Hematology Program


Board

Pr. Vahid Asnafi
Biologist
Pr. Olivier Hermine
Physician
Pr. Bénédicte Deau Fischer
Physician


Steering Committee

Pr. Michaela Fontenay - Biologist
Pr.Marina Cavazzana Calvo - Biotherapy
Dr. Sophie Kaltenbach - Biologist
Pr. Thierry Molina - Hematopathologist
Dr. Barbara Burroni - Hematopathologist
Dr. Ludovic Lhermitte - Biologist
Dr. Nicolas Chapuis - Biologist
Pr. Olivier Kosmider - Biologist
Dr. Thiago Maciel - Scientist
Dr. Isabelle Dusanter-Fourt
Dr. Anne Ségolène Cottereau - Nuclear Physician
Agnès Gantner - Manager

The clinical activity in hematology is spread over two sites: Cochin and Necker Hospitals. These two departments are respectively directed by Pr D Bouscary and Pr O Hermine. They treat all malignant hematological disorders and perform important autograft activities (90 procedures a year) at both sites and allograft activities (45 procedures a year) at the NCK site. In 2020, these two services will merge to form a single bi-sit department. In 2020, both hospitals will benefit from CAR T cells technology in B-ALL and DLBCL.

 

If we consider both sites, this represents the following hospital capacity: 24 beds in Intensive Care Unit, 24 beds in Conventional Hematology, 20 beds in Day Hospital. Patient’s recruitment of these two services is important for all the most common hematological pathologies (ALL, AML, CLL, NHL, Hodgkin lymphoma, Multiple Myeloma, MDS) (see details in indicators of activity) and it effectively represents the second most important recruitment of the region Paris-Ile de France after Saint Louis Hopital. In addition to this, Professor Olivier Hermine has developed strong nationally and internationally recognized certifications for rare malignant disorders such as mastocytosis, HTLV1-related lymphoproliferations and intestinal lymphomas. Due to hospital specificity, Cochin has an important recruitment in cerebral lymphoma (15-20/year), mediastinal bulky Hodgking lymphoma of the mediastinum and primitive bone lymphoma.

 

Historically and in practice, Cochin and NCK clinical departments have complementary expertise in myeloid and lymphoid pathology, respectively. This means that Cochin specificity is mainly oriented to myeloid pathology: acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), whereas NCK specificity is mainly oriented to lymphoid pathology: acute lymphoid leukemia (ALL) and non-Hodgkin lymphoma (NHL). This specificity is also true for the hematology biology departments, as very strong connections between clinicians from the two sites and biologists from the two hematological biology departments on both hospitals have been established from a long time. The biology department of Cochin is directed by Pr Michaela Fontenay and that of NCK by Pr Vahid Asnafi. They have developed different and complementary fields of competence that benefit the patients of the two sites: myeloid in Cochin and lymphoid in NCK. As consequence, they have developed and validated highly performant next-generation sequencing–based techniques adapted for myeloid (AML and MDS in Cochin) and lymphoid malignancies (ALL, T-cell and B-cell NHL in NCK) which allow rapid exchange of extensive molecular information’s which are discussed between physicians and biologists in two monthly organized multidisciplinary consultation meetings (MCM) : Myeloid (MMCM) in Cochin (whose leader is Pr Olivier Kosmider) and Lymphoid (LMCM) in NCK (whose leader is Dr Ludovic Lhermitte).

Contrary to clinical and biology departments, Coghin and NCK pathology departments have expertise in both myeloid and lymphoid diseases. In particular, both pathology departments are reference centers to the Lymphopath network whith 2 experts recognized per center.

Leaders of the clinical and biological departments are also leaders of research teams affiliated with INSERM (Institut national de la santé et de la recherche médicale), these pathology specificities being also strongly based on the development of specific research programs within research units at Cochin and NCK:

INSERM U1016: study of normal and pathological hematopoiesis;  co-directed by Pr M Fontenay and Pr D Bouscary in Cochin Institute. Cochin.

INSERM U 1151: normal and pathological lymphoid differentiation; directed by Pr Vahid Asnafi and Pr Elizabeth Macintyre in INEM : Institut Necker – Enfants Malades. NCK.

CIC1416. Centre d’Investigation Clinique en Biothérapie,. GHU Ouest (Necker – HEGP – Cochin).

Département de Biothérapie, Hôpital Necker, 149 rue de Sèvres, 75015 Paris ; directed by Pr Marina Cavazzana.

