Advancing CLL management in Chinese patients
The introduction of novel targeted agents has significantly improved treatment outcomes in chronic lymphocytic leukaemia (CLL). In an interview with MIMS Oncology, Professor Eric Tse of the Department of Medicine, University of Hong Kong, discussed recent advances in the diagnosis and treatment of patients with CLL, insights from a CLL registry in Hong Kong, and the concept of undetectable minimal residual disease (uMRD) as a treatment goal for the oral B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax.
Hong Kong CLL registry
CLL is the most common form of leukaemia in Western countries, with an annual incidence of 4.2 per 100,000 persons. [Ann Oncol 2015;26(Suppl 5):v78‐v84] In Hong Kong, the reported incidence is nearly 10 times lower. [Eur J Haematol 2010;85:492-495]
“Most data on the cytogenetic and molecular features of CLL and their impact on disease outcomes have been derived from Caucasian populations. As such, their applicability to Asian populations is not well known. The Hong Kong CLL registry was established in 2010 to address these issues in Chinese patients,” said Tse.
The registry recorded the clinical, pathological and molecular characteristics of CLL in a cohort of newly diagnosed Chinese patients in Hong Kong (n=139) and Singapore (n=73). [Oncotarget 2017;8:25455-25468] “In Hong Kong, Queen Mary hospital, Pamela Youde Nethersole Eastern Hospital, Queen Elizabeth Hospital, United Christian Hospital, Tseung Kwan O Hospital, Tuen Mun Hospital and Princess Margaret Hospital participated in the study,” said Tse.
“The clinicopathological features of the Chinese patients were similar to those of Western patients, except for a lower median age at diagnosis of 64 years vs 72 years reported for Caucasian CLL patients,” noted Tse. “There was a preponderance of males [approximately 3:1 male-to-female ratio], and 56 percent presented with Binet stage A CLL.” [Oncotarget 2017;8:25455-25468; Ann Oncol 2015;26(Suppl 5):v78‐v84]
Fluorescence in situ hybridization (FISH) revealed chromosome 17p deletion [del (17p)] in 7.8 percent of patients – comparable to that observed in Western cohorts. [Oncotarget 2017;8:25455-25468]
“Due to financial constraints, data collection for the CLL registry lasted for only about 3–4 years,” said Tse. “However, with renewed funding, this project has been restarted recently. The introduction of effective targeted therapies, such as ibrutinib and venetoclax, has changed the CLL treatment landscape in Hong Kong and will enable us to generate more comprehensive data on CLL management in the treatment-naïve as well as relapsed/refractory [R/R] settings.”
Impact of cytogenetic mutations on CLL prognosis
The presence of cytogenetic abnormalities, detected in more than 80 percent of CLL patients, has prognostic and therapeutic implications. Notably, del(17p) has been identified as the strongest predictor of poor treatment outcomes and poor survival. [N Engl J Med 2000;343:1910-1916]
“In Hong Kong, CLL patients are not routinely assessed for aberrations, such as NOTCH1, SF3B1, TP53, MYD88 and FBXW7 mutations or immunoglobulin heavy chain variable region [IGHV] gene mutations,” explained Tse. “However, data from the Hong Kong CLL registry showed that, similar to patients in the West, the presence of del(17p), TP53 mutations or unmutated IGHV status was associated with significantly shorter time to first treatment and/or adverse survival outcomes despite treatment with conventional chemoimmunotherapy [ie, FCR (fludarabine, cyclophosphamide and rituximab)].” [Oncotarget 2017;8:25455-25468]
As such, Tse advised that patients with unmutated IGHV gene or del(17p) should avoid chemoimmunotherapy and use novel treatments. “Even if there is an initial response with chemoimmunotherapy, the risk of relapse at the end of treatment is very high in patients with unmutated IGHV status,” he added. [Blood 2016;127:303-309]
uMRD as goal of venetoclax therapy in CLL
Recent clinical trials have demonstrated that achievement of uMRD predicts better long-term clinical outcomes in CLL. [Blood 2016;128:2770-2773; Blood 2019;134:111-122]
“The value of uMRD attainment as a treatment goal in CLL depends on the therapeutic regimen. A high percentage of patients treated with fixed-duration venetoclax-based therapy achieve uMRD, with associated improvement in progression-free survival [PFS]. Achieving uMRD should thus be the goal of treatment in patients receiving venetoclax,” said Tse. “With continuous ibrutinib therapy, however, complete remission or uMRD is uncommon despite the PFS improvement vs chemoimmunotherapy. Hence, uMRD may not be an applicable goal for patients receiving ibrutinib.” [N Engl J Med 2013;369:32-42; J Clin Oncol 2019;37:269‐277]
A retrospective analysis of data from three clinical trials in 62 CLL patients treated with venetoclax demonstrated improved PFS and overall survival associated with uMRD attainment in the peripheral blood (PB) and bone marrow (BM). (Figure) [Blood Adv 2020;4:165‐173]
“There is a high correlation for MRD status between PB and BM. As such, patients with uMRD in PB do not necessarily require confirmatory BM biopsy, although we would usually advice confirmatory BM biopsy when we see uMRD in PB,” noted Tse. [J Clin Oncol 37:269-277]
Venetoclax, in combination with rituximab, is prescribed for a fixed duration of 24 months to patients with CLL who have received at least one prior therapy. [VENCLEXTA Hong Kong Prescribing Information, Apr 2019] “Patients’ MRD status should be assessed within 1–2 months of treatment completion,” Tse advised.
In the phase III MURANO study, a higher rate of uMRD was observed at the end of combination treatment (6 months) among patients who received venetoclax plus rituximab vs bendamustine plus rituximab (62 percent vs 13 percent), with superiority sustained through month 24 (end of venetoclax monotherapy). [J Clin Oncol 37:269-277]
The aforementioned retrospective analysis also reported a median time to uMRD achievement of 18 months, with 90 percent of uMRD achieved by 24 months and no new uMRD attainment after 24 months without treatment intensification. [Blood Adv 2020;4:165‐173]
“Although dose escalation may deepen the response in some patients, these data suggest little benefit in extending venetoclax treatment beyond 24 months. The possibility of developing resistance after prolonged therapy is also a concern,” said Tse.
Chinese CLL patients have similar genetic abnormalities at diagnosis as those of Western populations. The presence of del(17p), TP53 mutations or the unmutated IGHV status is associated with poor outcomes after chemoimmunotherapy. Fixed-duration venetoclax-based therapy is an effective option for these patients. The achievement of uMRD on venetoclax is correlated with prolonged PFS, and hence, represents a potential therapeutic goal in CLL.