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Acute myeloid leukemia (AML) is a heterogenous disease associated with multiple chromosomal abnormalities and gene mutations. This diversity contributes to differential responses to chemotherapy regimens, and consequently survival rates, meaning treating AML presents a challenge for clinicians. 1Current treatment protocols for AML involve induction chemotherapy, usually cytarabine and an anthracycline, followed by consolidation for favorable-risk patients or allogeneic hematopoietic stem cell transplant (allo-HSCT) for adverse-risk patients. 2Allo-HSCT is potentially curative in eligible patients, but many patients are unable to receive transplants due to existing comorbidities, a lack of suitable donor, or the risk of complications. 3

Over the last two decades, few drugs have been approved for the treatment of AML, however increased understanding of the leukemic genome has allowed the development of targeted therapeutic agents. 2,3Between April 2017 and November 2018, eight new drugs in various different classes were approved, including: enasidenib, ivosidenib, midostaurin, glasdegib, venetoclax, and gilteritinib. 4An overview of mutations that can be targeted in AML is available on the AML Global Portal (AGP).

Some of these targeted agents are being investigated in novel combination therapies, as different lines of AML treatment, and some as monotherapy compared to standard chemotherapy. This article provides a summary of AGP content relating to novel agent-containing combinations to date and introduces the new editorial theme of ‘Novel combination therapies using targeted agents.’

Expert opinions: What are targeted therapies and how might they impact the treatment of AML?

The AGP were pleased to speak to Andrew Weiduring the European School of Haematology(ESH) Translational Research Conference on AML, 2019, about how targeted therapies will be used in the future treatment of AML. In this interview, available below, Andrew Wei discusses whether these targeted agents should be used in combination or sequentially.

How will targeted therapies be used in the future?

During the American Society of Clinical Oncology(ASCO) meeting in 2018, the AGP spoke to Uma Borateabout how targeted therapies will impact the treatment of AML. Uma Borate discussed targeted agents, such as venetoclax, azacitidine, ivosidenib, and enasidenib.

Precision medicine may have a particular role in the treatment of older patients, since this population are often unable to receive allo-HSCT or intensive chemotherapy regimens. During the 61 st American Society of Hematology(ASH) meeting, the AGP spoke to John Byrdabout how precision medicine may be used to improve the outcomes of older patients with AML.

How can precision medicine improve outcomes in older patients with AML?

The AGP interviewed Courtney DiNardoabout the treatment of elderly or frail patients with AML at the 1 st National Cancer Research Institute(NCRI) AML Academy Meeting. Watch Courtney DiNardo discuss how the treatment approach for this patient group has changed in recent years with the advent of combination therapies below.

What is the optimum treatment strategy for elderly or frail patients with AML?

Isocitrate dehydrogenase (IDH) inhibitor combinations

Studies have shown that epigenetic dysregulation can promote a preleukemic state that precedes leukemic transformation. Drugs targeting epigenetic dysregulation have been developed and include: azacitidine and decitabine, which are hypothesized to reverse DNA hypermethylation and reactivate repressed tumor suppressor genes; ivosidenib and enasidenib, which target IDH1and IDH2mutations thought to be involved in aberrant DNA hypermethylation. 2Combining these agents may improve patient outcome compared to azacitidine monotherapy.

Ivosidenib/enasidenib plus azacitidine: phase I/II study: AG221-AML-005 ( NCT02677922) 5,6,7

Patients with newly diagnosed AML, with either IDH1mutations ( mIDH1) or IDH2mutations ( mIDH2), were treated with azacitidine plus ivosidenib (for mIDH1) or enasidenib (for mIDH2).

  • The phase Ib resultswere presented at the European Hematology Association(EHA) meeting in 2018. 5,6
  • The ivosidenib cohort has progressed to a multicenter, double-blind placebo controlled, randomized, phase III trial, AGILE ( NCT03173248). This trial will compare ivosidenib versusplacebo in combination with azacitidine in previously untreated patients with AML with IDH1 5,6
  • Updated results from the phase II randomized study of enasidenib versusazacitidine monotherapy were recently presented at the 61st ASH meeting. 7The results showed enasidenib plus azacitidine significantly improved overall response rate (71% vs42%,respectively) and complete response rate (53% vs12% respectively) compared to azacitidine alone and was well tolerated. 7

Ivosidenib/enasidenib plus standard chemotherapy 8

  • Phase I study ( NCT02632708) of patients with AML who are unfit for intensive chemotherapy at diagnosis
  • Ivosidenib (n= 49) or enasidenib (n= 89) with cytarabine and either daunorubicin or idarubicin
    • Induction (1–2 cycles): ivosidenib or enasidenib with cytarabine and daunorubicin or idarubicin
    • Consolidation (≤4 cycles): ivosidenib or enasidenib plus cytarabine
    • Maintenance (up to two years from Day 1 of induction): ivosidenib or enasidenib
  • CR (ivosidenib vsenasidenib): 71% vs56%
  • Estimated 12-month overall survival (OS) after induction Day 1 (ivosidenib vsenasidenib): 79% vs75%

A phase III study, HOVON 150/AMLSG 29-18, is comparing enasidenib or ivosidenib (by mIDHstatus) plus chemotherapy (7+3) versusplacebo. 9An overview of IDH inhibitors, including further information on the data from trials involving these combination therapies, is available here.

