ATG Could Improve the Outcome Of Hematopoietic Stem Cell Transplant in Patients With Highly Aggressive T Cell Tumors

Acute Lymphoblastic Leukemia Clinical Trial

— HSCT  

Official title:

Hematology , Shanghai Jiaotong University Affiliated Shanghai First People's Hospital, Shanghai, China

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02290132
• Other study ID #: 2013(56)
• Status: Recruiting
• Phase: Phase 4
• First received: October 13, 2014
• Last updated: November 8, 2014
• Start date: August 2013
• Est. completion date: July 2017

Study information

• Verified date: November 2014
• Source: Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine
• Contact: yang jun, master
• Phone: 18001890183
• Email: yangjuan74[@]hotmail.com
• Is FDA regulated: No
• Health authority: China: Food and Drug Administration
• Study type: Observational [Patient Registry]

Clinical Trial Summary

The clinical application and effect of ATG based myeloablative conditioning regimen after allogeneic hematopoietic stem cell transplantation in adult patients with aggressive T-cell lymphomas.

Description:

Aggressive T-cell lymphomas (ATCLs), including peripheral T-cell lymphoma and T lymphoblastoid cell lymphoma/leukemia, represent 10% to 15% of non-Hodgkin's lymphomas (NHLs) in adults(1). ATCLs show a worse prognosis than that of B-cell lymphomas. Myeloablative allogeneic stem cell transplantation (allo-SCT) may be the only way to cure these patients, but the recurrence of the primary disease after transplantation is still an important prognostic factor (2). Optimizing the conditioning regimen is always the research hot topics in hematology fields. Polyclonal anti-thymocyte globulin (rabbit anti-thymocyte globulin, r-ATG) are currently used to prevent graft-versus -host(GVHD) disease in allogeneic stem cell transplantation, and also widely used for the prevention and treatment of acute rejection after solid organ transplant because of its strong immunomodulatory effects. ATG is used in allogeneic SCT for the prophylaxis of graft versus host disease by in vivo T cell depletion, including the complement-dependent cytotoxic response, antibody-dependent cell-mediated cytotoxicity, the opsonophagocytic role of phagocytic cells and induced apoptosis(3). But some scholars reported the ATG delayed immune reconstitution and hematologic reconstitution and leaded to the increase of the incidence of virus and fungal infections after transplantation. But it is often curable and does not affect the overall survival and quality of life of the patients (4). Because of its strong immune suppression and regulation, also on the basis of the above facts, ATG as GVHD prophylaxis is generally limited to the unrelated donor, or human leukocyte antigen（HLA）-mismatched related donor transplantation. But There are many issues still need to be studied. ATG has shown efficacy in preventing acute GVHD（aGVHD) in allo-SCT, but its efficacy in chronic GVHD (cGVHD) and long-term outcomes remains controversial. A systematic review and meta-analysis from Du k et al（5） reported that prophylactic use of ATG exerted a favorable effect in reducing cGVHD without survival impairment in a long term, although a higher relapse rate is a major threat.

Does the ATG also have the killing effect on the tumor cells of the lymphatic system? The vitro studies have confirmed this point recently. Grüllich(6) et al and the investigators study(7) both found that ATG can inhibit the proliferation and induce high level of apoptosis in the human lymphoblastic cell lines, such as Jurkat, Daudi, DG-75 , and myeloblastic cell lines K562, HL-60, KG1, and U937. ATG also has pro-apoptotic activity against the majority of primary leukemia cells, particularly those cells from lymphatic origin. In addition, ATG will not result in apoptosis of normal hematopoietic cells. Low-dose ATG can also stimulate normal hematopoietic colony growth. Therefore, ATG may be used as anti-lymphocyte tumor bio-therapeutics (such as rituximab) to increase the role of chemo-radiotherapy in the conditioning regimen. And ATG can remove the residual tumor lesions, which reduced the rate of tumor recurrence after transplantation. Although the vitro studies have clarified the role of ATG on the tumor cells of the lymphatic system, but no relevant reports on the anti-tumor effect of ATG in allo-SCT have been published. Further clinical observation need to be conducted.

