EXPERT INSIGHT

Bruton’s tyrosine kinase inhibitors delay disease progression and extend survival in patients with relapsed/refractory mantle cell lymphoma

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Prof. Tse, Wai-Choi Eric

Clinical Professor,
Department of Medicine,
Li Ka Shing Faculty of Medicine,
The University of Hong Kong

Mantle cell lymphoma (MCL) is a B cell malignancy that is typically clinically aggressive with a poor prognosis.1 When MCL patients progress into relapsed/refractory MCL (RRMCL), the median overall survival (OS) is usually reduced to around 1 year. Currently, three Bruton’s tyrosine kinase inhibitors (BTKis), ibrutinib, acalabrutinib and zanubrutinib, were approved by the United States Food and Drug Administration (FDA) for treating RRMCL.1,2 In Hong Kong, ibrutinib is the first licensed BTKi followed by acalabrutinib.1,2 In a recent phase 3 clinical trial, ibrutinib has demonstrated progression-free survival (PFS) and OS benefits in RRMCL patients with greater survival benefits observed in patients who have failed only one line of therapy prior.1,3 Professor Tse, Wai-Choi Eric, Clinical Professor at the Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, shared his insights on the unmet needs of RRMCL treatment and the potential of ibrutinib as the first licensed BTKi in Hong Kong for treating RRMCL.

The unmet needs for RRMCL to be addressed

While MCL is a rare malignancy that accounts for only 3% of all non-Hodgkin lymphoma (NHL) cases in Hong Kong, its prognosis is generally slightly poorer than patients with other B cell malignancies such as diffuse large B cell lymphoma (DLBCL).1,4 Indeed, MCL patients with an intermediate and high Mantle Cell Lymphoma International Prognostic Index (MIPI) risk score have a median OS of 51 and 29 months, respectively.5 In patients who have progressed into RRMCL, the prognosis is worsened to a median OS of approximately 1 year which is consistently observed in existing data across patient populations in Hong Kong, Asia and the Western countries.

Previously, MCL patients in Hong Kong were commonly treated with rituximab-based chemoimmunotherapy. However, the response rate and duration of response of traditional chemoimmunotherapy are often inadequate that results in poor PFS and OS among patients with relapsed/refractory diseases.6 At the same time, patients who have received prior chemoimmunotherapy in the first-line setting would be unsuitable for another round of chemoimmunotherapy in relapsed/refractory setting. To address these unmet needs, an alternative therapy would be required to extend the PFS and OS benefits in MCL treatment to relapsed/refractory patients.

BTKi as an alternative option in the current MCL treatment landscape

By inhibiting the B-cell receptor signaling pathway, BTKi can induce apoptosis and decrease levels of antiapoptotic proteins that can lead to cancer cell death in MCL patients.7 In the pivotal phase 2 ACE-LY-004 study, acalabrutinib was shown to have an overall response rate (ORR) of 81% with PFS of 20 months. 2 Similarly, the pivotal phase 2 BGB-3111-206 study showed that patients receiving zanubrutinib have an ORR of 85% with a PFS of 17 months.2 In the pivotal phase 3 MCL3001 study, ibrutinib had also demonstrated an ORR of 77% and a PFS of 16 months. 2 With demonstrated safety and tolerability profile, the FDA has approved all three BTKis for RRMCL treatment.2

In Hong Kong, ibrutinib is the first licensed BTKi for the treatment of RRMCL.1 As a first-in-class, once daily oral agent, ibrutinib treatment does not require hospitalization and is generally more tolerable than cytotoxic chemotherapies. Recently, the phase 3, international, open-label, randomized clinical RAY study has further demonstrated that ibrutinib as monotherapy has an ORR of 68%, where 21% of the RRMCL patients have achieved complete response (CR) with a median PFS of 13.9 months.1 In the 7.5-years extended follow-up pooled analysis of the SPARK, RAY and the PCYC-1104 studies, half of all patients treated with ibrutinib had a longer PFS than the prior regimen of chemoimmunotherapy before enrolling into the study with a quarter achieved ≥1 additional year of PFS benefit when compared to chemoimmunotherapy.8 At 5 years, 19% of patients were still progression-free and 41% of patients have survived.8 From local real-life experience, the response rate to treatment was also similarly higher among RRMCL patients receiving ibrutinib than those receiving chemoimmunotherapy.