INSERM U 1163: laboratory of : molecular mechanisms of hematologic disorders and therapeutic implications; directed by Pr Olivier Hermine in IMAGINE institute. NCK. 

 

The two hospitals also benefit from hemato-pathology departments that are very involved in hematological pathology and whose two leaders have well recognized national expertise in the field of lymphomas: Pr Thierry Molina in NCK and Pr Diane Damotte in Cochin and in myeloid diseases (MDS and MPN): Dr Barbara Burroni in Cochin. In that field and in collaborations with biologists and clinicians of different specialties, a program was developed at NCK entitled: “diagnosis of lymphoma in one day” that will be extended to both sites and that effectively blocks all appointments of patients with adenopathies over one day to rapidly perform the diagnosis in order to minimize the time required to implement the treatment.

 

The nuclear medicine department under the direction of Pr J Clerc, on the site of Cochin, has been recently equipped by a new PET-CT device, activity coordinated by Dr M Wartski. They have recruited Dr AS Cottereau, strongly involved in lymphoma imaging. She is a member of the LYSA imaging group, from the Lymphoma Study Association (LYSA) and part of the executive committee of the International Workshop on PET in Lymphoma and Myeloma.  She has opened the field of new prognostic indices by developing the measurement of the metabolic tumor volume, as a tumor burden surrogate, in different subtypes of lymphoma, and assessment of new parameters reflecting lesions dissemination. These new parameters could contribute to a better risk stratification at baseline for a tailored therapy.

Also unique for the two hospitals is the presence of the department of biotherapy located in NCK, directed by Pr Marina Cavazzana Calvo, internationally recognized in the field of genetic therapy of hematopoietic disorders which will be also at the center of the organization of the hematology patient journey for the therapeutic use of CAR T Cells.

 

We will add to this that most of the Hospitalo-University clinicians or biologists of the two hospitals have a research activity within the INSERM units which we have been detailed.

 

All leaders and Hospitalo-University clinicians or biologists are also heavily involved in teaching clinical, translational and fundamental hematology both at the different courses of teaching of hematology at the University of Paris and in the doctoral schools to which the research units are affiliated.

 

Moreover, the departments in Cochin and NCK have developed from a long time a similar and unique policy of identifying young dynamic hematologists who pass as fellowship in both clinical/biological departments and can complete their basic research course in one of the three research units with a view to acquiring a PhD.

 

Clinical research

Concerning clinical research, it is performed with 29 actually open ongoing clinical trials (22 phase III, 7 phase I-II). For NCK and Cochin, the number of new patients included in protocols was 184 and 155 in 2017 and 2018 respectively, with an active file of patients of 470. The clinical research encompass all the field of malignant hematological disease including protocols in allografting.

 

In the context of the bi-site clinical department, the organization of the clinical research will be done on the definition of binoma on Cochin and NCK which will represent the bi-site service in the French collaborating groups of hematological pathologies: Lysa lymphoma group, FILLO CLL and FILLO AML groups, GFM group for MDS. To carry out this clinical research, the two departments are assisted by four clinical research assistants.

Regarding nuclear medicine research, one prospective multicenter trial investigating a new radiopharmaceutical in lymphoma patient is ongoing (cf annexe 4). One retrospective study, initiated and coordinated by Dr Deau Fischer, also included PET data, that will be processed by Dr Cottereau: Adcetris as Maintenance in Hodgkin lymphoma : a REal LIfe Study.

 

Translational research

 

As described in the presentation, the translational research mainly involves three INSERM teams located in NCK and in Cochin with non-overlapping thematic in hematology. We briefly describe the main research activity of these 3 units:

1/ INSERM U1016: study of normal and pathological hematopoiesis. M Fontenay and D Bouscary.

 

Research is focused on the biology of AML and MDS with a part on normal hematopoietic stem cell biology. The composition of the team is made of 5 clinicians-scientists and 2 full-time researchers (see team composition). Three axes are developed:

  • Normal and pathological stem cells: The basic research explores the stem cell biology in normal adult hematopoiesis and has identified two RNA binding proteins (RBP), PUMILIO1/2, as key regulators of stemness. Closely related is the study of hematopoietic stem cells and progenitor compartments in MDS and leukemic cells in AML. The compartments in which mutations and microenvironment interactions drive the disease initiation, amplification and transformation to AML is also studied thanks to patient-derived xenografts of hematopoietic and mesenchymal cells to immune-suppressed mice.
  • Functional genomics in MDS and AML: Genomic, epigenetic and transcriptomic studies are conducted in MDS at the European level. These approaches are extended to AML to decipher new AML subgroups and also prognostic and theranostic biomarkers and large-scale screens are performed to discover intrinsic mechanisms of resistance to chemotherapy. Functional consequences of a splice genes mutations are addressed.
  • Signaling, translation regulation and metabolism in AML: Important deregulation of translation and metabolic pathways has been deciphered in AML by the team leading to the proposal of targeted therapies. The emerging role of RBP in the regulation of translation and metabolism is considered both in AML cells and in stromal stem cells. Both in MDS and in AML, the interaction of leukemic or preleukemic cells with their bone-marrow micro-environment, including its role to modulate new biological processes such as mitophagy and ferroptosis are studied.

Concerning translational research, recurrent mutations have been identified and genotype-phenotype relationship analysis demonstrated the association of splice gene mutations with cytopenias and the association of BCOR mutations in MDS. Looking for new drugs to treat anemia in MDS patients, we have filed two patents. As a laboratory of reference for cooperative groups GFM and FILO, the team has performed biological studies in the context of clinical trials. The mTORC1 inhibitor everolimus was evaluated in refractory/relapsed AML in association to chemotherapy during a phase Ib RAD001 clinical trial. Patients who received a dose of 70 mg on day 1 and 7 had a decreased phosphorylation of p70S6K and a trend to a better CR rate. In a clinical trial randomizing MDS patients to lenalidomide or lenalidomide plus recombinant erythropoietin, we identified genetic markers predictive of the response, demonstrated the transient efficacy of lenalidomide on clone size and provided evidence for a prominent immunomodulatory effect of the drug.

 

2/ INSERM U 1151: normal and pathological lymphoid differentiation. Pr Vahid Asnafi and Pr E Macintyre.

The field of research essentially involves analysis of the mechanisms controlling human T lymphoid ontogeny and oncogenic transformation in immature T lymphoid malignancies, particularly T-ALL and T-LBL. The composition of the team is made of 4 clinicians-scientists and 1 full-time researcher (see team composition). Two axes are developed:

  • From thymic block of maturation to targeted therapy. TLX1 and TLX3 interact with ETS-1, a transcriptional regulator. Recruitment of this complex onto the E-enhancer leads to the TLX-dependent repression of these activities. These data provided the demonstration for a link between defective TCRA gene recombination and the early cortical differentiation block seen in TLX+ T-ALL. TLX expression silencing rescued TCRA expression in TLX+ T-ALL cells, was accompanied by the resumption of T-cell differentiation followed by massive apoptosis. This led to the hypothesis that induction of persistent TCR signaling has anti-leukemic properties in T-ALL. Effectively, we observed that co-expression of the TEL-JAK2 oncogene with a transgene encoding TCR-HY, which induces negative selection only in male mice, specifically compromised leukemia onset in males. This indicated that sustained TCR activation severely impaired leukemia maintenance. As specific anti-TCR/CD3 antibodies can induce signaling, in vitro treatment with anti-CD3ε specifically induces TCR signaling followed by apoptosis in TCR-positive diagnostic T-ALL cases with preliminary data suggesting that OKT3 anti-leukemic effects results more on induction of a cell-intrinsic cell death program than on ADCC-type responses. Characterization of critical molecular effectors of this cell death program is ongoing and will allow identification of either synthetic lethal partners of anti-CD3 treatment or ways to bypass anti-CD3 itself in order to further improve the therapeutic potential of this pathway.
  • Transcriptional control of V(D)J recombination. The regulation of TCR rearrangements plays a decisive role in lymphoid differentiation and oncogenic transformation. TCR loci assembly is established through V(D)J recombination during lymphocyte development and is initiated by the multimeric RAG1/RAG2 complex (RAG1/2). Given the importance of ordered recombination, extensive research has led to the identification of a critical role of RAG targeting or “RAG loading” to specific RSS by transcription factors. We recently showed that human TCRD gene rearrangements are also strictly controlled by the RUNX1 transcription factor which behaves as a co-factor for the V(D)J recombinase. Altogether this identified RUNX1 as a critical regulator of the earliest human TCRD rearrangement by a protein-protein interaction involving RAG1. The function of RUNX1 as a cofactor of V(D)J recombination provides novel insight into its role in normal lymphopoiesis and lymphoid oncogenesis as loss of function of RUNX1 in the very early stages of thymic maturation led to failure of initiation of TCRD rearrangement, maturation arrest and the development of leukemia following the acquisition of additional mutational hits. This opens new perspectives in the comprehension of the role of RUNX1 somatic mutations in immature (FAB M0) Acute Myeloid Leukemia and ETP T-ALL, which are characterized by very early blocks to maturation in the myeloid and T lymphoid lineages, or a common precursor.

