Navigating secondary acute myeloid leukaemia in 2023

In 2022, both the WHO and ICC have updated the classification of acute myeloid leukaemia (AML) in order to reflect recent advances in disease understanding. In terms of secondary AML, there are now new definitions of therapy-related AML and AML with myelodysplasia-related changes. Furthermore, it is becoming more and more clear that also older patients benefit from intensive chemotherapy, followed by haematopoietic stem cell transplantation.

Secondary AML in 2023, what has changed and what has stayed the same?

The classification of acute myeloid leukaemia (AML) has recently been updated to reflect advances in disease understanding. In 2022, the World Health Organisation (WHO) and International Consensus Classification (ICC) have revised the classification of therapy-related AML (t-AML) or AML with myelodysplasia-related changes (AML-MRC). The new WHO classification of AML distinguishes between AML with defining genetic abnormalities and those defined by differentiation, which replaces the ‘AML not otherwise specified’. In particular, among AML with genetic abnormalities, ‘AML myelodysplasia-related (AML-MR)’ now replaces the previous AML-MRC. In the 2022 ICC, AML-MRC is now described as ‘AML with myelodysplasia-related cytogenetic abnormalities’ or ‘AML with myelodysplasia-related gene mutations’. For therapy-related AML, the WHO 2022 classification now uses the term AML-pCT (post cytotoxic therapy), which is a qualifier that can be applied to any subgroup or category to denote AML with a history of prior chemotherapy, radiation therapy or exposure to PARP1 inhibitors. In the ICC 2022 classification, these patients are still described as therapy-related AML and this is a qualifier that can be applied to any subgroup or category to denote AML with a history of prior chemotherapy, radiotherapy or immune intervention.

According to the European LeukemiaNet (ELN) 2022 guidelines for the treatment of patients diagnosed with AML, anthracyclines and cytarabine remain the backbone of intensive chemotherapy. For patients fit for intensive chemotherapy, Vyxeos Liposomal is recommended for patients with AML-MRC or t-AML, as defined by the WHO 2016, WHO 2022 or ICC classifications.

Improving treatment outcomes

To date, intensive chemotherapy regimens remain the cornerstone for long-term survival of older patients with high-risk or secondary AML. Only allogeneic haematopoietic stem-cell transplantation (HCT), performed when a patient is in remission, can be considered for longer survival. Therefore, treatment regimens that can increase the frequency and depth of response are of utmost value for these patients. Key factors to determine the patient’s fitness and their ability to tolerate intensive chemotherapy are age, performance status, comorbidities and/or geriatric assessment. While previously older adults were often not considered candidates for standard induction chemotherapy (e.g. a regimen of cytarabine for 7 days and daunorubicin for 3 days, the ‘7+3’ regimen) and HCT based on age alone, recent research has been changing the therapeutic landscape of these patients, demonstrating that also many older adults benefit from this approach. Indeed, HCT provides improved overall survival in patients aged 60-75 years diagnosed with de novo or secondary AML, compared to chemotherapy alone (5-year OS rate of 28.6% vs. 13.8%).

Vyxeos Liposomal is approved in the European Union for the treatment of adults with newly diagnosed, therapy-related AML or AML-MRC. In Study 301, older patients aged 60-75 years with newly diagnosed high-risk or secondary AML received Vyxeos Liposomal or conventional chemotherapy (the ‘7+3’ regimen). After a median follow-up of 60.91 years, median OS was 9.33 months with Vyxeos Liposomal and 5.95 months with 7+3 (HR[95%CI]: 0.70[0.55-0.91]). Furthermore, 35% of patients receiving Vyxeos Liposomal and 25% of patients receiving standard treatment received HCT. In patients who received Vyxeos Liposomal and underwent HCT, OS was maintained at >50% at five years post randomisation. In patients who underwent HCT, median OS from the date of HSCT was not reached (95%CI 16.23–not estimable) for Vyxeos Liposomal versus 10.25 months (6.21–16.69) for 7+3 (HR[95%CI]: 0.51[95%CI: 0.28–0.90]). However, also among patients aged 60-75 years who achieved CR/Cri and did not undergo HCT, median OS was numerically longer with Vyxeos Lyposomal (14.72 vs. 7.59 months, HR[95%CI]: 0.53[0.23-1.22]).

Furthermore, real-world European evidence could confirm that Vyxeos Liposomal is effective, regardless of the patient’s age and in those with poor prognostic factors, and results in a large proportion of patients that is able to proceed to HCT. As such, allogeneic transplantation after Vyxeos Liposomal can lay the foundation towards long-term survival in this patient population.

Conclusion

The approved indication for Vyxeos Liposomal was based on the WHO 2016 classification of AML. However, Vyxeos Liposomal continues to be recommended for the treatment of t-AML and AML-MRC as per the ELN 2022 recommendations, despite the evolution of AML classification. In addition, findings from European real-world studies now support the efficacy and safety seen with Vyxeos Liposomal in the randomised, controlled Study 301. Moreover, an allogeneic transplantation after Vyxeos Liposomal can lay the foundation towards long-term survival in older patients with secondary AML.

Reference

Rambaldi A, Lemoli R and Mehta P. A case study symposium: Navigating secondary Acute Myeloid Leukaemia (AML) in 2023. Presented at EHA 2023; Session HSS9038.