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931 Impact and Dynamics of TP53 Mutated Clones in Shwachman Diamond Syndrome in a Series of 80 Patients

Program: Oral and Poster Abstracts
Session: 508. Bone Marrow Failure: Poster I
Hematology Disease Topics & Pathways:
AML, Adult, Diseases, Bone Marrow Failure, Genetic Disorders, Pediatric, Biological Processes, Young Adult, Study Population, Myeloid Malignancies, Clinically relevant, hematopoiesis
Saturday, December 5, 2020, 7:00 AM-3:30 PM

Jean-Alain Martignoles1*, Pierre Hirsch, MD, PhD2*, Blandine Beaupain3*, Thomas Longval, MD4*, Nawa Hachem, MsC5*, Mira El-Khoury, PhD6*, Sophie Kaltenbach7*, Jean Soulier, MD, PhD8, Thierry Leblanc, M.D.9,10*, Pierre Simon Rohrlich, MD PhD11*, Eric Jeziorski, MD PhD12*, Isabelle Meyts13*, Dalila Adjaoud, MD14*, Vincent Barlogis, M.D., Ph.D.15*, Marlène Pasquet, M.D., Ph.D.16*, Laetitia Largeaud17*, Flore Sicre de Fontbrune18*, Claire Fieschi, MD, PhD19*, Virginie Gandemer, MD, PhD20*, Nathalie Aladjidi, MD21*, Fanny Fouyssac, MD22*, Guy Leverger, M.D.23*, Wadih Abou Chahla, M.D.24*, Stephane Blanche, MD25*, Despina Moushous, MD, PhD26*, Aline Moignet Autrel, MD27*, Yves Bertrand, M.D.28,29*, Cecile Renard29,30*, Pascale Flandrin-Gresta, MD31,32*, Jean Louis Stephan, MD PhD33*, Olivier Tournilhac, MD, PhD34,35*, Liana Carausu36*, Frederic Millot, M.D.37*, Marielaure Couec, MD38*, Claude Preudhomme, MD, PhD39,40,41,42, Hélène Lapillonne, MD, PhD43*, Vahid Asnafi, MD, PhD44,45,46*, Patrick Revy47*, Christine Bellanne-Chantelot, PhD, PharmD48,49*, Francois Delhommeau, MD, PhD2,50* and Jean Donadieu, MD, PhD51

1Sorbonne Université, UMRS 938 "hematopoietic and Leukemic Development", A, Paris, FRA
2APHP, Hôpital Saint Antoine, Service d'hématologie Biologique, Paris, France
3Registre francais des neutropénies chroniques, HôPital Trousseau, France, FRA
4APHP hopital saint antoine, Laboratoire hématologie, Paris, France
5laboratoire d’hématologie Saint-Antoine, Sorbonne Université CRSA UMRS938, paris, France
6Gustave Roussy, INSERM, UMR1170, Villejuif, France
7INSERM U768, Paris, FRA
8Hematology Laboratory and INSERM U944, Hopital Saint-Louis Centre Hayem 2ETG, Paris, France
9Pediatric Hematology Unit, Robert-Debré Hospital, AP-HP, Paris, France
10French Reference Center for Aplastic Anemia, Paris, France
11CHU L'Archet, Nice, FRA
12Pediatrics, CHU Montpellier, Montpeller, FRA
13UZ Leuven, Leuven, BEL
14hemato oncologie pédiatrique, CHU de Grenoble, Grenoble, France
15Department of Pediatric Hematology, La Timone Hospital, AP-HM, Marseille, France
16Pediatric Oncology Immunology Hematology Unit, Children’s hospital, CHU de Toulouse, Toulouse, France
17Institut Universitaire Du Cancer De Toulouse-Oncopole, Toulouse, FRA
18Centre de Référence Aplasie Médullaire, Service d’Hématologie Greffe, Assistance Publique des Hôpitaux de Paris, Hôpital Saint-Louis, Paris, France
19Service d’Immunologie clinique, Hôpital Saint-Louis, AP-HP, Paris, France
20CHU Hopital Sud, Rennes, FRA
2112. Unité d’Hématologie Pédiatrique, CIC 1401 INSERM CICP, CHU Bordeaux, Bordeaux, France
22hemato oncologie pédiatrique, CHU de Nancy, Nancy, France
23Pediatric Hematology Oncology Immunology Department, Armand-Trousseau University Hospital, AP-HP, Paris, France
24Department of Pediatric Hematology, Jeanne de Flandre Hospital, CHRU de Lille, Lille, France
25Department of Pediatric Immunology, Hematology and Rheumatology, Necker Enfants Malades University Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France
26Unité d'immuno hématologie rhumatologie pédiatrique, APHP université de Paris Hopital Necker enfants malades, Paris, France
27Clinical Hematology Department, Rennes CHU, Rennes, France
28Institute of Pediatric Hematology and Oncology, Civil Hospital of Lyon, Claude Bernard University, Lyon, France
29Claude Bernard University, Lyon 1, Lyon, France
30IHOPE, Civil Hospital of Lyon, Lyon, France
31Hopital Saint Antoine, Laboratoire d'Hématologie, AP-HP Hôpital Saint Antoine, Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine,, paris, France
32Laboratoire d'Hématologie, CHU de Saint-Etienne, Saint-Priest-en-Jarez, France
33Pediatric Hemato-Oncology, CHU de Saint Etienne , Hôpital Nord, Saint-priest-en-Jarez, FRA
34Service d'Hématologie Clinique et Thérapie Cellulaire, CHU, Université Clermont Auvergne EA7453 Chelter CIC-1405, Clermont-Ferrand, FRA
35Hématologie Clinique Adulte et Thérapie Cellulaire, CHU Hotel Dieu Hématologie, Clermont-Ferrand, France
36CHRU Brest, Brest, FRA
37Department of Pediatric Hematology-Oncology, University Hospital Poitiers, Poitiers, France
38hemato oncologie Pédiatrique, CHU Nantes, nantes, France
39Institut de Recherche contre le Cancer de Lille, UMR-S1172, Lille, France
40Centre de Biologie-Pathologie, CHU Lille, Lille, France
41UMR-S 1172, INSERM, Lille, France
42Cancer Research Institute, INSERM Unité Mixte de Recherche (UMR)-S 1172, F-59000 Lille, CHU Lille, Laboratory of Hematology, F-59000 Lille, Lille, France
43Pediatric Hematology and Oncology Department, Hôpital Armand Trousseau, Paris, France
44INSERM U1151, Université Paris Descartes Sorbonne Cité, Paris, France
45Laboratory of Onco-Hematology, Hôpital Necker Enfants-Malades, APHP, Paris, France
46Biological Hematology, Necker University Hospital, Paris, France
47Institut Imagine, Paris, FRA
48Hopital Pitié Salpétriére APHP, Département de Génétique, AP-HP Hôpital Pitié- Salpêtrière, UPMC Univ Paris 06, Paris, France
49Département de Neurologie, Hôpital Pitié-Salpêtrière, Paris, France
50INSERM U938, Paris, France
51Service d'Hémato-Oncologie Pédiatrique, Hopital Trousseau, Paris, Cedex, France

