In the phase III CLTR0310-301 study, CPX-351 (Vyxeos®) was shown to be associated with a significantly longer overall survival (OS) than 7+3 chemotherapy in older patients with high-risk newly diagnosed or secondary acute myeloid leukaemia (AML).1,2 Subsequently, real-world studies have consistently confirmed the efficacy and safety of CPX-351 in this setting. Furthermore, these real-world studies also addressed some of the remaining data gaps, including the use of CPX-351 in younger patients.1–3 This report provides a brief summary of the ‘real-world evidence portfolio’ for CPX-351, underscoring the reproducibility of the phase III data.
Real-World vs. 301 study
The achievement of a complete response (CR) or a complete response with incomplete haematological recovery (CRi) remains a key treatment objective in patients with AML. In fact, patients who achieve such a remission are more likely to proceed to allogeneic haematopoietic cell transplantation (HCT), which in turn improves the likelihood of long-term survival. Real-world studies with CPX-351 reported either higher (53-80%) or similar (44-50%) CR/CRi rates than what was reported with this agent in the 301 study (48%).1–21 Among patients with a CR/CRi, 38-64% proved to be measurable Residual Disease (MRD) negative after CPX-351 therapy.3,7,11,12,14,15,18,19,21 Of note, the broad range in this MRD-negativity rate probably reflects differences in the methods and thresholds that were used in the different studies.3 MRD-negativity was not evaluated in the phase III 301 study. As such, this further underscores the added value of these real-world studies in providing additional insights into the efficacy of CPX-351.3
Historically, it is uncommon to see a longer median OS in real-world studies than in randomized controlled trials (RCTs). This is a result of the fact that real-world patient populations are typically more diverse, and because the management and/or assessment of patients is less standardised.3 Interestingly, however, most real-world studies with CPX-351 did report a longer median OS (12.1-24.0 months or not reached) compared to the phase III trial (9.56 and 9.33 months in the primary and long-term follow-up analysis, respectively).1–6,8,11,12,14–20,22 In 2 other real-world studies, the median OS values were comparable to what was seen in the 301 study (9.1 and 10.4 months) to the 301 study.9,21 Finally, two retrospective studies from the US reported a shorter median OS value of 5.2 and 7.1 months, respectively.13,23 However, it is important to underscore that these studies included a high proportion of patients with prior hypomethylating agent (HMA) exposure (70% and 100% vs. 41% in the phase III trial), which is typically associated with poor outcomes.1,3,13,23
Most of the real-world studies primarily focussed on older patients, with about three-quarters of patients being at least 60 years of age. Among these patients, the median OS values ranged from 10.4 to 21 months.3,11,14,15,17,19,21,22 Several studies have compared the outcomes between younger and older patients receiving CPX-351, resulting in divergent findings.4,13,16 These discrepancies between studies may be attributed to different factors, including short follow-up times, small sample sizes and differences in patient populations.3 An analysis from the National Cancer Registration and Analysis Service (NCRAS) in England represents the largest dataset for CPX-351 (n=353) outside the US. This study includes 104 adult patients below 60 years of age and has mature Kaplan–Meier curves (up to 4 years), which allow a clear visualisation of the potential impact of a stem cell transplantation. The results of this study revealed that patients aged <60 had longer OS compared to those aged ≥60 (17.3 vs. 11.7 months, respectively), addressing the data gap in the <60s population and providing long-term OS data for both younger and older patients. Notably, 42% of patients in this population underwent a HCT. Of those, 54% vs. 38% were aged 60 and ≥60 years, respectively.22 Another important treatment goal of intensive induction therapy for patients with AML is to bridge patients to HCT, which can be associated with long-term survival and eventual cure. The percentage of patients proceeding to HCT in the available real-world studies ranges considerably, from 28% to 81%.4–9,11–24 However, most studies indicate a HCT percentage that is comparable to or higher than what was seen in the phase 3 trial (35%).1 Notably, of the nine studies with HCT rates ≥40%, two were conducted in younger adults. Importantly, post-HCT OS was typically not yet reached in most studies, suggesting that CPX-351 can provide a bridge to HCT leading to a prolonged post-HCT OS in younger and older adults with AML.3,8,23,9,11–16,1
