A Hong Kong public hospital’s approach to managing patients with CLL
The B-cell lymphoma-2 (BCL-2) inhibitor, venetoclax, has demonstrated promising efficacy in relapsed/refractory chronic lymphocytic leukaemia (CLL). However, the associated risk of tumour lysis syndrome (TLS) in certain patients necessitates prophylactic measures and close monitoring. In an interview with MIMS Oncology, Dr Keith Wong from the haematology department of a public hospital in Hong Kong discussed important treatment considerations for patients with CLL, and highlighted prophylactic and supportive measures established at his hospital to mitigate the risk of TLS complications associated with venetoclax-based therapy.
Presentation and first-line management
In Hong Kong, CLL is the most common form of lymphoproliferative disorder, accounting for 12.5 percent of all leukaemias. [Cancer 1994;74:174-181]
“In our hospital, we see about 10 new cases of CLL each year, which account for nearly 10 percent of our newly diagnosed haematological malignancy cases,” reported Wong.
“About 60 percent of our CLL patients present with asymptomatic lymphocytosis that triggers pathologic investigations, including blood smears and immunophenotyping of circulating B‐lymphocytes, leading to a diagnosis of CLL,” said Wong. “Roughly 20 percent present with lymphadenopathy, 10 percent with bone marrow failure, and 10 percent with extranodal symptoms. In terms of disease stage, around 60 percent are diagnosed with early-stage disease, 20 percent with intermediate-stage disease, and 20 percent with advanced-stage disease.”
“In terms of molecular features, we primarily perform fluorescence in-situ hybridization [FISH] analyses for our CLL patients. In selected cases, immunoglobulin heavy chain variable region [IGHV] mutation status is also checked. Cytogenetic testing is not routinely done,” he added. “Typically, around 20 percent of our CLL patients have a favourable risk, 30 percent have intermediate risk, and 20 percent have high-risk FISH abnormalities, including del17p.”
According to Wong, asymptomatic patients are managed initially with watchful waiting. During this period, patients are monitored through regular clinic visits, which involve physical examinations and blood count tests every 3–6 months, to identify signs of disease progression, such as lymph node enlargement, high lymphocyte count, and other organ function abnormalities. Treatment initiation is considered in patients with active or symptomatic disease or with advanced Binet or Rai stages.
“Several patient and disease factors can influence the decision to start treatment. Patients who are unfit for treatment due to comorbidities or poor performance status or those prefer a conservative [eg, palliative] approach may not proceed with drug treatment. In terms of disease characteristics, presence of B symptoms, symptomatic lymphadenopathy or splenomegaly, short lymphocyte doubling time, steroid-refractory autoimmune complication, symptomatic extranodal involvement and advanced-stage disease with marrow failure [ie, Binet stage C or Rai stage III/IV] are the instances that may warrant intervention,” explained Wong.
First-line regimens used in his hospital for CLL treatment include chlorambucil alone, chlorambucil plus steroid or obinutuzumab, FCR (fludarabine plus cyclophosphamide plus rituximab), BR (bendamustine plus rituximab), and novel agents.
“Medication cost, patient age and the presence of high-risk molecular features are important considerations in treatment selection,” noted Wong. “FCR, BR and chlorambucil-based treatments are government-subsidized in Hong Kong. Given that most of our patients with CLL are older, BR is more commonly used than FCR.”
Management of relapsed/refractory CLL
“Patients who fail first-line agents will be reassessed for changes in molecular features or disease transformation. Those without transformation who are able to afford novel agents will receive ibrutinib monotherapy or venetoclax-based therapy. Some patients have chosen venetoclax-based therapy over ibrutinib, due to its finite duration of treatment. Those who are too frail usually receive palliative treatment,” explained Wong.
“The criteria we use to select treatment regimens for patients with relapsed/refractory CLL include molecular status, previous treatment, and relapse duration,” he continued. “Patients with a 17p deletion are eligible for subsidized therapy with ibrutinib. Those who failed ibrutinib in the first-line setting may be advised to try venetoclax-based therapy. For patients who cannot afford novel agents, retreatment with the same regimens may be considered if they had a durable response in the frontline setting.” [Lancet Oncol 2018;19:65-75; Ann Hematol 2017;96:1185-1196]
Prophylactic measures and monitoring for venetoclax-based therapy
Wong described the procedures in place at his hospital for managing CLL patients receiving venetoclax-based regimens. (Figure)
“Before initiating treatment, the patient’s risk of developing TLS is assessed by evaluating tumour burden [ie, number of bulky lymph nodes and lymphocyte count]. In addition, any concomitant drug use that may require venetoclax dose adjustment is identified. Baseline serum uric acid level is also measured,” Wong explained.
“Before the venetoclax dose ramp-up phase, we encourage patients to increase oral hydration. Antihyperuricaemic therapy with allopurinol is initiated, while patients at high risk of TLS are given allopurinol and rasburicase,” said Wong. [VENCLEXTA Hong Kong Prescribing Information, April 2019]
Monitoring and supportive measures during ramp-up
Venetoclax therapy is initiated based on the recommended once-daily dosing schedule with a 5-week ramp-up phase. [VENCLEXTA Hong Kong Prescribing Information, April 2019]
“During the ramp-up phase, patients at high risk of TLS are hospitalized for the first venetoclax doses of 20 mg daily in week 1 and 50 mg daily in week 2, and closely monitored for signs of TLS. Patients also receive additional intravenous fluid support. If there is no evidence of TLS, the rest of the ramp-up doses will be administered on an outpatient basis with regular blood chemistry monitoring at prespecified time points,” explained Wong.
“We have a nursing team in our haematology department that plays a vital role in assisting us with prophylactic and supportive measures, dose ramp-up, monitoring, and patient education about how venetoclax should be taken and when patients should come for blood tests, to ensure adherence,” he said. “With these measures in place, we have not encountered TLS among CLL patients receiving venetoclax-based treatment at our hospital.”
Dose reduction or interruption
Venetoclax dose reduction or interruption may be needed in certain circumstances, including grade 3/4 neutropenia, nonhaematological toxicities, TLS or drug-drug interactions (eg, antifungal treatment). [VENCLEXTA Hong Kong Prescribing Information, April 2019]
“Venetoclax-based treatment has been well tolerated by CLL patients managed at our hospital. However, vigilance is needed for neutropenic complications, which can occur long after the ramp-up phase,” said Wong.
Treatment decisions for CLL are influenced by several factors, including disease stage, line of therapy, molecular profile, age, performance status, comorbidities, and cost. Venetoclax-based therapy is an effective, fixed-duration, chemotherapy-free option for patients with relapsed/refractory CLL. Before receiving venetoclax, patients should be assessed for TLS risk and receive appropriate prophylaxis, including hydration and antihyperuricaemics. More intensive measures, such as intravenous hydration, frequent monitoring and hospitalization, should be employed for high-risk patients.