Analyst Notes: AML treatment armamentarium ready to embrace more personalised therapies

Acute myeloid leukaemia (AML) is a rare and heterogeneous blood cancer with a dismal prognosis; five-year survival rates for patients in the US are approximately 26 percent. With a median diagnosis of 65 years, AML is considered a disease of older adults and patients have a high level of unmet need due to the high rates of relapse and significant lack of efficacious treatment options. For over 40 years, chemotherapy regimens dominated the AML treatment landscape with a notable absence of any targeted treatments.

In 2017, the AML therapeutic landscape witnessed a dramatic change with the approval of four new therapies in the US. Novartis' multi-kinase inhibitor Rydapt (midostaurin), Celgene/Agios Pharmaceuticals' IDH2 inhibitor Idhifa (enasidenib), Jazz Pharmaceuticals' liposomal chemotherapy Vyxeos (CPX-351) and Pfizer's anti-CD33 antibody-drug conjugate Mylotarg (gemtuzumab ozogamicin) were all approved for AML, marking an important milestone in drug development in this traditionally 'difficult-to-treat' disease.

Insights, Analysis & Opinion

Key opinion leaders (KOLs) interviewed by FirstWord for the report, Acute Myeloid Leukaemia: KOL Insight, are very pleased with the approval of new treatments in AML and believe a gradual shift in treatment patterns is now finally taking place.

Although KOLs are excited about the approval of the four therapies, they believe that each drug will have restricted use in niche patient settings initially. For example, Novartis' Rydapt is approved for upfront use in combination with 7+3 chemotherapy in patients with FLT3-mutations and KOLs believe it will become standard of care in this specific patient population. They deem it unlikely that Rydapt will be expanded to other settings until further data emerges. A similar situation is anticipated for Vyxeos with initial uptake limited to patients with secondary and/or high-risk AML.

The pipeline for AML encompasses many diverse mechanisms of action in Phase III development including next-generation FLT3 inhibitors (Daiichi Sankyo's quizartinib, Astellas' gilteritinib and Arog Pharma's crenolanib), Agios' IDH1 inhibitor ivosidenib and AbbVie/Roche's Bcl-2 inhibitor Venclexta/Venclyxto (venetoclax).

KOLs admit that Rydapt is likely to face fierce competition from the next-generation FLT3 drugs as soon as they are approved. They are particularly impressed with the QuANTUM-First study investigating quizartinib in the front-line setting and the ongoing head-to-head study comparing crenolanib with Rydapt. Experts also hold high hopes for pipeline agents venetoclax and ivosidenib based on the published Phase II data so far.

"The walls are crumbling for AML. The treatment has gotten much more complex. Patients will have their disease molecularly classified. About half of the [patients] are going to have a therapy dictated very specifically by the genetics, and the other half are going to have more options, such as drugs like venetoclax or Vyxeos. Outcomes are going to continue to improve overall. I think everything is continuing to go up, finally for the older patients as well." - US Key Opinion Leader

Although the treatment of AML has not shifted away from chemotherapy in decades, KOLs are now more hopeful that the treatment paradigm is gradually evolving towards the use of efficacious targeted agents in patients with specific mutations. The approval of Rydapt and Idhifa for FLT3-mutated and IDH2-mutated patients, respectively, has renewed KOL hopes that treatment of AML will become increasingly personalised in the near future.

"It'll be increasing patient stratification using molecular data and precision medicine approaches. We will be using these novel therapies alongside a backbone of chemotherapy, rather than individually." - EU Key Opinion Leader

While an influx of targeted agents are expected to enter the market, importantly, KOLs do stress that chemotherapy will remain as a crucial backbone onto which the targeted drugs will be added. KOLs also emphasise that 'non-targeted' agents such as Vyxeos and venetoclax will also help to dramatically improve outcomes for patients, particularly the older unfit patient subgroup and those with poor-risk profiles.

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