As noted earlier, a higher relapse rate may be a major threat after ATG use（5）.In China, the conventional dose of 2.5mg/kg/day, 2-3 days of Thymoglobulin is commonly used as GVHD prophylaxis in the unrelated donor, or HLA-mismatched related donor transplantation but not in the HLA matched related donor transplantation (8). In order to observe the anti-tumor effect of this conditioning regimen in the aggressive T-cell lymphomas patients(including peripheral T-cell lymphoma and T lymphoblastoid cell lymphoma/leukemia, complete remission, partial remission, relapse after remission or refractory recurrent invasive patients), the investigators improved the drugs of conditioning regimen and increased the Thymoglobulin dose in the conditioning regimen for four days 10mg/kg total even in the HLA matched related donor transplantation. The purpose of this clinical trial is to reduce the incidence of GVHD at the same time does not increase the recurrence of the primary disease. The investigators expect that this ATG based conditioning regimen does play anti-tumor effect, reduce primary disease recurrence after transplantation, improve disease-free survival (DFS) and overall survival rate (OS) , as well as reduce the incidence and severity of GVHD, but the incidence of infection need to be observed.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 63
• Est. completion date: July 2017
• Est. primary completion date: December 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• According to the World Health Organization (WHO) classification, diagnosis of T cell tumor of lymphatic system sources (including peripheral T-cell lymphoma and T lymphoblastoid cell lymphoma/leukemia) confirmed by pathological examination, morphology, cytochemistry, immunophenotyping and chromosome examination, molecular biology including complete remission, partial remission, relapse after remission or refractory recurrent invasive patients

• 18 to 60 years old. Male or female

• Performance status scores no more than 2 (ECOG criteria).

• Adequate organ function as defined by the following criteria:

alanine transaminase (ALT), aspartate transaminase(AST) and total serum bilirubin <2×ULN (upper limit of normal)

• Serum creatinine and blood urea nitrogen(BUN) <1.25×ULN.

• Adequate cardiac function without acute myocardial infarction, arrhythmia or atrioventricular block, heart failure, active rheumatic heart disease and cardiac dilatation(the patients has been improved after treatment of the disease and are not expected to affect transplant can include in the study).

• Absence of any other contraindications of stem cell transplantation.

• Willingness and ability to perform HSCT.

• Signed and dated informed consent document indicating that the patient (or legally acceptable representative) has been informed of all pertinent aspects of the trial prior to enrollment.

• Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.

Exclusion Criteria:

• Presence of any condition inappropriate for HSCT.

• Life expectancy < 3 months because of other severe diseases.

• Presence of any fatal disease, including respiratory failure, heart failure, liver or kidney function failure et al.

• Uncontrolled infection.

• Pregnancy or breastfeeding. 6.Has enrolled in anther clinical trials 7.Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or may interfere with the interpretation of study results, and in the judgment of the investigator would make the patient inappropriate for entry into this study.

Study Design

Observational Model: Case-Only, Time Perspective: Prospective

Related Conditions & MeSH terms

• Acute Lymphoblastic Leukemia
• Leukemia, Lymphoid
• Lymphoblastic Lymphoma
• Lymphoma, Non-Hodgkin
• Precursor Cell Lymphoblastic Leukemia-Lymphoma

Intervention

Drug:
• Rabbit Anti-human Thymocyte Globulin (ATG)
The conditioning regimen in this study consisted of Rabbit antithymocyte globulin (ATG 2.5 mg/kg×4 days) , total-body irradiation (10 Gy in five fractions), cyclophosphamide (60 mg/kg×2 days) and etoposide or teniposide (30-40mg/kg) .

