Jennifer Brown, MD, PhD

Insights From the ASH 2018 Annual Meeting: Chronic Lymphocytic Leukemia

Question

What are the most important takeaways from the American Society of Hematology (ASH) 2018 Annual Meeting for clinicians who treat patients with chronic lymphocytic leukemia (CLL)?

Answer

The results of 3 randomized trials comparing ibrutinib-based therapy to chemoimmunotherapy (CIT) were presented. Two studies were in older patients while the third was in younger patients. The 2 studies in older patients demonstrated improved progression-free survival (PFS) with ibrutinib-based therapy compared with CIT, with no difference in overall survival (OS). In the Alliance Intergroup study, however, the PFS curves were similar among the arms in the low risk IGHV-mutated subgroup.¹ Another useful take home point was that the Alliance trial directly compared ibrutinib with ibrutinib plus rituximab and demonstrated absolutely no difference in PFS with the addition of rituximab, suggesting that anti-CD20 antibody does not add benefit in the context of ibrutinib. It is important to note that the rate of death due to adverse events in the 3 separate ibrutinib-containing arms in the 2 studies ranged from 7.7% to 9%, whereas the rates in the CIT arms were approximately 3%. In the trial with younger patients, ibrutinib plus rituximab demonstrated improved PFS and OS compared with fludarabine, cyclophosphamide, and rituximab (FCR) with short follow-up and, again, without a significant difference in the lower risk IGHV-mutated subgroup, which in prior studies can achieve a 55% rate of very long-term PFS with FCR.²

These findings support the use of ibrutinib-containing regimens as a standard of care in patients of any age but most particularly in higher-risk patients. The findings also suggest that clinicians should continue to evaluate multiple factors when choosing therapy: patient age, comorbidities, disease risk, concerns about continuous therapy leading to adverse events, and cost.

Another key study was the update of the MURANO trial, which reported 3-year follow-up data for patients treated with venetoclax plus rituximab (as compared with bendamustine and rituximab), with a 3-year PFS of 71% in the entire intention-to-treat patient population.³ This update established the feasibility of discontinuation of venetoclax after 2 years as per the study design, with 87% of patients who completed 2 years of venetoclax remaining in response 1 year after discontinuation. A long-term follow-up report on the phase 1b study of venetoclax plus rituximab demonstrated that 11 patients with undetectable minimal residual disease (MRD) who discontinued venetoclax remained in remission at a median of 33 months, again demonstrating the feasibility of discontinuation in the setting of deep response. A couple other presentations demonstrated the association of higher levels of MRD with shorter PFS after venetoclax.

Question

There were a number of abstracts presented regarding CIT. How do you foresee CIT being used in combination with other therapeutic agents to maximize treatment efficacy?

Answer

The role of CIT in CLL is clearly diminishing with the results of randomized trials demonstrating ibrutinib benefit in PFS, although so far this is seen primarily in higher-risk patients as we await longer follow-up. Patients with low risk IGHV-mutated disease can experience prolonged PFS with effective CIT — in particular FCR in the young fit population, which results in a 55% PFS at 10 years or more. Adding ibrutinib to FCR-type regimens results in even deeper remissions, as reported at ASH 2018 with the ibrutinib, fludarabine, cyclophosphamide, and obinutuzumab regimen from the University of Texas MD Anderson Cancer Center and the ICLL-07 trial from the French Innovative Leukemia Organization (FILO).^4,5 Our group has also reported similar findings with ibrutinib and FCR. Hopefully these deeper remissions will lead to even higher PFS at 10 years in this potentially curable CLL subset.

At present, CIT even in older patients continues to offer a 6-month time limited regimen, which can have prolonged benefit in lower-risk patients without ongoing costs and toxicities. However, we will likely soon have data from the CLL14 trial (ClinicalTrials.gov Identifier: NCT02242942), which compared 1-year time limited venetoclax and obinutuzumab with chlorambucil and obinituzumab in an older patient population and has been reported to be positive in a press release.⁶ This study will likely start to establish time-limited novel agent therapy in the frontline setting, which will have the same advantages of a time-limited regimen but also the efficacy in higher-risk patients. We will therefore be likely to see more time-limited combinations of novel agents, which will take over for CIT, at least in this noncurative older patient setting.

Question

Did any research presented at the meeting offer new insights into the genetic mechanisms of CLL? If so, how might this influence your treatment strategy?

