Prognostic Significance of Molecular Markers and Targeted Regimens in the Management of Acute Myeloid Leukemia

Author: Martin Tallman MD 1
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  • 1 Presented by Martin Tallman, MD, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York.

The diagnosis, staging, and treatment of acute myeloid leukemia (AML) has evolved based on identification of important genetic alterations and drugs to target those genes. Cytogenetic abnormalities play a major role in managing AML. Achieving minimal residual disease is an increasingly important milestone. Four new targeted therapies are now available for the treatment of AML.

In 2018, state-of-the-art treatment for acute myeloid leukemia (AML) is characterized by 6 features:

  • Defined by cytogenetic and molecular interactions,
  • Intensified induction/less intensive consolidation,
  • Increased importance of minimal residual disease (MRD),
  • Expanded availability of allogeneic transplantation,
  • Paradigm shift in older patients, and
  • Incorporation of novel agents.

With increased understanding of the biological underpinnings of AML, it is possible to characterize patients according to molecularly defined risk groups. Patients with adverse risk comprise 34% of all patients, those with intermediate-risk disease account for 21%, and those with favorable risk account for 45%.1

“Over the last decade, there has been a dramatic increase in the knowledge of molecular genetics,” Martin Tallman, MD, Chief, Leukemia Service, Memorial Sloan Kettering Cancer Center, and Professor of Medicine, Weill Cornell Medical College, told listeners at the NCCN 23rd Annual Conference (Figure 1).2 “It is becoming increasingly important to become aware not only of a particular mutation but of the spectrum of mutations that occurs in a given patient. They have important interactions that lead to dramatic differences in overall survival (OS),” he explained. Dr. Tallman is also Vice Chair of the NCCN Guidelines Panel for AML.

For example, patients who are CEBPA-positive have the best survival if they are FLT3 wild-type (FLT-3wt) and NPM1mutant. Survival is worst with FLT3ITD and NPM1wt. Intermediate survival is observed for FLT3ITD/NPM1mutant and FLT3wt/NPM1wt.3 Further complicating the picture is that a patient can be FLT3ITD-positive and fall into favorable, intermediate, and adverse risk categories, according to the 2017 European LeukemiaNet (ELN) risk stratification (Figure 2).2 Essentially, an additional factor that influences risk is the allelic burden, or as illustrated in this context, how positive a patient is for the FLT3ITD mutation.

In general, older adults with AML tend to have a less favorable prognosis. Patients with favorable-risk AML (NPM1 mutations and mutations in other genes) can experience an overall complete remission rate of 81%, disease-free survival rates of 46%, and OS rate of 45%. In contrast, older patients with poor-risk AML (without NPM1 mutations) have a complete remission rate of 32%, disease-free survival rate of 2%, and OS rate of 4%.4

Next-generation sequencing and flow cytometry before transplantation are important assessment tools

Figure 1.
Figure 1.

Molecular classes of acute myeloid leukemia (AML) and recurrent gene mutations shows the complexity of the genetics of AML.

Reprinted with permission from the American Society of Hematology © 2017. Döhner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424–447.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0050

that can be used to predict outcomes after transplantation. If no evidence of MRD is found using flow cytometry and next-generation sequencing before transplantation, the outcome is likely more favorable than if either test is MRD-positive.

“Many institutions are turning to multiplex testing in AML,” Dr. Tallman noted. “However, some of these gene mutations are important in everyday practice and are ‘clinically actionable.’ Every patient with newly diagnosed AML should be tested for these genes,” Dr. Tallman said.

Newly Approved and Emerging Drugs

For the first time in 45 years, new drugs have been FDA-approved or were given breakthrough designation for AML: midostaurin (FLT3 inhibitor) for patients with FLT3 mutations and are treatment-naïve; gemtuzumab ozogamicin (GO; anti-CD33) for patients who are CD33-positive with core binding factor and possibly intermediate risk who are treatment-naïve (and may also be used in patients with relapsed/refractory AML); enasidenib (IDH2 inhibitor) for relapsed/refractory AML with IDH2 mutations; CPX-351 (new 5:1 liposomal formulation of cytarabine and daunorubicin) for treatment-naïve patients with therapy-related AML (t-AML) or AML with myelodysplasia-related changes (MRC); and venetoclax (BCL-2 inhibitor) for treatmentnaïve patients with low-dose cytarabine.

