Trial to Assess the Efficacy of a TCR Alfa Beta Depleted Graft in Pediatric Affected by ALL or AML and Receiving an HSCT

Myelodysplastic Syndromes Clinical Trial

Official title:

Phase I/II Study of Allogeneic Hematopoietic Stem Cell Transplantation From an HLA-partially Matched Family Donor After TCR Alfa Beta Negative Selection in Pediatric Patients Affected by Hematological Disorders

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01810120
• Other study ID #: OPBG_359.11
• Status: Completed
• Phase: Phase 1/Phase 2
• First received: January 17, 2012
• Last updated: January 20, 2017
• Start date: January 2012
• Est. completion date: December 2016

Study information

• Verified date: January 2017
• Source: Bambino Gesù Hospital and Research Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Allocation: Non-Randomized Endpoint Classification: Safety/Feasibility Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment Study to assess the feasibility and safety of the infusion of a T cells receptor (TCR) alfa beta depleted graft in pediatric patients affected by malignant and non-malignant hematological disorders and receiving an Hematopoietic stem cell transplantation (HSCT) from a Human leukocyte antigen (HLA) partially matched family donor.

Description:

In this study the hypothesis is that the transplantation of Peripheral blood stem cells (PBSC)selectively depleted of TCR alfa beta T lymphocytes would offers some advantages over the use of positively selected CD34+ stem cells because of the presence of other non-stem ancillary cells (in particular Natural killer (NK) and alfa beta T cells) that might have potential positive effects on the outcome of the transplant.

The clinical relevance of NK-cell alloreactivity has been demonstrated in adult patients affected by Acute myeloid leukemia (AML) and given T-cell depleted HSCT from an HLA-disparate relative where a subgroup of patients had a particularly low risk of leukemia relapse. These patients belonged to the group transplanted from a donor having NK cells that were alloreactive towards recipient targets i.e. the patient cells express HLA-class I alleles that do not share the inhibiting allelic determinants recognized by Killer immunoglobulin-like receptors (KIR) on donor NK cells. The emergence of this concept of NK-cell alloreactivity has represented a sort of revolution in the field of Haplo-identical hematopoietic stem cell translantation (haplo-HSCT), as the presence of alloreactive NK cells has been shown to positively affect the outcome of transplantation in adults and to display a Graft versus leukemia (GvL) effect that can compensate for the lack of T-specific anti-tumor effect.

The purpose of this study is to evaluate the feasibility and safety of the selective infusion of TCR alfa beta T cell depleted graft in pediatric patients affected by malignant or non malignant hematological disorders and receiving an HSCT from a partially matched family donor.

This study will provide new data on the feasibility and the safety of using a TCR alfa beta T cell depleted graft instead of fully T cell depleted graft to improve the outcome of patients receiving a haplo-HSCT for the treatment of hematological disorders.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: December 2016
• Est. primary completion date: September 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Months to 20 Years

Eligibility

Inclusion Criteria:

• Patients aged = 3 months and < 21 years

• Patients diagnosed with malignant hemopathies (Acute Lymphoblastic leukemia (ALL), Acute Myeloid Leukemia (AML), Non-Hodgkin Lymphoma (NHL)) in complete morphological remission or Myelodysplastic Syndromes (MDS), Solid Tumors or non malignant hematological disorders (SCID, Acquired and Congenital Aplastic Anemia, other Primary Immunodeficiencies, Life-threatening Cytopenia) eligible for an allogeneic transplantation and lacking a related or unrelated HLA-matched donor

• Patients displaying an HLA-partially matched family donor

• Lansky/Karnofsky score > 40, WHO > 4

• Signed written informed consent

Exclusion Criteria:

• Grade >II acute GvHD or chronic extensive GvHD at the time of inclusion

• Patient receiving an immunosuppressive treatment for GvHD treatment at the time of inclusion

• Dysfunction of liver (ALT/AST > 5 times normal value, or bilirubin > 3 times normal value), or of renal function (creatinine clearance < 30 ml / min)

• Severe cardiovascular disease (arrhythmias requiring chronic treatment, congestive heart failure or left ventricular ejection fraction <40%)

• Current active infectious disease (including positive HIV serology or viral RNA)

• Serious concurrent uncontrolled medical disorder

• Pregnant or breast feeding female patient

• Lack of parents' informed consent.

