• PE: BP 135/85, enlarged lymph nodes (~6cm), palpable spleen approx. 7cm below costal margin
• Laboratory findings:
  • WBC; 100 X 10⁹/L
  • Lymphocytes; 82 X 10⁹/L
  • Hb; 15.1 g/dL
  • Platelets; 125 X 10⁹/L
  • ANC; 1,800/mm³
  • LDH 250 u/L
• β2M, 4.3 mg/L
• FISH; normal
• Molecular analysis;IgVH-,TP53wild-type
• ECOG PS 1
• Rai Stage II