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First-line poly(ADP-ribose)polymerase (PARP) inhibitor maintenance therapy significantly increases progression-free survival (PFS) in high-grade ovarian cancer patients. However, questions remain regarding the ability of PARP inhibitors to increase the cure rate, the types of patients most likely to benefit from them, and when it is best to employ them. In a virtual small-group meeting with experts in Hong Kong, Professor Charlie Gourley of the University of Edinburgh, Edinburgh, UK discussed the criteria for optimal patient selection and the positioning of PARP inhibitors in the patient journey.

Dr. Kathleen Moore, 30 Sep 2020
Most patients with advanced ovarian cancer (OC) relapse after standard cytoreductive surgery and platinum-based chemotherapy. At a webcast organized by the Hong Kong Society of Clinical Oncology, Dr Kathleen Moore of the University of Oklahoma in Norman, Oklahoma, US, discussed the results of the SOLO-1 trial, which demonstrated significant progression-free survival (PFS) benefits associated with maintenance therapy using the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor, olaparib, in patients with newly diagnosed, advanced BRCA-mutated OC who had complete or partial response (CR/PR) to first-line platinum-based chemotherapy. 
05 Aug 2020
With ageing populations, many countries face increasing healthcare demands associated with the management of diseases and comorbidities common among the elderly, such as cancer, osteoarthritis and rheumatoid arthritis, and the pain associated with these conditions. In recent years, there has been growing evidence supporting the use of sustained-release (SR) oxycodone (OxyContin®, Mundipharma) as a pain management option for elderly patients, particularly those experiencing chronic cancer-related pain. This article summarizes the key points and evidence from two seminal papers – a consensus statement of an international expert panel on opioids and the management of chronic severe pain in the elderly as well as a multicentre, open-label randomized controlled trial investigating the efficacy and safety of SR oxycodone in cancer pain treatment. 
Dr. Thomas Chan, 05 Oct 2020
Current international guidelines on management of chronic lymphocytic leukaemia (CLL) recommend the use of B cell lymphoma-2 (BCL-2) inhibitors, such as venetoclax, in patients with relapsed or refractory (R/R) disease with or without chromosome 17p deletion, based on improvements in progression-free survival (PFS) and overall survival (OS) and a high rate of undetectable minimal residual disease (uMRD). Dr Thomas Chan, Specialist in Haematology & Haematological Oncology in Hong Kong, discussed these recent advances in R/R CLL management with MIMS Oncology.

Prophylaxis of AEs related to a fixed-duration therapy in an older patient with relapsed CLL

Dr. Herman Sung-Yu Liu
Specialist in Haematology and Haematological Oncology
Private practice, Hong Kong
30 Sep 2020

History, presentation and treatment

A 68-year-old woman was initially diagnosed with chronic lymphocytic leukaemia (CLL) in 2015 when she presented with weight loss, night sweats, generalized lymphadenopathies and lymphocytosis. Fluorescence in-situ hybridization (FISH) detected trisomy 12, but no 17p deletions or TP53 mutations. Her platelet count and ß2 microglobulin levels were normal. She also had mild anaemia and underlying hypertension and dyslipidaemia. She was treated with six cycles of bendamustine plus rituximab (BR). Her symptoms gradually improved during treatment and the disease went into complete remission.

The patient remained well for 4.5 years until late 2019, at an age of 73 years, when she relapsed with weight loss (2.3 kg), night sweats, lymphocytosis and reappearance of swollen lymph nodes. Her white blood cell (WBC) count was 20 x 109 cells/L. Within 2 years prior to relapse, she also developed paroxysmal atrial fibrillation (PAF). Testing for immunoglobulin heavy chain variable region (IGHV) mutation status confirmed the presence of mutated IGHV. Apart from trisomy 12, no additional chromosomal abnormalities were detected by FISH.

Second-line treatment with a chemotherapy-free regimen was preferred in view of the patient’s age and comorbidities. Venetoclax plus rituximab (VenR) was chosen as the patient preferred fixed-duration treatment.

The patient had normal renal function and uric acid level. She was hospitalized for 3 days and received intravenous hydration and urate-lowering febuxostat therapy as prophylaxis for tumour lysis syndrome (TLS). Venetoclax was given orally in a ramp-up schedule that was more intensive than the recommended 5-week ramp-up schedule,1 to a dose of 300 mg daily instead of the recommended 400 mg daily due to financial constraints, along with hydration and uric acid level monitoring. Voriconazole, a strong CYP3A4 inhibitor that can potentially increase the serum concentration of venetoclax, was given concomitantly.2

After completion of the venetoclax dose ramp-up phase, rituximab was administered intravenously on day 1 of each 28-day cycle for six cycles, at 375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2–6. The sixth cycle of rituximab ended in February 2020, after which the patient remained on venetoclax 300 mg daily.

The patient responded well to VenR. She experienced weight stabilization soon after treatment initiation, a decrease in night sweats and shrinkage of lymph nodes within 2 weeks, and normalization of lymphocytosis within 4 weeks, which obviated the need to increase venetoclax dose to 400 mg daily. CT scan performed after three cycles of VenR showed resolution of all enlarged lymph nodes (ie, complete response). (Figure) With continuous daily hydration and regular uric acid level monitoring, the patient has remained free of any signs of TLS.

HK-AVI-089mo_01

Treatment-related side effects included skin rash (offending agent not identified), which resolved with antihistamine use, and infusion reaction to rituximab that was limited to the first treatment cycle. The patient also experienced leucopenia, with a drop in WBC count to 1.8 x 109 cells/L and neutrophils to 0.7 x 109 cells/L, which normalized following administration of growth factors during the first cycle.

As of August 2020, the patient remained well on venetoclax 300 mg daily, which will be continued for 24 months from cycle 1 of rituximab.

