Leukemias, IDH2, R172W (c.514A>T)

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Expand Collapse Leukemias  - General Description Leukemia refers to cancers of cells residing in the blood and bone marrow. The bone marrow is a fluid compartment within bones, in which blood cells develop and mature. When the most immature cells (stem cells) mature, they first differentiate into either myeloid or lymphoid cells. Myeloid cells eventually develop into either 1) mature red blood cells, which carry oxygen throughout the body 2) platelets, which help form clots to stop bleeding and 3) a type of white blood cell known as granulocytes, which fight infection and disease. Lymphoid cells, on the other hand, develop into 3 different kinds of mature white cells that also fight infection (B lymphocytes, T lymphocytes or natural killer cells).

While there are many different forms of leukemia, they can be separated into chronic leukemias and acute leukemias, based on the aggressiveness of the disease. Leukemias are also named after the kind of blood stem cell involved (myeloid or lymphoid). In acute myeloid leukemia (AML), the bone marrow produces cancerous white blood cells (called myeloblasts). These cancerous cells crowd the marrow and suppress normal development of red cells, white cells and platelets. The disease usually worsens quickly without treatment. In contrast to AML, acute lymphocytic leukemia (ALL) is a disease where the bone marrow produces too many cancerous lymphocytes (lymphoblasts). Similar to AML, they crowd the marrow and suppress the development of healthy blood cells. ALL usually progresses quickly and is lethal without treatment. In chronic myeloid leukemia (CML), cancerous myeloid cells are involved, but the disease progresses slowly.

For CML, the FDA has approved the use of effective targeted therapies, including dasatinib (Sprycel), imatinib (Gleevec) and nilotinib (Tasigna) for the treatment of patients with CML. These drugs inhibit an abnormal protein present in the malignant cells of CML, and are highly effective in controlling the disease. However, despite significant efforts, therapeutic advances in the field of acute leukemias are lagging. Therefore, novel drugs and therapeutic strategies are desperately needed.

Source: National Cancer Institute, 2013
Acute leukemias are aggressive hematologic malignancies that result from the dysregulation and proliferation of hematopoietic precursors that are arrested in differentiation. Acute myeloid leukemia (AML) is a malignancy of aberrant myeloid precursors and is associated with a poor prognosis. The estimated number of yearly deaths (10,370 people according to 2013 data) is nearly as many as the number of new diagnoses (14,950 people). While the majority of those with AML achieve a complete remission with traditional cytotoxic induction therapy, approximately half ultimately relapse. Outcomes are worse for those with relapsed or high-risk AML, such as those who are older or have preceding myelodysplastic or myeloproliferative conditions. Over the last thirty years, advances in supportive care and consolidation therapy have resulted in incrementally improved outcomes. However, long-term survival of patients diagnosed with AML continues to be poor.

The outcomes for acute lymphoid leukemia (ALL) have dramatically improved in the pediatric population over the last 30 years. Children with ALL traditionally undergo intensive treatment strategies, including multi-agent induction therapy, early intensification, multi-agent consolidation therapy, as well as intrathecal treatment with ongoing long-term maintenance therapies. ALL in adults is distinguished from that in children by a higher proportion of poor-risk chromosomal alterations (such as the Philadelphia chromosome), a lower proportion of good-risk alterations (such as the TEL-AML1 gene fusion) and a lower prevalence of the poor-risk T-cell phenotype. Additionally, adults tend to experience increased toxicities and decreased tolerance to the traditional and intensive pediatric multi-agent therapies. Historically, adults with ALL have a worse prognosis when compared to pediatric patients, with reported event free survival (EFS) rates of 30-40% in adults as opposed to >80% for pediatric populations. The outcome is particularly worse for relapsed disease. Therefore, as with AML, clinical investigation of novel agents with therapeutic promise is needed, particularly for treatment in the adult population.

Chronic myeloid leukemia (CML) is characterized by a novel fusion gene, BCR-ABL, typically arising from a reciprocal translocation between chromosomes 9 and 22, leading to a constitutively activated tyrosine kinase. Prior to the development of targeted tyrosine kinase inhibitor (TKI) therapy for this disease, survival was poor, with 5-year survival rates of approximately 40% in patients 20-44 years of age. Imatinib mesylate, a tyrosine kinase inhibitor with activity against the novel BCR-ABL gene product, revolutionized both the care of this disease and the approach to molecular targets in cancer therapies. Imatinib, along with other second generation TKIs, such as dasatinib, nilotinib, and bosutinib, now constitute the backbone of CML treatment. As a result, clinical outcomes for patients with CML have dramatically improved over the course of the past decade.