Midostaurin

Midostaurin was approved by the FDA for induction and consolidation based on the RATIFY trial, which took 13 years to complete.5 The study showed that patients with FLT3 mutations (ITD or WT) had a 4-year survival of 51.4% on midostaurin versus

Figure 2.
Figure 2.

2017 ELN risk stratification by genetics.

Abbreviation: WT, wild-type

Reprinted with permission from the American Society of Hematology © 2017. Döhner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424–447.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 16, 5S; 10.6004/jnccn.2018.0050

44.2% on placebo (P=.0074), and the benefit was most pronounced in NPM1wt and FLT3high patients.

“This study is practice-changing, but more information is required to determine clinically meaningful impact based on long-term studies. The OS benefit is only 7%,” Dr. Tallman said, “and the benefit was greater in patients with the FLT3TKD mutation when compared with those with the FLT3ITD mutation, who have less favorable risk. Additionally, midostaurin is approved in Europe for maintenance, but not in the United States. We are not clear which phase of the disease is most important.”

Midostaurin is among the least potent FLT3 inhibitors. More potent FLT3 inhibitors in development are gilteritinib, quizartinib, and crenolanib.

Gemtuzumab Ozogamicin

GO was approved by the FDA in 2000, withdrawn, and then reintroduced. Currently, it is given in a fractionated schedule to reduce toxicity. An OS benefit is seen in favorable-risk patients and a trend toward improved survival is seen in intermediate-risk patients. Event-free survival was significantly improved with GO plus daunorubicin and cytarabine versus daunorubicin and cytarabine in the ALFA-0701 trial of patients aged 50 to 70 years with newly diagnosed AML (P=.003).6

CPX-351

CPX-351 uses a nanoscale delivery complex and is a fixed molar ratio of cytarabine to daunorubicin (5:1) to increase cytotoxicity.7 A randomized phase III trial found that CPX-351 improved response rates and OS compared with the conventional “7+3” regimen (cytarabine 7 days and daunorubicin 3 days). Complete response was seen in 37.3% of patients on CPX-351 versus 25.6% with the 7+3 regimen; median OS in the CPX-351 versus placebo groups were 9.56 versus 5.95 months, respectively (P=.005). A preliminary subset analysis suggested that, compared with patients treated with the 7+3 regimen, those treated with CPX-351 who went on to allogeneic transplant had considerably improved median survival (10.25 months vs not reached, respectively).8

Enasidenib and Ivosidenib

IDH is a cancer-associated metabolite that blocks normal cellular differentiation. A phase II study of the IDH2 inhibitor enasidenib in patients with relapsed/refractory AML showed an overall response rate of 37%, complete morphologic remission in 20% of patients, and stable disease in approximately 40% to 50%.9,10

Molecular complete response is seen in approximately 34% of patients with relapsed or refractory AML and 60% of previously untreated patients treated with the IDH inhibitor ivosidenib.9 Adverse events include differentiation syndrome, which can occur late (median, 48 days; range, 10–340 days).10 Complete response was seen in 21% by cycle 3, 68% by cycle 5, and 82% by cycle 7.10 The longest duration of complete response observed was >30 months. RAS mutations were associated with nonresponse to IDH inhibition.11 “It can take up to 7 months to achieve complete response, and therefore it requires patience to use these drugs,” Dr. Tallman said.

Next-generation trials are being planned or in progress with IDH inhibitors, including induction chemotherapy with and without IDH inhibitors, hypomethylating agents with or without IDH inhibitors, and IDH inhibitors combined with FLT3 inhibitors, venetoclax, or CPX-351.

Venetoclax

Venetoclax is a BCL2 inhibitor that sequesters proapoptotic proteins and initiates apoptosis. Venetoclax received a breakthrough therapy designation from the FDA for use in combination with low-dose cytarabine based on 2 major studies.12,13

“Response rates to venetoclax and cytarabine or azacytidine are impressive in previously untreated older adults with AML, who typically have a less favorable response,” Dr. Tallman stated. “In the studies with venetoclax and low-dose cytarabine, you can say that in AML, the rich get richer. Those who fare well are destined to fare well because of genetics. Outcomes are less favorable when p53 mutations are present. In addition, you see rapid [within 1 month] peripheral blood clearance and clearance of leukemia stem cells with venetoclax and azacytidine treatment.”