Discussion

Several factors should be considered when choosing an optimal treatment for CLL in the relapsed/refractory (R/R) setting. Given the advanced age and comorbidities, our patient would not have tolerated a chemotherapy-based regimen, such as FCR (fludarabine plus cyclophosphamide plus rituximab). Furthermore, she was not an ideal candidate for ibrutinib therapy, which is associated with an increased risk of AF.3 VenR was therefore initiated as the patient preferred fixed-duration treatment.

VenR is indicated for the treatment of adult patients with CLL who have received ≥1 prior therapy.1 In the randomized, open-label, phase III MURANO trial that included 389 patients with R/R CLL, VenR lowered the risk of disease progression or death by 83 percent vs BR (hazard ratio [HR], 0.17; 95 percent confidence interval [CI], 0.11 to 0.25; p<0.001).4 The progression-free survival (PFS) benefit extended across all patient subgroups, including those with adverse prognostic features, such as 17p deletions and/or TP53 mutations.4 An updated 4-year analysis of MURANO data, when all patients had been off venetoclax treatment for a median of 22 months, confirmed the sustained superiority of VenR over BR in terms of PFS (HR, 0.19; 95 percent CI, 0.14 to 0.25; p<0.0001), overall survival (HR, 0.41; 95 percent CI, 0.26 to 0.65; p<0.0001), and minimum residual disease (MRD)-negativity 2 years after cessation of treatment.5

As observed in our patient, infusion reactions to rituximab typically occur during the first infusion and should not be a cause for concern in the long-term.6 The most common grade 3/4 adverse events (AEs) associated with VenR in MURANO were neutropenia (57.7 percent), and infections and infestations (17.5 percent), while grade 3/4 TLS occurred in 3.1 percent of patients in the VenR arm.4 Appropriate prophylactic and supportive measures along with close monitoring, as those given to our patient, are important for preventing and managing these AEs.

Neutropenia tends to be more severe and occurs more frequently during the combination therapy phase than during venetoclax monotherapy.7,8 Complete blood counts should be monitored regularly throughout the treatment period. In addition to growth factor support, antibiotics and antifungals can be given to manage neutropenia and reduce the risk of infections.1 Patients who experience thrombocytopenia during treatment will require platelet transfusion, typically at a threshold of 20 x 109 cells/L.9

VenR should be used with caution in patients with underlying renal impairment, hyperuricaemia, or bulky disease because of the increased risk of TLS. Prophylactic measures that can mitigate this risk include hospitalization for close monitoring of renal function and uric acid levels, hydration, premedication with antihyperuricaemics, and a slower venetoclax dose ramp-up phase.1,10 If there are changes in biochemical markers or symptoms suggestive of TLS, treatment should be interrupted and resumed at a lower dose once symptoms have resolved.1

In summary, this case illustrates that VenR is a highly effective and appropriate treatment option for R/R CLL patients, especially those who are elderly with underlying cardiovascular risks and prefer a fixed duration of treatment. Patients with pre-existing cytopenia, high disease burden and renal impairment are at increased risk of serious AEs, such as neutropenia and TLS, and should be assessed and managed accordingly with appropriate prophylactic and supportive measures.

 

 

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Most Read Articles
Prof. Charlie Gourley, 30 Sep 2020

First-line poly(ADP-ribose)polymerase (PARP) inhibitor maintenance therapy significantly increases progression-free survival (PFS) in high-grade ovarian cancer patients. However, questions remain regarding the ability of PARP inhibitors to increase the cure rate, the types of patients most likely to benefit from them, and when it is best to employ them. In a virtual small-group meeting with experts in Hong Kong, Professor Charlie Gourley of the University of Edinburgh, Edinburgh, UK discussed the criteria for optimal patient selection and the positioning of PARP inhibitors in the patient journey.

Dr. Kathleen Moore, 30 Sep 2020
Most patients with advanced ovarian cancer (OC) relapse after standard cytoreductive surgery and platinum-based chemotherapy. At a webcast organized by the Hong Kong Society of Clinical Oncology, Dr Kathleen Moore of the University of Oklahoma in Norman, Oklahoma, US, discussed the results of the SOLO-1 trial, which demonstrated significant progression-free survival (PFS) benefits associated with maintenance therapy using the poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor, olaparib, in patients with newly diagnosed, advanced BRCA-mutated OC who had complete or partial response (CR/PR) to first-line platinum-based chemotherapy. 
05 Aug 2020
With ageing populations, many countries face increasing healthcare demands associated with the management of diseases and comorbidities common among the elderly, such as cancer, osteoarthritis and rheumatoid arthritis, and the pain associated with these conditions. In recent years, there has been growing evidence supporting the use of sustained-release (SR) oxycodone (OxyContin®, Mundipharma) as a pain management option for elderly patients, particularly those experiencing chronic cancer-related pain. This article summarizes the key points and evidence from two seminal papers – a consensus statement of an international expert panel on opioids and the management of chronic severe pain in the elderly as well as a multicentre, open-label randomized controlled trial investigating the efficacy and safety of SR oxycodone in cancer pain treatment. 
Dr. Thomas Chan, 05 Oct 2020
Current international guidelines on management of chronic lymphocytic leukaemia (CLL) recommend the use of B cell lymphoma-2 (BCL-2) inhibitors, such as venetoclax, in patients with relapsed or refractory (R/R) disease with or without chromosome 17p deletion, based on improvements in progression-free survival (PFS) and overall survival (OS) and a high rate of undetectable minimal residual disease (uMRD). Dr Thomas Chan, Specialist in Haematology & Haematological Oncology in Hong Kong, discussed these recent advances in R/R CLL management with MIMS Oncology.