Hematopoietic Stem Cell Transplantation May Lower the Risk of Leukemia in ELANE Neutropenia: Historical Trends from a French Severe Chronic Neutropenia Registry (FSCNR) Cohort

Abstract

Context: Congenital neutropenia (CN) is associated with high leukemia risk and high risk of severe infections. The risk of leukemia depends on the genotype (ELANE , SBDS…) and also on the exposure to GCSF, which can be measured by the cumulative dose or as the mean dose received by the patient (1, 2). Since 2005, in France, patients that receive a high daily dose of GCSF, above the threshold of 15 µg/kg/day, are eligible for hematopoietic stem cell transplantation (HSCT), in addition to patients with classic indications, like myelodysplasia/acute leukemia (MDS-AL), or GCSF refractoriness (typically above 50 µg/kg/day) (3). The FSCNR prospectively monitors all patients with CN, and a genetic diagnosis is recommended for all patients with CN (4). Here, we analyzed the effect of this policy among patients with the ELANE mutation, because this group is currently one of the most heavily treated with GCSF. The GCSF dose was calculated according to a previous publication(1). The follow up of the cohort, expressed in person-years, included data from each patient, followed from birth to the last follow up visit of the study, to the date of the event (MDS-AL), or to the date of HSCT.Results: Since 1993, a total of 935 patients with chronic neutropenia were registered in France. Among those patients, 138 carried ELANE mutations, including 47 with cyclic and 91 with permanent neutropenia. Patients were grouped by whether they were born before (n=86) or after (n=52) 2005. The cumulative observation times were 1483 person-years for the 86 patients born before 2005 till 2005, and 1053 person-years for the 52 patients born after 2005 and the 80 patients born before 2005, but followed since 2005 (6 patients born before 2005 no longer contributed to the follow up after 2005, because they presented with MDS-AL or were treated with HSCT). In the entire cohort, 108 patients received GCSF at a mean dose of 9.8 µg/kg/day and 30 patients did not receive GCSF. The maximum doses were less than 5 µg/kg/day (n=38, 27%), between 5 and 10 µg/kg/day (n=30, 21%), between 10 and 30µg/kg/day (n=25), and above 30 µg/kg/day (n=15, 10%) patients. Both the mean and the maximum doses received by these patients did not change with time. Five patients were considered fully refractive (ANC < 0.2 G/l after more than 50 µg/kg/day GCSF); 16 patients received allogeneic HSCTs; and 6 patients presented with MDS-AL. The total number of HSCTs and the incidence of MDS-AL significantly changed over the study period. Before 2005, 4 out 86 patients underwent HSCTs; since 2005, 12 out 132 patients susceptible to receive a HSCT underwent transplantations (i.e., the 52 patients born after 2005 and the 80 patients born before 2005, but were followed after 2005). The rate of HSCTs per person-year increased from 2.7 10-3 to 11.4 10-3 (p<0.001). The incidence rate of MDS-AL per person-year decreased from 4 10-3 to zero (p<0.02). After 2005, HSCT was indicated for GCSF refractoriness in 3 patients and for high GCSF doses (10-30 µg/kg/day) in 9 patients. Before 2005, HSCT was indicated for MDS in 2 patients and for GCSF refractoriness in 2 patients. Noteworthy, 14 out the 16 HSCT survived. The 2 deaths observed after HSCT were related to the procedure, as one patient dyed before 2005 from sepsis and one dyed after 2005 from a refractory grade IV GVHD with Transplant-associated thrombotic microangiopathy .Conclusion: Our results supported early HSCT in patients with ELANE mutations that received high GCSF doses (15 µg/kg and more but not considered as refractory to GCSF) might lower the risk of leukemic transformation and might be benefit for the survival of the patients.Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier and « Le Fond de dotation Contre la Leucémie“. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot (ASSQF) for their support..Reference List1. J. Donadieu et al., Haematologica90, 45 (2005).2. P. S. Rosenberg et al., Blood107, 4628 (2006).3. L. R. Peffault de la Tour et al., Bone Marrow Transplant.50, 1168 (2015).4. J. Donadieu, O. Fenneteau, B. Beaupain, N. Mahlaoui, C. C. Bellanne, Orphanet. J. Rare. Dis.6, 26 (2011). [Display omitted] DisclosuresNo relevant conflicts of interest to declare.