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16th December 2021
Addition of ivosidenib to azacitidine therapy in older patients with acute myeloid leukaemia (AML) improved overall survival, event-free survival and clinical response according to results presented at the ASH 2021 conference by researchers from Hospital Universitari i Politècnic La Fe, Valencia, Spain.
The results were derived from the AGILE trial which is a global, Phase III, multicentre, double-blind, randomised, placebo-controlled clinical trial to evaluate the efficacy and safety of Ivosidenib (IVO) and azacitidine (AZA) compared to placebo and azacitidine in adult patients with previously untreated isocitrate dehydrogenase 1 mutations (IDH1m) AML and who are considered appropriate candidates for non-intensive therapy.
Somatic mutations in IDH1 are present in between 6 and 10% of patients with AML and Ivosidenib, is an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme and approved by the FDA for adults with relapsed/refractory mIDH1 AML and those with newly diagnosed mIDH1 AML who are ≥ 75 years or have comorbidities that preclude use of intensive induction chemotherapy. Data from an earlier phase 1b study of 23 patients with newly diagnosed mIDH1 AML showed a favourable safety profile and encouraging clinical activity of the ivosidenib + azacitidine combination.
For the present study, the Spanish team randomised patients 1:1 to IVO 500 mg once daily + AZA 75 mg/m2 subcutaneously or intravenously, for 7 days in 28-day cycles, or placebo + AZA (PBO+AZA). Included patients were those with untreated AML, confirmed mIDH1 status and not eligible for induction chemotherapy. The primary endpoint of the study was event-free survival (EFS) defined as the time from randomisation until treatment failure, i.e. failure to achieve complete remission [CR] by week 24, relapse from remission, or death from any cause. The main secondary endpoints were the complete remission (CR) rate, overall survival (OS) and objective response rate (OOR). The researchers also examined the adverse event rates for both groups of patients.
A total of 146 patients were randomised to IVO+AZA or placebo+ AZA (PLA+ AZA) with 70 patients and a median age of 76 years randomised to IVO+AZA.
In terms of the primary outcome, EFS, this was statistically significant (hazard ratio, HR = 0.33, 95% CI 0.16 – 0.69, p = 0.0011) in favour of the IVO+AZA arm. In addition, the median OS was 24 months vs 7.9 months (IVO+AZA vs PLA+ AZA) (HR = 0.44, 95% CI 0.27 – 0.73, p = 0.0005) and CR rate with IVO+AZA was 47.2% vs 14.9% (PLA+AZA, p < 0.001), the median time to CR was 4.3 months with IVO+AZA vs 3.8 months with PLA+AZA and finally, the ORR was 62.5% vs 18.9% (IVO+AZA vs PLA+ AZA, p < 0.0001).
In terms of safety, common all-grade adverse events occurring in > 20% of patients receiving IVO+AZA vs PLA+AZA were nausea (42.3% vs 38.4%), vomiting (40.8% vs 26.0%), diarrhoea (35.2% vs 35.6%), pyrexia (33.8% vs 39.7%), anemia (31.0% vs 28.8%), febrile neutropenia (28.2% vs 34.2%), thrombocytopenia (28.2% vs 20.5%), constipation (26.8% vs 52.1%), and pneumonia (23.9% vs 31.5%).
A total of 66 (93.0%) patients receiving IVO+AZA compared with 69 (94.5%) patients receiving PLA+AZA experienced a grade ≥ 3 adverse event. Based on the recommendation of the Independent Data Monitoring Committee, further enrolment into the study was prematurely discontinued due to evidence of benefit.
The authors concluded that the IVO+AZA combination demonstrated the clinical benefit in this difficult-to-treat AML population.
Montesinos, P et al. AGILE: A Global, Randomized, Double-Blind, Phase 3 Study of Ivosidenib + Azacitidine Versus Placebo + Azacitidine in Patients with Newly Diagnosed Acute Myeloid Leukemia with an IDH1 Mutahttps://hospitalhealthcare.com/category/clinical/oncology/. ASH conference 2021
13th December 2021
End-of-life discussions with adults diagnosed with acute myeloid leukaemia (AML) often occur at a later stage of their disease when they are facing a health crisis suggesting that clinicians are missing an opportunity to have such conversations at an early stage when patients are best equipped to discuss their options and preferences. This was the finding of a study by researchers from the Department of Medicine, Massachusetts General Hospital, Boston, US, presented at ASH 2021.
Patients who have high-risk AML will often experience intense medical care such as hospitalisation and intensive care unit (ICU) admission towards the end of their lives. Moreover, despite a poor prognosis, many patients with AML and their caregivers often have substantial misconceptions about their prognosis. Such misconceptions might lead to difficult code status transitions (i.e., the type of emergency treatment a person would or would not receive if, for example, their heart or breathing were to stop) towards the end of their lives. However, studies examining code status transitions in patients with AML are lacking.
For the present study, the US researchers conducted a mixed-methods study of patients with high-risk AML enrolled in supportive care studies at their hospital and defined high-risk AML as either a new diagnosis in patients greater than 60 years of age or in those with relapsed/refractory AML.
Two physicians used consensus-driven medical record review to characterise code status transitions from time of diagnosis to death and identify patient, family, and palliative care involvement. Code status was coded as ‘full’ (confirmed or presumed), ‘restricted’ (i.e., do not resuscitate), or ‘comfort measures only’ (CMO). The researchers then used logistic regression to explore whether patient factors or features of the code status discussion were associated with the time between the last code status transition and death.
The study enrolled 200 patients and at the time of their diagnosis of high-risk AML, 86.0% of patients were ‘full code’ (38.5% presumed, 47.5% confirmed) and 8.5% had restrictions on end-of-life sustaining therapies. Overall, 57% experienced a code status transition, with a median of two transitions (range 1-8) during their illness course with a total of 206 code status transitions described across the cohort.
The median time from diagnosis to first code status transition was 212 days (range 7-4507), and from last transition to death was 2 days (range 0-350). Most of these final code status transitions (71.1%) were transitions to CMO near the end of life and only 60.5% of patients who underwent a code status transition participated in their last code status change.
In contrast, patients and families participated in 87.7% of the last code status transitions and palliative care was involved in nearly half (42.1%). A substantial minority of last code status transitions occurred in the ICU or emergency department (26.3%). We identified three processes leading to code status transitions: pre-emptive conversations prior to any clinical change (15.6%); anticipatory conversations at the time of acute clinical deterioration (32.2%) and finally, futility conversations after acute clinical deterioration, focused on withdrawing life-sustaining therapies (51.0%).
Both older age (p < 0.001) and receipt of non-intensive chemotherapy (p = 0.003) were associated with a longer time from the last code status transition to death. In contrast, futility conversations were associated with shorter time from last code status transition to death (p < 0.001) compared to pre-emptive or anticipatory conversations.
The authors concluded that almost half of patients were “presumed full code” at the time of their diagnosis and most experienced code status transitions at the end-of-life which focused on the futility of life-sustaining therapies after acute clinical deterioration. They added how these results suggest that goals of care discussions occur too late in the typical illness course of patients with poor prognosis, high-risk AML. Interventions focused on enhancing patient engagement in timely discussions regarding their end of life care preferences are warranted.
Abrams HR et al. Code Status Transitions in Patients with High-Risk Acute Myeloid Leukemia (AML). ASH Conference 2021