Newly Discovered Biomarkers Predict Response in AML
Acute myeloid leukemia (AML) is the most common acute leukemia diagnosed in adults, and most patients with AML relapse after achieving complete remission with induction therapy. Most patients with AML die from relapsed disease. Therefore, biomarkers that accurately predict outcome in AML are needed so patients can be matched to the most appropriate therapies, according to presenters at the American Society of Hematology 54th Annual Meeting.
Extensive mutational testing can be used to refine prognostication in AML and inform therapeutic approaches, said Ross L. Levine, MD, Memorial Sloan- Kettering Cancer Center, New York, NY. Novel disease alleles in AML are mutations in TET2, ASXL1, IDH1 and IDH2, PHF6, and DNMT3A. Integrated genetic analysis from 502 patients with AML enrolled in the Eastern Cooperative Oncology Group (ECOG) E1900 clinical trial revealed several genes with prognostic importance. Mutations in IDH2 R140, but not IDH2 R172 or IDH1, were associated with improved survival. Mutations in ASXL1 and PHF6 were associated with worse overall survival.
Risk can be further refined in patients with intermediate-risk AML by more extensive mutational analysis, said Dr Levine. Three distinct risk groups can be identified in FLT3-ITDnegative intermediate-risk AML based on mutational status; TET2, ASXL1, PHF6, and partial tandem duplications in MLL are poor-risk mutations associated with worse survival in the group of intermediate-risk patients with wild-type internal tandem duplications in FLT3.
In the ECOG E1900 trial, a post hoc analysis of mutational status found that high-dose daunorubicin improved outcomes markedly for patients with DNMT3A mutations. Patients with NPM1 or DNMT3A mutations, or MLL translocations, had a 3-year overall survival rate of 44% with high-dose daunorubicin induction chemotherapy compared with 25% rate when treated with standarddose daunorubicin.
Minimal residual disease (MRD) after treatment in AML predicts failure to maintain a morphologic complete response and negatively affects survival. Elisabeth Paietta, PhD, professor, department of medicine (oncology), Albert Einstein College of Medicine of Yeshiva University, Bronx, NY, reviewed approaches to monitoring MRD, noting that the best method is still a matter of debate and that MRD assessment assays need to be standardized. They are either immunophenotypic, done by multiparameter flow cytometry, or done by polymerase chain reaction to detect recurrent gene mutations or leukemia fusion transcripts. Very sensitive assays, perhaps next generation sequencing, are needed to find minor clones present at diagnosis that may lead to relapse. Even with detection of MRD, therapeutic options at present are limited, she said. Intensive therapeutic approaches have not worked in MRD-positive patients, said Dr Paietta.
Relapsed AML remains a clinical challenge, said Jeffrey Szer, MBBS, professor/ director, department of clinical haematology and BMT service, The Royal Melbourne Hospital, Parkville, Australia. Novel approaches to the treatment of relapse include clofarabine, a novel purine analogue, with or without cytarabine; tosedotat, an orally available aminopeptidase inhibitor that has shown significant clinical activity in a phase I/ II study; and FLT3 inhibitors, which may have a role as a bridge to transplantation. Inhibitors of the mammalian target of rapamycin (mTOR), such as everolimus and sirolimus, have potential utility given the role of the mTOR pathway in cytarabine activity. Hypomethylating agents are being studied as maintenance therapy after allo-stem cell transplant (SCT). Allo-SCT has the potential to cure relapsed or refractory disease, but only after patients have achieved a second complete remission or MRD.
Evidence-Based Approaches to Cytopenias Discussed
Diagnostic approaches to cytopenias require an understanding of their etiology, said presenters during the American Society of Hematology 54th Annual Meeting.
Neutropenia is often a secondary finding “to a far more significant underlying hematologic disorder, placing the patient at risk for infectious complications,” said Laurence A. Boxer, MD, a pediatric hematologist-oncologist at the University of Michigan Heath System, Ann Arbor.
In the case of severe congenital neutropenia (SCN), which is characterized by recurrent severe infections during the first months of life, bone marrow examination characteristically shows a myeloid “maturation arrest” at the promyelocyte-myelocyte stage of development. Mutations in the ELANE gene have been observed in 40% to 60% of patients with congenital neutropenia, and neutropenia caused by the ELANE mutation is associated with the most severe infectious complications, Dr Boxer said.
An autosomal-recessive subtype of SCN is Kostmann disease, in which mutations of the HAX1 gene are observed. Patients with both isoform A and isoform B HAX1-spliced variants can suffer from neurologic impairment that ranges from developmental delay to severe epilepsy.
Uncovering the cause of chronic anemia relies on a complete blood count (CBC), said Mark J. Koury, MD, professor of medicine, division of hematology/oncology, Vanderbilt University, Nashville. The 4 patterns encountered frequently in CBCs associated with chronic anemia are anemia with abnormal platelets and/or leukocyte counts, anemia with increased reticulocyte counts, a lifelong persistence of an abnormal CBC, and anemia with inappropriately low reticulocytes.
Diseases affecting early-stage hematopoietic progenitors, such as liver disease, will likely affect platelets and leukocytes. Underlying causes can include chronic alcohol intake and antiviral treatments for hepatitis C. The absence of an enlarged spleen usually indicates a primary bone marrow disease, including myelodysplasia or malignant invasion of the bone marrow, such as with multiple myeloma.
An increased number of reticulocytes with chronic anemia indicates lowgrade hemolysis or blood loss (possibly from upper gastrointestinal lesions or menorrhagia). Erythrocyte fragmentation on the blood smear is often associated with malignant tumors, large hemangiomas, prosthetic heart valve defects, or direct external trauma, said Dr Koury. Spherocytes suggest hereditary spherocytosis or immune hemolysis, the latter of which can be diagnosed by surface antibodies and/or complement components on erythrocytes in the direct antiglobulin test.
Bone marrow events responsible for low reticulocyte production include apoptosis of erythroid progenitor and precursor cells by intrinsic and extrinsic factors, development of macrocytosis when erythroblast DNA replication is impaired, and development of microcytosis due to heme-regulated elF2-alpha kinase inhibition of protein synthesis in iron-deficient or thalassemic erythroblasts.
Correct identification of the cause of thrombocytopenia is crucial for proper management, said Roberto Stasi, MD, PhD, department of haematology, St. George’s Hospital, London, UK. Thrombocytopenia may be the initial manifestation of infections (ie, HIV and hepatitis C virus). Examination of the peripheral blood smear remains the most important investigation to guide diagnostic approaches. Liver and renal function tests, a clotting screen with D-dimers, and measurement of lactate dehydrogenase are part of the basic laboratory evaluation.
A bone marrow aspirate and biopsy may be performed if the etiology of the thrombocytopenia is unclear, said Dr Stasi.
Primary immune thrombocytopenia (ITP) remains a diagnosis of exclusion, he said, with no consensus on the set of investigations. The role of the bone marrow biopsy and aspirate in ITP are controversial.
Thrombocytopenia in the hospitalized patient has many possible etiologies; special consideration should be given to drug-induced thrombocytopenia considering its frequency in this setting, said Dr Stasi. Heparin-induced thrombocytopenia is often a clinical emergency and typically develops after 5 to 10 days of exposure to heparin.
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Authorship Information: Concept and design; drafting of the manuscript; and critical revision of the manuscript for important intellectual content.