Source: National Cancer Institute, 2013
Leukemia refers to cancers of cells residing in the blood and bone marrow. The bone marrow is a fluid compartment within bones, in which blood cells develop and mature. When the most immature cells (stem cells) mature, they first differentiate into either myeloid or lymphoid cells. Myeloid cells eventually develop into either 1) mature red blood cells, which carry oxygen throughout the body 2) platelets, which help form clots to stop bleeding and 3) a type of white blood cell known as granulocytes, which fight infection and disease. Lymphoid cells, on the other hand, develop into 3 different kinds of mature white cells that also fight infection (B lymphocytes, T lymphocytes or natural killer cells).

While there are many different forms of leukemia, they can be separated into chronic leukemias and acute leukemias, based on the aggressiveness of the disease. Leukemias are also named after the kind of blood stem cell involved (myeloid or lymphoid). In acute myeloid leukemia (AML), the bone marrow produces cancerous white blood cells (called myeloblasts). These cancerous cells crowd the marrow and suppress normal development of red cells, white cells and platelets. The disease usually worsens quickly without treatment. In contrast to AML, acute lymphocytic leukemia (ALL) is a disease where the bone marrow produces too many cancerous lymphocytes (lymphoblasts). Similar to AML, they crowd the marrow and suppress the development of healthy blood cells. ALL usually progresses quickly and is lethal without treatment. In chronic myeloid leukemia (CML), cancerous myeloid cells are involved, but the disease progresses slowly.

For CML, the FDA has approved the use of effective targeted therapies, including dasatinib (Sprycel), imatinib (Gleevec) and nilotinib (Tasigna) for the treatment of patients with CML. These drugs inhibit an abnormal protein present in the malignant cells of CML, and are highly effective in controlling the disease. However, despite significant efforts, therapeutic advances in the field of acute leukemias are lagging. Therefore, novel drugs and therapeutic strategies are desperately needed.

Source: National Cancer Institute, 2013
Acute leukemias are aggressive hematologic malignancies that result from the dysregulation and proliferation of hematopoietic precursors that are arrested in differentiation. Acute myeloid leukemia (AML) is a malignancy of aberrant myeloid precursors and is associated with a poor prognosis. The estimated number of yearly deaths (10,370 people according to 2013 data) is nearly as many as the number of new diagnoses (14,950 people). While the majority of those with AML achieve a complete remission with traditional cytotoxic induction therapy, approximately half ultimately relapse. Outcomes are worse for those with relapsed or high-risk AML, such as those who are older or have preceding myelodysplastic or myeloproliferative conditions. Over the last thirty years, advances in supportive care and consolidation therapy have resulted in incrementally improved outcomes. However, long-term survival of patients diagnosed with AML continues to be poor.

The outcomes for acute lymphoid leukemia (ALL) have dramatically improved in the pediatric population over the last 30 years. Children with ALL traditionally undergo intensive treatment strategies, including multi-agent induction therapy, early intensification, multi-agent consolidation therapy, as well as intrathecal treatment with ongoing long-term maintenance therapies. ALL in adults is distinguished from that in children by a higher proportion of poor-risk chromosomal alterations (such as the Philadelphia chromosome), a lower proportion of good-risk alterations (such as the TEL-AML1 gene fusion) and a lower prevalence of the poor-risk T-cell phenotype. Additionally, adults tend to experience increased toxicities and decreased tolerance to the traditional and intensive pediatric multi-agent therapies. Historically, adults with ALL have a worse prognosis when compared to pediatric patients, with reported event free survival (EFS) rates of 30-40% in adults as opposed to >80% for pediatric populations. The outcome is particularly worse for relapsed disease. Therefore, as with AML, clinical investigation of novel agents with therapeutic promise is needed, particularly for treatment in the adult population.

Chronic myeloid leukemia (CML) is characterized by a novel fusion gene, BCR-ABL, typically arising from a reciprocal translocation between chromosomes 9 and 22, leading to a constitutively activated tyrosine kinase. Prior to the development of targeted tyrosine kinase inhibitor (TKI) therapy for this disease, survival was poor, with 5-year survival rates of approximately 40% in patients 20-44 years of age. Imatinib mesylate, a tyrosine kinase inhibitor with activity against the novel BCR-ABL gene product, revolutionized both the care of this disease and the approach to molecular targets in cancer therapies. Imatinib, along with other second generation TKIs, such as dasatinib, nilotinib, and bosutinib, now constitute the backbone of CML treatment. As a result, clinical outcomes for patients with CML have dramatically improved over the course of the past decade.

