Malignant Haematological Disease Clinical Trial
— GRAPAOfficial title:
Transplantation of Ex-vivo Expanded Human Cord Blood Hematopoietic Stem Cells Expanded: Evaluation of Hematopoietic and Immunologic Reconstitution After a Reduced-intensity Conditioning Regimen
This program offers the opportunity to receive an allogeneic transplant to try to control
the malignant hematologic in the absence of acceptable conventional donor and with a
risk-benefit ratio equivalent to that which would be expected with a transplant from a more
conventional donor.
An economy of means in that this method could serve as an alternative to 2 units of
placental blood transplantation. The current cost of disposal of a unit of placental blood
from a bank is approximately 22000 € (Source: Biomedicine Agency, 2007 rates). The
amplification process as controlled by "EFSAL" is 12000 €. Therefore, buying a unit and
ex-vivo amplification is more economical. Moreover, the availability of placental blood is
not infinite, and the use of one unit per patient will also save resources that can be
valuable for certain groups of patients.
In the longer term, methods of amplification of specific immunocompetent cells (from the
fraction of CD 34 neg cells) are already being evaluated in the laboratory. They allow to
consider a faster recovery, better and more targeted, including cells against the disease
for which transplantation is performed.
| Status | Completed |
| Enrollment | 16 |
| Est. completion date | September 2014 |
| Est. primary completion date | October 2013 |
| Accepts healthy volunteers | No |
| Gender | Both |
| Age group | 18 Years to 65 Years |
| Eligibility |
Inclusion Criteria: - Age = 18 and < 66 years - Patient with acute myeloid leukemia (AML) high risk in 1st complete remission: - CR1 obtained by 2 cycles of chemotherapy, - unfavorable Cytogenetics - FLT3 Duplication, - Or acute myeloid leukemia (AML) in 2nd complete remission, - Or acute lymphoblastic leukemia (ALL) High-risk 1st complete remission: - Presence of the translocation t (9; 22), - Or acute lymphoblastic leukemia (ALL) in 2nd complete remission, - Or Chronic Myeloid Leukemia (LCM) beyond the 1st chronic phase - Or Myelodysplasia or with IPSS score with 2 or more - Or Hodgkin's disease in sensitive relapse or beyond the 2nd complete remission. or following types of lymphoma : - Diffuse large B lymphoma cells relapsed or refractory after two lines of treatment or after a line with autologous hematopoietic stem cell, or - Mantle cell lymphoma relapsed or refractory after two lines of treatment or after a line with autologous hematopoietic stem cell - Others aggressive lymphoma for which an indication of allograft is selected (Burkitt lymphoma, lymphoblastic lymphoma, intravascular lymphoma, ...) - Lymphoma (low-grade follicular lymphoma, marginal zone lymphoma) in histological transformation. - Low-grade lymphoma for which an indication of allograft is retained - Unable to receive myeloablative conditioning because of age (> 45 years) and/or the existence of co-morbidities precluding a myeloablative conditioning (status ECOG > / = 2, DLCO <50%, fungal infection proven or probable in the previous 60 days) and / or prior treatment with total body irradiation at doses above 2 Gy or busulfan doses> 8 mg/kg - No contra-indication for a transplant in allogeneic non-myeloablative conditioning, - No HLA-identical sibling, - Absence of an unrelated donor on national or international registering with a 10/10 allelic matching or a 9/10 allelic matching with the only tolerated mismatches being: HLA-C. - No unit of placental blood available fulfilling the characteristics of compatibility (HLA compatible at least 4/6 allele or generic) and richness - Provision of at least 2 units of placental blood, whose compatibility is 4/6, 5/6 or 6/6 and whose richness is before thawing, > 2 x 107 and < 3 to 4 x 107 nucleated cells per/kg. - Patient affiliated to a social security scheme, - Free and informed consent signed by the patient and the investigator. Exclusion Criteria: - Age <18 and = 66 years - Malignant myeloid or lymphoid acute or chronic disease without indication for an allogeneic transplant according to the criteria of European Bone