Answer

The primary report of interest on genetic mechanisms included the identification of a mutation in BCL2 associated with resistance to venetoclax.⁷ Eventually this may lead to mutation screening that might enable alteration in therapy. My group also reported that mutations in the RAS-RAF-MAP2K1 pathway are associated with primary resistance to PI3K inhibitors.⁸ A couple additional studies also confirmed that clonal evolution is ongoing in patients on ibrutinib with high rates of BTK and PLCG2 mutations, providing another argument for moving toward time-limited combination therapy.^9,10

Question

What are the biggest challenges that you face in the management of Richter syndrome? Did any research at ASH 2018 shed light on novel therapeutic options that you may consider?

Answer

Richter syndrome remains a huge unmet need as patients have very poor OS regardless of what therapy we choose. A couple reports of regimens including PD-1 inhibitors were encouraging — in particular, a first report of pembrolizumab with the novel PI3K inhibitor umbralisib and the novel anti-CD20 antibody ublituximab.¹¹ The University of Texas MD Anderson Cancer Center also provided updated results of their nivolumab plus ibrutinib study.¹² The response rates are approximately 40%, but complete remissions with some durability have also been seen, which is encouraging. Further investigation of CAR T therapy in this setting is also warranted.

Question

Are there any other points that you think are important to make for clinicians who are treating patients with CLL?

Answer

CLL is a long-term chronic disease, and its overall course for a given patient continues to be governed by the key prognostic factors that include high risk cytogenetics and IGHV mutation status. Patients with low-risk disease can often do very well with little therapy, and it is important to avoid overtreating them, while those with higher-risk disease need our best novel agent therapy, which may often mean a combination on a clinical trial.

References

1. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Alone or in Combination with Rituximab Produces Superior Progression Free Survival (PFS) Compared with Bendamustine Plus Rituximab in Untreated Older Patients with Chronic Lymphocytic Leukemia (CLL): Results of Alliance North American Intergroup Study A041202. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 6.

2. Shanafelt TD, Wang V, Kay NE, et al. A randomized phase III study of ibrutinib (PCI-32765)-based therapy vs. standard fludarabine, cyclophosphamide, and rituximab (FCR) chemoimmunotherapy in untreated younger patients with chronic lymphocytic leukemia (CLL): a trial of the ECOG-ACRIN cancer research group (E1912). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA-4.

3. Seymour JF, Kipps TJ, Eichhorst B, et al. MURANO Trial Establishes Feasibility of Time-Limited Venetoclax-Rituximab (VenR) Combination Therapy in Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia (CLL). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 184.

4. Jain N, Thompson PA, Burger JA, et al. Ibrutinib, Fludarabine, Cyclophosphamide, and Obinutuzumab (iFCG) for Firstline Treatment of Patients with CLL with Mutated IGHV and without TP53 Aberrations. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 185.

5. Michallet A-S, Dilhuydy M-S, Subtil F, et al. High Rate of Complete Response (CR) with Undetectable Bone Marrow Minimal Residual Disease (MRD) after Chemo-Sparing and MRD-Driven Strategy for Untreated Fit CLL Patients: Final Results of the Icll 07 Filo Trial. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 1858.

6. AbbVie announces positive results from CLL14, a phase 3 trial evaluating a venetoclax combination as first-line therapy with a fixed duration of treatment in patients with chronic lymphocytic leukemia [published online October 31, 2018]. AbbVie. Accessed December 5, 2018.

7. Blombery P, Anderson MA, Gong J, et al. Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract LBA-7.

8. Murali I, Kasar S, McWilliams EM, et al. Activating MAPK pathway mutations mediate primary resistance to PI3K inhibitors in chronic lymphocytic leukemia (CLL). Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 587.

9. Quinquenel A, Fornecker LM, Letestu R, et al. High prevalence of BTK mutations on ibrutinib therapy after 3 years of treatment in a real-life cohort of CLL patients: a study from the French Innovative Leukemia Organization (FILO) group. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 584.

10. Spina V, Forestieri G, Zucchetto A, et al. Mechanisms of adaptation to ibrutinib in high risk chronic lymphocytic leukemia. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 585.

11. Mato AR, Svoboda J, Prak ETL, et al. Phase I/II Study of Umbralisib (TGR-1202) in Combination with Ublituximab (TG-1101) and Pembrolizumab in Patients with Relapsed/Refractory CLL and Richter’s Transformation. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 297.

12. Jain N, Ferrajoli A, Basu S, et al. A Phase II Trial of Nivolumab Combined with Ibrutinib for Patients with Richter Transformation. Oral presentation at: American Society of Hematology 60th Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA. Abstract 296.