Evolving Role of Chemotherapy in the Management of CLL
Chemotherapy and more specifically chemoimmunotherapy has been standard treatment for patients with CLL. Commonly used regimens are FCR (fludarabine, cyclophosphamide, rituximab), BR (bendamustine, rituximab), and chlorambucil plus obinutuzumab. FCR is commonly used for frontline treatment of younger patients with CLL without significant comorbidities. BR is used for older adults and for patients with renal dysfunction that may preclude use of fludarabine. Chlorambucil-based regimens were commonly used for patients deemed ineligible for intensive regimens such as FCR/BR. These are generally patients >65 years of age or those with significant comorbidities.
Ibrutinib, an oral therapy, targets BTK, and was approved initially for patients with CLL with relapsed CLL in 2014. Later, the approval was expanded for all patients with CLL. Idelalisib, which targets PI3K-delta, is approved for patients with relapsed CLL (in combination with rituximab). Venetoclax, an oral BCL2 inhibitor, is currently approved for patients with relapsed CLL with deletion 17p.
Since the introduction of these agents, the role of chemotherapy has declined. In the frontline setting, for older adults (patients >65 years of age), ibrutinib was shown to be superior to chlorambucil monotherapy in the RESONATE-2 trial. Though the comparator in RESONATE-2 was chlorambucil monotherapy, and not chlorambucil + obinutuzumab (approved standard for this patient population), the PFS curve with ibrutinib monotherapy are far superior to chlorambucil-based strategies. Therefore, in my opinion, there is no role for chlorambucil in treatment for patients with CLL.
For frontline treatment of younger patients with CLL, though ibrutinib is currently approved for treatment, there is limited data with the use of targeted agents. Hence, until the results of the randomized trials are available (ECOG trial: FCR vs. Ibrutinib + rituximab trial is fully accrued and awaiting results), chemoimmunotherapy remains the standard. This is especially valid for patients with mutated IGHV who derive the most long-term benefit from chemoimmunotherapy. For young patients with mutated IGHV, we prefer to continue to use chemoimmunotherapy such as FCR. For young patients with unmutated IGHV, given poor long-term outcomes with chemoimmunotherapy, we prefer to use targeted agents in clinical trials. For patients with deletion 17p (I would also include patients with TP53 mutation in this group), irrespective of the age group, treatment with ibrutinib should be standard of care.
Chemoimmunotherapy has very limited activity for patients with deletion 17p or TP53 mutation.
In relapsed CLL—the role of chemotherapy has declined significantly. The PFS curves with novel agents such as ibrutinib, idelalisib, and venetoclax appear superior to PFS with chemoimmunotherapy regimens. The MURANO trial, which compared BR with venetoclax + rituximab in relapsed CLL showed superiority of venetoclax + rituximab arm. This trial clearly establishes superiority of novel agent combination over chemoimmunotherapy (BR is a commonly used regimen in relapsed CLL).
There are several ongoing trials comparing novel agents with a chemoimmunotherapy backbone. The results of these trials when reported should provide further guidance on the appropriate regimen for frontline treatment of patients with CLL.
---- Nitin Jain, MD
Nitin Jain, MD, is Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.