Optimizing Frontline Therapy With Cost-Savings Considerations in CLL

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Matthew S. Davids, MD, MMSc, discusses data that were presented with novel combinations in chronic lymphocytic leukemia at the 2019 ASH Annual Meeting and the importance of conducting cost-effective analyses.

Matthew S. Davids, MD, MMSc

The chronic lymphocytic leukemia (CLL) armamentarium continues to expand with combinations of novel agents, according to Matthew S. Davids, MD, MMSc. The activity and cost-savings potential of these regimens will inform whether they will be given in a time-limited or continuous fashion in the future, he added.

For example, in November 2019, the FDA approved acalabrutinib (Calquence) for the treatment of patients with CLL or small lymphocytic lymphoma. The approval was based, in part, on data from the phase III ELEVATE-TN trial, which showed that acalabrutinib as a single agent or in combination with obinutuzumab (Gazyva) led to a significant improvement in progression-free survival versus obinutuzumab/chlorambucil in patients with newly diagnosed CLL.1

Additionally, data from the phase II CAPTIVATE trial showed that the combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) led to undetectable minimal residual disease (MRD) in 75% of previously untreated patients <70 years old.2

Moreover, in a phase II trial, the addition of acalabrutinib to venetoclax and obinutuzumab induced undetectable MRD in the bone marrow after only 8 monthly cycles of therapy in 48% of patients with newly diagnosed CLL, which increased to 75.0% after cycle 16.3

“We have many new tools in our tool kit, but many of these are novel agent—based therapies that are quite expensive,” said Davids. “We need to figure out the relative cost effectiveness of all these different regimens in order to define the economic effectiveness of a time-limited treatment approach versus a treat-to-progression or continuous therapy approach.”

To that end, investigators at Dana-Farber Cancer Institute compared the cost effectiveness of 1-year time-limited treatment with venetoclax and obinutuzumab versus chlorambucil and obinutuzumab based on the CLL14 trial. Other comparators included in the model included continuous treatment with bendamustine plus rituximab (Rituxan) and ibrutinib-based regimens. The cost effectiveness of venetoclax/obinutuzumab, which was measured by subtracting quality-adjusted life years from the total cost of the regimen, appears to be superior to chlorambucil/obinutuzumab and all ibrutinib-based regimens.4

In an interview with OncLive, Davids, director, Center for Lymphocytic Leukemia, physician, Dana-Farber Cancer Institute, and assistant professor of medicine, Harvard Medical School, discussed data that were presented with novel combinations in CLL at the 2019 ASH Annual Meeting and the importance of conducting cost-effective analyses.

OncLive: We saw a lot of exciting data in CLL at the 2019 ASH Annual Meeting. What were some of the highlights?

Davids: One of the highlights has been seeing some of the data with acalabrutinib. Acalabrutinib is a next-generation BTK inhibitor that does seem to be a bit better tolerated than ibrutinib; however, we don't have randomized data to support that yet. We do have long-term data with ibrutinib, which look very good. At the 2019 ASH Annual Meeting, we saw the data from the phase III ELEVATE-TN trial with acalabrutinib. To me, this is one of the more practice-changing studies from the meeting because it led to the approval of acalabrutinib in the frontline setting. The data look very promising in terms of tolerability as well as efficacy.

Our group has developed an investigator-initiated trial combining acalabrutinib with venetoclax and obinutuzumab. My colleague Benjamin Lampson, MD, PhD, of Dana-Farber Cancer Institute and Harvard Medical School, presented the data on the triplet in an oral abstract session [at the 2019 ASH Annual Meeting]. We have recruited 37 patients to this trial and seen very good tolerability with the triplet. The efficacy data are early, but even with only 4 cycles of the 3-drug combination, about half of patients have achieved undetectable MRD in the bone marrow. Certainly, these are promising data compared with other regimens.

We also saw some great data from the CAPTIVATE trial with ibrutinib plus venetoclax. These types of approaches are going to be great, particularly for younger, fitter patients with CLL, as well as those with high-risk disease. We need to remember that older patients may do very well with sequential novel monotherapies; that’s an approach that still needs to be studied.

What data have we seen in the relapsed/refractory setting?

In the relapsed setting, we’re looking at PI3K inhibitors and combinations with venetoclax; that looks like it's going to be a good approach. In an abstract presentation, Paul Barr, MD, of the University of Rochester Medical Center, presented data with the combination of ublituximab, a CD20-directed antibody, with umbralisib, a new PI3K inhibitor, with venetoclax. The data look very good in the relapsed patient population.

Jennifer Crombie, MD, of Dana-Farber Cancer Institute and Harvard Medical School, showed that duvelisib (Copiktra), another PI3K inhibitor, with venetoclax can also be a promising and feasible approach for patients with relapsed/refractory disease. As such, we have expanded our phase I study of duvelisib plus venetoclax into a phase II study, and we are actively accruing to that study.

Could you discuss the importance of conducting cost-effectiveness analyses?

[At the 2019 ASH Annual Meeting], I presented data on the cost effectiveness of venetoclax plus obinutuzumab in comparison with a variety of other regimens that have been developed for the frontline treatment of [patients with] CLL. Specifically, we compared the cost effectiveness of venetoclax plus obinutuzumab given as a 1-year, time-limited regimen to time-limited chemoimmunotherapy regimen—as well as treat-to-progression regimens, such as ibrutinib monotherapy or ibrutinib in combination with CD20-directed antibodies. With a 3-year time horizon, we found that 1 year of time-limited venetoclax plus obinutuzumab was significantly more cost effective than the treat-to-progression regimens. Each year, these novel agent-based therapies have additional costs if we continue to give them. Thus far, the durability of response with venetoclax and obinutuzumab suggests the possibility of a treatment holiday, in which patients can be off treatment, which can lead to cost savings. This is still a fairly preliminary analysis. We need to see what the longer-term follow-up is, as well as the economic analyses. Regardless, this is the type of study we need to be doing to help determine the optimal therapies for our patients.

How could this research impact clinical practice?

The implications of this kind of study are primarily directed at pairs. As physicians, we sit across from individual patients, and it's hard for us to rely on pharmacoeconomic analyses to make decisions. We just have to recommend what we believe is best for our patients. For payers and the governmental organizations in other countries that are helping to dictate these prices, this type of analysis can be very helpful to demonstrate the cost effectiveness of particular regimens. As more robust data sets become available, they will be used by these decision-making bodies to [help make these regimens] available to the physicians who need to prescribe them.


  1. Sharman JP, Banerji V, Fogliatto LM, et al. ELEVATE-TN: phase 3 study of acalabrutinib combined with obinutuzumab (o) or alone vs o plus chlorambucil (clb) in patients (pts) with treatment-naïve chronic lymphocytic leukemia (CLL). Blood. 2019;134(suppl 1):31. doi: 10/1182/blood-2019-128404
  2. Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Blood. 2019;134(suppl 1):35. doi: 10.1182/blood-2019-121424
  3. Lampson BL, Tyekucheva S, Crombie J, et al. Preliminary safety and efficacy results from a phase 2 study of acalabrutinib, venetoclax and obinutuzumab in patients with previously untreated chronic lymphocytic leukemia. Blood. 2019;134(suppl 1):32. doi: 10.1182/blood-2019-127506
  4. Davids MS, Chatterjee A, Ravelo A, et al. Cost-effectiveness of a 12-month fixed duration of venetoclax in combination with obinutuzumab in first-line chronic lymphocytic leukemia in the United States. Blood. 2019;134(suppl 1):4741. doi: 10.1182/blood-2019-123706
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