Companion diagnostics in leukemia – the importance of subtypes

Blood cancers such as leukemia, lymphoma, and myeloma are the third leading cause of cancer deaths in the United States. Acute myeloid leukemia (AML) is the most lethal of these cancers, and responsible for more than 10,000 deaths annually.^1,2,3 Despite treatment advances in other blood cancers, the standard of care for AML consists of a combination of chemotherapies, and has remained consistent for more than 40 years. The overall prognosis for AML patients continues to be poor, with a five-year survival rate below 20 percent for patients over age 60.²

AML is a form of blood cancer characterized by clonal expansion of poorly differentiated precursor blast cells of myeloid lineage. AML originates in the bone marrow and over time migrates to the blood. Proliferation of immature myeloid cells leads to accumulation of immature progenitor blasts and causes impairment of normal hemopoiesis.³ As a result, patients can develop severe infections, anemia and hemorrhages. Malignant cells can metastasize to other parts of the body including the lymph nodes, liver, spleen, central nervous system and testicles.² These rapidly occurring aspects of the disease make it imperative to be able to diagnose and treat as early as possible.

Diagnosing AML

AML is not staged like most other cancers because the malignant cells do not usually form tumors. Generally, the disease is widespread throughout the bone marrow and, in some cases, has spread to other organs, such as the liver and spleen. Therefore, the prognosis for a patient with AML greatly depends on the subtype of AML, which is determined by a series of diagnostic tests, the patient’s age and clinical history.^2,3,8 The diagnostic tests include an assessment of cells in the blood and bone marrow and specialty tests, such as cytogenetic analysis and other molecular assays.

AML Subtypes

Identifying the subtype of AML can be very important, as it can affect patient outcomes and help to identify the best treatment plan. For example, the acute promyelocytic leukemia (APL) subtype is often treated using drugs that are different from those used for other subtypes of AML.^2,3,8 There have been two systems followed to subtype AML. The French-American-British (FAB) classification for AML system, which relies on the microscopic analysis of the cells. While the World Health Organization (WHO) classification of AML includes genetic abnormalities common to AML subtypes, such as chromosomal translocations, specific gene fusions and gene mutations.^2,3

Prognostic factors for AML

The subtype of AML can be important in helping to determine a person’s prognosis; however, other factors can also affect why some patients with AML have a better outlook than others. Prognostic factors help clinicians to determine a person’s risk of relapse/recurrence after treatment, and if they should get intensive treatment.² The patient’s age, clinical presentation, cellular markers and chromosomal abnormalities observed via cytogenetics and molecular mutations all contribute to the prognosis of the patient.^2,3

AML cells can have many kinds of chromosome changes, and the National Comprehensive Cancer Network (NCCN) guidelines group chromosome abnormalities into three categories of risk stratification: favorable, intermediate and poor/adverse.^1,8

Favorable abnormalities⁸

• t(8;21)(q22;q22.1); RUNX1-RUNX1T1
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11
• Biallelic mutated CEBA
• Mutated NPM1 without FLT3-ITD or with FLT3-ITD (low allelic ratio)

Intermediate abnormalities⁸

• Mutated NPM1 and FLT3-ITD (high allelic ratio)
• Wild-type NPM1 without FLT3-ITD or with FLT-ITD (low allelic ratio) (without adverse-risk genetic lesions)

• t(9;11)(p21.3;q23.3); MLLT3-KMT2A
• Cytogenetic abnormalities not classified as favorable or adverse

Poor/adverse abnormalities⁸

• t(6;9)(p23;q34.1); DEK-NUP214
• t(v;11q23.3);KMT2A rearranged
• t(9;22)(q34.1;q11.2);BCR-ABL1
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2);GATA2,MECOC M(EV11)
• -5 OR DEL(5q);-7; -17/abn(17p)
• Complex karyotype, monosomal karyotype
• Wild-type NPM1 and FLT-ITD (high allelic ratio)
• Mutated RUNX1
• Mutated ASXL1
• Mutated TP53

Treating AML patients

For many years, the standard of care of for AML patients has been chemotherapy with the possibility of post-remission therapy that may include haemopoietic stem cell transplantation. A patient achieves remission when the signs and symptoms of cancer have lessened or are undetectable, having no evidence of disease. For AML, complete remission means, bone marrow specimens contain fewer than 5 percent blast cells, the complete blood counts are within normal limits and the patient usually demonstrates no signs or symptoms of the leukemia.

A complete molecular remission means there is no evidence of leukemia cells in the bone marrow, even when using very sensitive tests, such as those based on PCR (polymerase chain reaction).^2,3 Complete remission is at times difficult to achieve (as in refractory disease) or temporary, as approximately two-thirds of patients relapse after frontline therapy and most relapses occur within the first 18 months.⁹

As more information is learned about the molecular complexity of cancer, including AML, the involvement of specific genes and the proteins they express are being identified. This information is feeding the field of personalized medicine, which continues to evolve, as pharmaceutical companies work to develop and launch targeted therapies for oncology patients. For example, AML patients whose leukemia cells have specific gene mutations may benefit from advancements in personalized medicine.

