Inherited hematologic malignancies predisposition syndromes

Hereditary predispositions to hematologic malignancies occur in approximately 5─10% of cases. During the Society of Hematologic Oncology (SOHO) Eighth Annual Meeting, Courtney DiNardo gave a talk about the importance of recognizing patients with inherited cancer predisposition syndromes.¹

The identification of an inherited predisposition allows optimized treatment of the patient, more informed donor decisions (avoiding a related donor with the same predisposition), and opportunities for identification and screening of family members.¹

Inherited predisposition syndromes associated with leukemia and myeloproliferative neoplasms (MPN) are reported in Table 1.

Table 1. Leukemia and MPN predisposition syndromes¹

In 15─20% of cases, patients with either aplastic anemia, hypocellular myelodysplastic syndrome (MDS), or bone marrow failure have an inherited predisposition syndrome, such as Fanconi anemia, dyskeratosis congenita (DC), Shwachman–Diamond syndrome, Diamond Blackfan anemia, or others. These patients should be recognized and referred for genetic testing in order to provide optimal treatment strategies.¹

Genetic profiling of patients with inherited bone marrow failure syndromes is important because they

• respond poorly to anti-thymocyte globulin and cyclosporine (a shorter telomere length by flow-FISH [fluorescent in situ hybridization] in patients with aplastic anemia correlates with poor response to standard immune suppressive therapy);
• respond well to growth factors and androgens (effective in ˃ 50% of patients);
• should be treated with specialized reduced-intensity regimens to avoid excessive morbidity (avoid alkylating agents); and
• need surveillance for solid tumors.

Clinical evaluation¹

Dyskeratosis congenita

DC (also called short telomere syndrome, telomere biology disorder, or telomeropathy) is caused by mutations in genes important for telomere maintenance. Telomeres protect chromosome ends from degradation, and their length regulates the ability of a cell to duplicate. The instability resulting from an inadequate telomere maintenance can lead to uncontrolled cell growth and development of cancer.

Telomere flow-FISH is the technique used to detect DC. With telomere flow-FISH it is possible to distinguish DC from other causes of bone marrow failure.

Familial GATA2 (MonoMAC) syndrome

Familial GATA2 syndrome, also known as MonoMAC or Emberger syndrome, is due to autosomal dominant mutations or deletion of GATA2 and is associated with immunodeficiency and frequent infections. The median age at diagnosis is 18 years, and the lifetime risk of MDS/acute myeloid leukemia (AML) is 75–90%. It is particularly common in younger patients with MDS, with 10─15% of them having germline GATA2 mutations, and occurs frequently in those with MDS carrying monosomy of chromosome 7:

• 27% of children and young adults
• 72% of patients aged 12─19

In cases of transplants from a related donor, it is important to test family members to be sure that they are not GATA2 mutation-positive. However, overall survival and stem cell transplant outcomes appear to be independent of GATA2 status.

RUNX1, ANKRD26, and ETV6 variants

MDS and acute leukemia predisposition syndromes include autosomal dominant pathogenic variants in RUNX1 (21q), ANKRD26 (10p12), and ETV6 (12p13), which are associated with mild to moderate thrombocytopenia, platelet aggregation defects, and abnormal megakaryocytes.

RUNX1 was the first described, and about 40% of patients with germline mutations develop MDS/AML/T-cell acute lymphoblastic leukemia at a median age of 33 years. Thus, monitoring patients found to harbor these mutations is important to identify those at risk.

DDX41 mutations

Autosomal dominant mutations in DDX41 (5q35) have been recently identified to confer a predisposition to developing MDS/AML at a median age of 65 years. DDX41 is mutated in 1% of all patients with MDS/AML, and retrospective studies have shown that these patients are particularly sensitive to lenalidomide. The majority of DDX41 mutations leading to MDS/AML are germline mutations, and therefore inherited. The estimated risk of developing MDS/AML in family members of an individual with a DDX41 mutation is   ̴20─30%.

Genetic characterization of disorders

An 81-gene panel, called EndLeukemia panel, was developed in 2017 to allow comprehensive molecular profiling of a variety of hematologic malignancies.² Genes included in the panel, reported in Table 2, cover genetic alterations in AML, MDS, MPN, MDS/MPN, aplastic anemia, acute lymphoblastic leukemia, hairy cell leukemia, T-large granular lymphocytic leukemia, and T-prolymphocytic leukemia.²

When suspected germline variants are detected, a multidisciplinary review is required to identify patients that should be further evaluated; the workflow is reported in Figure 1.^1,3

Table 2. Genes included in the EndLeukemia panel¹

Figure 1. Workflow for the multidisciplinary review of suspected germline variants³

HHMC, hereditary hematologic malignancies clinic; WHO, World Health Organization. 

Current consensus statement¹

The recommendations for clinicians managing patients with familial hematologic malignancies syndrome are the following:

• Clinical exam with complete blood count one or two times a year;
• Bone marrow biopsy at the time of diagnosis, to identify any clonal changes or secondary mutations that may lead to the development of hematologic malignancies, and then every year for research surveillance;
• Consider allogeneic stem cell transplant at time of development of dysplasia, or clonal somatic cytogenetic or molecular abnormality; and

For younger and interested patients, suggest reproductive counseling and preimplantation genetic testing.