Locations

Country	Name	City	State
China	Shanghai First People's HOSPITAL	Shanghai	Shanghai

Sponsors (4)

Lead Sponsor	Collaborator
Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine	Tang-Du Hospital, The First Affiliated Hospital of Soochow University, The First Affiliated Hospital with Nanjing Medical University

Country where clinical trial is conducted

China, 

References & Publications (8)

Du K, Hu Y, Wu K, Huang H. Long-term outcomes of antithymocyte globulin in patients with hematological malignancies undergoing myeloablative allogeneic hematopoietic cell transplantation: a systematic review and meta-analysis. Clin Transplant. 2013 Mar-Apr;27(2):E91-E100. doi: 10.1111/ctr.12091. Epub 2013 Feb 6. Review. — View Citation

Grüllich C, Ziegler C, Finke J. Rabbit anti T-lymphocyte globulin induces apoptosis in peripheral blood mononuclear cell compartments and leukemia cells, while hematopoetic stem cells are apoptosis resistant. Biol Blood Marrow Transplant. 2009 Feb;15(2):173-82. doi: 10.1016/j.bbmt.2008.11.014. — View Citation

Liu H, Qin Y, Wang X, Xie K, Yang Y, Zhu J, Zhao C, Wang C. Polyclonal rabbit antithymocyte globulin induces apoptosis and has cytotoxic effects on human leukemic cells. Clin Lymphoma Myeloma Leuk. 2012 Oct;12(5):345-54. doi: 10.1016/j.clml.2012.05.006. E — View Citation

Meijer E, Cornelissen JJ, Löwenberg B, Verdonck LF. Antithymocyteglobulin as prophylaxis of graft failure and graft-versus-host disease in recipients of partially T-cell-depleted grafts from matched unrelated donors: a dose-finding study. Exp Hematol. 2003 Nov;31(11):1026-30. — View Citation

Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007 Jul;21(7):1387-94. Epub 2007 Apr 5. Review. — View Citation

Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J, Thomas ED. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant. 1995 Jun;15(6):825-8. Review. — View Citation

Rüdiger T, Weisenburger DD, Anderson JR, Armitage JO, Diebold J, MacLennan KA, Nathwani BN, Ullrich F, Müller-Hermelink HK; Non-Hodgkin's Lymphoma Classification Project. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol. 2002 Jan;13(1):140-9. — View Citation

Vose J, Armitage J, Weisenburger D; International T-Cell Lymphoma Project. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008 Sep 1;26(25):4124-30. doi: 10.1200/JCO.2008.16.4558. Epub 2008 Jul 14. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Progress free surviva(PFS) rate at 2 years	PFS were defined as the time from stem-cell infusion to relapse, disease progression,or death from any cause	2 YEARS	Yes
Secondary	Leukocyte engraftment	Leukocyte engraftment:(was defined as the first of three consecutive days of peripheral white blood count >1000/ul.	1 MONTH	Yes
Secondary	Platelet engraftment	Platelet engraftment:(was defined as the first of seven consecutive days of platelet counts of >50000/ul.	1 MONTH	Yes
Secondary	Donor chimerism:	Quantitative chimerism analyzes were performed using short-tandem-repeat-based polymerase chain reaction technique sat regular intervals for every 4 weeks after allografting in bone marrow.	2 YEARS	Yes
Secondary	Relapse incidence (RI)	1. T lymphoblastoid cell lymphoma/leukemia: Bone marrow blasts > 20% 2.peripheral T-cell lymphoma: any increased >50% in the sum of the diameter of any measurable lesions or the appearance of a new lesion.)	2 YEARS	Yes
Secondary	Overall survival rate	OS were defined as the time from stem-cell infusion to death from any cause)	2 YEARS	Yes
Secondary	Transplant related mortality(TRM)	TRM were defined as death within 100 days of high-dose therapy not related to the disease,relapse or progression	2 YEARS	Yes