Source: National Cancer Institute, 2013
PubMed ID's
10502596, 19959104, 19880497, 272207, 2943992, 11222362, 10749961, 17327603, 9716583, 18048644, 21327563, 12712476, 21576640, 22157290
Expand Collapse IDH2  - General Description
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Isocitrate dehydrogenase 2, encoded by the IDH2 gene, is an enzyme found in the powerhouse of the cells, known as mitochondria. This enzyme is similar to IDH1 in that it is involved in the transfer of energy from one molecule to another during certain biochemical reactions.

Mutations in IDH2 are predominately found in patients with acute myeloid leukemia, cancer of the bile duct (cholangiocarcinoma) and certain soft tissue tumors (sarcoma), and are found less frequently in patients with cancers of the central nervous system. Cancer mutations in the IDH2 gene primarily cause the amino acid arginine to be replaced by a different amino acid at the 140th or 172nd position in this protein. The change in sequence alters the structure of the protein, which results in loss of the normal enzymatic function of IDH2. Instead of producing its normal end-product (alpha-ketoglutarate), it produces the new metabolite R(-)-2-hydroxyglutarate (2HG), which is thought to contribute directly to the tumorigenic process by altering the activity of a number of proteins. The net effect is the inability to express a number of genes and the ability to activate signaling pathways involved in metabolism, and growth of new tumor vasculature.

The highest incidence of IDH2 gene mutations have been reported in acute myeloid leukemia (5-20%), cholangiocarcinoma (4-6%), and central cartilaginous tumors (~5%).
The IDH2 gene encodes for the metabolic enzyme isocitrate dehydrogenase 2. Unlike IDH1, IDH2 is localized within the mitochondria. While IDH2 functions similarly to IDH1 by catalyzing the oxidative decarboxylation of isocitrate to alpha-ketoglutarate, NAD+ is the final electron acceptor, thereby producing NADH.

Somatic mutations in IDH2 are found most frequently in acute myeloid leukemia, bile duct tumors (cholangiocarcinoma) and certain sarcomas, and to a much lesser extent in low-grade gliomas and secondary glioblastomas. These mutations result in decreased normal enzymatic activity and result in the neomorphic activity of producing the oncometabolite R(-)-2-hydroxyglutarate (2HG) as the end-product. Levels of 2HG can accumulate dramatically in IDH2-mutant tumors and this is thought to promote tumorigenesis by competitively inhibiting the activity of a number of dioxygenases. The net effect appears to involve the promotion of gene silencing through hypermethylation of DNA and histones, as well as the activation of the hypoxia-inducible factor signaling pathway.

The highest incidence of IDH2 gene mutations have been reported in acute myeloid leukemia (5-20%), cholangiocarcinoma (4-6%), and central cartilaginous tumors (~5%).
PubMed ID's
22234630, 22180306, 20884716, 21598255
Expand Collapse R172W (c.514A>T)  in IDH2
The IDH2 R172W mutation arises from a single nucleotide change (c.514A>T) and results in a substitution of the arginine (R) at position 172 by a tryptophan (W).
The IDH2 R172W mutation arises from a single nucleotide change (c.514A>T) and results in a substitution of the arginine (R) at position 172 by a tryptophan (W).

IDH2 mutations are more common in AML that also display an NPM1 gene mutation, as well as those cases in which chromosomal analysis of leukemic cells are normal or considered intermediate-risk.

The high levels of the metabolite produced by mutant IDH activity in cancer cells (2-HG) can be detected in the blood and urine of IDH2-mutant AML patients. Monitoring the extent of reduction (associated with treatment response) or rise (associated with disease relapse) in 2-HG levels during chemotherapy may provide a non-invasive means of following treatment effects in IDH2-mutant patients.

There remains significant debate regarding whether an IDH2 mutation in affects prognosis and outcomes among patients with AML. A large study of AML patients in the United Kingdom did suggest that the position of where the IDH2 alteration occurs may be important. In this study, IDH2 alterations occurring at amino acid position R140 were associated with a more favorable overall survival and relapse rate, when compared to cases with the alteration at amino acid position R172.


