Improved Outcome Of Stem Cell Transplantation for Severe Chronic Neutropenia With Or without Secondary Leukemia: A Long-Term Analysis of European Data For More Than 25 Years By the SCNIR
Authors: Zeidler Cornelia , Nickel Anna , Sykora Karl-Walter , Welte Karl 
Published: October 2019

Abstract
Severe chronic neutropenia is a group of rare disorders including inborn genetic defects (congenital neutropenia;CN and cyclic neutropenia; CyN) and acquired diseases associated with severe chronic neutropenia. CN includes a variety of genetic subgroups and is well known as one of the premalignant bone marrow failure syndromes with an overall incidence of secondary leukemia of more than 10 percent. Since the availability of G-CSF for the treatment of severe chronic neutropenia patients the life expectancy and quality of life has improved significantly. Therefore, stem cell transplantation is to date limited to few indications, e. g. G-CSF treatment non-response or secondary leukemia.
Here we report on the outcome of stem cell transplantations in 71 patients (70 CN, 1 CyN) documented by the SCNIR since 1994.

Results
Reason for SCT was myelodysplastic syndrome or secondary leukemia in 34 CN and 1 CyN patients (LEUK+), G-CSF treatment non-response in 17 CN patients and other non-malignant events (e.g. G-CSF receptor mutation) in 19 CN patients (LEUK-). In 56 of 71 patients genetic testing was available revealing 28 ELANE (11 LEUK+; 17 LEUK-), 7 HAX1 (6 LEUK+; 1 LEUK-), 7 SBDS (5 LEUK+; 2 LEUK-), 1 G6PT (LEUK+), 1 G6PC3 (LEUK-) 1 p14 (LEUK-), digenic mutation (HAX1 plus G6PC3) in 1 (LEUK-) and no gene mutation in 10 patients (6 LEUK+; 4 LEUK-). In 13 CN (7 Leuk+/6 Leuk-)and the CyN (Leuk+) patient no genetic testing was performed.
For further analysis patients were divided by SCT indication (35 LEUK+ versus 36 LEUK-) and both cohorts by year of SCT (before and since 2001) to acknowledge differences in SCT outcome over time due to improved HLA-typing and concomitant treatment (e. g. GvHD prophylaxis) and a change in SCT strategy in the LEUK+ cohort by introducing a new SCT protocol in 2001.
Patients are characterized as follows:
LEUK+ prior to 2001 (n=11):5/6 male/female. Median age at SCT 10 years. Median follow-up of 0.54 years (max. 13.2 years). Median time between leukemia diagnosis to SCT 6.5 months. Median G-CSF dose 4.5 mcg/kg/day.
LEUK+ since 2001 (n=24):9/15 male/female. Median age at SCT 12 years. Median follow-up of 4.5 years (max. 10.42 years). Median time between leukemia diagnosis to SCT 2.5 months. Median G-CSF dose 15.11 mcg/kg/day.
LEUK- prior to 2001 (n=9):4/5 male/female. Median age at SCT 8 years. Median follow-up of 10.9 years (max. 27.2 years). Median G-CSF dose 24.5 mcg/kg/day.
LEUK- since 2001 (n=27):15/12 male/female. Median age at SCT 5 years. Median follow-up of 3.08 years (max. 9.2 years). Median G-CSF dose 9.9 mcg/kg/day.
22 different chemo-conditioning regimens were used. Busulfan based regimens were chosen in the majority of LEUK+ and LEUK- patients independent from HLA-donor and stem cell resource.
In the LEUK+ cohort before 2001 SCT was performed mainly in 2ndremission following standard chemotherapy protocols, whereas since 2001 due to the new protocol SCT was performed immediately after leukemia diagnosis without standard anti-leukemic therapy. An increase of survival rate from 27.3% (8 deaths out of 11 patients) to 83.3% (4 deaths in 24 patients) in the LEUK+ cohort is highly significant (p<0,001).
In the LEUK- cohortsurvival has improved over time from 66.7% prior 2001 to 77.8% since 2001.

Conclusion
Secondary leukemia is the major reason for SCT in CN patients followed by G-CSF treatment non-response. Comparing SCT prior 2001 with SCT since 2001, SCT survival has improved in the LEUK- indications by 13 % independent from the conditioning regimens used for SCT and HLA match of SCT donors. These results may indicate improved HLA typing, GvHD prophylaxis and treatment for infectious episodes. In comparison, in the LEUK+ cohort a dramatic improvement was documented with an increase of survival rate from 27 % to 83% indicating the additional impact of a shortened time interval between leukemia diagnosis and SCT in combination with the avoidance of standard chemotherapy treatment prior to SCT by the new SCT protocol.

Disclosures:
No relevant conflicts of interest to declare.