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Changing Clinical Practice in CLL
Changing Clinical Practice in CLL

Released: February 25, 2016

Expiration: February 23, 2017

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This is a really exciting time for the treatment of patients with chronic lymphocytic leukemia (CLL). The pace of discovery and increased understanding of CLL has led to an unprecedented amount of change and evolution in the management paradigm for this disease. With that, here are a few insights on recently presented data that I think you will want to consider for your practice.

New Approaches With Currently Approved Agents
The phase III RESONATE-2 trial assessed the use of ibrutinib as frontline therapy in patients with CLL who were 65 years of age or older (N = 269), excluding patients with del(17p) cytogenetics. This trial compared ibrutinib with chlorambucil, since this was the standard comparator at the time the trial was designed. However, clinicians no longer use chlorambucil as a single agent based on data that have shown the superior efficacy of chlorambucil with an anti-CD20 monoclonal antibody (rituximab, ofatumumab, or obinutuzumab). Regardless, this trial showed a better outcome in elderly patients randomized to ibrutinib. At a median follow-up of 18.4 months, the median PFS (primary endpoint) was significantly improved with ibrutinib and the relative risk of death with ibrutinib was 84% lower than with chlorambucil. Most people were still alive even 24 months later; 98% of patients still alive with ibrutinib and 84% with chlorambucil.

The best response by investigator assessment was 86% with ibrutinib vs 35% with chlorambucil, including 4% of patients treated with ibrutinib achieving a PR with lymphocytosis (PRL) and 10% achieving a CR or CR with incomplete blood counts (CRi). Comparing these data with those in relapsed/refractory disease, you can see the more rapid response with first-line ibrutinib vs a longer time to achieve a similar depth of response in patients with relapsed/refractory CLL. One may argue that giving this agent earlier might allow for deeper responses sooner, rather than waiting for an extended time in the relapsed/refractory setting.

Atrial Fibrillation With Ibrutinib
In RESONATE-2, the incidence of atrial fibrillation was 6% for ibrutinib and 1% for chlorambucil. This is the third major phase III trial with a higher number of events of atrial fibrillation in patients treated with ibrutinib. Similar rates of atrial fibrillation were reported in the RESONATE study assessing ibrutinib in patients with relapsed/refractory disease and in the HELIOS trial with the addition of ibrutinib to bendamustine and rituximab in patients with relapsed/refractory disease.

At the ASH 2015 annual meeting, 3 different groups presented data on their experience with the risk for atrial fibrillation in patients with CLL who were treated with ibrutinib. In my own abstract, I characterized atrial fibrillation and bleeding risk in a population‑based retrospective analysis based on medical claims data in the United States. Farooqui and colleagues from the NIH presented data from a phase II trial that enrolled 86 patients, and Shanafelt and colleagues presented data from more than 2000 patients from the Mayo Clinic CLL database. Generally, each data set concluded that over time, the incidence of atrial fibrillation increases with age and over the course of the natural progression of CLL. Also important is that the incidence was very similar across each data set.

In our presentation, we calculated the incidence of atrial fibrillation per 10,000 person-days, which was 4.6 for all patients. However, in patients younger than 65 years of age the incidence was 1.6, and for patients older than 65 years of age, the incidence was 8.4. The incidence quoted by Shanafelt from 2444 patients was 12%, or 291 patients, with atrial fibrillation at some point during their disease. At the time of diagnosis, only 6% had atrial fibrillation, and then the incidence increased over time, with a 10‑year risk of atrial fibrillation of nearly 33%. Finally, Farooqui assessed the risk of atrial fibrillation based on age and saw that the risk was age dependent—the older a patient is, the higher the cumulative or annualized incidence of atrial fibrillation. However, their risk–benefit analysis favored continued use of ibrutinib, and no patient required discontinuation of therapy.

Although I think it is reasonable to consider ibrutinib even in patients with risk factors for atrial fibrillation, it is imperative that clinicians understand the risks and educate patients on the symptoms of this adverse event. Clinicians using ibrutinib should be able to tell patients, “If you have any new onset palpitations, shortness of breath, or chest pain, immediately call us and we will tell you what to do.” Once a patient or clinician recognizes this adverse event, quickly requesting a cardiology consultation is important.

Another known adverse event of ibrutinib is the possibility of bleeding events, which is another important point of discussion with patients, in terms of risks vs benefits for using anticoagulant medication, such as warfarin, in combination with ibrutinib.