Marrow Transplantation Group. - Able to receive a myeloablative conditioning because of age (<45 years) and the absence of co morbidities (status ECOG> / = 2, DLCO <50%, fungal infection proven or probable in 60 preceding days) and the absence of prior treatment with total body irradiation at doses above 2 Gy or busulfan doses> 8 mg / kg - Contra indication for a non-myeloablative conditioning, - HLA-identical sibling available - Availability of an unrelated donor on a national or international register with 10/10 or 9/10 HLA matching (HLA-C Mismatch tolerated). - At least one unit of cord blood available with the characteristics of compatibility (HLA compatible at least 4/6 allelic or generic) and richness (before thawing> / = 3 to 4 x 107 nucleated cells/kg recipient, by degree of compatibility) - Absence of at least 2 units of placental blood, whose compatibility is 4/6, 5/6 / or 6/6 and whose richness before thawing is > 2 x 107 and < 4 x 107 nucleated cells per/kg of recipient. - Women of childbearing age not using contraception, pregnant or lactating |
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
| Country | Name | City | State |
|---|---|---|---|
| France | Service d'hématologie et d'Oncologie Clinique - Hôpital Lapeyronie - 371 avenue du Doyen Gaston GIRAUD | Montpellier | |
| France | Service d'Hématologie, Hôpital Hôtel Dieu, CHU de Nantes - 1 Place Alexis Ricordeau | Nantes | |
| France | Service des maladies du sang - Hôpital Haut-Lévêque - avenue de Magellan | Pessac |
| Lead Sponsor | Collaborator |
|---|---|
| University Hospital, Bordeaux |
France,
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, McGlave PB, Miller JS, Verfaillie CM, Wagner JE. Transplantation of 2 partially HLA-matched umbilical cord blood units to enhance engraftment in adults with hematologic malignancy. Blood. 2005 Feb 1;105(3):1343-7. Epub 2004 Oct 5. — View Citation
Barker JN, Weisdorf DJ, DeFor TE, Blazar BR, Miller JS, Wagner JE. Rapid and complete donor chimerism in adult recipients of unrelated donor umbilical cord blood transplantation after reduced-intensity conditioning. Blood. 2003 Sep 1;102(5):1915-9. Epub 2003 May 8. — View Citation
Brunstein CG, Barker JN, Weisdorf DJ, DeFor TE, Miller JS, Blazar BR, McGlave PB, Wagner JE. Umbilical cord blood transplantation after nonmyeloablative conditioning: impact on transplantation outcomes in 110 adults with hematologic disease. Blood. 2007 Oct 15;110(8):3064-70. Epub 2007 Jun 14. — View Citation
Castello S, Podestà M, Menditto VG, Ibatici A, Pitto A, Figari O, Scarpati D, Magrassi L, Bacigalupo A, Piaggio G, Frassoni F. Intra-bone marrow injection of bone marrow and cord blood cells: an alternative way of transplantation associated with a higher seeding efficiency. Exp Hematol. 2004 Aug;32(8):782-7. — View Citation
Dazey B, Duchez P, Letellier C, Vezon G, Ivanovic Z; French Cord Blood Network. Cord blood processing by using a standard manual technique and automated closed system "Sepax" (Kit CS-530). Stem Cells Dev. 2005 Feb;14(1):6-10. — View Citation
Duchez P, Dazey B, Douay L, Vezon G, Ivanovic Z. An efficient large-scale thawing procedure for cord blood cells destined for selection and ex vivo expansion of CD34+ cells. J Hematother Stem Cell Res. 2003 Oct;12(5):587-9. — View Citation
Gluckman E, Rocha V. Donor selection for unrelated cord blood transplants. Curr Opin Immunol. 2006 Oct;18(5):565-70. Epub 2006 Aug 8. Review. — View Citation
Ivanovic Z, Duchez P, Dazey B, Hermitte F, Lamrissi-Garcia I, Mazurier F, Praloran V, Reiffers J, Vezon G, Boiron JM. A clinical-scale expansion of mobilized CD 34+ hematopoietic stem and progenitor cells by use of a new serum-free medium. Transfusion. 2006 Jan;46(1):126-31. — View Citation
Kobari L, Pflumio F, Giarratana M, Li X, Titeux M, Izac B, Leteurtre F, Coulombel L, Douay L. In vitro and in vivo evidence for the long-term multilineage (myeloid, B, NK, and T) reconstitution capacity of ex vivo expanded human CD34(+) cord blood cells. Exp Hematol. 2000 Dec;28(12):1470-80. — View Citation
Koh LP, Chao NJ. Umbilical cord blood transplantation in adults using myeloablative and nonmyeloablative preparative regimens. Biol Blood Marrow Transplant. 2004 Jan;10(1):1-22. Review. — View Citation
