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Is ibrutinib-based therapy the preferred initial treatment for all patients with CLL?
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Yes. Ibrutinib-based regimens should be the standard of care for all patients with CLL who require initial therapy.
CLL is the most common leukemia among adults. Standard treatment is combination chemoimmunotherapy with regimens such as chlorambucil plus obinutuzumab; bendamustine plus rituximab; or fludarabine and cyclophosphamide plus rituximab.
However, the treatment landscape is rapidly changing due to oral targeted agents, including ibrutinib and venetoclax.
The initial trial of ibrutinib for patients with CLL involved 101 previously treated patients and 31 treatment-naive patients. The treatment-naive patients have received ibrutinib continuously for the longest period, with an estimated 7-year PFS of 80%.
The RESONATE-2 trial was the first randomized trial involving ibrutinib therapy for treatment-naive patients. The trial compared ibrutinib with chlorambucil for patients aged 65 years or older, and results showed an 86% reduction in death or progressive disease compared with chlorambucil. Despite this impressive benefit, clinicians questioned whether ibrutinib was superior to standard chemoimmunotherapy.
Last year’s ASH Annual Meeting and Exposition provided a definitive answer.
The results of two randomized phase 3 trials sponsored by NCI and conducted by the North American Cooperative Groups demonstrated compelling evidence that ibrutinib-based therapy is superior to standard chemoimmunotherapy regimens.
The ECOG-ACRIN trial for patients aged 69 years or older showed not only superior PFS, but also longer OS with ibrutinib plus rituximab than with standard therapy. Importantly, the OS advantage was due to significantly more patients dying of CLL after receiving standard therapy, not from toxicity of the regimen.
The Alliance A041202 trial — which included patients aged 65 years and older — showed superior PFS but not OS with ibrutinib or ibrutinib plus rituximab than with bendamustine plus rituximab. In addition, the randomized phase 3 iLLUMINATE trial demonstrated superior efficacy with ibrutinib plus obinutuzumab compared with chlorambucil plus obinutuzumab. In all these trials, the benefit of ibrutinib was independent of clinical or genetic features.
Finally, results of the CLL14 trial demonstrated improved PFS with venetoclax plus obinutuzumab compared with chlorambucil plus obinutuzumab. Detailed results of this trial have not yet been presented.
Taken together, these trials will fundamentally change the treatment landscape for treatment-naive patients.
As clinicians, our obligation is to provide our patients with our best advice when considering initial therapy. This includes taking into consideration the extent of their disease, comorbidities and, importantly, goals of therapy for an individual patient. Ibrutinib should be a part of the conversation for all patients and will likely be the preferred therapy for most patients.
What of the future? Clearly, this will involve combination therapy with the goal of improving depth of response so that therapy eventually can be discontinued. We already have a glimpse into the future. Ibrutinib plus venetoclax, venetoclax plus obinutuzumab, and the combination of all three drugs have demonstrated not only nearly 100% response rates but also an impressive depth of response as measured by sensitive flow cytometry assays that are able to measure as few as one CLL cell in 10,000 leukocytes.
The death knell of chemotherapy for CLL has tolled. Ibrutinib now reigns as the initial treatment of choice.
But already, challengers in the guise of combination, time-limited therapy involving ibrutinib, venetoclax and perhaps others are knocking at the gate, with the potential to overthrow the newly crowned monarch, for the benefit of all our patients with CLL.
References:
The following were presented at ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego:
Byrd JC, et al. Abstract 3133.
Shanafelt T, et al. Abstract LBA-4.
Woyach JA, et al. Abstract 6.
Steven Edward Coutre, MD, is professor of medicine/hematology at Stanford University Medical Center. He can be reached at coutre@stanford.edu. Disclosure: Coutre reports no relevant financial disclosures.
No. There are many reasons why ibrutinib may not be the preferred initial treatment for a given patient.
Last year’s ASH Annual Meeting and Exposition featured presentations of results from three randomized trials that compared continuous ibrutinib-based therapy with standard chemoimmunotherapy. Two trials included older patients and one included a younger patient population. With relatively short 2- to 3-year follow-up, all three studies showed highly significant benefits in PFS with continuous ibrutinib-based therapy compared with 6 months of chemoimmunotherapy.
As expected, with short follow-up, the outcomes were driven by events among patients with high-risk IGHV-unmutated disease, in whom all of the benefit was accrued. None of the studies showed a statistically significant difference in PFS among patients with low-risk IGHV-mutated disease.
Although these results establish ibrutinib as a standard-of-care option for all patients with CLL, there remain many reasons why ibrutinib may not be preferred.
The young and fit patients with IGHV-mutated disease who do not have deletion 17p have the most to lose with continuous ibrutinib therapy, as three studies suggest the majority of these patients can achieve more than 10-year PFS and treatment-free survival with fludarabine, cyclophosphamide and rituximab. This is reasonably and normally called cure. At present, we have no long-term data in this population with ibrutinib. Even if ibrutinib were able to control the disease for a similar duration, it would be control and not cure. This would require continuous therapy that may not be tolerable given its associated toxicities and costs.
Long-term follow-up of the first 31 previously untreated patients who received ibrutinib has shown substantial ibrutinib discontinuation — now 45% at 67-month median follow-up. The toxicity of ibrutinib was quite clear, even with shorter follow-up in the two trials presented at ASH that included older patient populations. Nonhematologic grade 3 or worse toxicity was higher with ibrutinib than chemoimmunotherapy, including increased rates of atrial fibrillation and hypertension, similar rates of infection, and higher frequency of mortality during the treatment period — the latter at 1% with bendamustine plus rituximab vs. 7% in the ibrutinib-containing arms of the Alliance trial. Given all of this, for an older patient with low-risk disease who could have prolonged remission with 6 months of well-tolerated chemoimmunotherapy, it would be quite reasonable to wish to avoid these cumulative toxicities of ibrutinib, as well as the often-high out-of-pocket costs of the drug.
Venetoclax-based regimens hold great promise as frontline therapy. The CLL14 trial — designed to compare 1 year of frontline venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab — has been reported to be positive, and the full data are eagerly awaited. This likely upcoming approval will provide a time-limited regimen that achieves deep remissions and is typically better tolerated during therapy than ibrutinib.
As our understanding of CLL biology has increased, our ability to understand the often-marked heterogeneity of disease course and treatment response has correspondingly increased, yet this has not always been incorporated into prospective risk stratification for drug development. This is unfortunate, as patients can only benefit from therapeutic decisions targeted specifically to their disease type and situation.
As noted above, our low-risk patients in particular have many effective options that can be selected based on their goals, comorbidities and costs, without limitations imposed by data driven by outcomes among high-risk patients.
References:
Moreno C, et al. Lancet Oncol. 2018;doi:10.1016/S1470-2045(18)30788-5.
Rossi D, et al. Blood. 2015;doi:10.1182/blood-2015-05-647925.
Thompson PA, et al. Blood. 2016;doi:10.1182/blood-2015-09-667675.
Woyach JA, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1812836.
The following were presented at ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego:
Byrd JC, et al. Abstract 646.
Shanafelt T, et al. Abstract LBA-4.
Woyach JA, et al. Abstract 6.
Jennifer R. Brown, MD, PhD, is director of the CLL Center in the division of hematologic malignancies at Dana-Farber Cancer Institute and associate professor of medicine at Harvard Medical School. She can be reached at jennifer_brown@dfci.harvard.edu. Disclosure: Brown reports no relevant financial disclosures.