Discontinuations With Ibrutinib: The Real-World Experience
As agents move into the clinic, there are often differences in the “real-world” experience of clinicians compared with the efficacy and safety outcomes reported in clinical trials. At the ASH 2015 annual meeting, 3 different groups presented data on the outcome of ibrutinib treatment for CLL in their clinic. Finnes and colleagues presented data from 96 consecutive CLL patients (treatment naive and relapsed/refractory) who initiated ibrutinib off-protocol at the Mayo Clinic, Parikh and colleagues presented data from 135 CLL patients (treatment naive and relapsed/refractory) at the Mayo Clinic, and Sandoval-Sus and colleagues presented data from 54 patients treated with ibrutinib for relapsed/refractory CLL at the Moffitt Cancer Center.

The rates of discontinuation from these retrospective studies of patients treated outside of clinical trials were higher than reported in clinical trials. It is possible that patients in clinical trials had exhausted all available therapeutic options, so despite adverse events, they chose to remain on therapy, whereas patients in routine clinical practice may discontinue ibrutinib for reasons other than progression of disease since they are more likely to have other treatment options remaining.

In addition to these 3 studies, there was also a multicenter retrospective study, presented by Mato and colleagues from the University of Pennsylvania, of CLL patients who discontinued ibrutinib- or idelalisib-based therapy for any reason. This study found the same trend—in essence, approximately 1 of every 3 patients stopped their treatment after starting on these commercially available drugs due to adverse events. Of a total of 178 patients (93 receiving ibrutinib and 30 receiving idelalisib), 18% required dose modification for ibrutinib and 35% for idelalisib. A total of 43% of patients required dose interruption with ibrutinib and 64% with idelalisib, mainly due to toxicities. Approximately 20% of patients discontinued ibrutinib due to atrial fibrillation and 33% discontinued idelalisib due to pneumonitis. In clinical trials, atrial fibrillation with ibrutinib and pneumonitis during idelalisib therapy occurred in fewer than 10% of cases. If we look at efficacy, the median PFS for this cohort of patients from the start of either idelalisib or ibrutinib was approximately 10 months, which is short compared with clinical trial data. So, are patients relapsing sooner because of treatment discontinuation? We do not know if we are changing the natural history of the disease by stopping ibrutinib or idelalisib sooner or if it is simply that patients with CLL cannot tolerate the treatment and more rapidly switch to another regimen.

Although these agents continue to be very active and fairly safe, many patients do stop treatment in clinical practice due to adverse events. During clinical trial protocol, there is an impetus to push through and continue with dose adherence and the dose intensities so patients achieve the maximum benefit of the study drug. But, when you have these same therapies available to general practitioners, it seems that many patients and clinicians feel that they have other options and may decide sooner to stop or change therapy. Also, in clinical trials, patients must adhere to certain eligibility criteria and typically are healthier with less major comorbidities, so they may be able to tolerate therapy better because they are just more fit than patients in clinical practice.

It is likely a combination of both situations: The patients in “real-world” clinical practice are sicker and may have other conditions affecting and interacting with ibrutinib or idelalisib; the physicians themselves can be reluctant to push through with these agents if adverse events occur when they have other options available.

New Kid on the Block: Venetoclax for Relapsed/Refractory CLL
Venetoclax is a relatively new and promising agent for CLL. In a phase II trial presented by Jones and colleagues at the 2015 ASH meeting, venetoclax was used as a salvage treatment for patients who relapsed on or were refractory to ibrutinib or idelalisib. In a total of 54 patients, the best objective response rate was 61% for patients who had been previously treated with ibrutinib and 50% for patients who had been previously treated with idelalisib. These data highlight the encouraging efficacy for a new option once patients have stopped responding to ibrutinib or idelalisib.

Additional data on venetoclax were presented by Stilgenbauer and colleagues in patients with relapsed/refractory CLL and del(17p). This pivotal phase II study included a large cohort of patients with good performance status and no previous allogeneic transplantation (N = 107) and achieved an ORR of almost 80% with an MRD negativity rate of 40% in assessable patients. These data were impressive for patients with del(17p) cytogenetics, but the long-term data will be important to correlate these early trends with remission duration. We know that with chemoimmunotherapy, a deeper response and MRD negativity can result in a longer time in remission, but it is unclear if this also the case with the newer targeted treatment options.

What we do know, however, is that venetoclax seems to work well in patients with del(17p) as a monotherapy and additional data suggest that it could also be used as an effective combination approach with rituximab, obinutuzumab, or bendamustine/rituximab. Currently, venetoclax is under review by the FDA for approval for patients with relapsed/refractory CLL and del(17p).

Final Thoughts
These are just a few of the many interesting and important data on the treatment and management of patients with CLL. Leave a comment and let me know what recent data are changing your clinical practice.

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Which of the following do you consider the standard of care for elderly or unfit patients with previously untreated CLL?
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