Ljungman P, Bregni M, Brune M, Cornelissen J, de Witte T, Dini G, Einsele H, Gaspar HB, Gratwohl A, Passweg J, Peters C, Rocha V, Saccardi R, Schouten H, Sureda A, Tichelli A, Velardi A, Niederwieser D; European Group for Blood and Marrow Transplantation. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: current practice in Europe 2009. Bone Marrow Transplant. 2010 Feb;45(2):219-34. doi: 10.1038/bmt.2009.141. Epub 2009 Jul 6. — View Citation
Ljungman P, Urbano-Ispizua A, Cavazzana-Calvo M, Demirer T, Dini G, Einsele H, Gratwohl A, Madrigal A, Niederwieser D, Passweg J, Rocha V, Saccardi R, Schouten H, Schmitz N, Socie G, Sureda A, Apperley J; European Group for Blood and Marrow. Allogeneic and autologous transplantation for haematological diseases, solid tumours and immune disorders: definitions and current practice in Europe. Bone Marrow Transplant. 2006 Mar;37(5):439-49. — View Citation
Petersdorf EW. Risk assessment in haematopoietic stem cell transplantation: histocompatibility. Best Pract Res Clin Haematol. 2007 Jun;20(2):155-70. Review. — View Citation
Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y, Freed B, Madinger N, Hogan CJ, Slat-Vasquez V, Russell P, Blunk B, Schissel D, Hild E, Malcolm J, Ward W, McNiece IK. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant. 2002;8(7):368-76. — View Citation
Takahashi S. Leukemia: cord blood for allogeneic stem cell transplantation. Curr Opin Oncol. 2007 Nov;19(6):667-72. Review. — View Citation
* Note: There are 15 references in all — Click here to view all references
| Type | Measure | Description | Time frame | Safety issue |
|---|---|---|---|---|
| Primary | The number of granulocytes, which will be evaluated daily after transplantation. And chimerism to be measured on the cells (total nucleated cells and lymphocytes) from peripheral blood on days 15, 42, 60, 100, 180, 360. | Daily for Blood évaluation and on days 15-42-60-100-180-360 for chimérisme évaluation. | Yes | |
| Secondary | feasibility of expansion | during and after expansion | No | |
| Secondary | Immediate tolerance of a graft amplified injection. Determined by measurement of vital parameters during injection of the graft and within 3 hours of observation and clinical tolerance. | during injection of the graft and within 3 hours of observation | Yes | |
| Secondary | The payback of a platelet count> 20 000/microlitre bloodless. Measured by the blood count and platelet daily during hospitalization and at least 2 times a week. | until the payback of the platelet count : measured daily during hospitalization and at least 2 times a week after | Yes | |
| Secondary | The length of hospitalization since the beginning of conditioning until the first exit for more than 2 days. | lenght of hospitalization since the beginning of conditioning | No | |
| Secondary | The number of transfusions of red blood cells and platelets during the 1st hospitalization | during the first hospitalization | No | |
| Secondary | The incidence of graft loss or rejection within 6 months after transplantation, defined as the installation of a central cytopenia with loss of chimerism | Within 6 months after transplantation | Yes | |
| Secondary | The incidence of acute and chronic GVHD,determined by clinical examination Biopsies of target organs(skin, intestine, liver) will be conducted to confirm the diagnosis if possible. | daily during hospitalization and at least twice weekly until D 100 after transplantation and then weekly or bi-monthly until one year post transplant. | Yes | |
| Secondary | The mortality rate for transplantation in the year following the transplant, | in the year following the transplant | Yes | |
| Secondary | The incidence of relapse of hematologic malignancies, | in the year following the transplant | Yes | |
| Secondary | survival and disease-free survival in the year following the transplant | in the year following the transplant | Yes | |
| Secondary | Monitoring of immune reconstitution. This reconstruction will be followed by determining the rate of immunoglobulin G, M and A and the number of T lymphocytes CD3 +, CD4 + and CD8 + (assessments on days 15, 42, 60, 100, 180, 360). | on days 15, 42, 60, 100, 180, 360 | Yes |