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816 Congenital Neutropenia Is Also Associated with a High Cancer Risk: A Study from the French Severe Chronic Neutropenia Registry

Program: Oral and Poster Abstracts
Session: 201. Granulocytes, Monocytes, and Macrophages: Poster I
Hematology Disease Topics & Pathways:
Adult, Diseases, Bone Marrow Failure, Pediatric, Genetic Disorders, Study Population, Clinically relevant
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Jean Donadieu, MD, PhD1, Fares bou Mitri2*, Blandine Beaupain, MsC3*, Yves Bertrand, M.D.4,5*, Pierre Simon Rohrlich, MD PhD6,7*, Nathalie Aladjidi, M.D.8,9*, Alexia Rouland, MD10*, Felipe Suarez, MD, PhD11, Andre Vanoli12*, Jean Fraisse, MD13*, Olivier Hermine14,15,16,17,18,19,20,21, Philippe Descamps22*, Sylvie François, MD23,24*, Hélène Lapillonne, MD, PhD25*, Marlène Pasquet, M.D., Ph.D.26*, Matthieu Patient27*, Ilona Okhremchuck28*, Didier Blaise, MD29, Faezeh Legrand, MD30*, Claire Fieschi, MD, PhD31*, Flore Sicre de Fontbrune32,33,34*, Sarah cohen Beaussant2*, didier Simon Kamioner, MD35*, Francoise Bachelerie, PhD36*, Claire Deback, MD, PHD37,38*, Christine Bellanne-Chantelot, PhD, PharmD39* and Jean-François Emile, MD, PhD40*

1Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris, Cedex, France
2Centre de référence des neutropénies chroniques Registre des neutropenies, Hopital Trousseau, Paris, France
3Registre des Neutropénies, Hopital Trousseau, AP-HP, Paris, France
4Institute of Pediatric Hematology and Oncology, Civil Hospital of Lyon, Claude Bernard University, Lyon, France
5Claude Bernard University, Lyon 1, Lyon, France
6Hematology-Pediatry, Bensancon, FRA
7CHU L'Archet, Nice, FRA
8Centre de Référence National des Cytopénies Auto-immunes de l'Enfant (CEREVANCE), Bordeaux, France
9Pediatric Oncology Hematology Unit, Plurithématique CIC (CICP), Centre d’Investigation Clinique (CIC) 1401, INSERM, Bordeaux University Hospital, Bordeaux, France
10Endocrinology department, CHU Dijon, DIJON, France
11Service d'Hématologie adultes, Hôpital Universitaire Necker-Enfants Malades, AP-HP, Paris, France
12Département d'oncologie médicale, Clinique Sainte Marthe, Dijon, Bourgogne, France,, Dijon, France
13Department of pathology, Centre Georges-François Leclerc, DIJON, France
14Imagine Institute, INSERM U1163, University of Paris, Paris, France
15Department of Hematology, Necker Children's hospital, APHP, Paris, France
16Laboratory of Excellence Gr-Ex, Paris, France
17Department of Hematology, Necker Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
18Hematology Department, AP-HP Hôpital Necker, University Paris Descartes, Paris, France
19Clinical Hematology, Necker University Hospital, Paris, France
20Service Hèmatologie Adulte, Centre de référence des mastocytoses, Hôpital Universitaire Necker-Enfants Malades, Paris, France
21Centre de référence des déficits immunitaires héréditaires (CEREDIH), Necker Children's hospital, APHP, Paris, France
22Departement of gynecology, CHU Angers, angers, France
23Clinical Hematology, Angers University Hospital, Angers, France
24Service Maladies du sang, CHU Angers, Angers, France, Angers, France
25Pediatric Hematology and Oncology Department, Hôpital Armand Trousseau, Paris, France
26Pediatric Oncology Immunology Hematology Unit, Children’s hospital, CHU de Toulouse, Toulouse, France
27Oncology department, Hôpital d'Instruction des armées SAINTE ANNE, Toulon, FRA
28Department of pathology, Hôpital d'Instruction des armées SAINTE ANNE, toulon, France
29Institut Paoli Calmettes, Marseille, France
30Hematology department, Institut Paoli Calmettes, Marseille, France
31Service d’Immunologie clinique, Hôpital Saint-Louis, AP-HP, Paris, France
32Hematology and transplantation unit, Saint-Louis Hospital, Paris, France
33Centre de Référence Aplasie Médullaire, Service d’Hématologie Greffe, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France
34French Reference Center for Aplastic Anemia and Paroxysmal Nocturnal Hemoglobinuria, Saint Louis Hospital and University Paris Diderot, Paris, France
35oncology, Hopital Prive de l'ouest parisien, Trappes, France
36Immunologie 92296 Châtenay-Malabry, Université Paris Saclay Faculte de Pharmacie Inserm U996, Clamart, FRA
37Service de Virologie HOP PAUL BROUSSE, AP-HP. UNIVERSITÉ PARIS SACLAY, villejuif, France
38Inserm U996, inserm, CLAMART, France
39Hopital Pitié Salpétriére APHP, Département de Génétique, AP-HP Hôpital Pitié- Salpêtrière, UPMC Univ Paris 06, Paris, France
40Pathology Department,, Hôpital Ambroise-Paré APHP, Université Paris Saclay, Boulogne, FRA

