ATG Based Conditioning Regimen in HLA Related HSCT for Aggressive T-cell Tumors

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

ATG based conditioning regimen in HLA related allogeneic hematopoietic stem cell transplantation for aggressive T-cell tumors: multi-center, open, randomized controlled clinical study

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 antithymocyte 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. The result of our retrospective study in our hospital had already be published in blood cancer journal. We used the ATG as the part of the conditioning regimen and to evaluate the long-term antileukemia effect, the safety and complication in the patients with highly aggressive T-cell lymphomas. Twenty-three patients were enrolled into this study. At the time of transplant, six patients reached first or subsequent complete response, three patients had a partial remission and 14 patients had relapsed or primary refractory disease. The conditioning regimen consisted of ATG, total body irradiation, toposide and cyclophosphamide. The complete remission rate after transplant was 95.7%. At a median follow-up time of 25 months, 16 (69.6%) patients are alive and free from diseases, including nine patients in refractory and progressive disease. Seven patients died after transplant, five from relapse and two from treatment-related complications. The incidence of grades II-IV acute graft-vs-host disease (GvHD) was 39.1%. The maximum cumulative incidence of chronic GvHD was 30%. The most frequent and severe conditioning-related toxicities observed in 8 out of 23 patients were grades III/IV infections during cytopenia. Thus, ATG based conditioning is a feasible and effective alternative for patients with highly aggressive T-cell tumors（8）. In view of this convincing result, we designed a multi-center, open, randomized controlled clinical study. 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 (9). In order to observe the anti-tumor effect of this conditioning regimen in the aggressive T-cell lymphomas patients(complete remission, partial remission), we designed a multi-center, open, randomized controlled clinical study. The donors are all HLA matched related donors. In the therapy group, we added in the Thymoglobulin dose in the conditioning regimen for four days 10mg/kg. We 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. Reference:1. Rudiger T, Weisenburger DD, Anderson JR et al. Peripheral T-cell lymphoma (excluding anaplastic large-cell lymphoma): results from the Non-Hodgkin's Lymphoma Classification Project. Ann Oncol 2002; 13:140-149. 2. Armitage J, Vose J, Weisenburger D. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 2008; 26: 4124-4130 3. Mohty M .Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007 Jul;21(7):1387-94. Epub 2007 Apr 5 4. Baumann H, JudithD, Zey C et al. Antithymocyte globulin Fresenius or San gstat (Genzyme) as part of the conditioning for unrelated donor HSCT: emerging differences in posttransplant immune reconstitution. Bone Marrow Transplant, 2004; 33: S51. 5. Du K, Hu Y, Wu K, Huang H et al. 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;27(2):E91-E100. 6. Grullich G, Ziegler C, Finke J et al. Rabbit Anti T-Lymphocyte Globulin Induces Apoptosis in Peripheral Blood Mononuclear Cell Compartments and Leukemia Cells, While Hematopoietic Stem Cells Are Apoptosis Resistant. Biol Blood Marrow Transplant, 2009, 15:173-182. 7. Huixia Liu, chun wang, Youwen Qin,et al. Polyclonal Rabbit Antithymocyte Globulin induces apoptosis and has Cytotoxic Effects on human Leukemic Cells.Clinical Lymphoma, Myeloma & Leukemia 2012,12: 345-54 8. J Yang, C wang, Y Cai,et al.Anti-thymocyte globulin could improve the outcome of allogeneic hematopoietic stem cell transplantation in patients with highly aggressive T-cell tumors.Blood Cancer Journal (2015) 5, e332; doi:10.1038/bcj.2015.54 9. Jacobsen ED, Kim HT, Ho VT，et al. A large single-center experience with allogeneic stem-cell transplantation for peripheral T-cell non-Hodgkin lymphoma and advanced mycosis fungoides/Sezary syndrome. Annals of Oncology 2011( 22): 1608-1613

Rabbit Anti-human Thymoglobulin (r-ATG 2.5 mg/kg×4 days) were extra used in the treatment group. The conditioning include of Busulfex 3.2mg/kg*4d,CTX 60mg/kg *4d.

Rabbit Anti-human Thymoglobulin (r-ATG) were not used as intervention in the treatment group. The conditioning include of Busulfex 3.2mg/kg*4d,CTX 60mg/kg *4d.

PFS were defined as the time from stem-cell infusion to relapse, disease progression,or death from any cause

Leukocyte engraftment:(was defined as the first of three consecutive days of peripheral white blood count >1000/ul.

Platelet engraftment:(was defined as the first of seven consecutive days of platelet counts of >50000/ul.

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.

TRM were defined as death within 100 days of high-dose therapy not related to the disease,relapse or progression

Inclusion Criteria: According to the World Health Organization (WHO) classification, diagnosis of T cell tumor of lymphatic system sources (T lymphoblastoid cell lymphoma/leukemia) confirmed by pathological examination,morphology, cytochemistry, immunophenotyping and chromosome examination, molecular biology including complete remission, partial remission. 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. Has enrolled in anther clinical trials 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.

Rudiger T, Weisenburger DD, Anderson JR, Armitage JO, Diebold J, MacLennan KA, Nathwani BN, Ullrich F, Muller-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. doi: 10.1093/annonc/mdf033.

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.

Mohty M. Mechanisms of action of antithymocyte globulin: T-cell depletion and beyond. Leukemia. 2007 Jul;21(7):1387-94. doi: 10.1038/sj.leu.2404683. Epub 2007 Apr 5.

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.

Grullich 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.

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. Epub 2012 Jun 6.

Meijer E, Cornelissen JJ, Lowenberg 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. doi: 10.1016/s0301-472x(03)00204-2.

Yang J, Cai Y, Jiang JL, Wan LP, Yan SK, Wang C. Anti-thymocyte globulin could improve the outcome of allogeneic hematopoietic stem cell transplantation in patients with highly aggressive T-cell tumors. Blood Cancer J. 2015 Jul 31;5(7):e332. doi: 10.1038/bcj.2015.54.

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.