Presentation by Dr Tara Graff, Mission Cancer + Blood
At the Total Health 2023 Best of Hematology Conference held in Vail, Colorado, Dr Tara Graff from Mission Cancer + Blood provided updates in chronic lymphocytic leukemia (CLL) from the past year’s American Society for Hematology (ASH) meeting.
General Concepts in CLL Treatment
Dr Graff began with a general overview of CLL treatment, noting that just a diagnosis of CLL does not necessarily imply a need for treatment, nor does a relapse of CLL necessarily require treatment. In addition, since the median age of patients with CLL is about 70 years, comorbid conditions are often present, so toxicities and tolerability of treatments is important to consider. The disease process in CLL also varies widely between individuals, so a molecular analysis of each patient’s tumor cells (i.e., “cytogenetic analysis”) is essential to perform at diagnosis. In this regard, Dr Graff notes that in the US, only about 30% of patients are receiving such testing at diagnosis, and this really constitutes suboptimal care. Some of the most important molecular alterations that can impact treatment and outcomes are del(17p), TP53 mutation, and what is known as “complex karyotype”, all of which are high-risk factors. Patients with non-mutated immunoglobulin heavy chain (IGHV), del(17p) and del(11q) alterations also tend to have a shorter progression-free survival (PFS). Dr Graff also noted, with the exception of IGHV, it is important to re-check the patient’s cytogenetics again, for example, after a relapse, as most of the molecular alterations such as del(17p) and TP53 can change over time, and this has treatment implications.
Dr Graff noted that the goal of treatment for a defined period of time (i.e., “finite-duration” therapy) is for patients to have a “deep response”, which means a longer time period in remission. Another important treatment parameter is whether the patient achieves undetectable levels of residual cancer cells in the body, which is termed ‘undetectable minimal residual disease’, or ‘uMRD’. If patients develop progression while on a targeted therapy, this is known as treatment resistance, although retreatment with the same agent can be an option for some patients, or another finite-duration therapy can be used. The duration of remission is another important parameter, as this has treatment implications. Also important to note is that treatment for CLL, even for high-risk patients, is only indicated if constitutional symptoms are present, which can include fevers, chills, night sweats, and severe fatigue that can adversely impact patient quality of life. Other indications for treatment include a severely enlarged spleen or lymph nodes, autoimmune complications such as anemia, and bone marrow failure.
For patients meeting the criteria for CLL treatment, Dr Graff notes that participation in clinical trials is always encouraged, however, first line (1L) therapy is generally based on the patient’s TP53 status. If TP53 is disrupted, treatment with a Bruton’s tyrosine kinase inhibitor (BTKi) is indicated, of which there are several available, in combination with an antibody therapy directed against the CD20 molecule, called Obinutuzumab. If TP53 is not disrupted, based on the patient’s IGHV status (i.e., mutated or un-mutated), patients generally receive treatment with a combination of a BTKi, Obinutuzumab, or another BCL2 inhibitor (BCL2i) agent, venetoclax, and treatment depends on their overall health status (i.e., ‘fit’ or ‘unfit’). Dr Graff emphasized that a range of treatment options are available (which is good for the patient), and patients will generally do well on any of these combinations. For patients with relapsed CLL, Dr Graff likens the treatment approach to “changing dance partners”, meaning that, depending on which therapy was used previously, and the tolerability of each treatment for the individual patient, different combinations of treatment can be used, and as noted above, re-treatment with the same agent is possible. She also noted that a new class of ‘non-covalent’ BTKi drug (pirtobrutinib) is also available, as well as cellular therapies which have helped to greatly expand the treatment choices for recurrent CLL patients.
Clinical Trial Updates from ASH
In the second portion of her presentation, Dr Graff outlined some of the key developments from this past year’s ASH meeting, which included a summary of results from 5 key clinical trials for different treatments in the CLL space.
