Response to High Dose G-CSF Treatment (20µg/kg/d or Higher) of Patients with Congenital Neutropenia: An Analysis By the Scnir in Europe

Abstract

Background: Congenital neutropenia (CN) is a group of rare inborn genetic disorders of hematopoiesis including a variety of different gene mutations and different patterns of inheritance. Independent of the underlying genetic subtypes, CN patients benefit from G-CSF maintenance treatment, which improved the life expectancy and quality of life significantly. The majority of CN patients documented by the SCNIR Europe respond well to G-CSF treatment and achieve and maintain neutrophil response with an anticipated ANC of greater 1000/µL with a median G-CSF dose of 4.77 µg/kg/day. However, the G-CSF dose used is very heterogeneous and dose increase is dependent on the decision of each treating physician. Here we report on the incidence, clinical characteristics and outcome of patients receiving G-CSF doses of 20µg/kg/d or higher. Methods: In the European database of the SCNIR we have identified 420 CN patients with different genetic subtypes (including SDS and GSD1b) who are treated with G-CSF. Non-response is defined as median neutrophil counts below 500/µL upon G-CSF doses of 20µg/kg/day or higher. Partial responders have median ANCs of 500 to 999/µL with these G-CSF doses or severe infections despite ANCs of greater 1000/µL. Eighty of the 420 pts received G-CSF doses of 20µg/kg/d or higher. Results: According to the above described response criteria we identified 26 non- responders (6.2%), 18 partial responders (4.3%) and 36 patients reaching ANCs above 1000 with G-CSF doses of 20µg/kg/d or higher (32 patients receiving 20 to 39µg/kg/d; 4 patients receiving more than 50µg/kg/d) out of the 420 CN patients treated with G-CSF. Although patients with different genotypes receive long-term G-CSF treatment, only ELANE or JAGN1 mutations were identified in both non- and partial responders. Analysing ELANE patients separately, 9.3% were non-responders and 5.3 % partial responders to G-CSF. While gender ratio male/female is almost even in the CN cohort (1.08 including 6 males with x-linked TAZ mutations) as well as in the ELANE subgroup (0.87), the gender ratio for ELANE non-responders is 0.2 and 0.4 in ELANE partial responders. In 50% of the identified non- and partial responders the genotype is still unclassified. In 3 patients who were not included in the analysis G-CSF non-response was due to a homozygous CSF3R mutation. These patients respond well to GM-CSF but not to G-CSF. Conclusions: Non-response or partial response to high doses of G-CSF treatment is correlated with distinct genotypes (ELANE, JAGN1, SRP54 and so far unclassified). However, requirement of high G-CSF doses (20µg/kg/d or higher) does not per se indicate non-response, since a substantial number of patients reach sufficient ANCs with these G-CSF doses, especially in patients with ELANE and HAX1 genotype. Treating physicians often do not increase G-CSF doses to >20µg/kg/d to rule out response to high doses. Patients with CSF3R homozygous mutations cannot respond to G-CSF, but respond well to GM-CSF, while ELANE or JAGN1 patients do not respond to GM-CSF. While patients with HAX1 mutations may require high G-CSF doses, but then respond well, patients with SBDS or other mutations (e.g. G6PC3, CXCR4, GFI-1, TAZ etc.) did not require high G-CSF doses for a longer period or were non-responsive to G-CSF treatment. Our data support the dosing recommendation of the SCNIR not to stop G-CSF at 20µg/kg/day, but to increase further, since a substantial number of patients are still responsive. Disclosures No relevant conflicts of interest to declare.

Precision medicine: The use of tailored therapy in primary immunodeficiencies

“…In terms of patient management, prophylactic therapeutics to prevent viral, fungal and bacterial infections are widely used ( 35 ) and it is generally recommended the administration of granulocyte colony stimulating factor (G-CSF) to first increase and then to maintain the neutrophil levels. This last treatment contributes to an improvement of life expectancy but is associated to an increased risk of myelodysplastic syndrome and acute myeloid leukaemia ( 35 , 37 ). Although the use of hematopoietic growth factors can only be considered a semi-tailored treatment in patients with congenital neutropenia, it has been understood in recent years that the response differs between patients and for specific mutations, allowing to tailoring the doses or even the type of myeloid hematopoietic growth factors ( 36 , 37 ).…”

“…This last treatment contributes to an improvement of life expectancy but is associated to an increased risk of myelodysplastic syndrome and acute myeloid leukaemia ( 35 , 37 ). Although the use of hematopoietic growth factors can only be considered a semi-tailored treatment in patients with congenital neutropenia, it has been understood in recent years that the response differs between patients and for specific mutations, allowing to tailoring the doses or even the type of myeloid hematopoietic growth factors ( 36 , 37 ). The analysis of severe chronic neutropenia international registry (SCNIR) identified a group of mutated genes, ELANE, JAGN1, SRP54 , associated to a non-response (absolute neutrophil count (ANC) below 500/μL) or to a partial response (ANC 500-999/μL) to G-CSF doses of 20 mg/kg/day or higher ( 37 ), showing that the use of G-CSF seems not to be effective to all type of genotypes.…”

“…Although the use of hematopoietic growth factors can only be considered a semi-tailored treatment in patients with congenital neutropenia, it has been understood in recent years that the response differs between patients and for specific mutations, allowing to tailoring the doses or even the type of myeloid hematopoietic growth factors ( 36 , 37 ). The analysis of severe chronic neutropenia international registry (SCNIR) identified a group of mutated genes, ELANE, JAGN1, SRP54 , associated to a non-response (absolute neutrophil count (ANC) below 500/μL) or to a partial response (ANC 500-999/μL) to G-CSF doses of 20 mg/kg/day or higher ( 37 ), showing that the use of G-CSF seems not to be effective to all type of genotypes. Homozygous mutations in CSF3R ( R547X CSF3R ), affecting the extracellular domain of G-CSF receptor, were refractory to this treatment and only responding to granulocyte-macrophage colony stimulating factor (GM-CSF) ( 36 , 37 ).…”

“…The analysis of severe chronic neutropenia international registry (SCNIR) identified a group of mutated genes, ELANE, JAGN1, SRP54 , associated to a non-response (absolute neutrophil count (ANC) below 500/μL) or to a partial response (ANC 500-999/μL) to G-CSF doses of 20 mg/kg/day or higher ( 37 ), showing that the use of G-CSF seems not to be effective to all type of genotypes. Homozygous mutations in CSF3R ( R547X CSF3R ), affecting the extracellular domain of G-CSF receptor, were refractory to this treatment and only responding to granulocyte-macrophage colony stimulating factor (GM-CSF) ( 36 , 37 ). These two hematopoietic growth factors differ not only in structure, but also in the biologic effect, with GM-CSF receptors being expressed in a higher number of cells, not only neutrophils and monocytes, but also in eosinophils, dendritic cells and basophils ( 38 ).…”