Patient-reported outcomes in Chinese patients with chronic myeloid leukemia receiving olverembatinib: Quality of life matters!

Before the introduction of tyrosine kinase inhibitors (TKIs) that inhibit BCR::ABL1 kinase activity, patients with chronic myeloid leukemia (CML) had a markedly shortened median survival compared with that achieved in the TKI era. Currently, patients who have CML in chronic phase (CML-CP) have a life expectancy comparable to that of the normal population, with a remarkable reduction in CML-related deaths.¹

Globally, most patients with newly diagnosed CML-CP receive upfront imatinib as a TKI therapy, and approximately 70% achieve a complete cytogenetic response (CCyR) after 12 months of therapy. However, during follow-up, nearly 40% of these patients fail first-line imatinib therapy.² In patients who fail first-line imatinib, second-generation TKIs (2G-TKIs) are commonly used; and, in those who fail a 2G-TKI and/or harbor a T315I mutation, third-generation TKIs (3G-TKIs) are the treatment of choice.³

Olverembatinib (HQP-1351) is a 3G-TKI that acts as an adenosine triphosphate (ATP)-binding site inhibitor and is designed to potently inhibit both wild-type and mutant BCR::ABL1 kinases, including the gatekeeper mutation T315I.⁴ The effectiveness and safety of olverembatinib have been previously demonstrated in Chinese patients with CML who failed multiple lines of TKI therapies⁵ and, later, in patients outside of China.⁶

Because CML patients are expected to have life spans nearly as long as normal healthy individuals, the duration of TKI exposure is extended, leading to a possible increased risk of TKI-related adverse events (AEs). Previously, it was demonstrated that TKI toxicities and symptom burden have a negative effect on health-related quality of life (HRQoL) in patients with CML.^{7, 8} Specifically, information on patient-reported outcomes (PROs), including HRQoL and symptom profiles, is necessary to improve overall treatment outcomes of TKI therapy in patients with CML.^{9, 10} In the literature, there are data on HRQoL measures mainly from patients with CML who received ATP-competitive TKIs^11-13 and asciminib¹⁴; however, data are lacking on PROs in patients with CML who receive olverembatinib.

In this issue of Cancer, Yu et al.¹⁵ published their results of a multicenter PRO study in 146 patients with CML-CP (n = 114) or CML in accelerated phase (CML-AP; n = 32) who had failed on prior imatinib and/or 2G-TKI and then were switched to olverembatinib, gathering data from their previously published phase 1/2 trial.⁵ The median time from CML diagnosis to the start of olverembatinib was 5.5 years, and >80% of patients had received two or more prior TKI therapies that did not include ponatinib. One hundred fourteen patients had a T315I mutation either alone (n = 92) or with another mutation (n = 22). At the 3-year follow-up, a major molecular response and a molecular response^4,5 were achieved in 87 (60%) and 33 (23%) patients, respectively, and all patients experienced at least one AE, of which 120 (82%) were grade 3/4.¹⁵

During the study, HRQoL and anxiety and depression symptom scales were assessed by using the Chinese version of the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30), the Self-Rating Anxiety Scale (SAS), and the Self-Rating Depression Scale (SDS) at the start of olverembatinib and at different time points, respectively.¹⁵

Regarding HRQoL measures at the time of olverembatinib initiation, the three most severe symptom burdens reported by the patients were financial difficulties, fatigue, and insomnia, among many others.¹⁵ Multivariate analysis indicated that an interval from CML diagnosis to olverembatinib initiation ≥5 years (vs. <5 years) was significantly associated with poor cognitive functioning (p = .014). The lack of a BCR::ABL1 mutation (vs. T315I mutation with or without other mutations) was significantly associated with poor cognitive functioning (p = .014), poor emotional functioning (p = .030), and severe constipation (p = .021).¹⁵ During follow-up, as the number of olverembatinib therapy cycles increased, most HRQoL parameters improved. Compared with patients who had CML-AP, for those who had CML-CP, many items improved with olverembatinib treatment; whereas no items improved, and some even worsened, during olverembatinib treatment in patients who had CML-AP.¹⁵

As indicated above, anxiety and depression were assessed by using the SAS and SDS, respectively, and 83 (82%) and 56 (55%) patients had no anxiety or depression symptoms at baseline, respectively.¹⁵ Under olverembatinib therapy, the standard SAS scores decreased significantly in both the CML-CP and CML-AP groups (both p < .001); however, the standard SDS score decreased significantly in patients with CML-CP (p = .021), but not in those with CML-AP (p = .702).¹⁵

The HRQoL of patients, as evaluated by using PRO measures, may provide direct information from the patients' perspectives about their symptoms and functioning without an interpretation of their responses by their physicians.¹⁶ Almost a decade ago, in a multicenter Italian study by Efficace et al.,¹⁷ those authors clearly demonstrated that there were disparities in the reporting of health status and symptom severity related to imatinib therapy between patients with CML and their treating physicians. For all symptoms, patients reported higher severity more often than their physicians, and physicians tended to underestimate symptom severity. The authors concluded that PRO measures should be used to improve physicians' awareness of the symptom burden of their patients and help them better manage the disease and improve HRQoL.¹⁷

