Over the past 5 years, the most exciting therapeutic advance in chronic lymphocytic leukemia (CLL) has been the development and subsequent widespread adoption of targeted therapies. A brief glance at the CLL trials accruing on ClinicalTrials.gov will show that targeted therapies, with or without the addition of chemotherapy, are of great interest. Here I will propose that chemotherapy can be eliminated altogether in the management of CLL.
It is a fairly easy argument that chemotherapy does not have a role in the management of relapsed CLL. The 5-year follow-up data from the phase Ib/II PCYC-1102 study of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib as a single agent show a median progression-free survival (PFS) of 52 months, which is clearly better than any chemotherapy-only regimen that has been studied. For patients with only one or two previous lines of therapy, PFS was further improved to 63 months; for those without a complex karyotype, the median PFS has yet to be reached. While data for the combination of ibrutinib plus chemotherapy have also been impressive, no data exist to demonstrate that chemotherapy adds to the durable remissions seen with ibrutinib.
Other single-agent BTK inhibitors have also shown impressive efficacy, although follow-up is shorter.[3-5] Data are less mature for the BCL2 inhibitor venetoclax, but in a phase I study, the 15-month PFS rate was 69% for those on the 400-mg dose, again demonstrating a significant advantage over historical data with chemotherapy. Currently, the National Comprehensive Cancer Network (NCCN) guidelines list ibrutinib, idelalisib plus rituximab, and venetoclax as the preferred agents for relapsed/refractory CLL. While there may still be situations in which chemotherapy could be considered, such as resource-constrained settings, if targeted agents are available, chemotherapy does not have a place in the management of relapsed CLL.
In the frontline setting, the role of chemotherapy is more complicated, and best discussed separately for older and younger patients. For the older patient population, while bendamustine plus rituximab and chlorambucil plus obinutuzumab are effective, ibrutinib appears to have superior efficacy when looking across trials. In the PCYC-1102 study noted previously, the cohort of 31 treatment-naive patients had a 5-year PFS rate of 92%. The phase III RESONATE-2 study has similarly impressive data, with a PFS rate of 89% at 29 months. These data compare extremely favorably with the data that have been published for frontline studies of chemoimmunotherapy in CLL. While it can be argued that ibrutinib has not yet been compared with a standard frontline therapy in CLL, the phase III Alliance A041202 study (NCT01886872) is comparing ibrutinib alone vs ibrutinib in combination with rituximab vs bendamustine plus rituximab in patients 65 years and older. Once completed, this trial will establish whether ibrutinib is superior to the most effective chemoimmunotherapy regimen for older patients.
For younger patients, the question of whether chemotherapy can be eliminated entirely is less straightforward, and may somewhat depend on genetic risk. It is possible that of the group of patients who are IGHV mutated with good-risk cytogenetics, some would benefit from chemoimmunotherapy over a targeted therapy in terms of inducing a cure. However, those patients are also very likely to do well on ibrutinib as frontline therapy, without the associated risk of a therapy-related myeloid neoplasm. For young patients with IGHV-unmutated disease or poor-risk cytogenetics, cross-trial comparisons seem to favor ibrutinib, even when compared against the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. In the CLL8 study, patients with IGHV-unmutated disease had a 3-year PFS rate of 55% after FCR. In RESONATE-2, the 18-month PFS rate for this group of patients was 89%; this rate was the same as that for mutated patients. Assuming that this lack of disease progression persists, these patients likely would have a longer PFS with ibrutinib than FCR. However, just like for elderly patients, a completed and maturing phase III study—ECOG-E1912 (NCT02048813)—will definitively determine which combination is more effective in younger CLL patients.
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