HLA Haploidentical Bone Marrow Transplant in Patients With Severe Sickle Cell Disease

NCT ID: NCT03240731

Last Updated: 2025-09-02

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 25 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-08-10
• Study Completion Date: 2024-04-08

Brief Summary

multicentric interventional biomedical research phase II, prospective, non-randomized evaluating a haploidentical marrow transplants after reduced-intensity conditioning and prevention of GvHD based on cyclophosphamide administration post transplantation in patients with severe sickle cell disease.

Detailed Description

Sickle cell disease is a severe disease with frequent occurrence of painful crises and progressive installation of a multi organ injuries. Despite the progress in its management, particularly since the introduction of hydroxycarbamide, the median age of death in sickle cell patients was about 40 years in a recent US study. Severe forms resistant to hydroxyurea or cerebral vasculopathy require transfusion programs throughout susceptible to risks of iron overload and alloimmunization. The bone marrow transplantation cures almost 95% of children and adolescents transplant from an HLA-identical siblings. In patients without HLA-identical donor, interesting results have been reported in haploidentical transplants marrow without ex vivo T cell depletion taken after non myeloablative conditioning regimen and GvHD prevention with cyclophosphamide high dose injection after bone marrow transplant . This approach performed in 14 patients was effective to cure 50% of the patients and 50% have rejected the transplant . No death or severe GvHD were related to the procedure.

DREPHAPLO protocol aims to evaluate that approach in a population of sickle cell patients with severe complications of the disease, bringing direct benefit to patients with a cure of the disease in at least half of them.

Conditions

Sickle Cell Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

bone marrow transplant

All the included patient will receive an haploidentical bone marrow transplant with the following protocol concerning the conditioning and GvHD prevention

Conditioning

• THYMOGLOBULINE : 0.5mg/kg at D-9 and 2 mg/kg at D-8 and D-7
• THIOTEPA: 10mg/kg/j at D-7
• CYCLOPHOSPHAMIDE (Endoxan®):14.5mg/kg/j at D-6 and D-5
• FLUDARABINE (Fludara®): 30mg/m2 per Day from D-6 to D-2
• TBI : 2GY : D -1 Graft : Injection at D0 of G-CSF-stimulated bone marrow transplant.

Prophylaxis of GvHD

• CYCLOPHOSPHAMIDE (Endoxan®): 50mg/Kg per Day from D+3 to D+4
• Sirolimus and MycophénolateMofétil (MMP) from D+5. In the absence of acute GvHD (aGvHD), stop of MMP to D35 and pursuit of sirolimus 1 year after the graft.

Group Type: EXPERIMENTAL

bone marrow transplant

Intervention Type: BIOLOGICAL

haploidentical bone marrow transplant

Interventions

bone marrow transplant

haploidentical bone marrow transplant

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

• Age: 13 years-40 years
• Severe Sickle cell with at least one of the following criteria:

• Stenosing vasculopathy with abnormal MRA despite prolonged transfusion program
• PAH confirmed by right catheterization with mPAP> 25mmHg
• Systolic ejection fraction <55% and tricuspid regurgitation speed> 2.5m /s at distance from an acute episode
• No possibility of blood transfusion or very complicated blood transfusion
• Report albumin / creatinine> 30 mg / mmol, confirmed 3 times, away at distance from acute episode and persistent despite hydroxyurea or IEC
• GFR <80ml / min /1.73m2 (CKD-Epi without ethnic criterion)
• Previous history of acute liver sequestration with liver failure
• Acute chest syndrome or vaso-occlusive crises under hydroxyurea
• Complications of sickle cell transfusion imposing an exchange program with no possible withdrawal beyond a period of one year
• Not having geno-identical donor, but a haploidentical major donor (parent, sibling, adult child, or HbAA AS)
• Having red and understood the information letter and signed the informed consent
• Patients affiliated to a social security system (Social Security or Universal Medical Coverage)

• Age> 18 years and <60 years
• Viral serologic economy allows the graft
• No contraindication for general anesthesia
• No contraindication the administration of G-CSF (the existence of sickle cell trait is not a contraindication)
• Lack antigens HLA recognized by the recipient antibody
• Hemoglobin S <50%
• When several donors are compatible: choose according to the ABO recipient: prefer ABO compatibility and major incompatibility and minor incompatibility, and finally major and minor incompatibility.
• Signature of informed consent

Exclusion Criteria

• Patient with a geno-identical donor
• Performans status: ECOG> 1
• lung disease: FEV1 and FVC <50% predicted,
• score of PAH NYHA≥2
• Liver disease with bilirubin> 50 .mu.mol / L
• heart failure defined by NYHA≥3 score ejection fraction <45% or shortening fraction <24%
• anti HLA alloimmunization against the donor or against red cell antigens of the donor
• Serology or HIV viral load positively
• Patients who for family, social or geographical reasons, do not wish to be regularly monitored in consultation
• severe uncontrolled infection at the time of inclusion or graft
• pregnant woman (positive beta HCG) or during lactation
• incapable adult patient, trust, guardianship, or safeguard justice

• Minimum Eligible Age: 13 Years
• Maximum Eligible Age: 40 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Keocyt

UNKNOWN

Sponsor Role: collaborator

Association Clinique Thérapeutique Infantile du val de Marne

OTHER

Sponsor Role: collaborator

Centre Hospitalier Intercommunal Creteil

OTHER

Sponsor Role: lead

Responsible Party

Nathalie Dhédin

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

CHU Henri-Mondor

Créteil, , France

intercommunal hospital of Créteil

Créteil, , France

CHU La Timone

Marseille, , France

Hospital Necker

Paris, , France

Hospital Robert-Debré

Paris, , France

Saint-Louis hospital

Paris, , France

CHU Strasbourg

Strasbourg, , France

Countries

France

References

Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014 Sep 10;312(10):1033-48. doi: 10.1001/jama.2014.10517.

Reference Type: BACKGROUND

PMID: 25203083 (View on PubMed)

Habibi A, Arlet JB, Stankovic K, Gellen-Dautremer J, Ribeil JA, Bartolucci P, Lionnet F; centre de reference maladies rares << syndromes drepanocytaires majeurs >>. [French guidelines for the management of adult sickle cell disease: 2015 update]. Rev Med Interne. 2015 May 11;36(5 Suppl 1):5S3-84. doi: 10.1016/S0248-8663(15)60002-9. French.

Reference Type: BACKGROUND

PMID: 26007619 (View on PubMed)

Lanzkron S, Carroll CP, Haywood C Jr. Mortality rates and age at death from sickle cell disease: U.S., 1979-2005. Public Health Rep. 2013 Mar-Apr;128(2):110-6. doi: 10.1177/003335491312800206.

Reference Type: BACKGROUND

PMID: 23450875 (View on PubMed)

Bernaudin F, Socie G, Kuentz M, Chevret S, Duval M, Bertrand Y, Vannier JP, Yakouben K, Thuret I, Bordigoni P, Fischer A, Lutz P, Stephan JL, Dhedin N, Plouvier E, Margueritte G, Bories D, Verlhac S, Esperou H, Coic L, Vernant JP, Gluckman E; SFGM-TC. Long-term results of related myeloablative stem-cell transplantation to cure sickle cell disease. Blood. 2007 Oct 1;110(7):2749-56. doi: 10.1182/blood-2007-03-079665. Epub 2007 Jul 2.

Reference Type: BACKGROUND

PMID: 17606762 (View on PubMed)

Kuentz M, Robin M, Dhedin N, Hicheri Y, Peffault de Latour R, Rohrlich P, Bordigoni P, Bruno B, Socie G, Bernaudin F. Is there still a place for myeloablative regimen to transplant young adults with sickle cell disease? Blood. 2011 Oct 20;118(16):4491-2; author reply 4492-3. doi: 10.1182/blood-2011-07-367490. No abstract available.

Reference Type: BACKGROUND

PMID: 22021455 (View on PubMed)

Angelucci E, Matthes-Martin S, Baronciani D, Bernaudin F, Bonanomi S, Cappellini MD, Dalle JH, Di Bartolomeo P, de Heredia CD, Dickerhoff R, Giardini C, Gluckman E, Hussein AA, Kamani N, Minkov M, Locatelli F, Rocha V, Sedlacek P, Smiers F, Thuret I, Yaniv I, Cavazzana M, Peters C; EBMT Inborn Error and EBMT Paediatric Working Parties. Hematopoietic stem cell transplantation in thalassemia major and sickle cell disease: indications and management recommendations from an international expert panel. Haematologica. 2014 May;99(5):811-20. doi: 10.3324/haematol.2013.099747.

Reference Type: BACKGROUND

PMID: 24790059 (View on PubMed)

Hsieh MM, Fitzhugh CD, Weitzel RP, Link ME, Coles WA, Zhao X, Rodgers GP, Powell JD, Tisdale JF. Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA. 2014 Jul 2;312(1):48-56. doi: 10.1001/jama.2014.7192.

Reference Type: BACKGROUND

PMID: 25058217 (View on PubMed)

Bolanos-Meade J, Fuchs EJ, Luznik L, Lanzkron SM, Gamper CJ, Jones RJ, Brodsky RA. HLA-haploidentical bone marrow transplantation with posttransplant cyclophosphamide expands the donor pool for patients with sickle cell disease. Blood. 2012 Nov 22;120(22):4285-91. doi: 10.1182/blood-2012-07-438408. Epub 2012 Sep 6.

Reference Type: BACKGROUND

PMID: 22955919 (View on PubMed)

Kamani NR, Walters MC, Carter S, Aquino V, Brochstein JA, Chaudhury S, Eapen M, Freed BM, Grimley M, Levine JE, Logan B, Moore T, Panepinto J, Parikh S, Pulsipher MA, Sande J, Schultz KR, Spellman S, Shenoy S. Unrelated donor cord blood transplantation for children with severe sickle cell disease: results of one cohort from the phase II study from the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). Biol Blood Marrow Transplant. 2012 Aug;18(8):1265-72. doi: 10.1016/j.bbmt.2012.01.019. Epub 2012 Feb 16.

Reference Type: BACKGROUND

PMID: 22343376 (View on PubMed)

Luznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, Gooley TA, Piantadosi S, Kaup M, Ambinder RF, Huff CA, Matsui W, Bolanos-Meade J, Borrello I, Powell JD, Harrington E, Warnock S, Flowers M, Brodsky RA, Sandmaier BM, Storb RF, Jones RJ, Fuchs EJ. HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. 2008 Jun;14(6):641-50. doi: 10.1016/j.bbmt.2008.03.005.

Reference Type: BACKGROUND

PMID: 18489989 (View on PubMed)

McCurdy SR, Kanakry JA, Showel MM, Tsai HL, Bolanos-Meade J, Rosner GL, Kanakry CG, Perica K, Symons HJ, Brodsky RA, Gladstone DE, Huff CA, Pratz KW, Prince GT, Dezern AE, Gojo I, Matsui WH, Borrello I, McDevitt MA, Swinnen LJ, Smith BD, Levis MJ, Ambinder RF, Luznik L, Jones RJ, Fuchs EJ, Kasamon YL. Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood. 2015 May 7;125(19):3024-31. doi: 10.1182/blood-2015-01-623991. Epub 2015 Mar 26.

Reference Type: BACKGROUND

PMID: 25814532 (View on PubMed)

Bashey A, Zhang X, Sizemore CA, Manion K, Brown S, Holland HK, Morris LE, Solomon SR. T-cell-replete HLA-haploidentical hematopoietic transplantation for hematologic malignancies using post-transplantation cyclophosphamide results in outcomes equivalent to those of contemporaneous HLA-matched related and unrelated donor transplantation. J Clin Oncol. 2013 Apr 1;31(10):1310-6. doi: 10.1200/JCO.2012.44.3523. Epub 2013 Feb 19.

Reference Type: BACKGROUND

PMID: 23423745 (View on PubMed)

Bashey A, Zhang X, Jackson K, Brown S, Ridgeway M, Solh M, Morris LE, Holland HK, Solomon SR. Comparison of Outcomes of Hematopoietic Cell Transplants from T-Replete Haploidentical Donors Using Post-Transplantation Cyclophosphamide with 10 of 10 HLA-A, -B, -C, -DRB1, and -DQB1 Allele-Matched Unrelated Donors and HLA-Identical Sibling Donors: A Multivariable Analysis Including Disease Risk Index. Biol Blood Marrow Transplant. 2016 Jan;22(1):125-33. doi: 10.1016/j.bbmt.2015.09.002. Epub 2015 Sep 7.

Reference Type: BACKGROUND

PMID: 26359881 (View on PubMed)

Ciurea SO, Mulanovich V, Saliba RM, Bayraktar UD, Jiang Y, Bassett R, Wang SA, Konopleva M, Fernandez-Vina M, Montes N, Bosque D, Chen J, Rondon G, Alatrash G, Alousi A, Bashir Q, Korbling M, Qazilbash M, Parmar S, Shpall E, Nieto Y, Hosing C, Kebriaei P, Khouri I, Popat U, de Lima M, Champlin RE. Improved early outcomes using a T cell replete graft compared with T cell depleted haploidentical hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2012 Dec;18(12):1835-44. doi: 10.1016/j.bbmt.2012.07.003. Epub 2012 Jul 11.

Reference Type: BACKGROUND

PMID: 22796535 (View on PubMed)

Raiola AM, Dominietto A, Ghiso A, Di Grazia C, Lamparelli T, Gualandi F, Bregante S, Van Lint MT, Geroldi S, Luchetti S, Ballerini F, Miglino M, Varaldo R, Bacigalupo A. Unmanipulated haploidentical bone marrow transplantation and posttransplantation cyclophosphamide for hematologic malignancies after myeloablative conditioning. Biol Blood Marrow Transplant. 2013 Jan;19(1):117-22. doi: 10.1016/j.bbmt.2012.08.014. Epub 2012 Aug 29.

Reference Type: BACKGROUND

PMID: 22940057 (View on PubMed)

Kanakry CG, Ganguly S, Zahurak M, Bolanos-Meade J, Thoburn C, Perkins B, Fuchs EJ, Jones RJ, Hess AD, Luznik L. Aldehyde dehydrogenase expression drives human regulatory T cell resistance to posttransplantation cyclophosphamide. Sci Transl Med. 2013 Nov 13;5(211):211ra157. doi: 10.1126/scitranslmed.3006960.

Reference Type: BACKGROUND

PMID: 24225944 (View on PubMed)

Ganguly S, Ross DB, Panoskaltsis-Mortari A, Kanakry CG, Blazar BR, Levy RB, Luznik L. Donor CD4+ Foxp3+ regulatory T cells are necessary for posttransplantation cyclophosphamide-mediated protection against GVHD in mice. Blood. 2014 Sep 25;124(13):2131-41. doi: 10.1182/blood-2013-10-525873. Epub 2014 Aug 18.

Reference Type: BACKGROUND

PMID: 25139358 (View on PubMed)

Stem Cell Trialists' Collaborative Group. Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials. J Clin Oncol. 2005 Aug 1;23(22):5074-87. doi: 10.1200/JCO.2005.09.020.

Reference Type: BACKGROUND

PMID: 16051954 (View on PubMed)

Yang JZ, Zhang JQ, Sun LX. Mechanisms for T cell tolerance induced with granulocyte colony-stimulating factor. Mol Immunol. 2016 Feb;70:56-62. doi: 10.1016/j.molimm.2015.12.006. Epub 2015 Dec 17.

Reference Type: BACKGROUND

PMID: 26703218 (View on PubMed)

Jun HX, Jun CY, Yu ZX. In vivo induction of T-cell hyporesponsiveness and alteration of immunological cells of bone marrow grafts using granulocyte colony-stimulating factor. Haematologica. 2004 Dec;89(12):1517-24.

Reference Type: BACKGROUND

PMID: 15590404 (View on PubMed)

Deotare U, Al-Dawsari G, Couban S, Lipton JH. G-CSF-primed bone marrow as a source of stem cells for allografting: revisiting the concept. Bone Marrow Transplant. 2015 Sep;50(9):1150-6. doi: 10.1038/bmt.2015.80. Epub 2015 Apr 27.

Reference Type: BACKGROUND

PMID: 25915812 (View on PubMed)

Couban S, Messner HA, Andreou P, Egan B, Price S, Tinker L, Meharchand J, Forrest DL, Lipton J. Bone marrow mobilized with granulocyte colony-stimulating factor in related allogeneic transplant recipients: a study of 29 patients. Biol Blood Marrow Transplant. 2000;6(4A):422-7. doi: 10.1016/s1083-8791(00)70033-4.

Reference Type: BACKGROUND

PMID: 10975510 (View on PubMed)

Isola L, Scigliano E, Fruchtman S. Long-term follow-up after allogeneic granulocyte colony-stimulating factor--primed bone marrow transplantation. Biol Blood Marrow Transplant. 2000;6(4A):428-33. doi: 10.1016/s1083-8791(00)70034-6.

Reference Type: BACKGROUND

PMID: 10975511 (View on PubMed)

Ji SQ, Chen HR, Wang HX, Yan HM, Pan SP, Xun CQ. Comparison of outcome of allogeneic bone marrow transplantation with and without granulocyte colony-stimulating factor (lenograstim) donor-marrow priming in patients with chronic myelogenous leukemia. Biol Blood Marrow Transplant. 2002;8(5):261-7. doi: 10.1053/bbmt.2002.v8.pm12064363.

Reference Type: BACKGROUND

PMID: 12064363 (View on PubMed)

Morton J, Hutchins C, Durrant S. Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells. Blood. 2001 Dec 1;98(12):3186-91. doi: 10.1182/blood.v98.12.3186.

Reference Type: BACKGROUND

PMID: 11719353 (View on PubMed)

Serody JS, Sparks SD, Lin Y, Capel EJ, Bigelow SH, Kirby SL, Gabriel DA, Wiley JM, Brecher ME, Schell MJ, Folds J, Shea TC. Comparison of granulocyte colony-stimulating factor (G-CSF)--mobilized peripheral blood progenitor cells and G-CSF--stimulated bone marrow as a source of stem cells in HLA-matched sibling transplantation. Biol Blood Marrow Transplant. 2000;6(4A):434-40. doi: 10.1016/s1083-8791(00)70035-8.

Reference Type: BACKGROUND

PMID: 10975512 (View on PubMed)

Other Identifiers

DREPHAPLO

Identifier Type: -

Identifier Source: org_study_id