A Controlled Trial of Sheng-Yu-Tang for Post-Hematopoietic Stem Cell Transplantation Leukemia Patients: A Proposed Protocol and Insights From a Preliminary Pilot Study

Tom Fleischer, Tung-Ti Chang, Jen-Huai Chiang, Hung-Rong Yen, Tom Fleischer, Tung-Ti Chang, Jen-Huai Chiang, Hung-Rong Yen

Abstract

Hematopoietic stem cell transplantation has become a well-established treatment for hematologic disorders including acute leukemia. However, long-term survival rates following this procedure are still extremely low, due to posttransplantation relapse, infections, and graft-versus-host disease. We propose that adjunctive Chinese herbal medicine may benefit posttransplantation patients. In preparation for a randomized clinical trial, we conducted a pilot trial. Methods and Analysis: Between September 2015 and June 2017, 18 patients were consecutively enrolled at China Medical University Hospital and followed for up to 1 year. Fresh blood samples were obtained on a monthly basis, and immune reconstitution was analyzed. In addition to the standard-care treatment administered by their oncologist, a number of patients also received a Chinese herbal formula (Sheng-Yu-Tang) for up to 6 months. Results were used to improve on study protocol and estimate required sample size for a future randomized trial. Ethics and Dissemination: Study protocol was approved by the institutional review board of China Medical University Hospital (DMR-105-005), and all participants provided informed consent.

Trial registration: ClinicalTrials.gov NCT02580071.

Keywords: Chinese herbal medicine; HSCT; acute leukemia; immune reconstitution.

Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Average differences in immune reconstitution of CD4+ and CD8+ T cells. Patient sample size of current data is insufficient to draw conclusions; however, these data demonstrate the possible contribution of this type of analysis. There is, for example, a distinct difference in relative proportion of CD4+ naïve cells and CD8+ terminally differentiated cells, between the 2 groups. Missing columns represent time points at which no samples were collected from any patients. Abbreviations: TCM, traditional Chinese medicine; PT, pretransplantation; CM, central memory; EM, effector memory; TEMRA, terminally differentiated effector memory.
Figure 2.
Figure 2.
Immune reconstitution of various other cell compartments. Because there is no certain way to predict in advance which, if any, subset of cells will be affected by Sheng-Yu-Tang, it would be preferable to track the reconstitution of as many cell compartments as possible. Abbreviations: TCM, traditional Chinese medicine; PT, pretransplantation; NK, natural killer.
Figure 3.
Figure 3.
Secretion of IL-2, TNF-α, and IFN-γ by peripheral blood mononuclear cells obtained from 7 patients, following in vitro co-culture with Sheng-Yu-Tang. None of the differences between any 2 columns reached significance level; however, a possible trend may be observed in the concentration levels of TNF-α.
Figure 4.
Figure 4.
Suggested design for future controlled trial. One-hundred patients are to be randomized to control or treatment group, 3 months following transplantation. Peripheral blood samples will be obtained at months 1, 2, 3, 6, 9, and 12 (noted in figure by the blood vial). Abbreviation: SYT, Sheng-Yu-Tang herbal formula.