The novel enzymatic activity conferred by IDH2 gene mutations is believed to provide a desirable target for effective anti-cancer therapies. Indeed, agents targeting mutant IDH activity are under active development clinical study. A clinical trial studying an IDH2 inhibitor, AG-221, is currently accruing patients at the MGH Cancer Center.

IDH2 mutations are more common in AML with a concurrent NPM1 mutation, and normal or intermediate-risk cytogenetics. IDH2-mutant AML has also been associated with a hypermethylation phenotype, and thus gene silencing, with the oncometabolite 2-HG suspected to play a leukemogenic role.

The high levels of the metabolite 2-HG, produced by mutant IDH activity in leukemic cells, can be detected in the blood and urine of patients with IDH2-mutant AML. Monitoring the extent of reduction (associated with treatment response) or increase (associated with disease relapse) in 2-HG levels during chemotherapy has been studied and may provide a non-invasive means of following disease activity in IDH2-mutant AML patients.

There remains significant debate regarding whether an IDH2 mutation in AML provides prognostic insight. A large retrospective evaluation of 1,473 AML patients in the United Kingdom did suggest that the position of IDH2 alteration may be important. In this study, alterations impacting amino acid position R140 displayed a more favorable overall survival and relapse rate when compared to cases where position at R172 were impacted. Additional study is necessary to confirm these findings.


The novel enzymatic activity conferred by IDH2 gene mutations in cancer is believed to provide a robust target for therapeutic intervention. Novel therapies targeting mutant IDH activity are under active development and clinical study. A clinical trial of the IDH2 inhibitor,
AG-221, is currently accruing patients with AML and other myeloid malignancies at the MGH cancer center.

PubMed ID's
21596855, 24760710, 20171147, 20368543, 20538800, 20625116, 23074281, 20142433, 20421455, 21596855, 21130701, 22417203
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Your Matched Clinical Trials

Trial Matches: (D) - Disease, (G) - Gene, (M) - Mutation
Trial Status: Showing all 10 results Per Page:
Protocol # Title Location Status Match
NCT02481154 Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation Study of Orally Administered AG-881 in Patients With Advanced Solid Tumors, Including Gliomas, With an IDH1 and/or IDH2 Mutation MGH Open DGM
NCT02577406 An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation An Efficacy and Safety Study of AG-221 (CC-90007) Versus Conventional Care Regimens in Older Subjects With Late Stage Acute Myeloid Leukemia Harboring an Isocitrate Dehydrogenase 2 Mutation MGH Open DG
NCT02632708 Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation Safety Study of AG-120 or AG-221 in Combination With Induction and Consolidation Therapy in Patients With Newly Diagnosed Acute Myeloid Leukemia With an IDH1 and/or IDH2 Mutation MGH Open DG
NCT02848248 A Safety Study of SGN-CD123A in Patients With Acute Myeloid Leukemia A Safety Study of SGN-CD123A in Patients With Acute Myeloid Leukemia MGH Open D
NCT02421939 A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation A Study of ASP2215 Versus Salvage Chemotherapy in Patients With Relapsed or Refractory Acute Myeloid Leukemia (AML) With FMS-like Tyrosine Kinase (FLT3) Mutation MGH Open D
NCT02537613 A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia A Study of Ibrutinib + Obinutuzumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia MGH Open D
NCT01830777 Brentuximab Vedotin + Chemo for AML Brentuximab Vedotin + Chemo for AML MGH Open D
NCT02841540 Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia Phase 1 Trial to Evaluate the Safety, Pharmacokinetics and Pharmacodynamics of Splicing Modulator H3B-8800 for Subjects With Myelodysplastic Syndromes, Acute Myeloid Leukemia, and Chronic Myelomonocytic Leukemia MGH Open D
NCT02587598 Study of INCB053914 in Subjects With Advanced Malignancies Study of INCB053914 in Subjects With Advanced Malignancies MGH Open D
NCT02074839 Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation Study of Orally Administered AG-120 in Subjects With Advanced Hematologic Malignancies With an IDH1 Mutation MGH Open D
MGH has many open clinical trials for other cancers not shown on the Targeted Cancer Care website. They can be found on the MassGeneral.org clinical trials search page.

Additional clinical trials may be applicable to your search criteria, but they may not be available at MGH. These clinical trials can typically be found by searching the clinicaltrials.gov website.
Trial Status: Showing all 10 results Per Page:
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