CPX-351 vs. historical controls or HMA/venetoclax
A retrospective analysis comparing AML patients treated with CPX-351 to historical cohorts treated with conventional chemotherapy proved to be favourable for CPX-351 and yielded data that were consistent with the 301 study and with other real-world datasets.1-25 In this study, a CR/CRi rate of 52% was reported with a HCT rate of 34%, and 54% of patients being MRD negative after therapy. The median OS post-HCT was not yet reached. While CPX-351 proved to be associated with a numerically better OS (10.3 months) than historical chemotherapy (9.1 months), this difference was not significant, probably due to the small sample size and lacking data on gene mutations or prior HMA exposure in the historical cohort.25 CPX-351 was also compared to venetoclax (Ven) + HMA in two real-world studies. Importantly, there were significant differences in patient characteristics between treatment cohorts in both studies. In a retrospective study from the US mainly including older adults, the OS advantage with CPX-351 over Ven/HMA (17.3 vs. 11.1 months; p= 0.007) was attributed to the larger percentage of patients undergoing HCT after CPX-351 (48% vs. 19%; p< 0.001).3,17 A second US study of patients from a multicentre group and the Flatiron Health database also noted a significantly higher proportion of patients proceeding to HCT after CPX-351 (28% vs. 10%; p <0.0005). Notably, OS was improved among patients proceeding to HCT after CPX-351 vs. Ven/HMA (HR:1.27).3,5
Safety
No new safety concerns were identified with CPX-351 treatment in real-world analyses. Importantly, early mortality was relatively infrequent across the different studies, with several studies reporting a lower early mortality rate than what was seen in the phase III 301 trial (day 30: 6%; day 60: 14%).1,3,4,6,10,15,17–20 Across studies, most adverse Events (AEs) did not exceed grade 1 or 2 in severity and proved to be manageable. The most frequently reported AEs were infections, which was not unexpected given the delay in neutrophil recovery after CPX-351.6,9–11,14–16,18,24 A study from the non-profit Italian organisation SEIFEM analysed 200 patients with AML treated with CPX-351. Of the 249 febrile events that were recorded in this cohort, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. Importantly, the infection-related mortality was low (6%), and lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis (p=0.004).26
Real-world studies of CPX-351 exhibit consistently positive outcomes that align with those of the pivotal 301 study. In these studies, a considerable number of patients treated with CPX-351 achieved high CR/CRi rates and MRD negativity, alongside prolonged survival. Additionally, a significant proportion of patients were successfully bridged to HCT and these patients displayed long-term or not yet reached OS post-transplantation. Moreover, CPX-351 exhibited a manageable safety profile without new safety concerns and low early mortality rates. In addition, these data also confirmed the efficacy and safety of CPX-351 in younger adults who were not included in the 301 study. Consequently, these data further strengthen the ‘portfolio of real-world evidence’ for CPX-351, demonstrating the reproducibility of the pivotal 301 study outcomes.
BE-VYX-2400004, date of approval March 2024
| Vyxeos Liposomal 44 mg/100 mg, powder for concentrate for solution for infusion., 1 vial 50 mg Price 5200 euro, excl. BTW/hors TVA. |
NAME OF THE MEDICINAL PRODUCT. Vyxeos liposomal 44 mg/100 mg powder for concentrate for solution for infusion. QUALITATIVE AND QUANTITATIVE COMPOSITION. Each vial of powder for concentrate for solution for infusion contains 44 mg of daunorubicin and 100 mg of cytarabine. After reconstitution the solution contains 2.2 mg/mL daunorubicin and 5 mg/ mL cytarabine encapsulated in liposomes in a fixed combination in a 1:5 molar ratio. PHARMACEUTICAL FORM. Powder for concentrate for solution for infusion. Purple, lyophilised cake. CLINICAL PARTICULARS. Therapeutic indications. Vyxeos liposomal is indicated for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukaemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Posology and method of administration. Vyxeos liposomal treatment should be initiated and monitored under the supervision of a physician experienced in the use of chemotherapeutic medicinal products. Vyxeos liposomal has a different posology than daunorubicin injection and cytarabine injection and it must not be interchanged with other daunorubicin and/or cytarabine containing products. Posology. Vyxeos liposomal dosing is based on the patient’s body surface area (BSA) according to the following schedule: First induction: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1, 3, and 5. Second induction: daunorubicin 44 mg/m2 and cytarabine 100 mg/m2 on days 1 and 3. Consolidation: daunorubicin 29 mg/m2 and cytarabine 65 mg/m2 on days 1 and 3. Recommended dosing schedule for induction of remission. The recommended dosing schedule of Vyxeos liposomal 44 mg/100 mg/m2, administered intravenously over 90 minutes: on days 1, 3, and 5 as the first course of induction therapy. on days 1 and 3 as subsequent course of induction therapy, if needed. A subsequent course of induction may be administered in patients who do not show disease progression or unacceptable toxicity. The attainment of a normal-appearing bone marrow may require more than one induction course. Evaluation of the bone marrow following recovery from the previous course of induction therapy determines whether a further course of induction is required. Treatment should be continued as long as the patient continues to benefit or until disease progression up to maximum of 2 induction courses. Recommended dosing schedule for consolidation. The first consolidation cycle should be administered 5 to 8 weeks after the start of the last induction. The recommended dosing schedule of Vyxeos liposomal is 29 mg/65 mg/m2, administered intravenously over 90 minutes: on days 1 and 3 as subsequent courses of consolidation therapy, if needed. Consolidation therapy is recommended for patients achieving remission who have recovered to absolute neutrophil count (ANC) > 500/µL and the platelet count has recovered to greater than 50,000/µL in the absence of unacceptable toxicity. A subsequent course of consolidation may be administered in patients who do not show disease progression or unacceptable toxicity within the range of 5 to 8 weeks after the start of the first consolidation. Treatment should be continued as long as the patient continues to benefit or until disease progression, up to maximum of 2 consolidation courses. Recommended dose adjustments during treatment. Patients should be monitored for haematologic response and toxicities. Dosing should be delayed or permanently discontinued, if necessary, as described below. Patients may be pre-medicated for nausea and vomiting. An anti-hyperuricemic therapy should be considered (e.g., allopurinol) prior to initiating Vyxeos liposomal. Hypersensitivity. For mild hypersensitivity symptoms (e.g., mild flushing, rash, pruritus), the treatment should be stopped, and the patient should be supervised, including monitoring of vital signs. The treatment should be restarted slowly once the symptoms have resolved, by halving the rate of infusion and intravenous diphenhydramine (20-25 mg) and intravenous dexamethasone (10 mg) should be given. For moderate hypersensitivity symptoms (e.g., moderate rash, flushing, mild dyspnoea, chest discomfort) the treatment should be stopped. Intravenous diphenhydramine (20-25 mg or equivalent) and intravenous dexamethasone (10 mg) should be given. The infusion should not be restarted. When the patient is retreated, Vyxeos liposomal should be given at the same dose and rate and with premedication. For severe/life-threatening hypersensitivity symptoms (e.g., hypotension requiring vasopressor therapy, angioedema, respiratory distress requiring bronchodilation therapy, generalised urticaria), the treatment should be stopped. Intravenous diphenhydramine (20-25 mg) and dexamethasone (10 mg) should be given, and an epinephrine (adrenaline) or bronchodilators should be added if indicated. Do not reinitiate infusion, and do not retreat. Treatment with Vyxeos liposomal should be permanently discontinued. Patients should be monitored until symptoms resolve. Cardiotoxicity. Assessment of cardiac function prior to start of treatment is recommended, especially in patients with a high risk of cardiac toxicity. Vyxeos liposomal treatment should be discontinued in patients who develop signs or symptoms of cardiomyopathy, unless the benefits outweigh the risks. Missed dose. If a planned dose of Vyxeos liposomal is missed, the dose should be administered as soon as possible and the dosing schedule adjusted accordingly, maintaining the treatment interval. Special populations. Renal impairment. Dose adjustment is not required for patients with mild (creatinine clearance [CrCL] 60 mL/min to 89 mL/min by Cockcroft Gault equation [C-G]), moderate (CrCL 30 mL/min to 59 mL/min) or severe (CrCL<30 mL/min) renal impairment. There is no experience with Vyxeos liposomal in patients with end-stage renal disease managed with dialysis. Hepatic impairment Dose adjustment is not required