Unsurprisingly, the effectiveness of ibrutinib salvage therapy is influenced by the number of prior lines of therapy and the duration of response to prior therapy.8 When compared to those treated in later lines of therapy, patient s treated with ibrutinib in the second line had extended median PFS and increased likelihood of CR.8 In fact, patients with 1 prior line of therapy had a median PFS and OS of 25.4 and 61.6 months, respectively. In patients who have achieved CR, the median PFS has extended to with a not reportable OS and further demonstrated ibrutinib to be most beneficial among patients who had received only one prior line of therapy.8 Compared to those receiving more than one prior lines of therapy, patients who have only one prior line of therapy have an improved median PFS of 15.1 months (Figure 1).8 Overall, ibrutinib showed an evident delay in disease progression when compared to chemoimmunotherapy and have demonstrated efficacy among RRMCL patients with increased benefit in those with only one prior line of therapy. To maximize its benefit, ibrutinib should be given as early as possible after first-line therapy.

Ibrutinib presents a more favorable safety profile

In terms of safety, ibrutinib showed no late unexpected toxicity in the 7.5 years extended follow-up study, with pneumonia (13.2%), atrial fibrillation (5.7%) and dyspnea (4.3%) being the most commonly reported serious adverse events.8 Low-grade neutropenia and thrombocytopenia were also the most commonly reported hematological adverse events.8 From local experience, most RRMCL patients found ibrutinib to be well-tolerated with adverse events being transient. Mild adverse events such as diarrhea and nausea are also easily managed with appropriate medications. Dose adjustments or discontinuation of treatment are rare, and patient complaints on ibrutinib treatment are uncommon.

In particular to patients at risk of cardiovascular events, blood pressure monitoring with appropriate antihypertension medications as needed can be prescribed to help manage the adverse effects of ibrutinib. For those at risk of atrial fibrillation, regular electrocardiogram (ECG) should be conducted to monitor the heart rhythm and rate. While the European Society for Medical Oncology (ESMO) has listed ibrutinib as contraindicated in patients with high bleeding risk, bleeding is rarely observed among local patients receiving ibrutinib.9 Nonetheless, caution must be taken in patients receiving aspirin or other anticoagulants to avoid an increased risk of bleeding.

A shift in RRMCL treatment landscape

Currently, ibrutinib is indicated for RRMCL patients who have previously failed at least one line of therapy and is recommended by the Asian Lymphoma Study Group (ALSG) as the first choice for MCL patient s who are in refractory or have relapsed disease.1 Previously in clinical practice, chemoimmunotherapies were of ten prescribed to patients who were presented with aggressive disease. Now, ibrutinib, as an oral therapeutic agent, could be administered in the outpatient setting which can help reduce patient resistance to therapy when compared to traditional cytotoxic agents. While there is no “per fect cure” to RRMCL, ibrutinib can provide suf ficient disease control, and in some patients, prolong PFS and OS that is clinically meaningful to the patient and should be prescribed early to maximize its benefit.

Message to the hematologists and oncologists

With the convenience of oral administration, ibrutinib treatment in patients with RRMCL can improve patient ’s quality of life while providing survival benefits in PFS and OS. Compared to chemoimmunotherapy, ibrutinib has demonstrated a relatively safer profile and could be a viable option for a wider range of patients who have failed first-line therapy. With studies highlighting the greatest survival benefits observed in patients with only one line of prior treatment, the decision to prescribe ibrutinib should be made as soon as the patient progresses into relapsed/refractory disease to maximize its benefit. However, as RRMCL tends to relapse eventually, clinicians should also consider consolidating other approved treatment strategies such as CAR-T cell therapy and stem cell transplant in younger patients when the disease progresses after ibrutinib treatment.

Conclusion

Compared to other B cell malignancies, RRMCL patients usually have poorer prognosis, and the traditional rituximabbased chemoimmunotherapy is often limited in response rate and duration of response. With the phase 3 clinical trial highlighting the survival benefits in PFS and OS with ibrutinib treatment, it is expected that there will be a shift in the RRMCL treatment landscape in Hong Kong towards the use of ibrutinib as second-line treatment. In the RRMCL set ting, the oral administration route of ibrutinib has improved patient compliance and is considered safer than its chemoimmunotherapy alternative. As the first licensed BTKi in Hong Kong, the early use of ibrutinib can benefit a wide range of patient s including those with relapsed/refractory diseases by extending PFS and OS.

This article is sponsored by Janssen, a division of Johnson & Johnson (HK) Ltd

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