References

    1. Gooley TA, Chien JW, Pergam SA, et al. Reduced mortality after allogeneic hematopoietic-cell transplantation. N Engl J Med. 2010;363:2091-2101.
    1. Tanaka Y, Kurosawa S, Tajima K, et al. Analysis of non-relapse mortality and causes of death over 15 years following allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant. 2016;51:553-559.
    1. Duval M, Klein JP, He W, et al. Hematopoietic stem-cell transplantation for acute leukemia in relapse or primary induction failure. J Clin Oncol. 2010;28:3730-3738.
    1. Barrett AJ, Battiwalla M. Relapse after allogeneic stem cell transplantation. Expert Rev Hematol. 2010;3:429-441.
    1. Aversa F, Tabilio A, Velardi A, et al. 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;339:1186-1193.
    1. Aversa F, Terenzi A, Tabilio A, et al. 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;23:3447-3454.
    1. Scheper W, Grunder C, Straetemans T, Sebestyen Z, Kuball J. Hunting for clinical translation with innate-like immune cells and their receptors. Leukemia. 2014;28:1181-1190.
    1. Locatelli F, Bauquet A, Palumbo G, Moretta F, Bertaina A. Negative depletion of α/β+ T cells and of CD19+ B lymphocytes: a novel frontier to optimize the effect of innate immunity in HLA-mismatched hematopoietic stem cell transplantation. Immunol Lett. 2013;155:21-23.
    1. Schumm M, Lang P, Bethge W, et al. Depletion of T-cell receptor alpha/beta and CD19 positive cells from apheresis products with the CliniMACS device. Cytotherapy. 2013;15:1253-1258.
    1. Holderness J, Jackiw L, Kimmel E, et al. Select plant tannins induce IL-2Ralpha up-regulation and augment cell division in gammadelta T cells. J Immunol. 2007;179:6468-6478.
    1. Ismail ZM, Amin NM, Yacoub MF, Mohamed AM. Myelo-enhancement by astragalus membranaceus in male albino rats with chemotherapy myelo-suppression. Histological and immunohistochemical study. Int J Stem Cells. 2014;7:12-22.
    1. Fleischer T, Chang TT, Chiang JH, Sun MF, Yen HR. Improved survival with integration of Chinese herbal medicine therapy in patients with acute myeloid leukemia: a nationwide population-based cohort study. Integr Cancer Ther. 2017;16:156-164.
    1. Yen HR, Lai WY, Muo CH, Sun MF. Characteristics of traditional Chinese medicine use in pediatric cancer patients: a nationwide, retrospective, Taiwanese-registry, population-based study. Integr Cancer Ther. 2017;16:147-155.
    1. Kuo YT, Chang TT, Muo CH, et al. Use of complementary traditional Chinese medicines by adult cancer patients in Taiwan: a nationwide population-based study [published online June 1, 2017]. Integr Cancer Ther. doi:10.1177/1534735417716302.
    1. Fleischer T, Chang TT, Yen HR. Post-hematopoietic stem cell transplantation in patients with hematologic disorders: Chinese herbal medicine for an unmet need. J Integr Med. 2016;14:322-335.
    1. Seggewiss R, Einsele H. Immune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update. Blood. 2010;115:3861-3868.
    1. Moretta L. Dissecting CD56dim human NK cells. Blood. 2010;116:3689-3691.
    1. Palmer JM, Rajasekaran K, Thakar MS, Malarkannan S. Clinical relevance of natural killer cells following hematopoietic stem cell transplantation. J Cancer. 2013;4:25-35.
    1. Zhao X, Wang X, Chang Y, et al. Non-traditional CD4+CD25–CD69+ regulatory T cells is correlated to leukemia relapse after allogeneic hematopoietic stem cell transplantation. Blood. 2013;122:3259.
    1. Edinger M, Hoffmann P, Ermann J, et al. CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med. 2003;9:1144-1150.
    1. Di Ianni M, Falzetti F, Carotti A, et al. Tregs prevent GVHD and promote immune reconstitution in HLA-haploidentical transplantation. Blood. 2011;117:3921-3928.
    1. Perko R, Kang G, Sunkara A, Leung W, Thomas PG, Dallas MH. Gamma delta T cell reconstitution is associated with fewer infections and improved event-free survival after hematopoietic stem cell transplantation for pediatric leukemia. Biol Blood Marrow Transplant. 2015;21:130-136.
    1. Godder KT, Henslee-Downey PJ, Mehta J, et al. Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation. Bone Marrow Transplant. 2007;39:751-757.
    1. Abdel-Azim H, Elshoury A, Mahadeo KM, Parkman R, Kapoor N. Humoral immune reconstitution kinetics after allogeneic hematopoietic stem cell transplantation in children: a maturation block of IgM memory B cells may lead to impaired antibody immune reconstitution. Biol Blood Marrow Transplant. 2017;23:1437-1446.
    1. Avanzini MA, Locatelli F, Dos Santos C, et al. B lymphocyte reconstitution after hematopoietic stem cell transplantation: functional immaturity and slow recovery of memory CD27+ B cells. Exp Hematol. 2005;33:480-486.
    1. Ogonek J, Juric MK, Ghimire S, et al. Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol. 2016;7:507.
    1. Reddy V, Iturraspe JA, Tzolas AC, Meier-Kriesche HU, Schold J, Wingard JR. Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. Blood. 2004;103:4330-4335.
    1. Leon AC, Davis LL, Kraemer HC. The role and interpretation of pilot studies in clinical research. J Psychiatr Res. 2011;45:626-629.
    1. Henden AS, Hill GR. Cytokines in graft-versus-host disease. J Immunol. 2015;194:4604-4612.
    1. Cooke KR, Hill GR, Crawford JM, et al. Tumor necrosis factor-alpha production to lipopolysaccharide stimulation by donor cells predicts the severity of experimental acute graft-versus-host disease. J Clin Invest. 1998;102:1882-1891.
    1. Piguet PF, Grau GE, Allet B, Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med. 1987;166:1280-1289.
    1. Atkins MB, Lotze MT, Dutcher JP, et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. J Clin Oncol. 1999;17:2105-2116.
    1. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N Engl J Med. 2011;365:2055-2066.
    1. Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med. 2011;365:2067-2077.
    1. Fuchs EJ. Related haploidentical donors are a better choice than matched unrelated donors: point. Blood Adv. 2017;1:397-400.
    1. Alho AC, Kim HT, Chammas MJ, et al. Unbalanced recovery of regulatory and effector T cells after allogeneic stem cell transplantation contributes to chronic GVHD. Blood. 2016;127:646-657.
    1. Burns DM, Tierney R, Shannon-Lowe C, et al. Memory B-cell reconstitution following allogeneic hematopoietic stem cell transplantation is an EBV-associated transformation event. Blood. 2015;126:2665-2675.
    1. Abboud I, Peraldi MN, Hingorani S. Chronic kidney diseases in long-term survivors after allogeneic hematopoietic stem cell transplantation: monitoring and management guidelines. Semin Hematol. 2012;49:73-82.
    1. Ellis MJ, Parikh CR, Inrig JK, Kanbay M, Patel UD. Chronic kidney disease after hematopoietic cell transplantation: a systematic review. Am J Transplant. 2008;8:2378-2390.
    1. Lee BC, Choi JB, Cho HJ, Kim YS. Rehmannia glutinosa ameliorates the progressive renal failure induced by 5/6 nephrectomy. J Ethnopharmacol. 2009;122:131-135.
    1. Li X, Wang H. Chinese herbal medicine in the treatment of chronic kidney disease. Adv Chronic Kidney Dis. 2005;12:276-281.
    1. Parimon T, Au DH, Martin PJ, Chien JW. A risk score for mortality after allogeneic hematopoietic cell transplantation. Ann Intern Med. 2006;144:407-414.
    1. Sorror ML, Maris MB, Storb R, et al. Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912-2919.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다