Familial Predisposition to AML

Educational Objectives

The goal of this program is to improve diagnosis of inherited leukemias. After hearing and assimilating this program, the clinician will be better able to:

1. Explain the biologic features of pure leukemia syndromes.
2. List germline GATA2 mutations and their characteristics.
3. Identify patients with inherited bone marrow failure syndrome.

Summary

A simple classification: inherited leukemias can be classified into 4 categories, including 1) isolated familial acute myeloid leukemia (AML) syndrome, 2) AML with platelet abnormalities, 3) AML with other systemic diseases, and 4) inherited bone marrow failure syndrome (IBMFS) associated with AML or myelodysplastic syndromes (MDS)

Pure leukemia syndromes: involves 2 genes (ie, CEBPA and DDX41); AML with sporadic CEBPA mutation has good prognosis; CEBPA gene encodes a hematopoietic transcription factor that regulates granulocyte and monocyte differentiation; sporadic form involves a single mutation and the familial form a biallelic mutation; DDX41 is involved in mRNA and RNA splicing across different cell lines; DDX41 mutation is associated with multiple diseases; DDX41 gene is located on chromosome 5q; germline variants convey a strong predilection to MDS and a second hit may lead to AML transformation; a single hit may result in T-cell malignancies

Case 1: a patient with pancytopenia was treated with methotrexate for a small T-cell large granular lymphocyte (LGL) clone; a bone marrow biopsy (BMB) a year later showed MDS; a donor search revealed that his human lymphocyte antigen (HLA)-identical sister was mildly pancytopenic and was diagnosed with AML; the patient had DDX41 mutation and underwent matched, unrelated peripheral blood stem-cell transplantation (SCT), after which he had difficulty understanding simple instructions; patients with DDX41 mutation have developmental delays and learning disabilities; the patient's sister did not respond to salvage chemotherapy; a trial of lenalidomide failed

Upfront transplantation: the question of upfront transplantation (with associated risks and morbidity) in young patients with an inherited predisposition and good prognosis has evaded consensus

Next-generation sequencing (NGS): identification of mutations can lead to personalized therapy (eg, lenalidomide for 5q deletion MDS); rapid assessment of donor can prevent donor-derived leukemia in patients with inherited predisposition

AML with platelet abnormalities: patients have a long-standing history of thrombocytopenia, easy bruising or bleeding, and, oftentimes, a family history of refractory immune thrombocytopenia (ITP); the 3 most common types are familial platelet disorder (FPD) with a RUNX1 mutation, thrombocytopenia 2 with an ANKRD26 mutation, and thrombocytopenia 5 with an ETV6 mutation; RUNX1 encodes subunit 1 of a heterodimeric transcription factor that controls hematopoiesis; ANKRD26 is a scaffolding protein for other proteins required for platelet function; mutations in transcription factors involved in platelet differentiation and function may lead to thrombocytopenia and platelet dysfunction

Case 2: a patient with a long-standing history of easy bruising and mild thrombocytopenia and a treatment history for refractory ITP was diagnosed with AML (50% blasts, hypocellular marrow); cytogenetics showed an isochromosome 21q; NGS showed SRSF2 mutation and RUNX1 R166Q mutation (germline; confirmed by skin fibroblast culture [SFC]); his HLA-identical brother and daughter (with normal counts) tested positive for RUNX1 mutation

RUNX1 FPD with AML: is common and has variable penetrance; family members without disease manifestation may require regular follow-up; a history of long-standing cytopenias should raise suspicion for inherited syndromes; SCT may be considered for intermediate-risk AML with genetic predisposition, owing to risk of relapse or a second AML

AML with systemic diseases: GATA2 deficiency syndrome is common; SAMD9L mutation is very rare; GATA2 is a zinc-finger transcription factor, which is essential for hematopoiesis and lymphatic development

Case 3: the patient's sister was recently diagnosed with AML; she has multiple viral infections and developed complication (bacterial skin infection) during induction chemotherapy; she tested positive for GATA2 mutation; different mutations occurring in GATA2 gene produce varied phenotypic features; the patient, though positive for GATA2 mutation, has a different phenotype; his blood tests are normal, except for a mild decrease in immunoglobulin levels; follow-up plan for him involves a repeat bone marrow biopsy (BMB) if the counts drop and genetic counseling for his children

Germline GATA2 mutations: may present as 3 different syndromes; 1) familial AML/MDS syndrome has an early onset with poor prognosis; 2) MonoMAC syndrome is characterized by severe deficiency of monocytes, lymphocytes, and natural killer (NK) cells leading to opportunistic, recurrent viral, and atypical mycobacterial infections; 3) Emberger syndrome is characterized by lymphedema of the lower extremities and genitalia, deafness, cutaneous warts, and AML/MDS with monosomy 7;

Take-home points: patients with myeloid malignancies and atypical infections should be evaluated for hereditary predisposition; if positive, screening of at-risk family members and finalizing a stem-cell donor are recommended

IBMFS in AML and MDS: Although most subtypes including Fanconi anemia, Diamond-Blackfan anemia, and Shwachman-Diamond syndrome are encountered predominantly by pediatricians, IBMFSs are phenotypically variable and may present later in life

