SCT for Secondary AML in a Patient with Glycogen Storage Disease Type 1b
Authors: Zeidler Cornelia , Kafa Kinan , Sauer Martin G. , Maecker-Kolhoff Britta , Greil Johann , Welte Karl , Kratz Christian P , Sykora Karl-Walter 
Published: October 2019

Abstract
Abstract 4402
It is well established that patients with congenital neutropenia due to mutations of ELANE or HAX1 have a strongly increased risk of developing secondary leukemia. In contrast, the leukemia risk is not strongly increased in patients with specific other neutropenia subtypes (e. g. cyclic neutropenia with ELANE mutations). Here we report the first glycogen storage disease type Ib (GSD1b) patient in our registry who developed acute myelogenous leukemia (AML). GSD1b is an autosomal recessive disorder of glycogen metabolism with intracellular accumulation of glycogen caused by mutations in the glucose-6-phosphate translocase gene. Patients present with hepatomegaly, growth retardation, hypoglycemia, lactic acidosis as well as neutropenia and neutrophil dysfunction predisposing to bacterial infections. G-CSF has been shown to be an effective long-term treatment for GSD1b patients leading to an increase in neutrophil counts and enhancement of neutrophil function resulting in fewer infections and improved quality of life. The European Branch of the Severe Chronic Neutropenia International Registry (SCNIR) has collected long-term data from 23 patients with GSD1b. Median age was 17 years, 3 patients expired from infections at an age of 8; 9 and 26 years, respectively. All 23 patients received G-CSF treatment for a median duration of 9.5 years, 22 patients received continuous G-CSF with a median dose of 3.4 mcg/kg/day (range 0.8 to 5 mcg/kg/day), one patient received G-CSF interventionally only.
Our patient was diagnosed with AML FAB classification M2 linked to cytogenetic aberrations involving trisomy 21. Leukemia cells also harboured a missense RUNX 1 mutation in exon 3. G-CSF treatment was initiated at age 5 months at a dose of 2.3 mcg/kg/d and was continued until AML diagnosis at age 10 years. The G-CSF dose was increased due to low ANCs and infectious episodes with otitis media and pneumonitis up to 4.05 mcg/kg/day. After initial AML treatment with a hypometylating chemotherapy consisting of azacytidine and cytarabine she developed partially reversible renal insufficiency and oxygen dependent pneumonitis which led to a reduction of chemotherapy despite persistence of AML blasts.
Remission was achieved with the use of mylotarg. Subsequently, she received a conditioning regimen with melphalan, fludarabine and treosulfan plus ATG-Fresenius followed by infusion of 10/10 HLA matched peripheral blood stem cells from an unrelated donor. Leukocyte engraftment occurred on day +18 followed by neutrophil engraftment on day +21. Post-SCT she developed grade III skin GvHD on day +8 which was responsible to steroid treatment.

Discussion:
Up to date 3 GSD1b patients with development of AML have been reported in the literature. Two patients were on long-term G-CSF treatment (Pinsk et al. J Pediatr. 2002; Schroeder et al. J Medical Case Reports 2008), one patient transformed predating the availability of G-CSF (Simmons et al. J Pediatr. 1984).

Conclusion:
According to the literature, leukemic transformation in patients with GSD1b is a rare event. However, with a total of four patients reported with secondary AML with or without G-CSF treatment, GSD1b patients may have a higher leukemia risk than previously anticipated. Independent from G-CSF treatment, regular bone marrow examinations (morphology, cytogenetics, mutation analysis of candidate genes such as RUNX1) may help to detect malignant transformation early and therefore avoid chemotherapy prior to SCT. SCT is a treatment option for AML in GSD1b, but further data is required.

Disclosures:
No relevant conflicts of interest to declare.