Future directions
| Management of asymptomatic patients with high/very high-risk CLL/SLL |
| The S1925 trial is evaluating early fixed-duration Ven-O in asymptomatic patients with high/very high-risk CLL/SLL based on the CLL-IPI but who do not meet iwCLL criteria to initiate treatment, compared with initiation of Ven-O when traditional iwCLL criteria are met (ClinicalTrials.gov identifier: NCT04269902). If early therapy results in an improvement in the primary end point of OS among high-risk patients, this would affect recommendations.21 |
| Optimal sequencing of first- and second-line therapies in CLL/SLL |
| Prospective data directly comparing current recommended frontline treatment options are unavailable to determine a single standard initial treatment for patients with CLL/SLL. We await results from the ongoing CLL17 trial, in which previously untreated patients requiring therapy are randomized to receive ibrutinib (continuous), Ven-O (12 mo), or Ven-ibrutinib (15 mo) (ClinicalTrials.gov identifier: NCT03406156).40 If an OS difference is observed, or if PFS favors a time-limited regimen, this would inform treatment sequencing, for example, whether it is best to lead with a cBTKi or Ven-O. In contrast, if a PFS difference alone favors continuous administration of ibrutinib over either time-limited regimen, this would be difficult to interpret. |
| Potential future impact of cBTKi/BCL2i combinations in CLL/SLL |
| Fixed-duration ibrutinib-Ven is available in Europe and the United Kingdom based on the GLOW trial41 but ibrutinib-Ven is not approved in the United States. We await results from registrational phase 3 trials of (A) acalabrutinib-Ven w/wo obinutuzumab vs chemoimmunotherapy (ClinicalTrials.gov identifier: NCT03836261), and (B) zanubrutinib-sonrotoclax vs Ven-O in treatment-naïve CLL/SLL (ClinicalTrials.gov identifier: NCT06073821), as well as the phase 3 trial of acalabrutinib-Ven vs Ven-O (ClinicalTrials.gov identifier: NCT05057494). If acalabrutinib-Ven or zanubrutinib-sonrotoclax are approved for US patients with CLL/SLL, this would raise new questions regarding optimal second-line treatment after a fixed-duration, frontline cBTKi/BCL2i regimen. |
| Novel therapies in CLL/SLL |
| Novel investigational therapeutic agents currently under development for patients with CLL/SLL include, among others, next-generation covalent and noncovalent BTKis and BCL2 inhibitors, as well as BTK degraders and CD20×CD3 bispecific antibodies (ClinicalTrials.gov). Additionally, although the current available data do not support use of a triplet regimen in CLL/SLL (ie, Ven-O combined with ibrutinib, acalabrutinib, or zanubrutinib), we await results from long-term follow-up of the CLL13 trial (Ven-O vs IV vs Ven-O combined with ibrutinib).38 |
| MRD-guided therapy |
| Measurement of MRD provides prognostic information in patients with CLL/SLL receiving Ven-based therapy or liso-cel. However, to the best of our knowledge, there is no evidence that MRD-based treatment results in improved clinical outcomes. Many therapeutic trials in CLL/SLL incorporate MRD-based treatment decisions. Although these data might inform use of MRD in the routine care of patients with CLL/SLL, we are not aware of any studies designed to establish whether a patient’s clinical outcome is better because MRD was used to guide their care. Future trial designs could incorporate randomization to an MRD-based treatment decision vs standard of care. |
| Role of resistance mutation testing in routine clinical care |
| We await additional follow-up of patients receiving covalent and noncovalent BTKis with subsequent progression. These data might reveal differences in the pattern of resistance mutations with different BTKis, and correlation between specific resistance mutations and clinical outcomes on present and subsequent therapies might ultimately inform subsequent treatment selection and sequencing. |
| Management of asymptomatic patients with high/very high-risk CLL/SLL |
| The S1925 trial is evaluating early fixed-duration Ven-O in asymptomatic patients with high/very high-risk CLL/SLL based on the CLL-IPI but who do not meet iwCLL criteria to initiate treatment, compared with initiation of Ven-O when traditional iwCLL criteria are met (ClinicalTrials.gov identifier: NCT04269902). If early therapy results in an improvement in the primary end point of OS among high-risk patients, this would affect recommendations.21 |
| Optimal sequencing of first- and second-line therapies in CLL/SLL |
| Prospective data directly comparing current recommended frontline treatment options are unavailable to determine a single standard initial treatment for patients with CLL/SLL. We await results from the ongoing CLL17 trial, in which previously untreated patients requiring therapy are randomized to receive ibrutinib (continuous), Ven-O (12 mo), or Ven-ibrutinib (15 mo) (ClinicalTrials.gov identifier: NCT03406156).40 If an OS difference is observed, or if PFS favors a time-limited regimen, this would inform treatment sequencing, for example, whether it is best to lead with a cBTKi or Ven-O. In contrast, if a PFS difference alone favors continuous administration of ibrutinib over either time-limited regimen, this would be difficult to interpret. |
| Potential future impact of cBTKi/BCL2i combinations in CLL/SLL |
| Fixed-duration ibrutinib-Ven is available in Europe and the United Kingdom based on the GLOW trial41 but ibrutinib-Ven is not approved in the United States. We await results from registrational phase 3 trials of (A) acalabrutinib-Ven w/wo obinutuzumab vs chemoimmunotherapy (ClinicalTrials.gov identifier: NCT03836261), and (B) zanubrutinib-sonrotoclax vs Ven-O in treatment-naïve CLL/SLL (ClinicalTrials.gov identifier: NCT06073821), as well as the phase 3 trial of acalabrutinib-Ven vs Ven-O (ClinicalTrials.gov identifier: NCT05057494). If acalabrutinib-Ven or zanubrutinib-sonrotoclax are approved for US patients with CLL/SLL, this would raise new questions regarding optimal second-line treatment after a fixed-duration, frontline cBTKi/BCL2i regimen. |
| Novel therapies in CLL/SLL |
| Novel investigational therapeutic agents currently under development for patients with CLL/SLL include, among others, next-generation covalent and noncovalent BTKis and BCL2 inhibitors, as well as BTK degraders and CD20×CD3 bispecific antibodies (ClinicalTrials.gov). Additionally, although the current available data do not support use of a triplet regimen in CLL/SLL (ie, Ven-O combined with ibrutinib, acalabrutinib, or zanubrutinib), we await results from long-term follow-up of the CLL13 trial (Ven-O vs IV vs Ven-O combined with ibrutinib).38 |
| MRD-guided therapy |
| Measurement of MRD provides prognostic information in patients with CLL/SLL receiving Ven-based therapy or liso-cel. However, to the best of our knowledge, there is no evidence that MRD-based treatment results in improved clinical outcomes. Many therapeutic trials in CLL/SLL incorporate MRD-based treatment decisions. Although these data might inform use of MRD in the routine care of patients with CLL/SLL, we are not aware of any studies designed to establish whether a patient’s clinical outcome is better because MRD was used to guide their care. Future trial designs could incorporate randomization to an MRD-based treatment decision vs standard of care. |
| Role of resistance mutation testing in routine clinical care |
| We await additional follow-up of patients receiving covalent and noncovalent BTKis with subsequent progression. These data might reveal differences in the pattern of resistance mutations with different BTKis, and correlation between specific resistance mutations and clinical outcomes on present and subsequent therapies might ultimately inform subsequent treatment selection and sequencing. |
CLL-IPI, CLL-International Prognostic Index.