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CME Corner

Navigating the Complexities of Novel Treatment Sequencing for AML

Authored by

Daniel A Pollyea, MD, MS

Affiliation

University of Colorado School of Medicine, Denver, CO

Disclosures

Dr Pollyea has acted as a consultant for AbbVie, Agios, Astellas, Celgene, Daiichi Sankyo, Gilead, and Pfizer. He has received Grant/Research support from AbbVie, Inc.

Citation

J Clin Pathways. 2020;6(2):40-41. doi:10.25270/jcp.2020.3.00007

This section called “CME Corner,” highlights, when available, relevant continuing medical education (CME) opportunities deemed to be of use to readers. Articles include an overview of a specific area where key opinion leaders have determined there to be an educational need and a link to the available CME program. This piece was compiled from an interview with Dr Pollyea.

The CME program titled "Looking to the Future With Hope: Advances in the Treatment of AML" is currently available on this topic until April 30, 2020.


Acute myeloid leukemia (AML) is a difficult malignancy to manage for a variety of reasons. By many standards, it can be considered among the most aggressive malignancies. In any setting, this represents a major challenge.

The traditional way to treat AML involves intensive induction chemotherapy, a very toxic and morbid treatment regimen. However, the median age at diagnosis is approximately 67 years1; this represents a major obstacle because the majority of patients who are diagnosed with this disease are not good candidates for the conventional treatment approach, due to their age and comorbidities.

However, with a host of new agents coming to market, we are potentially reducing the need for intensive chemotherapy regimens. These new therapies are set to augment and possibly replace intensive chemotherapy strategies.2

Recently Approved Targeted Agents, Liposomal Chemotherapy

The majority of recently approved treatments for AML can be divided into the following categories: genomically targeted therapies for patients with single-gene mutations; nonspecific targeted therapies; antibodies; and a liposomal agent.

Patients with specific mutations can be candidates for mutationally-directed targeted therapies. The most common recurrent mutation in AML is FLT3; midostaurin, which is approved for FLT3 positive AML patients deemed eligible for intensive chemotherapy, is prescribed as an add-on to standard induction.3 Gilteritinib is approved as a single agent for relapsed or refractory FLT3-positive AML and has demonstrated superiority to standard chemotherapy regimens.4 These are the only two FLT3-targeted therapies that are currently approved.

More than 20% of patients with AML have an IDH1/2 mutation.5 There are two approved drugs there for this type of disease. Enasidenib, an IDH2 inhibitor, is used as a single agent for relapsed or refractory IDH2 positive AML.6 Ivosidenib, an IDH1 inhibitor, has the same approval for relapsed or refractory IDH1 positive AML as well as an additional labeled indication for upfront IDH1 positive, newly diagnosed patients who are unfit for standard treatment.7

There are other targeted therapies that are not based on a patient’s mutational status but could be applicable to patients regardless of mutational status. Glasdegib—an inhibitor of the Hedgehog signaling pathway—is approved for newly diagnosed patients who are unfit for standard chemotherapy, in combination with low-dose cytarabine.8 There is also venetoclax—the BCL 2 inhibitor—which is also approved for newly diagnosed patients who are unfit for standard chemotherapy.9 Venetoclax is used in combination with either a hypomethylating agent (ie, azacitidine or decitabine) or low-dose cytarabine.

Gemtuzumab ozogamicin is an antibody therapy approved in any setting for patients with CD33 positive AML.10

Lastly, there is CPX 351, which is a liposomal formulation of 7+3 which is approved for induction eligible patients with secondary AML (AML that arises from myelodysplastic syndrome) or treatment-related AML.11

There is early evidence for some of these therapies to be used in various combinations and to incorporate more genomically targeted therapies into the up-front treatment setting. Very early data with relatively few patients has been presented at meetings showing the
possibility of increased efficacy in the upfront setting when you add an IDH inhibitor to a hypomethylating agent. There is also preliminary data about adding an IDH inhibitor to intensive induction chemotherapy for upfront treatment.

