ELANE neutropenia (EN) is associated with myelodysplasia/acute-leukemia (MDS-AL) as well as severe infections. As the risk of MDS-AL has been shown to be associated with the exposure to GCSF, since 2005, in France, patients that receive a high daily dose of GCSF (>15 μg/kg/day), are eligible for hematopoietic stem cell transplantation (HSCT), in addition to classic indications of HSCT (MDS-AL, or GCSF refractoriness). We analyzed the effect of this policy
Among 144 patients with ELANE neutropenia enrolled in the French Severe Chronic Neutropenia Registry (FSCNR), prospectively followed, we defined 2 groups according to the period of follow up. The first group called “before 2005” included patients born before 2005 and followed till 31/12/2004 (1588 person-years). The second one designed by “after 2005” comprised patients born after 2005 or patients born before 2005 but followed after 2005 till 31/03/2019 (1327 person-years).
16 HSCT has been performed in our cohort (14 with long term survival) and 6 MDS-AL has been observed. 6 leukemic transformations occurred in the group “before 2005” and no “after 2005”. (Incidence 3.8 x 10-3 “before 2005” vs. 0 “after 2005”; p< 0.01) while 4 HSCT has been performed before 2005 and 12 since 2005 (incidence of HSCTs increased 2.5 x 10-3“before 2005” vs. 9 x 10-3 “after 2005”; p< 0.01).
Our results supported early HSCT in patients with ELANE mutations that received high GCSF doses (>15 μg/kg/day but not considered as refractory to GCSF) might lower the risk of leukemic transformation.
Shwachman-Diamond Syndrome (SDS) due to SBDS mutations is associated with a high rate of leukemic transformation. Mutational somatic profile was evaluated on a cohort of patients from the french SCN registry
Hematological data were correlated with targeted NGS performed in SDS cohort of 57 patients.
We detect the presence of an acquired TP 53 mutation in 32/57 SDS patients (56%) with VAF (Variant Allele Frequency) ranging from 0.5% to 82.6%. Five patients had more than one mutation either concomitantly or at different times of evolution. The other mutations detected affect the DNMT3A (2 patients), IDH1, SF3B1, PHF6, SMC1A, ASXL2, FLT3 and KRAS genes. The longitudinal follow-up of 13 patients shows that the VAFs of TP53 mutations can grow or decrease and that clones can become detectable or undetectable over time in the same patient. In 11 patients we detected TP53 mutations with VAFs greater than 10% (affecting more than 20% of the cells analyzed). Of these, 5 patients were in fatal leukemic transformation with complex karyotype, 1 were at the SMD stage with excess blasts, 2 were in severe cytopenia without SMD, and 3 had no severe cytopenia with stable or decreased VAF over time. In the rest of the cohort, we observe that patients who do not have mutated TP53 clone clones or clones with low VAF (<10%) have few severe hematologic complications.
Mutations of TP53 are detected in half of the SDS and constitute a somatic event essential in the evolution in SMD or LAM, detectable early.