Lymphoid Malignancies in Shwachman-Diamond Syndrome

Many marrow failure conditions are associated with myeloid malignancy predisposition and a subset carry an increased risk of both myeloid and lymphoid malignancies. The increased risk of myeloid malignancy is known in Shwachman-Diamond syndrome (SDS), however, the risk of lymphoid malignancy in SDS has not been previously reported. Through the North American SDS Registry (SDSR), we identified multiple patients with SDS diagnosed with lymphoma. We report the clinical outcomes and molecular characteristics of lymphoma in SDS as well as the incidence rates of lymphoma, myelodysplastic syndrome (MDS), and acute myeloid leukemia (AML) in this cohort.

Patients with biallelic SBDS mutations enrolled on the SDSR were included for analysis. Age- and sex-specific incidence rates from the SEER Program (2016-2020) were multiplied by person-years of observation to obtain expected numbers of events. The crude rate per 100,000 (100,000*observed number of malignancies/person-years of follow-up) and the standardized incidence ratio (SIR) were calculated. Using validated targeted next-generations sequencing, somatic mutation and copy number variant analyses were conducted on tumor DNA extracted from lymphoma tissue samples.

Four patients had a diagnosis of lymphoma:

1) 16 year-old male with primary mediastinal B-cell lymphoma

2) 24 year-old male with a kappa-restricted diffuse large B-cell lymphoma (DLBCL), later diagnosed with lambda-restricted DLBCL concurrently with AML at age 27

3) 12 year-old male with classical Hodgkin lymphoma

4) 12 year-old male with DLBCL

All patients achieved complete remission (including patient 2 for each malignancy diagnosis) but experienced a number of infectious and end-organ complications with standard chemotherapy regimens.

A total of 217 patients with biallelic SBDS mutations contributed 3,281 person-years to the analysis of malignancy risk. The median age in our cohort was 12.8 years (range: 0.3 - 52.8); 62.7% of the patients were male (136/217). We observed 4, 13, and 14 patients with lymphoma, MDS, and AML, respectively. The crude rates per 100,000 person-years were 120 for lymphoma, 396 for MDS, and 420 for AML. The observed risk of lymphoma in patients with SDS was 38 (95% CI:[10, 97]) times higher than expected in the general population. The observed risk of MDS and AML were 5,409 (95% CI:[2880,9250]) and 469 (95% CI:[256, 786]) times higher, respectively, than expected in the general population.

Lymphoma tissue was available from patient 2 who experienced 2 instances of DLBCL, the second occurring concurrently with AML. Somatic mutation analysis conducted on tissue from the initial lymphoma diagnosis revealed an EZH2 variant (EZH2 c.1921 T>C, p.Y641H, 25% VAF) as well as two TP53 variants (TP53 c.993G>A, p.Q331Q, 16% VAF; TP53 c.524G>A, p.R175H, 15% VAF). Somatic mutation analysis conducted on tissue from the second lymphoma diagnosis demonstrated a third TP53 variant (TP53 c.838A>G, p.R280G, 73% VAF) occurring concurrently with a deletion of chromosome 17p raising concern for a biallelic TP53-mutated clone. The TP53 and EZH2 variants identified at initial diagnosis (a kappa-restricted lymphoma) were not detected in the specimen from his second diagnosis (now lambda-restricted). Copy number variant profile differed considerably between the two lymphoma specimens. Overall, these molecular profiles indicate the patient experienced a second primary TP53-mutated lymphoma rather than relapse.

Our results establish that SDS is a marrow failure condition predisposing to both myeloid and lymphoid malignancies. Patients with SDS are known to develop somatic TP53 mutations, giving hematopoietic cells a selective, albeit maladaptive, advantage in the setting of ribosomal defect constraints on cell fitness. Acquisition of second mutations leading to biallelic TP53-mutated clones has been associated with progression to myeloid malignancy in SDS. However, this same mechanistic driver toward malignancy has not been previously described in lymphoid cells in SDS. We identified for the first time the presence of TP53 variants in lymphoid cells of a patient with SDS. The biological and clinical impact of the cell of origin for a somatic mutation warrants further exploration. Additionally, the role of bone marrow transplant and non-genotoxic therapies should be investigated for treatment of lymphoma in patients with genetic predisposition to myeloid malignancy.

Farrar:Novartis: Research Funding. Lau:Johnson & Johnson: Current Employment. Myers:Incyte: Research Funding; Elixirgen Therapeutics: Research Funding. Shimamura:Fulcrum: Consultancy; X4 pharma: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees.