Acute Lymphoblastic Leukemia in Shwachman-Diamond Syndrome: Challenges and Treatment Outcomes
Authors: Cacace Fabiana , Rossitti Emanuela , Pagano Gennaro , Caprioli Valeria , D'Amico Maria Rosaria , De Simone Giuseppina , Giagnuolo Giovanna , Parasole Rosanna , Sabbatino Maria Simona , Stellato Pio , Wierda William G. , Tambaro Francesco Paolo 
Published: December 2024

Introduction
Shwachman-Diamond Syndrome (SDS) is a rare multisystem disorder characterized by skeletal abnormalities, pancreatic exocrine insufficiency, and bone marrow dysfunction. Individuals affected by SDS are predisposed to severe cytopenia and have an increased susceptibility to myeloid malignancies.
Methods
We report our experience of a young girl diagnosed with SDS who developed Acute Lymphoblastic Leukemia (ALL) at the age of 15-years.
Results
At the age of 14 months, the patient was diagnosed with SDS. Hematological follow-up was initiated to monitor for myelodysplastic syndrome(MDS)/Acute Myeloid Leukemia (AML) progression, a long side treatment for gastroenterological and nutritional complications.
In September 2020, the patient was diagnosed with B-Cell-ALL. A dose-reduced AIEOP-BFM ALL 2017 protocol, containing vincristine and daunorubicin and omitting asparaginase to prevent pancreatic toxicity was started. Due to prolonged cytopenia following the first course, following the administration of day +8 vincristine and daunorubicin, chemotherapy was discontinued and patient received two courses of Blinatumomab treatment achieving complete remission (CR) with undetectable minimal residual disease (MRD). Patient then received consolidation therapy with allogeneic-stem cell transplantation (SCT).
The conditioning regimen consisted of 12 Gy- total body irradiation (TBI)plus etoposide and graft versus host disease (GVHD) prophylaxis was obtained with Cyclosporin A; no short-course methotrexate (MTX) was given in order to minimizing toxicities.
In September 2021, the patient experienced a molecular relapse detected by two consecutive bone marrow evaluations. Treatment involved Blinatumomab (1 cycle) and 4 DLI, resulting in a second CR. The patient is currently in molecular CR with full donor chimerism, 41 months after HSCT.
Conclusions
SDS is associated with predisposition to develop MDS or AML. Children with SDS develop AML in 12-25% of cases. Lymphoid malignancies are rare in SDS patients, with four cases reported cases in the literature: two patients with a diagnosis of ALL and 2 patients affected by CNS and primary mediastinal B cell lymphoma respectively treated with standard chemo-or chemo-immunotherapy. To our knowledge, our patient represents the fifth reported lymphoid malignancy in SDS who achieved a CR in a relatively short time and is the only one alive and in CR after transplantation with a follow-up exceeding three years from diagnosis.
Second ALL can be very aggressive disease with poor prognosis, particularly challenging to treat in patients with SDS where treatment experience is limited. The BFM-inspired protocols emphasize the importance of dose density and intensity for achieving CR, which is difficult to obtain due to the SDS features, such as long time to bone marrow recover and the pancreatic insufficiency which did not allow the use of a crucial drug of the chemotherapy protocol
Blinatumomab emerged as the optimal treatment option for low toxicity and well tolerable profile with no gastrointestinal/pancreatic side effects and low-grade hematological toxicities allowing adherence to the treatment and serving as a bridge toallogeneic-SCT performed to consolidate the CR based on the consideration that a secondary ALL is per se an high risk disease.