FLT3 inhibitor combinations

Other new targets for AML therapies are the FLT3 pathways. FLT3 is a transmembrane tyrosine kinase with two mutational subtypes: an internal tandem duplication (ITD) or point mutations in the tyrosine kinase domain (TKD). 4A third of patients with de novoAML have mutations in the FLT3gene and patients with FLT3-ITD AML have a poor prognosis. FLT3 is therefore an attractive target for therapeutic agents, with several FLT3 inhibitors in clinical development, such as sorafenib, midostaurin, quizartinib, crenolanib, and gilteritinib. 2,4

Examples of combination therapies involving FLT3 inhibitors are shown in Table 1below. One example of a trial involving a FLT3 inhibitor is the RATIFY ( NCT00651261) trial. The RATIFY trial assessed whether the addition of midostaurin to standard chemotherapy could prolong survival in newly diagnosed adult patients with FLT3-ITD AML compared to placebo + chemotherapy. The results showed midostaurin prolonged median OS and event-free survival (EFS) compared to placebo 10:

  • Median OS (midostaurin vsplacebo): 74.7 (95% CI, 31.5–not reached) vs 25.6 (95% CI, 18.6–42.9) months
    • Hazard ratio (HR) for death: 0.78; 95% CI, 0.63–0.96; p= 0.009
  • Median EFS (midostaurin vsplacebo): 8.2 (95% CI, 5.4–10.7) vs 3.0 (95% CI, 1.9–5.9) months
    • HR for an event: 0.78; 95% CI, 0.66–0.93; p= 0.002

However, the authors questioned if more specific FLT3inhibitors could further improve outcomes. 10

Table 1.Examples of combination therapies containing FLT3inhibitors 4,11,12

AML, acute myeloid leukemia; chemo, chemotherapy; LDAC, low dose cytarabine; ND, newly diagnosed; R/R, relapsed/refractory  

Targeted agent

In combination with/ versus

Patient population

Trial name/NCT reference

Midostaurin

Induction chemo

ND AML with FLT3-ITD or TKD mutations

RATIFY

NCT00651261

Quizartinib

Induction chemo

ND AML with FLT3-ITD mutations

QuANTUM-First

NCT02668653

Crenolanib

vsmidostaurin, in combination with induction chemo

ND AML with FLT3-ITD mutations

NCT03258931

Gilteritinib

Induction chemo

ND AML

NCT02310321

Sorafenib

Induction chemo

ND AML <60 years old

SORAML

NCT00893373

Learn more about FLT3 inhibitors in AML here.

During the 2019 EHA meeting, the AGP spoke to Alexander Perlabout gilteritinib for the treatment of relapsed/refractory (R/R) AML.

What effect does gilteritinib have on FLT3 mutated relapsed/refractory AML?

Venetoclax combinations

Another example of a targeted agent for the treatment of AML is venetoclax, which is a Bcl-2 inhibitor. Venetoclax is approved by the U.S. Food & Drug Administration(FDA) for the treatment of newly diagnosed patients with AML who are not eligible for intensive induction chemotherapy, in combination with azacitidine, decitabine, or low dose cytarabine. 13

Results from a phase Ib study( NCT02203773) investigating venetoclax with decitabine or azacitidine showed that these combination therapies led to a 61% complete remission or complete remission with incomplete marrow recovery rate in newly diagnosed patients with AML aged 65 and over. 14A phase III study ( NCT02993523) comparing venetoclax plus azacitidine to azacitidine alone in patients with treatment-naïve AML is ongoing. 15

During the Acute Leukemias XVII Biology and Treatment Strategies biennial symposium, Andrew Wei gave a presentation on novel therapeutic combinations containing venetoclaxfor the treatment of AML.

There are a number of ongoing studies of venetoclax in combination therapies and examples of these include 4:

  • Venetoclax + gilteritinib — R/R AML — NCT03625505
  • Venetoclax + ivosidenib — IDH1mutated AML — NCT03471260
  • Venetoclax + azacitidine vsazacitidine alone — treatment-naïve patients with AML who are ineligible for standard induction — NCT02993523

During the 2018 ASCO meeting, the AGP spoke to Courtney DiNardo about the combination of venetoclax with hypomethylating agents (HMAs).