In fact, 7 percent to 14 percent of AML patients have isocitrate dehydrogenase 1 (IDH1) mutations, which are associated with unfavorable prognosis in older adults, especially with a cytogenetically normal karyotype.⁵ The product of mutated IDH1, is the molecule 2-hydroxyglutarate (2-HG), an oncometabolite, that has been shown to inhibit normal cell differentiation(development). Tibsovo (Ivosidenib) is an isocitrate dehydrogenase-1 (IDH1) inhibitor that decreases abnormal production of 2-HG, thus allowing normal myeloblasts to continue with normal development. With the highly targeted mechanism of action of Tibsovo, it is necessary to identify the specified patients who could benefit from this therapy. In this case, patients who are either 75 years or older, or have comorbidities precluding them from receiving intensive induction chemotherapy, or those with refractory or relapsed AML, harboring a mutation in the IDH1 gene as detected by the FDA-approved companion diagnostic, are eligible for Tibsovo.^5,10

Additionally, between 10 percent and 20 percent of people with AML have a mutation in the Isocitrate dehydrogenase-2 (IDH2) gene, which, similarly to the IDH1 mutation, prevents myeloblasts from maturing, due to an accumulation of 2-HG.³ Unlike standard AML therapies, that aggressively target all white blood cells, IDHIFA (Enasidenib) inhibits the mutated IDH2 gene, reducing the amount of 2HG being produced, allowing immature white blood cells to naturally mature.^3,7 As with inhibition of mutated IDH1, IDHIFA specifically targets the mutated IDH2 enzyme. Therefore, it is indicated for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with an isocitrate IDH2 mutation as detected by an FDA-approved companion diagnostic.⁷

The field of hematology has shown significant progress in recent years, with several new drugs gaining approval for the treatment of adults with acute myeloid leukemia.^2,9 Therefore, having the right diagnostic tools to identify these treatment specific mutations (companion diagnostic), as well as distinguishing the molecular characteristics of the various subtypes of AML, is critical both for patient treatment and research. Research efforts to understand the genomic background of AML, including the mechanisms by which each subtype drives the disease phenotype, will be crucial – not only in risk stratification of AML but also in developing novel targeted therapies.

References:

1. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, Bloomfield CD, Cazzola M, Vardiman JW. Blood. 2016 May 19;127(20):2391-405. doi: 10.1182/blood-2016-03-643544. Epub 2016 Apr 11.
2. Acute Myeloid Leukemia (AML) Subtypes and Prognostic Factors. https://www.cancer.org/cancer/acute-myeloid-leukemia/detection-diagnosis-staging/how-classified.html#references. Accessed March 27, 2020.
3. Acute myeloid leukaemia. Nicholas J Short, Michael E Rytting, Jorge E Cortes. www.thelancet.com/ Vol 392 August 18, 2018.
4. FDA Approves Abbott CDx, Agios Drug for AML Patients with IDH1 Mutation. https://www.genomeweb.com/regulatory-news/fda-approves-abbott-cdx-agios-drug-aml-patients-idh1-mutation#.XnziL6hKg2x. Accessed March 27, 2020.
5. IDH1-mutated relapsed or refractory AML: current challenges and prospects. Juan Eduardo Megías Vericat. Octavio Ballesta-López, va Barragán,Pau Montesinos. Blood and Lymphatic Cancer: Targets and Therapy. 2019:9 19–32.
6. The Role of Companion Diagnostics in Oncology Care. Nalley, Catlin. Oncology Times: May 10, 2017;39(9)24-26.
7. IDHIFA (enasidenib) website https://www.idhifapro.com/ Accessed April 1, 2020. 
8. NCCN Guidelines with NCCN Evidence Blocks AML. https://www.nccn.org/professionals/physician_gls/pdf/aml_blocks.pdf. Accessed March 27, 2020.
9. Late relapse in acute myeloid leukemia (AML): clonal evolution or therapy-related leukemia? Musa Yilmaz, Feng Wang, Sanam Loghavi, Carlos Bueso-Ramos, Curtis Gumbs, Latasha Little, Xingzhi Song, Jianhua Zhang, Tapan Kadia, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Nicholas Short, Guillermo Garcia-Manero, Zeev Estrov, Hagop Kantarjian, Andrew Futreal, Koichi Takahashi and Farhad Ravandi. Yilmaz et al. Blood Cancer Journal (2019) 9:7.
10. Tibsovo (Ivosidenib) website and package insert. https://www.tibsovo.com/about/#about-aml and https://www.tibsovopro.com/pdf/prescribinginformation.pdf. Accessed April 1, 2020.