Background Shwachman Diamond syndrome (SDS) is characterized by genetic predisposition to bone marrow failure and TP53-mutated myeloid malignancies. Data are scarce to guide surveillance strategies.

Objectives This study aims to characterize the presentation and outcomes of hematologic complications in 218 patients with SDS with the goal of informing surveillance.

Design/Method Data was obtained from medical records of 218 study subjects with biallelic mutations in SBDS/DNAJC21/ EFL1, or heterozygous mutations in SRP54 consented to the SDS Registry or the Bone Marrow Failure/MDS study which are longitudinal prospective cohort studies.

Results The median age of the study cohort was 12.2 years (yr) (range 0.1-52.8 yr). Of 204 patients with SBDS mutations, 12 developed severe BMF requiring transplant (median age 2.9 yr, range 0.4-39.5), 16 developed MDS (median age 15.9 yr, range 0.5-45), 11 developed AML (median age 27.7 yr, range 9.4-47.3) and 2 developed lymphoma (ages 17.0 and 23.8 yr). Of the 48 subjects with SBDS mutations who were adults >18 years (median 25.5, range 18.5-52.8), 16 (33%) developed a myeloid malignancy. Of 20 patients with an SRP54 mutation, 1 developed AML at age 15.2. One patient with biallelic EFL1 mutations died of BMF at age 0.7 yr.

Further analysis focused on patients with SBDS mutations. Five patients with MDS and 1 patient with AML were on G-CSF at the time of malignancy diagnosis. Only 2 patients who developed AML had had surveillance, but neither included somatic mutation analysis. The diagnosis of SDS was unrecognized prior to malignancy diagnosis for 5 with MDS (age range 13.8 to 21.5 yr) and 2 with AML (age 37.8 and 47.3 yr). Three patients were diagnosed with MDS on surveillance marrow exam. All patients with AML presented with symptoms which led to diagnosis.

Of the 16 patients who initially presented with MDS, 5 progressed to AML. Median survival for those who presented with MDS was 1.3 yr (range 0.2-14.9). Ten were deceased, 4 were alive with median follow up of 3.4 yr (range 1.0-14.9). Two additional patients were <100 days out from HSCT. Of 9 patients with MDS who proceeded to HSCT without prior cytoreductive therapy, 4 were alive with a median follow up of 3.1 yr (range 0.2-14.4) post-HSCT, 5 were deceased from treatment related mortality (TRM) (n=2), relapsed/refractory disease (n=2) or osteosarcoma at 10 years post-HSCT (n=1). Of 6 patients who received cytoreductive therapy, 3 died prior to HSCT with active disease (n=2) or TRM (n=1). Of the 3 who proceeded to HSCT post-cytoreductive therapy, 2 are alive at 0.1 and 0.7 yr post HSCT, and 1 died of TRM. One patient who received no therapy died 7.7 years post-diagnosis.

Median survival following AML diagnosis was 1 year (range 0.2-5.6). Of the 11 patients with AML, 8 died with relapsed/refractory disease, 1 died of TRM, and 2 survive in remission at 2 and 5.6 years post-AML diagnosis. Of the two patients who proceeded directly to HSCT, one is alive 5.6 years post-HSCT. Nine patients received a variety of cytoreductive regimens for AML, including AraC/Idarubicin, hypomethylating agents +/- venetoclax, of whom 6 were able to proceed to HSCT. None of the 9 adult patients >18 years with SBDS mutations and AML survived.

Eight patients with SDS undergoing surveillance marrow exams developed high risk features (HRF), including progressive dysplasias, dropping blood counts with rising marrow cellularity, high risk clonal cytogenetic abnormalities, and large or rapidly growing TP53 clones. Median age of patients with HRF was 19.7 yrs (range 1.3-40.9). All 6 patients transplanted for HRF are alive and well with a median follow up of 1.8 yr (0.1-4.5) post-BMT (Figure 1); 2 patients are currently undergoing evaluation for HSCT. None of the patients transplanted for HRF developed grade 3 or 4 GVHD. One patient with a large TP53 clone prior to transplant is alive without a detectable TP53 clone 0.9 years post-BMT.

Conclusions AML carries a poor prognosis for patients with SBDS mutations, so early referral for novel therapies should be considered. Marrow surveillance including morphology, cytogenetics, FISH, and somatic mutation analysis identified patients who developed HRF. Survival was excellent for patients transplanted for HRF. Although SDS is rare and patient numbers are small, these data show that regular comprehensive marrow surveillance can identify HRF to inform the need for closer monitoring or transplant prior to progression to malignancy.

Davies:Elixirgen Therapeutics: Other: Industry sponsored Clinical trial research . DiNardo:Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Forma: Research Funding; Kura: Honoraria, Membership on an entity's Board of Directors or advisory committees; LOXO: Research Funding; Cleave: Research Funding; ImmuneOnc: Honoraria, Research Funding; GenMab: Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria; Gilead: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Bluebird Bio: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Astex: Research Funding. Fleming:DISC medicine: Current holder of stock options in a privately-held company, Honoraria.

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