ABSTRACT
CONTEXT: In CML-CP, the BCR::ABL1 T315I mutation confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs), except ponatinib and olverembatinib. In a previous analysis of the phase I, dose-escalation trial X2101, asciminib-a BCR::ABL1 inhibitor that binds to the ABL myristoyl pocket-demonstrated efficacy and a favorable safety profile in heavily pretreated patients with T315I-mutated CML. We report updated efficacy and safety data in patients with CML-CP with the T315I mutation (data cutoff: January 6, 2021). OBJECTIVE: Provide updated safety and efficacy data for patients with T315I-mutated CML-CP after added exposure. DESIGN: Patients with T315I-mutated CML-CP and treated with >=1 prior TKI were enrolled and received asciminib 200mg twice daily (BID). RESULTS: 48 patients were included;25 patients (52.1%) received >=3 prior TKIs. At data cutoff, treatment was ongoing in 27 patients (56.3%). 45 of 48 patients were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable patients, 19 (42.2%) achieved MMR by week 24 and 22 (48.9%) by week 96. Evaluable patients included 26 ponatinib-pretreated and 19 ponatinib-naive patients;34.6% and 68.4%, respectively, achieved MMR by week 96. The probability of maintaining MMR for >=96 weeks was 84% (95% CI, 68.1%-100.0%). 23 of 37 patients (62.2%) with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS <=1% by week 96. The safety/tolerability profile of asciminib remained favorable after =9 months of added exposure (median duration of exposure, 2.08 years;range, 0.04-4.13 years). The most common (>=10%) grade >=3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations) and thrombocytopenia (14.6%). Arterial occlusive events occurred in 4 patients (8.3%);none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation occurred in 5 patients (10.4%). Only 2 study deaths, both due to COVID-19, occurred in this patient population. CONCLUSIONS: After a median exposure of >2 years, asciminib monotherapy 200mg BID exhibited a sustained, favorable safety profile and clinical efficacy in patients with T315I-mutated CML-CP-a population with high unmet medical need. This updated analysis confirms asciminib as a treatment option for patients with T315I-mutated CML-CP, including those previously treated with ponatinib.
ABSTRACT
Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.
ABSTRACT
Objectives: The Melanoma UK digital registry, launched in collaboration with Melanoma UK in 2017, captures real-world patient-reported quality of life (QoL), symptoms, and side effects of melanoma treatment using a mobile application. 729 UK patients with melanoma have since joined the registry, with approximately 60% of participants in Stage 3 and 4 of the disease. Due to the COVID-19 pandemic, a national lockdown was announced in the UK in March 2020 with an instruction to stay at home, particularly for vulnerable people with health conditions. The impact of the fundamental changes in day-to-day living and the delivery of healthcare on people diagnosed with melanoma needs to be better understood. This study explored if the COVID-19 pandemic was associated with changes in Melanoma UK registry participants’ QoL. Methods: QoL data, measured using EQ-5D and QLQ-C30 from 423 participants, were analysed. Data submitted between 03/2019 and 02/2020 were deemed pre-COVID-19 data;data submitted between 03/2020 and 03/2021 were considered as peri-pandemic data. A monthly average score was calculated for each domain of EQ-5D and QLQ-C30. T-tests were conducted to compare the individual domain scores calculated for the pre- and peri-pandemic periods. Results: EQ-5D: Mobility (p=0.03), self-care (p=0.03), usual activities (p=0.003), pain symptoms (p=0.03), and health in general (p=0.0004) improved during the pandemic. QLQ-C30: There was an observed improvement in physical (p=0.02), role (p=0.01), and social functioning (p=0.003). Fatigue (p=0.002) and pain symptoms (p=0.05) decreased during the pandemic. Participants also reported experiencing less financial difficulty (p=0.02) in comparison with the pre-pandemic period. No change in emotional well-being was observed. Conclusions: The QoL of patients with melanoma improved during the COVID-19 pandemic. Future research should involve qualitative interviews with melanoma patients and their caregivers to explore the mechanisms of this change, the role of support networks, and the impact on caregivers.
ABSTRACT
Introduction: COVID-19 has had a large impact upon UK society and healthcare, however little is currently known about its impact upon UK herbal medicine practice. This survey aimed to identify: changes to herbal medicine practice since the start of the pandemic, common herbs used to support people with COVID-19 symptoms and types of advice patients are seeking from herbal practitioners. Methods: We developed a mixed-methods e-survey for herbal practitioners, disseminated in June 2020 through practitioner professional bodies and social media. Quantitative results were analysed descriptively and qualitative results were analysed using basic content analysis. Results: Findings from 59 complete responses indicated that most practitioners have moved to phone or video consultations only, whilst 37% had observed a decline in patients with other conditions. 56% respondents reported seeing patients with COVID-19 symptoms and 27% seeing patients with a COVID-19 diagnosis. Herbal practitioners reported that patients most commonly asked for information about herbs to support the immune system (46/59, 78%) and herbs to support them during COVID-19 symptoms (36/59, 61%), although the percentage of patients asking for COVID-19 advice varied. Practitioners described using a range of herbs to support people with COVID-19 symptoms, most commonly Glycyrrhiza glabra L. (15/31, 48%), Echinacea spp. (13/31, 42%) and Andrographis paniculata (Burm.f.) Nees (8/31, 26%). Practitioners also recommended vitamin D (14/29, 48%) and C (8/29, 28%). Herbal practitioners’ main sources of information about COVID-19 were webinars from other herbalists (56%), research databases (58%) and NHS guidance (49%). Conclusions: The COVID-19 pandemic has had a substantial impact upon herbal medicine practice. Herbal practitioners are a source of information and support for patients with COVID-19 symptoms. However, herbal medicines used varied widely. Future research needs to evaluate these herbal medicines and to develop a comprehensive database on herbal substances used and their potential benefits and risks. Keywords: Herbal medicine, COVID-19, survey;herbal practitioners;practice delivery