Combination therapy with novel agents for acute myeloid leukaemia: Insights into treatment of a heterogenous disease

Abstract

SummaryThe treatment landscape of acute myeloid leukaemia (AML) is evolving rapidly. Venetoclax in combination with intensive chemotherapy or doublets or triplets with targeted or immune therapies is the focus of numerous ongoing trials. The development of mutation‐targeted therapies has greatly enhanced the treatment armamentarium, with FLT3 inhibitors and isocitrate dehydrogenase inhibitors improving outcomes in frontline and relapsed/refractory (RR) AML, and menin inhibitors showing efficacy in RR NPM1mut and KMT2A‐rearranged AML. With so many new drugs approved, the number of potential combinatorial approaches to leverage the maximal benefit of these agents has increased dramatically, while at the same time introducing clinical challenges, such as key preclinical and clinical data supporting the development of combinatorial therapy, how to optimally combine or sequence these novel agents, how to optimise dose and duration to maintain safety while enhancing efficacy, the optimal duration of therapy and the role of measurable residual disease in decision‐making in both intensive and low‐intensity therapy settings. In this review, we will outline the evidence leading to the approval of key agents in AML, their on‐label current approvals and how they may be optimally combined in a safe and deliverable fashion to further improve outcomes in AML.

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“…In the last two decades, several efforts have provided appropriate tools to determine which patients are fit or unfit for ICT or non-ICT in clinical practice [83,86,87]. However, recent progress in understanding the genetic factors affecting AML outcomes has expanded treatment options for older patients, including targeted and lower-intensity therapies (Tale 3) [45][46][47][48][49][50] in both frontline and relapsed/refractory (R/R) settings [88,89]. In particular, combining HMAs, mainly azacytidine, with venetoclax is the current standard of care for AML patients unfit for ICT [51,[88][89][90][91].…”

“…However, recent progress in understanding the genetic factors affecting AML outcomes has expanded treatment options for older patients, including targeted and lower-intensity therapies (Tale 3) [45][46][47][48][49][50] in both frontline and relapsed/refractory (R/R) settings [88,89]. In particular, combining HMAs, mainly azacytidine, with venetoclax is the current standard of care for AML patients unfit for ICT [51,[88][89][90][91]. The availability and approval of this innovative treatment have led to significant changes in current clinical practice for which a recent Italian retrospective survey suggested modifications to the "Ferrara criteria" to accommodate the use of venetoclax/HMA, used in other than one-third of AML patients, compared to 2008-2016 [92].…”

“…Interestingly, in responsive patients fit for allogeneic SCT, CPX-351 is a feasible bridging measure [96]. Notably, low-intensity therapy, such as HMA/venetoclax [88][89][90][91]97,98] and molecularly tailored treatments [54,56,99], have been proven reliable bridges to allogeneic SCT. However, due to the frailty of older patients with comorbidities as well as socioenvironmental factors, the decision to undergo a transplant must be carefully considered by evaluating the treatment-related morbidity associated with allogenic SCT [1,4.88,92].…”

“…Before 2017, older AML patients who were considered fit were typically treated with standard ICT chemotherapy, while unfit patients aged 75 years and older received a hypomethylating agent (HMA) as a single agent [45][46][47][48][49][50]101]. However, the approval of new therapeutic combinations incorporating venetoclax [51,[88][89][90][91][92], which induces apoptosis in AML cells by BCL-2 inhibition, has changed this treatment landscape. The phase 3 VIALE-A trial included 431 patients 75 years older or with significant comorbidities.…”

“…Compared to LDAC alone, glasdegib with LDAC led to a significantly longer OS and a higher CR rate (8.8 vs. 4.9 months and 17% vs. 1%, respectively) [104]. Other than these therapeutic options relying on dysregulated biological activities, different treatment modalities have been developed based on recognizing somatic mutations druggable by specific targeted agents [13,14,89]. With this regard, the approval of IDH1 inhibitors for patients with IDH1-mutated ND AML unsuitable for ICT and those with R/R disease [56][57][58]105] allows targeted therapy in this setting.…”