In general, the strategy of moving targeted therapies into the upfront setting seems logical. Time will tell if these studies will support this strategy. I would say the RATIFY study, Stone et al, is the best/only example at the moment.12

Adverse Event Profiles of Novel AML Agents

The adverse event (AE) profiles of novel therapies is always a concern, especially for those approved for AML. Often, new agents are associated with new AEs, which practicing clinicians do not have much experience managing. The IDH inhibitors, for example, present the unique challenge of differentiation syndrome. Approximately 10% of patients receiving IDH inhibitors for AML experience this complication.13,14 However, IDH inhibitor-induced differentiation syndrome is different than the typical differentiation syndrome with respect to the time course for the development of this complication.  

Midostaurin has some unique complications with respect to liver and gastrointestinal toxicity, as well as complications related to rashes. These can be difficult to tolerate. In contrast, gilteritinib is relatively well tolerated. 

Venetoclax is also generally well tolerated. There are some concerns about myelosuppression, but these are readily managed by those experienced with this regimen through the use of treatment interruptions and on occasion growth factor support.15 Tumor lysis syndrome was a concern with venetoclax administration, especially given the data of administering this agent for chronic lymphocytic leukemia (CLL).10 However, the incidence rates in AML are significantly less than in CLL.16,17

CPX 351 is associated with many of the same toxicities that are associated with intensive induction chemotherapy. It was not associated with a significant improvement in the safety profile, but it is important to remember that CPX-351 should only be used for induction chemotherapy eligible patients, in whom toxicities are expected.

Conclusion

Important strides toward more effective treatments for AML have been made over the last few years, with several new targeted treatments and a liposomal chemotherapy treatment approved in the last 3 years. These rapid changes in the AML treatment landscape require education on new clinical data and expert guidance to facilitate the clinical integration of these changes.


The CME program titled "Looking to the Future With Hope: Advances in the Treatment of AML" is currently available on this topic until April 30, 2020.

References

1. Sehgal A, Boyiadzi. AML treatment in older adults. Aging (Albany NY). 2015;7(9):611-612. doi:10.18632/aging.100816

2. DiNardo CD, Wei AH. How I treat acute myeloid leukemia in the era of new drugs. Blood. 2020;135(2):85-96. doi:10.1182/blood.2019001239

3. Rydapt [package insert]. East Hanover, NJ: Novartis Pharmaceutical Corporation; 2017. 

4. Xospata [package insert]. Northbrook, IL: Astellas Pharma US, Inc; 2018. 

5. Medeiros BC, Fathi AT, DiNardo CD, Pollyea DA, Chan SM, Swords R. Isocitrate dehydrogenase mutations in myeloid malignancies. Leukemia. 2017;31:272-281. doi:10.1038/leu.2016.275 

6. Idhifa [package insert]. Cambridge, MA: Agios Pharmaceuticals; 2017. 

7. Tibsovo [package insert]. Cambridge, MA: Agios Pharmaceuticals; 2018. 

8. Daurismo [package insert]. New York, NY: Pfizer Labs; 2018. 

9. Venclexta [package insert]. North Chicago, IL: AbbVie Inc. South San Francisco, CA: Genentech USA; 2016. 

10. Mylotarg [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals Inc; 2000.  

11. Vyexos [package insert]. Palo Alto, CA: Jazz Pharmaceuticals, Inc; 2017. 

12. Stone RM, Mandrekar SJ, Sanford BL, et al. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med. 2017;377(5):454-464. doi:10.1056/NEJMoa1614359 

13. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731. doi:10.1182/blood-2017-04-779405 

14. DiNardo CD, Stein EM, de Botton S, et al. Durable remissions with ivosidenib in IDH1-mutated relapsed or refractory AML. N Engl J Med. 2018;378(25):2386-2398. doi:10.1056/NEJMoa1716984

15. Jonas BA, Pollyea DA. How we use venetoclax with hypomethylating agents for the treatment of newly diagnosed patients with acute myeloid leukemia. Leukemia. 2019;33(12):2795-2804. doi:10.1038/s41375-019-0612-8

16. DiNardo CD, Pratz K, Pullarkat V, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133(1):7-17. doi:10.1182/blood-2018-08-868752 

17. Wei AH, Strickland SA Jr, Hau J, et al. Venetoclax combined with low-dose cytarabine for previously untreated patients with acute myeloid leukemia: results from a phase Ib/II study. J Clin Oncol. 2019;37(15):1277-1284. doi:10.1200/JCO.18.01600

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