CAPTIVATE was a randomized phase II study assessing the efficacy and safety of a first line (1L), fixed-duration, all-oral, combination treatment with a BTKi (ibrutinib) + a BCL2i (venetoclax) in patients, 70 years or younger, with good performance status (PS) with CLL or small lymphocytic lymphoma (SLL). In earlier studies, these agents were shown to have synergistic activity and non-overlapping toxicities. Dr Graff noted the primary results from the 3-year update of the trial, which showed an overall response rate (ORR) of approximately 97% regardless of patient’s mutational status. PFS was also above 80%, with favorable overall survival (OS) regardless of patient’s mutational status. For those patients who achieved a confirmed uMRD, a second portion of the trial assessed the impact of continued treatment with patients randomized to either ibrutinib or placebo. Although overall the number of patients was small (n=43 each group), Dr Graff noted a slightly higher percentage of high-risk patients in the demographics of the ibrutinib arm.
In the updated follow up of the uMRD cohort (n=86), results for the primary endpoint showed a 3-year disease-free survival (DFS) rate (starting at the beginning of treatment with ibrutinib or placebo) of 93% versus 85%, respectively, and the difference was not statistically significant (difference, 8.3%; P=0.1621). At 48 months, the secondary endpoints of PFS (95% vs. 88%) and overall survival (OS, 98% vs. 100%) were also similar between the treatment groups. The PFS rates in patients with unmutated IGHV were similar to overall population, and 3-year DFS, 4-year PFS and OS rates in patients with high-risk features like del(17p), TP53, or complex karyotype were also similar to the overall population.
Complete response (CR) rates, a secondary endpoint, continued to improve in both the placebo (12% improvement) and in the ibrutinib arms (14% improvement). Efficacy outcomes were largely similar across the subgroups of patients with del(17p), TP53 mutations, and in those with complex karyotype. The percentage of patients with negative MRD status was also sustained at 3-years post-randomization and was similar in patients randomized to continued ibrutinib or placebo. PFS rates also remained high and were durable in both arms. At 48 months, PFS was 95% with continued ibrutinib versus 88% with placebo. PFS rates among patients with unmutated IGHV were also similar to those of the total population. OS rates also continued to be high across the study arms. Dr Graff noted that overall, results from CAPTIVATE show that even for patients randomized to continue placebo versus ibrutinib, outcomes for patients on fixed duration treatment are excellent.
The GLOW trial compared a fixed duration of the BTKi ibrutinib + the BCL2i venetoclax (I/V) with chlorambucil + Obinutuzumab (C/O) as a first line (1L) treatment for CLL. Importantly, this trial was conducted in the clinically relevant population of older, and/or less fit CLL patients (>65 years, or <65 years with comorbid conditions). Results of the trial after 4 years of follow up showed that I/V reduced the risk for disease progression or death by 79% as compared to C/O (74.6% vs. 24.8% respectively), and this represents the first fixed-duration treatment with an OS advantage as compared to C/O as 1L treatment. Patients also achieved uMRD early, and over time this percentage declined by approximately 10% per year. At two years post-treatment, nearly 40% of patients had uMRD. PFS was also better sustained with I/V versus C/O, regardless of their MRD status at end of therapy plus 3 months.
Dr Graff noted, in this previously treated older/comorbid population, an estimated 75% were alive and free of progression at 3.5 years using an orally administered, once daily, fixed-duration treatment, as compared with an estimated 25% of C/O treated patients. PFS at 3.5 years was also higher for patients with I/V versus C/O regardless of IGHV status (mutated/unmutated) and PFS was better sustained with I/V versus C/O regardless of the patients MRD status (≥10-4) as assessed 3 months after the end of treatment. In this regard, at 2 years following end of treatment, the estimated PFS was ≥ 90 percent for patients with mutant IGHV, (independent of their MRD status), and for those patients with unmutated IGHV who reached uMRD status.
Dr Graff reviewed results from late-breaking ASH abstract with final results from the ALPINE phase III study, which examined the use of BTKi zanubrutinib versus ibrutinib in patients with relapsed/refractory CLL/SLL requiring treatment, with measurable disease by imaging and without prior BTKi treatment. The results showed an improved ORR of 86.2% with zanubrutinib versus 75.7% with ibrutinib. There was also improved PFS with zanubrutinib over ibrutinib in the overall population, as well as major subgroups, including those with del(17p)/TP53 mutation.