Similarly, in a very recent multicenter study from China with 1882 adult patients who had CML and 305 physicians in which almost 70% of patients had received imatinib as a first-line TKI therapy and only 0.1% (n = 2) received olverembatinib during follow-up, it was demonstrated that physicians and patients agreed on treatment options and treatment challenges; conversely, physicians largely ignored many symptoms, with a negative impact on HRQoL.¹⁸ Because there were no previous data on PROs or HRQoL measures among patients with CML receiving olverembatinib, the data presented here by Yu and colleagues are of great interest.¹⁵

In an international study among patients with newly diagnosed CML who were receiving first-line imatinib and 2G-TKIs (bosutinib, dasatinib, and nilotinib) that was conducted across the United States and Italy, in addition to improving HRQoL, the investigators demonstrated that PRO monitoring from the beginning of TKI therapy was beneficial and also improved adherence to therapy and response rates.¹⁹ Although no direct data on the TKI adherence were shared in the study by Yu and colleagues,¹⁵ achieving a major molecular response was associated with significantly less nausea and vomiting. Conversely, as stated by the authors, some TKIs are partially reimbursed in China, which, obviously, may result in a financial burden for some patients, resulting in lack of adherence and inferior response rates.¹⁵

Similar to olverembatinib, ponatinib and asciminib are treatment options for patients who fail one or more lines of TKIs and in those who harbor a T315I mutation.^{20, 21} In the literature, HRQoL data on ponatinib are very limited, restricted only to a phase 2 study evaluating the first-line use of ponatinib²²; however, ponatinib is not approved in the upfront setting because of its vascular toxicities. In the phase 2 OPTIC trial (Optimizing Ponatinib Treatment in CML-CP; ClinicalTrial.gov identifier NCT02467270) trial, the efficacy and safety of ponatinib using a novel response-based dose-adjustment strategy in patients with CML-CP who were resistant to two or more TKIs or who harbored a T315I mutation were evaluated.²³ Results from the OPTIC primary analysis demonstrated an improved risk:benefit ratio for ponatinib using a response-based dosing strategy starting with 45 mg daily followed by a dose reduction to 15 mg daily upon attaining ≤1% BCR::ABL1^IS (International Scale-standardized). In the 3-year follow-up update of the study, the results regarding both efficacy and safety were consistent with the initial report²⁴; and, most probably, the reduction in the rates of AEs would improve HRQoL measures in patients receiving ponatinib with this dosing strategy. Asciminib allosterically inhibits BCR::ABL1 through specifically targeting the ABL myristoyl pocket, acting in a different way than the current ATP-competitive TKIs.²¹ ASCEMBL is an open-label, randomized phase 3 study comparing asciminib with bosutinib in terms of both efficacy and toxicity in patients with CML-CP who were previously treated with two or more TKIs (ClinicalTrials.gov identifier NCT03106779).²⁵ Asciminib demonstrated superior response rates with better tolerability over bosutinib both in the initial report²⁵ and also during the extended follow-up.²⁶ In a report evaluating PRO data from the ASCEMBL study, it was clearly shown that patients receiving asciminib demonstrated a trend for improvement in CML disease-related and treatment-related symptoms and HRQoL compared with baseline and relative to bosutinib within the first 48 weeks of treatment; and asciminib-treated patients did not report worsening of treatment-related symptoms.¹⁴ In addition, very recently, early results of the ASC4FIRST trial (ClinicalTrials.gov identifier NCT04971226) have indicated that asciminib produced fewer AEs than imatinib and 2G-TKIs in patients who had newly diagnosed CML-CP at a median follow-up of approximately 1.5 years.²⁷ The rates of treatment discontinuation because of AEs among patients who received asciminib, imatinib, and 2G-TKIs were 4.5%, 11.1%, and 9.8%, respectively; and the better tolerability of asciminib over imatinib and 2G-TKIs most probably would translate into better HRQoL among this patient population with a longer follow-up.

In conclusion, because patients with CML-CP live longer in the era of TKIs, evaluating HRQoL, especially by using PRO measures, plays an extremely important role in the management of their diseases. Although there have been numerous studies published in the literature on this topic, there are still limited data on the newer TKIs, including olverembatinib. Therefore, although the number of patients included in this study was relatively small, as stated by the authors, the data presented here by Yu and colleagues¹⁵ are very valuable. It was also underlined by the authors that health care systems differ from country to country; and, because olverembatinib recently has been tested outside of China,⁶ further prospective studies with increased numbers of patients from different populations are still warranted to evaluate HRQoL by using PRO measures in patients receiving treatment with olverembatinib.

Ahmet Emre Eşkazan reports advisory board honoraria and speakers' bureau honoraria from Bristol Myers Squibb, Novartis, and Pfizer, outside the current work.