for patients with a bilirubin level less than or equal to 50 µmol/L. There is no experience with Vyxeos liposomal in patients with hepatic impairment resulting in a bilirubin level greater than 50 µmol/L. Vyxeos liposomal should only be used in patients with severe hepatic impairment if the benefits outweigh the risks. Elderly population. No dose adjustment is required in elderly patients (≥65 years). Paediatric population. Outside its authorised indications Vyxeos liposomal has been studied in paediatric and young adult patients aged 1-21 years with relapsed AML. Due to the limited size of these studies, it is not possible to conclude that the benefits of the use outweigh the risks. Currently available data are described in sections 5.1 and 5.2, but no recommendation on a posology can be made. Method of administration. Vyxeos liposomal is for intravenous use only. It must not be administered via an intramuscular, intrathecal, or subcutaneous route. Vyxeos liposomal is administered by intravenous infusion over a period of 90 minutes. Care should be taken to ensure there is no extravasation to prevent the risk of tissue necrosis. For instructions on reconstitution and dilution of the medicinal product before administration, see section 6.6. Contraindications. History of serious hypersensitivity to the active substances or to any of the excipients. Undesirable effects. Summary of the safety profile. The most frequently occurring adverse reactions (ADRs) were hypersensitivity including rash (66.9%), febrile neutropenia (63.5%), oedema (52.3%), diarrhoea/colitis (49.9%), mucositis (49.9%), fatigue (46.4%), musculoskeletal pain (44.5%), abdominal pain (36.3%), decreased appetite (33.9%), cough (33.9%), headache (32.3%), chills (31.2%), arrhythmia (30.4%), pyrexia (29.6%), sleep disorders (25.1%), and hypotension (23.7%).The most serious and frequently occurring ADRs were infection (58.7%), cardiotoxicity (18.7%) and haemorrhage (13.1%). Tabulated list of adverse reactions. ADRs have been included under the appropriate category in the table below according to the highest frequency observed in any of the main clinical studies. Frequencies are defined as: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. For classification of ADRs which occur at Grades 3-5, a comprehensive listing is available from the NCI at NCI CTCAE. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4), with specific parameters according to the organ system involved. Death (Grade 5) is used for some of the criteria to denote a fatality. Table 3: ADRs reported in clinical studies in patients treated with Vyxeos liposomal (n=375). ADRs/Frequency (%). Infections and infestations. Very common: Infection (78.1). Blood and lymphatic system disorders. Very common: Febrile neutropenia (63.5). Common: thrombocytopenia (4.5), Neutropenia (3.7), Anaemia (3.2). Immune systems disorders. Very common: Hypersensitivity (including rash) (66.9). Metabolism and nutrition disorders. Common: Tumour lysis syndrome (7.5). Psychiatric disorders. Very common: Sleep disorders (25.1), Anxiety (17.3), Delirium (15.5). Nervous system disorders. Very common: Headache (32.3), Dizziness (23.2). Eye disorders. Very common: Visual impairment (10.4). Cardiac disorders. Very common: Cardiotoxicity (72), Arrhythmiaa (30.4), Chest pain (17.6). Vascular disorders. Very common: Haemorrhage (69.1), Hypotension (23.7), Hypertension (17.3). Respiratory, thoracic and mediastinal disorders. Very common: Dyspnoea (36.5), Cough (33.9), Pleural effusion (13.9). Gastrointestinal disorders. Very common: Nausea (51.7), Diarrhoea/colitis (49.9), Mucositis (49.9), Constipation (42.7), Abdominal pain (36.3), Decreased appetite (33.9), vomiting (27.7). Common: Dyspepsia (9.6). Skin and subcutaneous tissue disorders. Very common: Pruritus (17.3), Hyperhidrosis (10.1). Common: Night sweats (8.3), Alopecia (3.2). Uncommon: Palmar-plantar erythrodysaesthesia syndrome (0.8). Musculoskeletal and connective tissue disorders. Very common: Musculoskeletal pain (44.5). Renal and urinary disorders. Very common: Renal insufficiency (10.4). General disorders and administration site conditions. Very common: Oedema (52.3), Fatigue (46.4), Chills (31.2), Pyrexia (29.6). Grade 3-5 ADRs/Frequency (%). Infections and infestations. Very common: Infection (58.7). Blood and lymphatic system disorders. Very common: Febrile neutropenia (62.4). Common: Thrombocytopenia (3.7), Neutropenia (3.5), Anaemia (2.1). Immune systems disorders. Common: Hypersensitivity (including rash) (9.1). Metabolism and nutrition disorders. Common: Tumour lysis syndrome (2.7). Psychiatric disorders. Common: Delirium (2.4). Uncommon: Sleep disorders (0.5). Nervous system