As reviewed in this issue of The ASCO Post, Burger and colleagues recently reported findings of the RESONATE-2 trial of ibrutinib (Imbruvica) vs chlorambucil (Leukeran) as initial therapy for elderly patients with chronic lymphocytic leukemia (CLL).¹ The study met its primary endpoint of independent review committee–assessed progression-free survival improvement. Moreover, ibrutinib was superior with regard to overall survival, which is particularly striking in light of the crossover option upon confirmed disease progression that was allowed in this trial. Ibrutinib was not only by far superior with regard to efficacy, but it also showed a favorable adverse-event profile in line with previous data.

Among the few points of concern in this study was the small but significant rate of hemorrhage and atrial fibrillation, which have previously been associated with ibrutinib. The genetic-risk profile of the population was favorable, with a high rate of mutated-IGHV status and exclusion of 17p- CLL. Nevertheless, these results provide statistically significant and clinically compelling evidence of superiority of ibrutinib vs chlorambucil in the front-line treatment of elderly patients with CLL and will lead to the availability of this treatment in this population.

From Biology to Therapy

Based on our better understanding of disease biology, numerous novel treatment options have been developed in CLL and other B-cell malignancies and are currently revolutionizing the treatment landscape. Among the most promising options are inhibitors of B-cell signalling and possibly other receptor-signaling pathways. Agents targeting Bruton’s tyrosine kinase, such as ibrutinib and ACP-196 (acalabrutinib), have generated a lot of excitement. In addition, options for targeting a different disease paradigm, namely apoptosis deregulation, with BCL2 inhibitors such as venetoclax (formerly ABT-199) will also be available shortly. Of note, these agents provide not only dramatic efficacy but also outstanding tolerability.

Nevertheless, several issues will become pertinent with the availability of these agents, and the questions arising are of similar magnitude as the advances that have been made:

Outcome of certain disease subgroups (eg, deletion 17p CLL, complex karyotype) appears much better than with traditional treatment but still inferior compared with other subgroups, and therefore challenges in these patients will remain.

Treatment with novel agents fails in few patients, and the outcome of these patients has traditionally been viewed as very poor, whereas it looked much more favorable in the current study by Burger et al in the front-line setting.¹ This poses the question of what the patterns of failure will be like in different disease scenarios.

Richter’s transformation has been a recurring theme of treatment failure in earlier trials enrolling patients with much heavier prior therapy but less so in the front-line setting. Therefore, improved diagnostic procedures and management of Richter’s transformation need to be developed.

Although minimal residual disease assessment has proved to be a strong prognostic marker for outcome with conventional treatment, its value needs to be reestablished in the era of agents that induce persistence of benign disease in the blood and the marrow.

New adverse events that have not been associated with classic chemotherapy (such as bleeding, atrial fibrillation, colitis, pneumonitis, tumor-lysis syndrome) have been identified with the novel agents. Therefore, and despite the outstanding tolerability of these approaches, education is required for awareness of novel side effects.

As a range of novel agents targeting disease biology will continue to become available, the question arises if combination or sequential use of these agents will lead to better long-term outcomes.

The indefinite treatment duration and need for prolonged intake of these drugs may lead to compliance issues despite the low-grade and low-incidence side-effect profiles. This, combined with the high cost of these treatments, brings about the need to develop strategies for finite treatment durations with the novel agents.

Last, despite the easy availability by oral route and unproblematic handling due to the favorable adverse-event profile, the cost of these agents seriously puts into question the availability, sustainability, and equality of access to these agents.

Dramatic Progress and Bright Prospects

Despite these open issues, it is clear that the principle of targeted therapy in CLL results in a paradigm shift in treatment. This was only made possible through an intimate link of research into disease biology and its translation into novel therapeutic approaches. To move beyond the success we have witnessed already and to address the above questions, we need to continuously strive in this direction with well-designed clinical trials and interlinked laboratory research to make further progress.

Changing Standard of Care?

Although the current study by Burger et al has clearly proved superiority of ibrutinib over chlorambucil, the standard of care in these elderly patients had in the meantime changed to antibody (obinutuzumab [Gazyva] or ofatumumab [Arzerra]) combined with chlorambucil. Nevertheless, the results described by Burger et al will make ibrutinib available as a clinically highly useful and scientifically exciting treatment option for these patients. It is clear that this study sets a new standard of care in the front-line treatment of elderly/unfit CLL patients—providing a better therapy option for these ‘worse’ patients.

Moreover, when comparing the current results with ibrutinib in elderly patients against historical data achieved with chemoimmunotherapy such as FCR (fludarabine, cyclophosphamide, rituximab [Rituxan]) in the front-line setting of young and fit CLL patients, it is tempting to speculate that ibrutinib could also be superior to intensive chemoimmunotherapy in this population. Not without reason are multiple trials underway led by major institutions and study groups around the world, comparing classic standards in the front-line treatment of young/fit CLL patients against chemotherapy-free treatment options with the novel agents. Although these trials still need time to play out, current data already suggest that CLL may soon become a disease in which the use of chemotherapy in the front-line setting is a thing of the past. ■

Disclosure: Dr. Stilgenbauer reported no potential conflicts of interest.

Reference

1. Burger JA, Tedeschi A, Barr PM, et al: Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med 373:2425-2437, 2015.