Expanded Options for Induction Chemotherapy in Younger Patients

Typically, intensive induction chemotherapy with the 7+3 regimen is used. Since 2017, in patients with FLT3 mutations (either ITD or tyrosine kinase domain [TKD]), midostaurin may also be given after induction on days 8 to 21 and during consolidation chemotherapy. CPX-351 can be given for secondary AML or AML with MRC. GO can be given to patients who are CD33-positive with 7+3 induction and consolidation therapy on days 1, 4, and 7 or as a single agent days 1 and 8.

The 2018 NCCN Guidelines for AML state that after standard-dose cytarabine induction, bone marrow biopsy should be performed 14 to 21 days later. Patients who experience complete response go on to consolidation postremission therapy (depending on risk factor status). For induction failure, matched transplant or high-dose cytarabine (alone or with another induction regimen) are recommended options. A clinical trial is recommended for all patients, including those with relapsed/refractory disease, Dr. Tallman continued. For patients who are candidates for intensive chemotherapy, treatment is guided by genetics.

Dr. Tallman has disclosed that he has received consulting fees/honoraria from Seattle Genetics, and grant/research support from ADC Therapeutics, Arog, Bioline, Cellerant, and Orsenix LLC, and has served as a scientific advisor for Daiichi-Sankyo Co.

References

  • 1.

    Grimwade D, Hills RK. Independent prognostic factors for AML outcome. Hematology Am Soc Educ Program 2009:385395.

  • 2.

    Dohner H, Estey E, Grimwade D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424447.

    • Search Google Scholar
    • Export Citation
  • 3.

    Taskesen E, Bullinger L, Corbacioglu A. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011;117:24692475.

    • Search Google Scholar
    • Export Citation
  • 4.

    Eisfeld AK, Kohlschmidt J, Mrozek K. Mutation patterns identify adults with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies [published online February 25, 2018]. Leukemia. doi: 10.1038/s41375-018-0068-2

    • Search Google Scholar
    • Export Citation
  • 5.

    Stone RM, Mandrekar SJ, Sanford BL. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454464.

    • Search Google Scholar
    • Export Citation
  • 6.

    Castaigne S, Pautas C, Terre C. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukemia (ALFA-0701): a randomized, open-label, phase 3 study. Lancet 2012;379:15081516.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lancet JE, Uy GL, Cortes JE. Final results of a phase III randomized trial of VYXEOS (CPX-351) versus 7+3 in older patients with newly diagnosed high-risk (secondary) AML [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 7000.

    • Search Google Scholar
    • Export Citation
  • 8.

    Lancet JE, Hoering A, Uy GL. Survival following allogeneic hematopoietic cell transplantation in older high-risk acute myeloid leukemia patients initially treated with CPX-351 liposome injection versus standard cytarabine and daunorubicin: subgroup analysis of a large phase III trial [abstract]. Blood 2016;128:Abstract 906.

    • Search Google Scholar
    • Export Citation
  • 9.

    Stone RM, Choe S, Zhang V. Genetic profiling and deep IDH1 mutation clearance to ≤0.04% in ivosidenib (AG-120)-treated patients with mutant IDH1 relapsed or refractory and untreated AML [abstract]. Blood 2017;130:Abstract 2684.

    • Search Google Scholar
    • Export Citation
  • 10.

    Stein EM, Dinardo CD, Pollyea DA. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017;130;722731.

  • 11.

    Amatangelo MD, Quek L, Shih A. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 2017;130:732741.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wei A, Strickland SA, Roboz GA. Phase 1/2 study of venetoclax with low dose cytarabine in treatment-naïve, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes [abstract]. Blood 2017;130:Abstract 890.

    • Search Google Scholar
    • Export Citation
  • 13.