disorders. Common: Headache (1.1). Uncommon: Dizziness (0.8). Eye disorders. Uncommon: Visual impairment (0.3). Cardiac disorders. Very common: Cardiotoxicity (18.7). Common: Arrhythmiaa (4.3), Chest pain (1.9). Vascular disorders. Very common: Haemorrhage (13.1). Common: Hypertension (6.9), Hypotension (4.5). Respiratory, thoracic and mediastinal disorders. Very common: Dyspnoea (13.1). Uncommon: Pleural effusion (0.8). Description of selected adverse reactions. Infections. Due to the neutropenia experienced with Vyxeos liposomal, infections of various types were very common ADRs. Pneumonia, sepsis and bacteriaemia were the most frequently seen serious infection ADRs in the clinical studies population. The incidence of infection events was 78.1%; the incidence of non-serious events of infections was 73.1%, the incidence of serious events of infections was 28.5%; the incidence of infections which led to discontinuation is 0.5%. The incidence of fatal infections was 6.9%. The fatal infections experienced were sepsis and pneumonia. Haemorrhage. Due to the thrombocytopenia experienced with Vyxeos liposomal a variety of haemorrhagic events were seen in clinical studies. The most common haemorrhagic event was epistaxis, and the majority of these were considered not serious (29.1%). The incidence of haemorrhage events is 69.1%; the incidence of non-serious events of haemorrhage was 67.2 %; the incidence of serious events of haemorrhage is 5.6%; the incidence of haemorrhage which led to discontinuation is 0. The incidence of fatal haemorrhage was 2.1%. Serious or fatal haemorrhagic events, including fatal central nervous system (CNS) haemorrhages, associated with severe thrombocytopenia were seen in patients treated with Vyxeos liposomal. Cardiotoxicity. Cardiotoxicities were seen in Vyxeos liposomal clinical studies. The most frequently reported serious ADRs were decreased ejection fraction and congestive cardiac failure. Cardiotoxicity is a known risk of anthracycline treatment. The incidence of all cardiotoxicity events was 72.0%; the incidence of non-serious events of cardiotoxicity was 68.5 %; the incidence of serious events of cardiotoxicity was 9.1%; the incidence of cardiotoxicity which led to discontinuation is 0.5%. Incidence of fatal cardiotoxicity events is 0.5%. Cardiac arrest was reported as a fatal event; the patient experienced thrombocytopenia and neutropenia which contributed to cardiac arrest. Hypersensitivity. Hypersensitivity reactions were very common ADRs in Vyxeos liposomal clinical studies. The most frequently reported hypersensitivity ADRs were rash and the majority of these were not serious (38.9%). The incidence of all hypersensitivity events was 66.9%; the incidence of non-serious events of hypersensitivity was 66.4 %, of which 38.9 % were rash; the incidence of serious events of hypersensitivity is 1.1%; the frequency of hypersensitivity which led to discontinuation is 0. The frequency of fatal hypersensitivity events was 0. Paediatric population. The safety profile of Vyxeos liposomal in 38 paediatric patients with relapsed AML in study AAML1421 appeared to be in general similar to that observed in the approved indication in adults with newly treated AML treated with Vyxeos liposomal. However, adverse reactions in study AAML 1421 observed in paediatric patients that were different from or more severe than those seen in adults (acknowledging limitations of cross study comparisons) included rash maculo-papular (47.4%), electrocardiogram QT prolongation (28.9%), the early onset of cardiotoxicity (defined as > 10% decrease LVEF to final LVEF < 50% LVEF; 21.0%), severe hypokalaemia (13.2%), hyperglycaemia (7.9%) and ALT increased (7.9%). Hypertension was observed in 18.2% of these paediatric patients. No paediatric long-term safety data beyond the study duration (26 months) are available. There is, thus, no paediatric safety data to address the long-term cardiotoxicity of Vyxeos liposomal, including long-term cardiotoxicity when used at doses above the maximum life-time cumulative anthracycline dose. There are no data on the effects of Vyxeos liposomal treatment on growth and maturation. Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the FAGG Afd. Vigilantie, Galileelaan 5/03, 1210 BRUSSEL, www.eenbijwerkingmelden.be, e-mail: adr@fagg.be. MARKETING AUTHORISATION HOLDER. Jazz Pharmaceuticals Ireland Ltd 5th Floor, Waterloo Exchange Waterloo Road Dublin, D04 E5W7, Ireland. MARKETING AUTHORISATION NUMBER(S). EU/1/18/1308/001 1 vial, EU/1/18/1308/002 2 vials, EU/1/18/1308/003 5 vials. DATE OF REVISION OF THE TEXT. 06/2023. DELIVERY MODE. Medicinal prescription.
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