The combined cellular and molecular translational research program is based on analysis of optimally annotated clinical material from patients enrolled on prospective institutional multicenter trials, which requires organisation of centralised diagnostics on reference platforms. These structures are well established in an integrated Cancer diagnostics laboratory (Onco-hematology, Hematopathology and somatic Genetics) and INCA-labelled human biological resources platforms at Necker for all adult and pediatric leukemias and lymphomas which are the object of the cognitive projects described above, but also for several translational studies, in partnership with the corresponding clinical cooperative groups. As example, we identified a significant subgroup of poor prognosis adult T-ALL patients with genetic anomalies of either the PI3K/PTEN/Akt/mTOR or the Ras/Raf/MEK/ERK pathway and developed an oncogenetic classifier of T-ALL as an extension of our previous NOTCH/FBXW7 (N/F) based classification: Adults with N/F-mutated, RAS/PTEN germline T-ALL comprise approximately 50% of patients and have an excellent prognosis. This classifier is used within the prospective GRAALL-2014 trial for therapeutic stratification with centralization of diagnostic sample for NGS-capture mutational screening in the laboratory. We also recently performed comprehensive clinic-biological, genetic and survival analyses of a large cohort of adult T-ALL patients, demonstrating that the use of response-based risk stratification and therapy intensification abrogates the poor prognosis of adult ETP-ALL.

3/ CIC1416. Centre d’Investigation Clinique en Biothérapie: Department of Biothérapy, Necker Hospital. Pr Marina Cavazzana.

Marina CAVAZZANA Biotherapy Department’s main research and clinical interests are the development of the hematopoietic immune system, and cell and gene therapy for inherited and acquired disease of the hematopoietic system. Her group studies the means to improve the clinical results of hematopoietic stem cell transplantation, crossing HLA-barriers, and the differentiation of mouse and human stem cells towards lymphocyte lineages. Marina CAVAZZANA Biotherapy Department’s has initiated several clinical trials based on the use of ex vivo gene modified hematopoietic stem cells to treat patients with inherited disorders, the preliminary clinical results of which are encouraging.

4/ INSERM U 1163: laboratory of molecular mechanisms of hematologic disorders and therapeutic implications. Pr Olivier Hermine.

The laboratory is involved in the research in the following fields related to cancer therapy.

  • The study of normal erythropoiesis has long been of major interest for the laboratory. We are now also studying the physiopathology of rare anemias to raise new targeted therapies in haematological malignancies and cancers. For instance, we have identified new autocrine and paracrine roles for serotonin in MDS and a role of GDF-11 in the biology of diverse haematological malignancies. Extending from the knowledge of the transferrin receptor acquired in erythropoiesis, we have developed therapeutic strategies to specifically target this receptor by using a monoclonal antibody and more generally the iron metabolism in diverse haematological malignancies including AML and lymphomas.
  • We also have a great experience in clinical management and molecular spectrum characterization of mastocytosis and we have discovered new targeted therapies in this disease. We also study genetic of familial forms to discover new targeted therapies.
  • Beyond the pathology of mast cells role, we also study the role of those cells in the genral physiopathology of cancer and their role in metastasis.
  • Immunotherapy is also is at the center of our interests and we are developing new strategies of immune therapies including bi-specific antibodies and CAR-T cells by targeting NRP1 and its ligands.
  • In the domain of bone marrow transplantation, we are developing ex vivo tests that could predict GVHD (iNKT cells) and new strategies of allogeneic bone marrow transplantation, including the role of NKT Cells.

From a long time, rare lymphoma study is one of our specialties and we wish to understand the physiopathology and develop new therapeutic strategies for such rare lymphomas including NKT lymphoma, Mantle cell lymphoma, Primary immune deficiency lymphoma, Virus infected lymphoma (HCV and HTLV-1), Gastrointestinal tract lymphoma (by using human and dogs models).

Based on our strengths, for the next years,  we aim:

  • to allow protocol inclusion rates of 20 to 30 per cent.
  • to be able to generate and to be leaders of protocols in rare hematological pathologies.
  • to develop in the laboratory biological tests from the samples of patients allowing, alongside strictly clinical trials, the development of ex vivo or in vivo predictive functional tests, of the effectiveness of a given therapy
  • to improve patient’s management by shortening the time needed to diagnose patients and allowing for a better integration of their overall therapeutic pathway. This has already been initiated for the diagnosis of “lymphoma in a day” but will need to be applied to other hematological pathologies, apart from emergency situations, through the creation of interfaces between the different medical and biological specialties involved in a diagnosis.
  • to welcome hematology students as well as possible at all stages of their training and enabling them, within a homogeneous and integrated structure, to acquire the most advanced knowledge in all areas of malignant hematology. Because of the close links between biologists and clinicians, we will give them access to these two specialties so that they can choose one or the other. However, we do not dissociate clinical and biological hematology which are closely intrinsic in the management of patients due to the emergence of personalized molecular medicine and wish to train them to the best of clinic and of the basic research

More coming soon…

Clinical research:

  1. Thompson AA, Walters MC, Kwiatkowski J, Rasko JEJ, Ribeil JA, Hongeng S, Magrin E, Schiller GJ, Payen E, Semeraro M, Moshous D, Lefrere F, Puy H, Bourget P, Magnani A, Caccavelli L, Diana JS, Suarez F, Monpoux F, Brousse V, Poirot C, Brouzes C, Meritet JF, Pondarré C, Beuzard Y, Chrétien S, Lefebvre T, Teachey DT, Anurathapan U, Ho PJ, von Kalle C, Kletzel M, Vichinsky E, Soni S, Veres G, Negre O, Ross RW, Davidson D, Petrusich A, Sandler L, Asmal M, Hermine O, De Montalembert M, Hacein-Bey-Abina S, Blanche S, Leboulch P, Cavazzana M. Gene therapy for transfusion-dependent β-thalassemia. N Engl J Med. 2018; 378(16):1479-1493.

 

  1. Petit A, Trinquand A, Chevret S, Ballerini P, Cayuela JM, Grardel N, Touzart A, Brethon B, Lapillonne H, Schmitt C, Thouvenin S, Michel G, Preudhomme C, Soulier J, Landman-Parker J, Leverger G, Macintyre E, Baruchel A, Asnafi V. Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-Cell Acute Lymphoblastic Leukemia. 2018. 131(3):289-300.

 

  1. Le Gouill S, Thieblemont C, Oberic L, Moreau A, Bouabdallah K, Dartigeas C, Damaj G, Gastinne T, Ribrag V, Feugier P, Casasnovas O, Zerazhi H, Haioun C, Maisonneuve H, Houot R, Jardin F, Van Den Neste E, Tournilhac O, Le Dû K, Morschhauser F, Cartron G, Fornecker LM, Canioni D, Callanan M, Béné MC, Salles G, Tilly H, Lamy T, Gressin R, Hermine O; LYSA Group. Rituximab after Autologous Stem-Cell Transplantation in Mantle-Cell Lymphoma. N Engl J Med. 2017 Sep 28;377(13):1250-1260.

 

  1. Lortholary O, Chandesris MO, Bulai Livideanu C, Paul C, Guillet G, Jassem E, Niedoszytko M, Barete S, Verstovsek S, Grattan C, Damaj G, Canioni D, Fraitag S, Lhermitte L, Georgin Lavialle S, Frenzel L, Afrin LB, Hanssens K, Agopian J, Gaillard R, Kinet JP, Auclair C, Mansfield C, Moussy A, Dubreuil P, Hermine O. Masitinib for treatment of severely symptomatic indolent systemic mastocytosis: a randomised, placebo-controlled, phase 3 study. 2017 Feb 11;389(10069):612-620.

 

  1. Bond J, Graux C, Lhermitte L, Lara D, Cluzeau T, Leguay T, Cieslak A, Trinquand A, Pastoret C, Belhocine M, Spicuglia S, Lheritier V, Leprêtre S, Thomas X, Huguet F, Ifrah N, Dombret H, Macintyre E, Boissel N, Asnafi V. Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol. 2017 Aug 10;35(23):2683-2691.

 

  1. Ribeil JA, Hacein-Bey-Abina S, Payen E, Magnani A, Semeraro M, Magrin E, Caccavelli L, Neven B, Bourget P, El Nemer W, Bartolucci P, Weber L, Puy H, Meritet JF, Grevent D, Beuzard Y, Chrétien S, Lefebvre T, Ross RW, Negre O, Veres G, Sandler L, Soni S, de Montalembert M, Blanche S, Leboulch P, Cavazzana M. Gene Therapy in a Patient with Sickle Cell Disease. N Engl J Med. 2017 Mar 2;376(9):848-855.

 

 

  1. Mondesir J, Alary AS, Sibon D, Willems L, Deau B, Suarez F, Hermine O, Fontenay M, Bouscary D, Kosmider O, Tamburini J. Impact of genotype in relapsed and refractory acute myeloid leukaemia patients treated with clofarabine and cytarabine: a retrospective study. Br J Haematol. 2019 Oct;187(1):65-72.

 

  1. Birsen R, Willems L, Pallud J, Blanc E, Burroni B, Legoff M, Le Ray E, Pilorge S, Deau B, Franchi P, Vignon M, Kirova Y, Edjlali M, Houillier C, Soussain C, Varlet P, Dezamis E, Damotte D, Bouscary D, Tamburini J. Efficacy and safety of high-dose etoposide cytarabine as consolidation following rituximab methotrexate temozolomide induction in newly diagnosed primary central nervous system lymphoma in immunocompetent patients. Haematologica. 2018 Jul;103(7):e296-e299. doi: 10.3324/haematol.2017.185843.

 

 

  1. Cottereau AS, Versari A, Loft A, Casasnovas O, Bellei M, Ricci R, Bardet S, Castagnoli A, Brice P, Raemaekers J, Deau B, Fortpied C, Raveloarivahy T, Van Zele E, Chartier L, Vander Borght T, Federico M, Hutchings M, Ricardi U, Andre M, Meignan M. Prognostic value of baseline metabolic tumor volume in early-stage Hodgkin lymphoma in the standard arm of the H10 trial. 2018 Mar 29;131(13):1456-1463

 

 

  1. Cottereau AS, Versari A, Luminari S, Dupuis J, Chartier L, Casasnovas RO, Berriolo-Riedinger A, Menga M, Haioun C, Tilly H, Tarantino V, Federico M, Salles G, Trotman J, Meignan M. Prognostic model for high-tumor-burden follicular lymphoma integrating baseline and end-induction PET: a LYSA/FIL study. 2018 May 31;131(22):2449-2453.

 

 

  1. Paubelle E, Zylbersztejn F, Maciel TT, Carvalho C, Mupo A, Cheok M, Lieben L, Sujobert P, Decroocq J, Yokoyama A, Asnafi V, Macintyre E, Tamburini J, Bardet V, Castaigne S, Preudhomme C, Dombret H, Carmeliet G, Bouscary D, Ginzburg YZ, de Thé H, Benhamou M, Monteiro RC, Vassiliou GS, Hermine O, Moura IC. Vitamin D Receptor Controls Cell Stemness in Acute Myeloid Leukemia and in Normal Bone Marrow. Cell Rep. 2020 Jan 21;30(3):739-754.e4. doi: 10.1016/j.celrep.2019.12.055.

 

  1. Sibon D, Coman T, Rossignol J, Lamarque M, Kosmider O, Bayard E, Fouquet G, Rignault R, Topçu S, Bonneau P, Bernex F, Dussiot M, Deroy K, Laurent L, Callebert J, Launay JM, Georgin-Lavialle S, Courtois G, Maroteaux L, Vaillancourt C, Fontenay M, Hermine O, Côté F. Enhanced Renewal of Erythroid Progenitors in Myelodysplastic Anemia by Peripheral Serotonin. Cell Rep. 2019 Mar 19;26(12):3246-3256.

 

  1. Bondu S, Alary AS, Lefèvre C, Houy A, Jung G, Lefebvre T, Rombaut D, Boussaid I, Bousta A, Guillonneau F, Perrier P, Alsafadi S, Wassef M, Margueron R, Rousseau A, Droin N, Cagnard N, Kaltenbach S, Winter S, Kubasch AS, Bouscary D, Santini V, Toma A, Hunault M, Stamatoullas A, Gyan E, Cluzeau T, Platzbecker U, Adès L, Puy H, Stern MH, Karim Z, Mayeux P, Nemeth E, Park S, Ganz T, Kautz L, Kosmider O, Fontenay M. A variant erythroferrone disrupts iron homeostasis in SF3B1-mutated myelodysplastic syndrome. Sci Transl Med. 2019 Jul 10;11(500). pii: eaav5467. doi: 10.1126/scitranslmed.aav5467.

 

  1. Petit A, Trinquand A, Chevret S, Ballerini P, Cayuela JM, Grardel N, Touzart A, Brethon B, Lapillonne H, Schmitt C, Thouvenin S, Michel G, Preudhomme C, Soulier J, Landman-Parker J, Leverger G, Macintyre E, Baruchel A, Asnafi V. Oncogenetic mutations combined with MRD improve outcome prediction in pediatric T-cell acute lymphoblastic leukemia. Blood. 2018 Jan 18;131(3):289-300. doi: 10.1182/blood-2017-04-778829.

 

 

Translational research

 

  1. Bond J, Graux C, Lhermitte L, Lara D, Cluzeau T, Leguay T, Cieslak A, Trinquand A, Pastoret C, Belhocine M, Spicuglia S, Lheritier V, Leprêtre S, Thomas X, Huguet F, Ifrah N, Dombret H, Macintyre E, Boissel N, Asnafi V. Early Response-Based Therapy Stratification Improves Survival in Adult Early Thymic Precursor Acute Lymphoblastic Leukemia: A Group for Research on Adult Acute Lymphoblastic Leukemia Study. J Clin Oncol. 2017 Aug 10;35(23):2683-2691.

 

  1. Poulain L, Sujobert P, Zylbersztejn F, Barreau S, Stuani L, Lambert M, Palama TL, Chesnais V, Birsen R, Vergez F, Farge T, Chenevier-Gobeaux C, Fraisse M, Bouillaud F, Debeissat C, Herault O, Récher C, Lacombe C, Fontenay M, Mayeux P, Maciel TT, Portais JC, Sarry JE, Tamburini J, Bouscary D (co-auth), Chapuis N (co-auth). High mTORC1 activity drives glycolysis addiction and sensitivity to G6PD inhibition in acute myeloid leukemia cells. Leukemia. 2017 Nov;31(11):2326-2335.

 

  1. Lagresle-Peyrou C, Luce S, Ouchani F, Soheili TS, Sadek H, Chouteau M, Durand A, Pic I, Majewski J, Brouzes C, Lambert N, Bohineust A, Verhoeyen E, Cosset FL, Magerus-Chatinet A, Rieux-Laucat F, Gandemer V, Monnier D, Heijmans C, van Gijn M, Dalm VA, Mahlaoui N, Stephan JL, Picard C, Durandy A, Kracker S, Hivroz C, Jabado N, de Saint Basile G, Fischer A, Cavazzana M, André-Schmutz I. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene. J Allergy Clin Immunol. 2016; 138(6):1681-1689.e8.

 

  1. Trinquand A, Dos Santos NR, Tran Quang C, Rocchetti F, Zaniboni B, Belhocine M, Da Costa de Jesus C, Lhermitte L, Tesio M, Dussiot M, Cosset FL, Verhoeyen E, Pflumio F, Ifrah N, Dombret H, Spicuglia S, Chatenoud L, Gross DA, Hermine O, Macintyre E, Ghysdael J, Asnafi V. Triggering the TCR Developmental Checkpoint Activates a Therapeutically Targetable Tumor Suppressive Pathway in T-cell Leukemia. Cancer Discov. 2016 Sep;6(9):972-85.

 

  1. Naudin C, Hattabi A, Michelet F, Miri-Nezhad A, Benyoucef A, Pflumio F, Guillonneau F, Fichelson S, Vigon I, Dusanter-Fourt I, Lauret E. PUMILIO/FOXP1 signaling drives expansion of hematopoietic stem/progenitor and leukemia cells. Blood. 2017 May 4;129(18):2493-2506.

Annex 1:  Recruitment of patients and main indicators of activity

Number of2016201720182019
New acute myeloid leukemias65687268
New myelodysplastic syndromes45485251
New diffuse large B-Cell lymphomas 1103838471
New acute lymphoid leukemias12121212
New myeloma65746457
New Hodgkin lymphoma35254238

Annex 2:  Ongoing Clinical Trials

 
Sponsor TitlePhaseNCT numberCoordinator / Investigator
AGIOS : A Phase 3, Multicenter, Double-Blind, Randomized, Placebo-Controlled Study of AG-120 in Combination with Azacitidine in Subjects ≥ 18 Years of Age with Previously Untreated Acute Myeloid Leukemia with an IDH1 MutationIIINCT03173248F Suarez
ALPHA. Etude observationnelle de cohorte de patients agés de plus 60 ans, atteints de Leucémie Aigue Myéloïde (LAM) et recevant un traitement standard de chimiotherapie par idarubicine-cytarabineIVNCT01966497D Bouscary –  F Suarez
ALK Observatoire. ETUDE PROSPECTIVE DE LA VALEUR PRONOSTIQUE DE NOUVEAUX MARQUEURS CHEZ DES ADULTES ATTEINTS D’UN LYMPHOME ANAPLASIQUE A GRANDES CELLULES ALK-POSITIFNANCT03603847D Sibon
Analyse de 4 marqueurs biologiques du remodelage osseux (CTX, NTX, DKK-1 et SOST) dans le cadre d’un traitement par biphosphonate intraveineux chez les patients avec un myelome multipleNANCT 04111809L Frenzel
Etude prospective, contrôlée, multicentrique souches hématopoïétiques dans les lymphomes T cutanées épidermotropes de stade avance avec facteurs de mauvais pronosticIVNCT02520908F Suarez
phase 3 randomisée, ouverte, comparant l’isatuximab avec le pomalidomide et la dexamethasone a faible dose au pomalidomide et a la dexamethasone a faible dose chez des patients souffrant d’un myelome multiple réfractaire ou récidivant et réfractaireIIINCT02990338L Frenzel
IFM-2014-04 A Multicentre Open label Phase II study of Daratumumab in Combination with Dexamethasone in Multiple Myeloma resistant or refractory to Bortezomib and Lenalidomide and PomalidomideIIINCT02626481L Frenzel
Polarix; III, MULTICENTRIQUE, RANDO, EN DOUBLE AVEUGLE ET CONTROLEE PAR PLACEBO ANALYSANT L’EFFICACITE ET LA TOLERANCE DU POLATUZUMAB VEDOTIN ASSOCIE AU RITUX+ CHP (RCHP) Vs RITUX + CHOP (R-CHOP) dans le LYMPHOME DIFFUS A GRANDES CELLULES B JAMAIS TRAITEIIICT03274492D Sibon
A Phase 2b Open-label, Randomized Two-arm Study Comparing High and Low Doses of Selinexor (KPT-330) in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma (DLBCL)I-IINCT02227251D Sibon
“An International, Phase 2, Open-Label, Randomized Study of BGB-3111 Combined with Obinutuzumab Compared With Obinutuzumab Monotherapy in Relapsed/Refractory Follicular Lymphoma”I-IINCT03332017D Sibon
BLU-285-2202. An Open-label, Single Arm, Phase 2 Study to Evaluate Efficacy and Safety of Avapritinib (BLU-285), A Selective KIT Mutation-targeted Tyrosine Kinase Inhibitor, in Patients with Advanced Systemic MastocytosisI-IINCT03580655O Hermine
Etude de Phase II du brentuximab vedotin chez des patients atteints de lymphome peripherique T recidivant ou refractaire traites par gemcitabine suivi d’une maintenance par brentuximab vedotinI-IINCT03496779D Sibon
Tomy : Etude de phase 1/2 de la combinaison d’irradiation Ostéo Médullaire Totale (IOMT) en escalade de dose par TOMothérapie hélicoidale et d’une chimiothérapie par Melphalan à dose fixe de 140 mg/m² et ré-injection de cellules souches périphériques (CSP) dans les Myélomes multiples en première rechuteI-IINCT2012-001473-91D Bouscary
Essai de phase III évaluant chez les patients âgés souffrant d’un lymphome primitif du système nerveux central, l’intérêt d’une stratégie de maintenance versus surveillance après réponse complète à une chimiothérapie de première ligne à base de méthotrexate à haute dose.IIINCT2014-002597-37L Willems
GRALL 2014. Protocole multicentrique de traitement des leucémies aigues Lymphoblastiques (LAL) de l’adulte jeune (18-59 ans)IIINCT2014-002146-44J tamburini
Usefulness of PET using 18F-fludarabine (Fluda-PET) for initial staging and therapeutic evaluation in three subtypes of newly diagnosed lymphomas (diffuse large B cell lymphoma, Hodgkin lymphoma and follicular lymphoma): A prospective exploratory multicenter trialIIEudraCT No. 2019-001778-27AS Cottereau/ J Clerc/ M Wartski/ B Deau-Fischer
If you are interested by this program and want to candidate to a PhD, post doctoral position, contact the leader
Pr. Didier Bouscary

Contact us

Centre Universitaire des Saints-Pères Etage 4 – Pièce 446B 45 rue des Saints-Pères -75006 Paris

Carina Binet : Secrétaire Général du CARPEM
Tél. : 01 76 53 43 85 – carina.binet@carpem.fr

Aurore Hattabi, PhD : Coordinatrice Scientifique du CARPEM
Tél : 01 76 53 43 85 – aurore.hattabi@carpem.fr

contact@carpem.fr