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia
• Leukemia Acute Myeloid - AML
• Leukemia, Lymphoid
• Leukemia, Myeloid, Acute
• Lymphoma, Non-Hodgkin
• Myelodysplastic Syndromes
• Non-Hodgkin Lymphoma
• Precursor Cell Lymphoblastic Leukemia-Lymphoma
• Preleukemia

Intervention

Biological:
• TCR alfa beta T cell depletion
total nucleated cells from the leukapheresis product will undergo TCR alfa beta negative selection and the product of the depletion will be infused to the patient

Locations

Country	Name	City	State
Italy	Department of Oncology/Hematology of the Hospital Bambino Gesù (Roma)	Rome

Sponsors (1)

Lead Sponsor	Collaborator
Mariella Enoc

Country where clinical trial is conducted

Italy, 

References & Publications (23)

Antoine C, Müller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A; European Group for Blood and Marrow Transplantation.; European Society for Immunodeficiency.. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968-99. Lancet. 2003 Feb 15;361(9357):553-60. — View Citation

Aversa F, Tabilio A, Terenzi A, Velardi A, Falzetti F, Giannoni C, Iacucci R, Zei T, Martelli MP, Gambelunghe C, et al. Successful engraftment of T-cell-depleted haploidentical "three-loci" incompatible transplants in leukemia patients by addition of recombinant human granulocyte colony-stimulating factor-mobilized peripheral blood progenitor cells to bone marrow inoculum. Blood. 1994 Dec 1;84(11):3948-55. — View Citation

Aversa F, Tabilio A, Velardi A, Cunningham I, Terenzi A, Falzetti F, Ruggeri L, Barbabietola G, Aristei C, Latini P, Reisner Y, Martelli MF. Treatment of high-risk acute leukemia with T-cell-depleted stem cells from related donors with one fully mismatched HLA haplotype. N Engl J Med. 1998 Oct 22;339(17):1186-93. — View Citation

Aversa F, Terenzi A, Tabilio A, Falzetti F, Carotti A, Ballanti S, Felicini R, Falcinelli F, Velardi A, Ruggeri L, Aloisi T, Saab JP, Santucci A, Perruccio K, Martelli MP, Mecucci C, Reisner Y, Martelli MF. Full haplotype-mismatched hematopoietic stem-cell transplantation: a phase II study in patients with acute leukemia at high risk of relapse. J Clin Oncol. 2005 May 20;23(15):3447-54. — View Citation

Bachar-Lustig E, Rachamim N, Li HW, Lan F, Reisner Y. Megadose of T cell-depleted bone marrow overcomes MHC barriers in sublethally irradiated mice. Nat Med. 1995 Dec;1(12):1268-73. — View Citation

Ciceri F, Labopin M, Aversa F, Rowe JM, Bunjes D, Lewalle P, Nagler A, Di Bartolomeo P, Lacerda JF, Lupo Stanghellini MT, Polge E, Frassoni F, Martelli MF, Rocha V; Acute Leukemia Working Party (ALWP) of European Blood and Marrow Transplant (EBMT) Group.. A survey of fully haploidentical hematopoietic stem cell transplantation in adults with high-risk acute leukemia: a risk factor analysis of outcomes for patients in remission at transplantation. Blood. 2008 Nov 1;112(9):3574-81. doi: 10.1182/blood-2008-02-140095. — View Citation

Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006 Apr 27;354(17):1813-26. Review. — View Citation

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Hayday AC. Gammadelta T cells and the lymphoid stress-surveillance response. Immunity. 2009 Aug 21;31(2):184-96. doi: 10.1016/j.immuni.2009.08.006. — View Citation

Janeway CA Jr, Medzhitov R. Innate immune recognition. Annu Rev Immunol. 2002;20:197-216. Review. — View Citation