    Pollyea DA, Stevens BM, Winters A. Venetoclax with azacitidine for untreated elderly acute myeloid leukemia patients unfit for induction chemotherapy: single center clinical experience and mechanistic insights from correlative studies [abstract]. Blood 2017;130:Abstract 181.

    • Search Google Scholar
    • Export Citation

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Correspondence: Martin Tallman, MD, Leukemia Service, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Email: tallmanm@mskcc.org
  • View in gallery

    Molecular classes of acute myeloid leukemia (AML) and recurrent gene mutations shows the complexity of the genetics of AML.

    Reprinted with permission from the American Society of Hematology © 2017. Döhner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424–447.

  • View in gallery

    2017 ELN risk stratification by genetics.

    Abbreviation: WT, wild-type

    Reprinted with permission from the American Society of Hematology © 2017. Döhner H, Estey E, Grimwade D, et al: Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424–447.

  • 1.

    Grimwade D, Hills RK. Independent prognostic factors for AML outcome. Hematology Am Soc Educ Program 2009:385395.

  • 2.

    Dohner H, Estey E, Grimwade D. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood 2017;129:424447.

    • Search Google Scholar
    • Export Citation
  • 3.

    Taskesen E, Bullinger L, Corbacioglu A. Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity. Blood 2011;117:24692475.

    • Search Google Scholar
    • Export Citation
  • 4.

    Eisfeld AK, Kohlschmidt J, Mrozek K. Mutation patterns identify adults with de novo acute myeloid leukemia aged 60 years or older who respond favorably to standard chemotherapy: an analysis of Alliance studies [published online February 25, 2018]. Leukemia. doi: 10.1038/s41375-018-0068-2

    • Search Google Scholar
    • Export Citation
  • 5.

    Stone RM, Mandrekar SJ, Sanford BL. Midostaurin plus chemotherapy for acute myeloid leukemia with a FLT3 mutation. N Engl J Med 2017;377:454464.

    • Search Google Scholar
    • Export Citation
  • 6.

    Castaigne S, Pautas C, Terre C. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukemia (ALFA-0701): a randomized, open-label, phase 3 study. Lancet 2012;379:15081516.

    • Search Google Scholar
    • Export Citation
  • 7.

    Lancet JE, Uy GL, Cortes JE. Final results of a phase III randomized trial of VYXEOS (CPX-351) versus 7+3 in older patients with newly diagnosed high-risk (secondary) AML [abstract]. J Clin Oncol 2016;34(Suppl):Abstract 7000.

    • Search Google Scholar
    • Export Citation
  • 8.

    Lancet JE, Hoering A, Uy GL. Survival following allogeneic hematopoietic cell transplantation in older high-risk acute myeloid leukemia patients initially treated with CPX-351 liposome injection versus standard cytarabine and daunorubicin: subgroup analysis of a large phase III trial [abstract]. Blood 2016;128:Abstract 906.

    • Search Google Scholar
    • Export Citation
  • 9.

    Stone RM, Choe S, Zhang V. Genetic profiling and deep IDH1 mutation clearance to ≤0.04% in ivosidenib (AG-120)-treated patients with mutant IDH1 relapsed or refractory and untreated AML [abstract]. Blood 2017;130:Abstract 2684.

    • Search Google Scholar
    • Export Citation
  • 10.

    Stein EM, Dinardo CD, Pollyea DA. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood 2017;130;722731.

  • 11.

    Amatangelo MD, Quek L, Shih A. Enasidenib induces acute myeloid leukemia cell differentiation to promote clinical response. Blood 2017;130:732741.

    • Search Google Scholar
    • Export Citation
  • 12.

    Wei A, Strickland SA, Roboz GA. Phase 1/2 study of venetoclax with low dose cytarabine in treatment-naïve, elderly patients with acute myeloid leukemia unfit for intensive chemotherapy: 1-year outcomes [abstract]. Blood 2017;130:Abstract 890.

    • Search Google Scholar
    • Export Citation
  • 13.

    Pollyea DA, Stevens BM, Winters A. Venetoclax with azacitidine for untreated elderly acute myeloid leukemia patients unfit for induction chemotherapy: single center clinical experience and mechanistic insights from correlative studies [abstract]. Blood 2017;130:Abstract 181.

    • Search Google Scholar
    • Export Citation
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