Venetoclax plus HMAs in elderly AML patients

Subsequently, during the Society of Hematologic Oncology(SOHO) meeting in 2019, the AGP spoke to Jeffrey Lancetabout the potential of venetoclax + HMAs to replace induction chemotherapy.

Can hypomethylating agents plus venetoclax replace chemotherapy induction for patients with AML?

The AGP spoke to Marina Konoplevaat the 2019 EHA meeting about Bcl-2 as a universal target in AML.

BCL-2 as a universal target in AML

Conclusion

The development of targeted therapies and novel combinations holds promise for the treatment of AML, especially when compared to currently approved options. In some cases, these combinations may be more efficacious than intensive induction chemotherapy. In addition, some patients have been able to undergo allo-HSCT following treatment with a novel combination, which may indicate that the future of AML treatment will be in novel combinations and involve less chemotherapy. Additionally, these combinations appear tolerable to date.

Despite the promising results seen so far, not all patients respond equally. In order to maximize response to these therapies, it will be important to identify the right patient subgroups, with specific mutations, and may require particular combinations of agents to be used. 2

Expert Opinion

"In AML, intensive chemotherapy has always been seen as a prerequisite for a potentially curative treatment approach to this aggressive disease. However, due to age and comorbidities, the majority of patients with AML are not eligible and would receive ‘palliative’ treatment options with single agent chemotherapy or hypomethylating agents, inducing a median overall survival of less than a year. New hope has come with the arrival of novel combination therapies using targeted agents, such as ivosidenib, venetoclax, or midostaurin, achieving outcomes comparable or even better than intensive chemotherapy in these patients. If results can be confirmed in phase III trials, we might see a shift towards chemotherapy-free induction therapies in AML in the future."

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  2. Khan M., Mansoor A-e-R& Kadia T.M.Future prospects of therapeutic clinical trials in acute myeloid leukemia. Future Oncol.2017 Mar;13(6):523–535. DOI: 10.2217/fon-2016-0262
  3. Larkin K.& Blum W.Novel Therapies in AML: Reason for Hope or Just Hype? American Society of Clinical Oncology Educational Book 34 (November 13, 2019) e341-e351. DOI: 10.14694/EdBook_AM.2014.34.e341
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  6. DiNardo C.Det al. Poster presented at: ISAL 2019. ACUTE LEUKEMIAS XVII Biology and Treatment Strategies Meeting,Munich, DE
  7. DiNardo C.Det al. Enasidenib Plus Azacitidine Significantly Improves Complete Remission and Overall Response Compared with Azacitidine Alone in Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) with Isocitrate Dehydrogenase 2 (IDH2) Mutations: Interim Phase II Results from an Ongoing, Randomized Study. 2019 Dec 9. Oral Abstract #643. 61st American Society of HematologyAnnual Meeting & Exposition, Orlando, US
  8. Stein E.Met al. Ivosidenib or Enasidenib Combined with Induction and Consolidation Chemotherapy in Patients with Newly Diagnosed AML with an IDH1 or IDH2 Mutation Is Safe, Effective, and Leads to MRD-Negative Complete Remissions.  Abstract #560. 60th American Society of HematologyAnnual Meeting and Exposition, San Diego, US
  9. HOVON:Clinical picture: AML (acute myeloid leukemia) Trial: HOVON 150 AML. Available at: http://www.hovon.nl/studies/studies-per-ziektebeeld/aml.html?action=showstudie&studie_id=150&categorie_id=4 [Accessed 2019 March 15] 
  10. Stone R.M.  et al.Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation.  N Engl J Med. 2017 Jun 23; 377:454–464 DOI:  10.1056/NEJMoa1614359.
  11. Clinicaltrials.gov.A Study of ASP2215 in Combination With Induction and Consolidation Chemotherapy in Patients With Newly Diagnosed Acute Myeloid Leukemia. Available at:https://clinicaltrials.gov/ct2/show/NCT02310321. Published 2014 Dec 08. [Accessed 2020 Feb 04]
  12. Clinicaltrials.gov.Study Evaluating Sorafenib Added to Standard Primary Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia Less Than 60 Years of Age (SORAML). https://clinicaltrials.gov/ct2/show/NCT00893373Published 2009 May 06. [Accessed 2020 Feb 04]
  13. FDA.Accelerated Approval Letter. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2018/208573Orig1s009ltr.pdfPublished 2018 Nov 21. [Accessed 2020 Feb 05]
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