Introduction: Hematological complications (HC) as Aplastic anemia (AA) and myelodysplasia and acute leukemia (MDS/AL) are frequent and life threatening in patients with Shwachman Diamond Syndrome (SDS) with SBDS mutations. The therapy of such events is based on Hematopoetic stem cell transplantation (HSCT), which results remain quite poor, especially in case of malignancy. So far, it is difficult to anticipate to such HC and a lot is expected from the study of clonal evolution prior HC.

Methods: A Targeted panel of 43 genes involved in MDS/AL (sensibility 1%) has been evaluated in 80 patients with SBDS mutation, representative of a nation based cohort of 154 patients. This cross sectional study has been completed by a prospective study for 40 patients evaluated at several time points.

Results: The evaluation was performed in various situations: steady state i.e. no haematological complication, in MDS/AL and AA and lastly after HSCT. At the first evaluation, somatic mutation was found in 21 patients (30%) among the 70 in steady state and in 7 of the 8 cases with HC (6/6 cases with MDS/AL, in 1 among the 2 cases with AA) while the 1 of the 2 patients long term survivors after HSCT have no mutation and the other one kept a TP53 clone with a normal blood count and a low (1.5%) variant allele frequency (VAF). Among the 40 patients with several time points, 17 have a mutation at the first time points, but 10 others had additional mutation later. Globally, the most frequent gene involved was TP53 (82%) while mutations in other genes have been observed rarely. VAF in patients with vs without HC is lower (median VAF 0% vs 22.8% respectively p < 0.001) . Complex caryotype, monosomy 7, Iso7q were associated with P53 clone while in Del20q, 8 patients out 14 have a P53 mutations. The comparison between blood and bone marrow results allow the possibility to monitor such mutations in blood. Clonal evolution in one patient who presents a MDS in the course of the follow up had shown a competition between clones.

Conclusion: Acquired TP53 is extremely frequent in patients with SBDS mutations, even in the absence of HC, but the prevalence as well as the VAF increased in case of HC. When sequential evaluation could be performed, competition between clones is frequent and a clinical decision remains therefore difficult, just on the evaluation of a time point.

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: Sicre de Fontbrune: Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Renard: Jazz Pharmaceuticals: Research Funding. Tournilhac: ABBVIE: Consultancy, Honoraria, Other: Travle grant; INNATE Pharma: Consultancy, Honoraria; GILEAD: Consultancy, Honoraria, Other: Travel Grant; Takeda: Consultancy, Honoraria, Other: Travel grant; Janssen: Consultancy, Honoraria, Other: Travel grant.

*signifies non-member of ASH