Additional Hematopoietic Malignancy Predispositions Accounted for in Updated Surveillance Recommendations

Researchers of a new paper have detailed updated surveillance recommendations for children with certain germline gene variants associated with an increased risk of myelodysplastic syndromes (MDS) and other hematopoietic malignancies (HMs).¹

The recommendations for surveillance account for newly identified hematopoietic malignancy predispositions (HMP) and HMP genes, as well as a greater understanding of the prevalence of germline variants putting children as an increased risk of MDS and other HMs. Surveilling children with these predispositions was previously recommended in 2017.²

“These updated recommendations are primarily categorized based on each HMP’s associated risk for MDS, although general principles, such as physical examination at least annually, education about the signs and symptoms of HM, referral to or consultation with centers with expertise in HMP, and consultation with an HSCT specialist, are broadly applicable to all conditions,” explained the researchers.¹

Similar to the previous recommendations, these updated recommendations, published in Clinical Cancer Research, generally recommend routine monitoring of complete blood counts (CBC) and bone marrow assessments. These evaluations are recommended for all patients with HMP, though the frequency differs based on HMP. Other surveillance evaluations include deep sequencing with somatic gene panels to identify any changes in genes associated with progression of HM.

For example, CBC with differential and reticulocyte count, bone marrow aspirate and biopsy with morphology and cytogenetic analysis (BMA/Bx), and a somatic gene panel are all recommended for patients with a DDX41-associated predisposition to myeloid and lymphoid neoplasms—a newly identified HMP and also the most common HMP. The group recommends a CBC every 6-12 months, as well as BMA/Bxand somatic gene panel every 1-3 years. DDX41-associated predisposition to myeloid and lymphoid neoplasms carries a low risk of hematologic malignancy before the age of 40 years though the risk increases to nearly 50% (49%) by the age of 90 years. 

Meanwhile, for GATA2 deficiency, which carries a predisposition to MDS and acute myeloid leukemia (AML), CBC is recommended every 3-4 months with BMA/Bx and a somatic gene panel recommended every year.

Since 2017, several other HMPs have been identified and accounted for in the surveillance recommendations. These include Diamond-Blackfan anemia (DBA), a disorder of low red blood cell counts primarily driven by germline heterozygous variant in a gene responsible for coding for small or large ribosomal proteins. Patients with DBA are estimated to have a cumulative incidence of a malignancy, most commonly MDS, of 13.7% by the age of 45 years. Surveillance recommendations for this HMP includes CBC every 4 to 6 months and BMA/Bx as clinically indicated.

Other HMPs now accounted for in the updated recommendations include IKAROS-associated predisposition to lymphoid neoplasms, SAMD9/SAMD9L-associated predispositions to myeloid neoplasms, and Shwachman-Diamond syndrome, which predisposes patients with MDS and AML.

The group also outlined genes that have newly been identified as predisposing patients to hematologic malignancies since the original recommendations.

“Although the understanding of the natural history of these syndromes, including the penetrance and nature of HM, is expected to evolve with time, the working group has tentatively included screening recommendations for these HMP, based on the current estimated risks, and consistency with the syndromes that are more well-described, and the collective experience of the expert panel.”

The genes outlined by the group include ERCC6L2, MBD4, MECOM, SH2B3, TYK2, USP9X. Among the genes are predispositions to BMF and myeloid malignancies, certain leukemias, and MDS.

References:

1. Maese LD, Wlodarski MW, Kim SY, et al. Update on recommendations for surveillance for children with predisposition to hematopoietic malignancy. Clin Cancer Res. 2024;30:4286–4295. doi:10.1158/1078-0432.CCR-24-0685
2. Porter CC, Druley TE, Erez A, et al. Recommendations for surveillance for children with leukemia-predisposing conditions. Clin Cancer Res. 2017;23(11):e14-e22. doi:10.1158/1078-0432.CCR-17-0428