Dr Graff noted that the tolerability of zanubrutinib was improved over that of ibrutinib, with a lower rate of Grade 3 or higher adverse events (AEs) and AEs leading to discontinuation/dose reduction. She also emphasized that cardiotoxicity is important to consider when treating patients with BTKi, and in this regard, cardiotoxic events with zanubrutinib were also improved over ibrutinib with fewer serious cardiac AEs (1.9% vs. 7.7%), and cardiac AEs leading to discontinuation or death (0.3% vs. 4.3%). Notably, this was the first head-to-head comparison among the BTKi to demonstrate superiority in patients with relapsed/refractory CLL/SLL and both PFS and ORR were improved with zanubrutinib as compared to ibrutinib.
Dr Graff then reviewed results from an updated analysis of the phase 1/2 BRUIN trial, examining the efficacy of pirtobrutinib, a newer, ‘non-covalent’ type BTKi, in CLL/SLL patients who were previously treated with a ‘covalent type’ BTKi. She noted that patients who have previously been treated with a covalent type BTKi have limited treatment options and in most cases have also been treated with a BCL2i treatment like ventetoclax, so this represents a significant unmet clinical need. Updated results from the BRUIN trial continued to show a clinically meaningful treatment benefit, and responses were durable, with over 2 years of additional follow up. The ORR for patients with prior BTKi treatment was 82.2%, and for patients with prior BTKi and BCL2i treatment was 79.0%. Efficacy was observed despite multiple prior lines of therapy, and regardless of mutations such as BTK C481, TP53 and/or del(17p) status. Response rates were also consistently high across all relevant patient subgroups. Dr Graff noted there were low-rates of Grade ≥3 AEs and discontinuations due to drug-related AEs, and as such, pirtobrutinib continues to be well-tolerated. She also noted an additional four randomized phase III trials evaluating pirtobrutinib in CLL/SLL, which are ongoing.
Lastly, Dr Graff reviewed findings from the phase II AVO study in untreated CLL enriched for high-risk, TP53-mutated patients, who were treated with a combination of acalabrutinib, venetoclax, and Obinutuzumab (AVO). Patients received treatment with the triple regimen first, and thereafter received treatment depending on their MRD status. Patients who were MRD positive received an additional course of acalabrutinib + venetoclax. Results of the trial showed that, by cycle 16, 83% of TP53 mutated patients had uMRD, and 93% of patients overall were free of disease progression after a median of 35 months of follow up. Dr Graff noted that the AVO triple combination therapy was well tolerated in the trial, and there was a low incidence of cardiac or infectious complications. Overall, the findings support the use of this fixed-duration combination treatment for CLL patients, particularly those with high-risk disease, using an MRD-guided approach. The combination therapy is also being evaluated in an ongoing, phase III clinical trial, the ACE-CL-311/AMPLIFY trial (Clinicaltrials.gov number: NCT03836261).
· Median age of CLL patients is about 70 years, and as such, comorbid conditions and tolerability of treatments are an important consideration.
o Cytogenetic analysis for CLL patients is essential at diagnosis, as molecular alterations can impact both treatment and outcomes.
o Treatment for CLL, even for high-risk patients, is only indicated if constitutional symptoms are present.
· Bruton’s tyrosine kinase inhibitors (BTKi), anti-CD20 inhibitors (Obinutuzumab), and BCL2 inhibitors (BCL2i) such venetoclax, are approved therapies in CLL, based on the patient’s mutational status.
· Results from at least 5 clinical trials in CLL were reported at this past year’s ASH meeting, including CAPTIVATE, GLOW, ALPINE, BRUIN, and AVO.
o Findings from these trials have shown efficacy and tolerability of combination BTKi (ibrutinib) and BCL2i (venetoclax) regimens, a new class of non-covalent BTKi agents (pirtobrutinib), and triple combination therapies, in CLL patients.
· The increasing number of effective therapies for CLL, even for patients with high risk and/or relapsed disease, is providing patients with a wider range of treatment options.
You can view Dr Graff's full presentation from 2023 Best of Hematology Conference here: