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

Sickle Cell Disease Clinical Trial

— DREPHAPLO  

Official title:

Bone Marrow Transplantation HLA Haploidentical After a Reduced Intensity Conditioning and Prevention of GvHD Based on Post-transplant Cyclophosphamide Administration in Patients With Severe Sickle Cell Disease

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT03240731
• Other study ID #: DREPHAPLO
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: August 10, 2017
• Est. completion date: September 2025

Study information

• Verified date: September 2023
• Source: Centre Hospitalier Intercommunal Creteil
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 18
• Est. completion date: September 2025
• Est. primary completion date: March 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 13 Years to 40 Years

Eligibility

Inclusion criteria recipient:

• 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)

Exclusion Criteria recipient:

• 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

Inclusion criteria donor

• 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

• Non-inclusion criteria donors: ß HCG positive or known pregnancy

Related Conditions & MeSH terms

• Anemia, Sickle Cell
• Sickle Cell Disease

Intervention

Biological:
• bone marrow transplant
haploidentical bone marrow transplant

Locations

Country	Name	City	State
France	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

Sponsors (3)

Lead Sponsor	Collaborator
Centre Hospitalier Intercommunal Creteil	Association Clinique Thérapeutique Infantile du val de Marne, Keocyt

Country where clinical trial is conducted

France, 

References & Publications (26)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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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. — View Citation

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. — View Citation

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* Note: There are 26 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Survival rate	Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild	2 years
Secondary	Survival rate	Survival without sickle cell survival rate (electrophoresis of hemoglobin similar to that from the donor, that is to say a percentage of HbS not exceeding 10% of that of distance donor transfusions and that of a stable manner and without GvHDc other than mild	1 year
Secondary	haematologic reconstitution	defined as a neutrophil count> 500 / mm3 and platelets> 20000 / mm3, for three consecutive days.	2 years
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 1
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 2
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 3
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 4
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 5
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 6
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 9
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 12
Secondary	Chimerism	Chimerism in the peripheral blood of the total population and the CD3 + population with the techniques usually employed by the centers	at month 24
Secondary	hemoglobin electrophoresis		at 1 month
Secondary	hemoglobin electrophoresis		at 2 month
Secondary	hemoglobin electrophoresis		at 3 months
Secondary	hemoglobin electrophoresis		at 4 months
Secondary	hemoglobin electrophoresis		at 5 months
Secondary	hemoglobin electrophoresis		at 6 months
Secondary	hemoglobin electrophoresis		at 9 months
Secondary	hemoglobin electrophoresis		at 12 months
Secondary	hemoglobin electrophoresis		at 24 months
Secondary	occurence of graft versus host disease	evaluated monthly from M1 to M6, and M9, M12, M24	at month 24
Secondary	grade of graft versus host disease	Incidence and grade of GvHD, toxic deaths and infectious complications and secondary cancer	at month 24
Secondary	occurrence of toxic deaths		at month 24
Secondary	occurrence of infectious complications		at month 24
Secondary	occurrence of secondary cancer		at month 24
Secondary	Lymphocyte immunophenotyping	Lymphocyte immunophenotyping T, B and NK + The Extended Phenotype including activation markers, assessment of naive people and memories, T reg populations etc) and plasma protein electrophoresis: 1 month, 3 months, 6 months, 12 months and 24 months post-transplantation.	2 years
Secondary	ECOG score value	Index Trading ECOG complete physical examination with determination of weight	2 years
Secondary	Assessment of sickle cell disease complications	Microalbuminuria, creatinuria; echocardiography for measurement of systolic ventricular ejection fraction (February), PAH research and measurement IT Vmax; respiratory function tests with measurement of DLCO; MRI brain with ARM and Cervical Pre-transplant anomalies; Radio of the pelvis	at 1 year
Secondary	ferritin dosage	Evaluation of iron overload by ferritin	at month 3
Secondary	ferritin dosage	Evaluation of iron overload by ferritin	at month 6
Secondary	MRI iron overload	hepatic and cardiac MRI to assess the iron overload	at 12 months