Introduction: Congenital neutropenia (CN) is characterized by chronic neutropenia due to a constitutional genetic defect.1 To date, these diseases have not been considered to be frequently associated with malignant solid tumors, unlike the risk of secondary myelodysplastic syndrome leukemia, which is well-known in CN.

Methods: The French Severe Chronic Neutropenia Registry (FSCNR) has prospectively enrolled CN patients since 1993. Solid tumors, identified during routine patient follow-up, were classified according to WHO criteria. We included localized lymphoma in the spectrum of malignant solid tumors. We calculated the incidence of malignant solid tumors in a cohort of CN patients.

Results: Among 868 patients with various CN subtypes followed for a total of 16617 person-years, 24 patients who developed a malignant solid tumor were identified. Those cancers are described in Table 1, including the CN genetic anomaly. Cancers were almost always diagnosed in adulthood, with median age at diagnosis of 38.1 (range 10–72) years; only 3 cancers were diagnosed before age of 20 years. The cancer rate was 1.2% at 30 years of age, 7% at 40 years and 24% at 50 years (Fig. 1A). The risk-of-cancer percentages depended mainly on the associated genetic deficiency. Solid tumors were roughly distributed as follows: 33% among WHIM (CXCR4) patients, 5.3% among GATA2 patients, 2.7% among ELANE patients, 1.9 % among SBDS patients and 0.8% among for all other subtypes combined (Fig. 1B). Human papillomavirus (HPV) was the cause of cancer for 2/5 in WHIM patients and 2/6 in GATA2 patients. Three Lymphoma were identified, one in GATA2 patient and 2 in WHIM patients. Notably, our cohort’s follow-up is skewed to the right, with less efficient monitoring of adults, with still limited long-term follow-up beyond 40 years. Therefore, we probably underestimated the solid-tumor risk in CN patients, as many patients, if alive, are no longer followed in hematology centers. Among 103 patients who underwent hematopoietic stem-cell transplantation (HSCT), 76 were long-term survivors. None of them developed solid tumors, which differs strikingly from the high malignancy risk associated with Fanconi anemia post-HSCT. Lastly, the FSCNR also includes and follows patients with idiopathic neutropenia. Among the 232 idiopathic neutropenia patients, followed for a total of 2866 person-years, no malignancy has been observed so far.

Conclusion: Our data lead us to advance that CN patients should be considered at risk of developing solid cancers, especially after the age of 30 years. This risk, at first glance, depended on the CN-associated genetic anomaly, with CXCR4 mutation, GATA2, SBDS and ELANE being the most frequent. HSCT was not associated with a higher risk and may, in contrast, be protective. These findings warrant confirmation but represent a compelling reason to prolong follow-up into adulthood of CN patients diagnosed during childhood. No indication was found of a specific high solid-tumor risk associated with idiopathic neutropenia.


  1. Donadieu J, Beaupain B, Fenneteau O, Bellanne-Chantelot C. Congenital neutropenia in the era of genomics: classification, diagnosis, and natural history. Br.J.Haematol. 2017; 179(4): 557-574.

Acknowledgments: The French SCN registry is supported by grants from Amgen, Chugai, Prolong Pharma, X4 Pharma, Inserm, the Association 111 les Arts, the Association RMHE, the Association Sportive de Saint Quentin Fallavier. The authors thank the association IRIS and Mrs Grosjean and Mr Gonnot(ASSQF), the association Barth France for their support.

Disclosures: Hermine: Roche: Consultancy; Celgene BMS: Consultancy, Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Alexion: Research Funding; Novartis: Research Funding. Blaise: Jazz Pharmaceuticals: Honoraria. Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. cohen Beaussant: X4 Pharmaceuticals, Inc.: Current Employment.

*signifies non-member of ASH