Updates on CLL and the SoC evolution in the frontline setting
Exciting data for the frontline treatment of CLL have been published in the last year, shifting the SoC from chemoimmunotherapy-based regimens towards small-molecule agents.
Until recently, fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy was the frontline SoC for young, fit patients with CLL. Now, the superiority of small molecule therapies like ibrutinib and venetoclax in the frontline CLL setting has been validated predominantly in three phase III randomized clinical trials: ECOG, ALLIANCE and iLLUMINATE. Prof. Nitin Jainprovided a summary of these trials which compared ibrutinib to standard chemoimmunotherapy and discussed the evolution of the frontline treatment of CLL at SOHO 2019. 1
The ALLIANCEtrial ( NCT01886872) compared bendamustine plus rituximab versusibrutinib, or ibrutinib plus rituximab in older patients (³65 years old) with untreated CLL. The study demonstrated that in this patient population ibrutinib-based therapy resulted in significantly higher progression-free survival (PFS) than bendamustine with rituximab. 2Similarly, the ECOG-ACRIN E1912trial ( NCT02048813) compared FCR to ibrutinib plus rituximab in younger patients (<70 years old) with previously untreated CLL. The trial demonstrated that ibrutinib plus rituximab led to superior PFS and overall survival (OS) in younger patients when compared to FCR. 3The iLLUMINATE(NCT02264574) study compared chlorambucil plus obinutuzumab versusibrutinib plus obinutuzumab in first-line CLL. Once again, the ibrutinib combination therapy was superior leading to a better PFS. 4All three studies showed that ibrutinib should be the SoC for the majority of the frontline patients with CLL, changing completely the treatment dogma in the field.
More recently, the randomized, phase III CLL14 study( NCT02242942) compared venetoclax plus obinutuzumab (VenG) versuschlorambucil plus obinutuzumab in previously untreated older patients with CLL and comorbidities. VenG was associated with a superior PFS compared with chlorambucil plus obinutuzumab, which led to its approval by the FDA as a time-limited strategy for fixed duration (one year) treatment of patients with CLL in the frontline setting. 5
Currently, the two approved regimens for patients with CLL in the first-line setting are: i) ibrutinib monotherapy and ii) VenG for a one-year duration. This is an exciting time as the field is moving away from chemoimmunotherapy regimens. Nevertheless, there are still certain patient populations that can benefit from FCR-based chemoimmunotherapy. Among those, are young patients with IGHVmutations. According to the research of Prof. Nitin Jain, patients with mutated IGHVbut without the 17p deletion or a TP53mutation achieve remission and long-term benefits with FCR-based regimens. 1This was shown in a phase II trial that evaluated the efficacy of ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab (iFCG) in naïve patients with CLL with mutated IGHVbut without TP53aberrations. 1At 12 months following iFCG treatment, 73% of patients achieved complete response (CR) or CR with incomplete hematological recovery (CRi) and 100% were measurable residual disease (MRD) negative. So far, these findings are also consistent with the ECOG-ACRIN E1912 study that reported similar outcomes with ibrutinib- and FCR-based treatments in patients with mutated IGHV. Therefore, for this subgroup of patients chemoimmunotherapy is still the most appropriate regimen. For the rest of the patients in the first-line setting, targeted small molecule regimens (ibrutinib, VenG) have become the desired strategies. 1
The role of CD20 antibodies in the treatment of CLL is still unclear and currently under investigation. In the front-line setting, evidence on the role of rituximab, a CD20 antibody, was provided by the ALLIANCEstudy. Two of the three randomized arms of the study consisted of ibrutinib monotherapy or ibrutinib + rituximab. PFS was the same between these two arms indicating that rituximab addition does not confer an extra benefit in older patients with CLL. Similarly, in the relapsed/refractory (R/R) and high-risk setting rituximab addition to ibrutinib did not lead to improved PFS. 6Nevertheless, it is still unknown whether obinutuzumab (another anti-CD20 antibody) might actually provide a clinical benefit in patients with either R/R or untreated CLL. More data are expected by the end of the year during ASH 2019that will shed more light into the role of CD20 antibodies in first-line CLL. At the moment they are not recommended in addition to ibrutinib for naïve patients with CLL.
There are still many unanswered questions with ibrutinib monotherapy. These were highlighted by William Wierdain his interviewwith the Lymphoma Hub at SOHO 2019. The frontline treatment strategy at the moment is for patients to continue ibrutinib combination therapy for a couple of years until they achieve MRD-negativity and then to stop therapy and go into observation. However, it remains unclear for how long these patients need to be treated and what happens to the ones that relapse following ibrutinib therapy or venetoclax-based therapy. Is it possible to re-treat them with small molecule agents and for how long? Also, how can patients that develop Richter’s transformation or secondary cancers after first-line treatments be managed? These are only a few of the current unknowns with small molecule therapies that need to be further investigated in the future.