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 Jain provided 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 ALLIANCE trial (NCT01886872) compared bendamustine plus rituximab versus ibrutinib, 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.2 Similarly, the ECOG-ACRIN E1912 trial (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.3 The iLLUMINATE (NCT02264574) study compared chlorambucil plus obinutuzumab versus ibrutinib plus obinutuzumab in first-line CLL. Once again, the ibrutinib combination therapy was superior leading to a better PFS.4 All 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) versus chlorambucil 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 IGHV mutations. According to the research of Prof. Nitin Jain, patients with mutated IGHV but without the 17p deletion or a TP53 mutation achieve remission and long-term benefits with FCR-based regimens.1 This 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 IGHV but without TP53 aberrations.1 At 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 ALLIANCE study. 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.6 Nevertheless, 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 2019 that 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 Wierda in his interview with 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.
Beyond ibrutinib and venetoclax, Jennifer Woyach presented at SOHO 2019, the next generation small molecules that are being developed for CLL in order to overcome drug-related resistance and toxicities.7 Among those are the covalent BTK inhibitors acalabrutinib and zanubrutinib, both of which are currently in phase I clinical trials. So far, both seem to be associated with a lower risk of developing atrial fibrillation or other cardiac comorbidities that are very prevalent with ibrutinib treatment. Reversible non-covalent BTK inhibitors like ARQ 531 and vecabrutinib are also under investigation. In patients becoming resistant to ibrutinib a mutation on BTK at the BTK binding site develops. These novel inhibitors block BTK at sites distinct from that one so as to overcome ibrutinib-related resistance. So far, preliminary phase I clinical data from ARQ 531 and vecabrutinib were presented at EHA 2019 with encouraging activity and safety profiles.7
Reassessing prognostic factors in CLL
Adrian Wiestner at SOHO 2019 presented how prognostic factors have changed with all these exciting new therapies.8 The three most important prognostic markers in CLL are the Rai stage, the IGHV mutation status, and the FISH cytogenetic markers (del17p, del11q). The CLL-International Prognostic Index (IPI) has been developed based on these prognostic markers and separates patients in four groups with distinct risk probabilities: low, intermediate, high, and very high risk. However, this model was developed at the time when chemoimmunotherapy was the frontline SoC for CLL, so with the new available small molecules for the CLL frontline setting there is now a need to reassess the prognostic factors.8
For distinguishing patients that need to receive first-line treatment, IGHV status and FISH cytogenetics (del13q, del11q) are currently the best prognostic markers.8 Moreover, CD49d also shows potential with CD49d-positive patients progressing more quickly than those negative for CD49d expression. The precise prognostic role of CD49d is still uncertain and in need of further validation in the ibrutinib setting.8
Prognosis following first-line chemoimmunotherapy has so far been possible through IGVH status. However, IGHV has lost its prognostic value following ibrutinib- and venetoclax-based treatments, with no differences in PFS, OS or overall response rates.7 For ibrutinib-based therapies, the number of prior therapies seems to be prognostic of PFS, with patients with >4 prior lines having a very poor outcome. Moreover, in the ibrutinib setting, TP53 aberrations seem to be the main prognostic marker of relapse in both the frontline and R/R settings. Patients with TP53 anomalies have inferior PFS than those without, after receiving ibrutinib as first-line or following relapse. Prof. Adrian Wiestner presented a prognostic PFS model that they have developed for single-agent ibrutinib therapy across CLL patients. The significant variables of the model are treatment history, TP53 aberrations and β2 microglobulin (b2M) levels. Patients with prior therapies, TP53 abnormalities and b2M>4 mg/L have a significantly high risk of early progression following ibrutinib monotherapy.8
Other factors have also been suggested as potential identifiers of patients likely to relapse following ibrutinib. One of those is complex karyotype, whose prognostic value remains unclear. In the long-term analysis of the RESONATE study complex karyotype status was not prognostic of CLL relapse.9 Nevertheless, in another detailed examination, it was shown that del17q was associated with complex karyotype and that was a powerful marker of R/R CLL. Further investigation and verification of the independent prognostic value of complex karyotype are still needed as data remains conflicting.8
This is an exciting time for the frontline setting of CLL. Novel treatments are steering the SoC away from chemoimmunotherapy which has been the gold standard since the 1990s. Along with this change comes the need for the reassessment of prognostic factors, toxicity management and further investigation of the efficacy of these small molecules in the R/R CLL setting.