Case 4: a male patient (38 yr of age) with mild aplastic anemia (AA) was advised allogenic transplantation and presented with gray hair; BMB showed normal hematopoiesis; NGS revealed a new variant of the TERT gene

Telomere biology disorders (TBD): telomeres are repeat sequences (TTAGGG); shelterin complex protects the telomere caps, and the telomerase complex maintains telomere length; mutations in these complexes lead to abnormally short telomeres and an increased risk for leukemia; cutaneous manifestations of TBD include a triad of dystrophic nails, oral hairy leukoplakia, and hyperpigmented reticular skin rash (dyskeratosis congenita); other manifestations include pulmonary fibrosis, liver fibrosis, dental caries, and increased risk for squamous cell cancers (SCC); telomere length (TL) at birth is ≈11 kb and at 90 yr of age it is ≈6 kb; TL is assessed by flow cytometry with fluorescent in situ hybridization (flow-FISH); the above-discussed patient had early graying, bone marrow failure, and short telomeres (a novel syndrome); TBD has variable penetrance and strong anticipation (increased likelihood of an inherited syndrome in the succeeding generations)

Fanconi anemia: mutations in the Fanconi complex (involved in DNA repair) lead to apoptosis and secondary malignancies including SCC and IBMFS

Patient considerations: flow-FISH aids in the diagnosis and helps the patient understand their phenotypic course; limited family history hinders the detection of IBMFS with variable penetrance; syndromes with germline mutations warrant hereditary hematologic malignancy (HHM) workup

Diagnostic considerations: suspicion for HHM syndromes (HHMS) is warranted when young patients are diagnosed with monosomy 7 or new AA; a family history of AA, MDS, or leukemia, a history of chronic cytopenias, bleeding tendencies, or malignancies, a family member with cytopenias, or germline mutations should also raise suspicion; in such patients, look for various physical manifestations of HHMS (eg, edema, extragenital warts); eliciting a family history is complicated by patients' lack of awareness and diagnosis bias; barriers to diagnosis include financial considerations, logistics of performing a skin biopsy (SFC takes ≈8 wk), and obtaining a relevant family history; peripheral blood samples for NGS are not recommended in hematologic malignancies; prophylactic SCT in patients with complete penetrance, the question of disclosing incidental mutations, and prenatal diagnostic testing for patients with phenotypic variability are controversial; dedicated HHM clinics collaborate and help overcome challenges in the diagnosis and management of HHMS

Readings

Alter BP. Inherited bone marrow failure syndromes: considerations pre- and posttransplant. Blood. 2017; 130(21):2257-2264. doi:10.1182/blood-2017-05-781799; Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127(20):2391-2405. doi:10.1182/blood-2016-03-643544; DiNardo C. Hereditary hematologic malignancies. Clin Lymphoma Myeloma Leuk. 2020; 20 Suppl 1:S27-S29. doi:10.1016/S2152-2650(20)30451-1; Fenaux P, Platzbecker U, Ades L. How we manage adults with myelodysplastic syndrome. Br J Haematol. 2020; 189(6):1016-1027. doi:10.1111/bjh.16206; Galera P, Dulau-Florea A, Calvo KR. Inherited thrombocytopenia and platelet disorders with germline predisposition to myeloid neoplasia. Int J Lab Hematol. 2019; 41 Suppl 1:131-141. doi:10.1111/ijlh.12999; Kam MLW, Nguyen TTT, Ngeow JYY. Telomere biology disorders. NPJ Genom Med. 2021; 6(1):36. Published 2021 May 28. doi:10.1038/s41525-021-00198-5; Kico JM, Mullighan CG. Advances in germline predisposition to acute leukaemias and myeloid neoplasms. Nat Rev Cancer. 2021; 21(2):122-137. doi:10.1038/s41568-020-00315-z; Niewisch MR, Savage SA. An update on the biology and management of dyskeratosis congenita and related telomere biology disorders. Expert Rev Hematol. 2019; 12(12):1037-1052. doi:10.1080/17474086.2019.1662720; Sahoo SS, Kozyra EJ, Wlodarski MW. Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes. Best Pract Res Clin Haematol. 2020; 33(3):101197. doi:10.1016/j.beha.2020.101197; Talati C, Sallman D, List A. Lenalidomide: Myelodysplastic syndromes with del(5q) and beyond. Semin Hematol. 2017; 54(3):159-166. doi:10.1053/j.seminhematol.2017.06.003.

Disclosures

Dr. Patel is on the advisory boards for Agios, Bristol Myers Squibb Inc., OncLive, and Servier; is a consultant for Jazz Pharmaceuticals Inc.; is a research program reviewer for NCCN/Taiho Oncology; and is on the Speakers’ Bureau for MU Peerview. Members of the planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Patel was recorded at Clinical Hematology and Oncology: 2022, held on February 22, 2022, in San Diego, CA, and presented by Scripps MD Anderson Cancer Center. For more information about upcoming CME activities from this presenter, please visit scripps.org. Audio Digest thanks the speakers and Scripps MD Anderson Cancer Center for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

ON131202

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.

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