Klingebiel T, Cornish J, Labopin M, Locatelli F, Darbyshire P, Handgretinger R, Balduzzi A, Owoc-Lempach J, Fagioli F, Or R, Peters C, Aversa F, Polge E, Dini G, Rocha V; Pediatric Diseases and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation (EBMT).. Results and factors influencing outcome after fully haploidentical hematopoietic stem cell transplantation in children with very high-risk acute lymphoblastic leukemia: impact of center size: an analysis on behalf of the Acute Leukemia and Pediatric Disease Working Parties of the European Blood and Marrow Transplant group. Blood. 2010 Apr 29;115(17):3437-46. doi: 10.1182/blood-2009-03-207001. — View Citation

Locatelli F, Pende D, Maccario R, Mingari MC, Moretta A, Moretta L. Haploidentical hemopoietic stem cell transplantation for the treatment of high-risk leukemias: how NK cells make the difference. Clin Immunol. 2009 Nov;133(2):171-8. doi: 10.1016/j.clim.2009.04.009. — View Citation

Martelli MF, Aversa F, Bachar-Lustig E, Velardi A, Reich-Zelicher S, Tabilio A, Gur H, Reisner Y. Transplants across human leukocyte antigen barriers. Semin Hematol. 2002 Jan;39(1):48-56. Review. — View Citation

Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L. What is a natural killer cell? Nat Immunol. 2002 Jan;3(1):6-8. Review. — View Citation

Moretta A, Locatelli F, Moretta L. Human NK cells: from HLA class I-specific killer Ig-like receptors to the therapy of acute leukemias. Immunol Rev. 2008 Aug;224:58-69. doi: 10.1111/j.1600-065X.2008.00651.x. Review. — View Citation

Moretta L, Ciccone E, Mingari MC, Biassoni R, Moretta A. Human natural killer cells: origin, clonality, specificity, and receptors. Adv Immunol. 1994;55:341-80. Review. — View Citation

Moretta L, Moretta A. Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J. 2004 Jan 28;23(2):255-9. Review. — View Citation

Parham P. Innate immunity: The unsung heroes. Nature. 2003 May 1;423(6935):20. — View Citation

Pende D, Marcenaro S, Falco M, Martini S, Bernardo ME, Montagna D, Romeo E, Cognet C, Martinetti M, Maccario R, Mingari MC, Vivier E, Moretta L, Locatelli F, Moretta A. Anti-leukemia activity of alloreactive NK cells in KIR ligand-mismatched haploidentical HSCT for pediatric patients: evaluation of the functional role of activating KIR and redefinition of inhibitory KIR specificity. Blood. 2009 Mar 26;113(13):3119-29. doi: 10.1182/blood-2008-06-164103. — View Citation

Reisner Y, Kapoor N, Kirkpatrick D, Pollack MS, Cunningham-Rundles S, Dupont B, Hodes MZ, Good RA, O'Reilly RJ. Transplantation for severe combined immunodeficiency with HLA-A,B,D,DR incompatible parental marrow cells fractionated by soybean agglutinin and sheep red blood cells. Blood. 1983 Feb;61(2):341-8. — View Citation

Reisner Y, Martelli MF. Stem cell escalation enables HLA-disparate haematopoietic transplants in leukaemia patients. Immunol Today. 1999 Aug;20(8):343-7. Review. — View Citation

Rocha V, Locatelli F. Searching for alternative hematopoietic stem cell donors for pediatric patients. Bone Marrow Transplant. 2008 Jan;41(2):207-14. Review. — View Citation

Trinchieri G. Biology of natural killer cells. Adv Immunol. 1989;47:187-376. Review. — View Citation

* Note: There are 23 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	CD34+ cells	Target number of CD34+ cells in at least 80% of the patients	up to 3 month
Secondary	Primary and secondary graft failure	Cumulative incidence of primary and secondary graft failure	up to 24 months after transplantation
Secondary	Acute and chronic GvHD	Cumulative incidence and severity of acute and chronic GvHD occurring after the transplantation	up to 24 months after transplantation
Secondary	Overall survival (OS) and disease-free survival	The overall survival (OS) and disease-free survival probability compared with a cohort of historical controls	up to 24 months after transplantation
Secondary	TCR alfa beta cells	The immunological reconstitution of TCR alfa beta cells compared with a cohort of historical controls	up to 12 months after the transplantation