Top

Published in:

Open Access 01-02-2015 | Original Article

Maitake mushroom extract in myelodysplastic syndromes (MDS): a phase II study

Authors: Kathleen M. Wesa, Susanna Cunningham-Rundles, Virginia M. Klimek, Emily Vertosick, Marci I. Coleton, K. Simon Yeung, Hong Lin, Stephen Nimer, Barrie R. Cassileth

Published in: Cancer Immunology, Immunotherapy | Issue 2/2015

Abstract

Background

Myelodysplastic syndromes (MDS) are characterized by ineffective erythropoiesis with dysplastic bone marrow leading to peripheral cytopenia, risk of infection, and progression to acute myelogenous leukemia. Maitake mushroom beta-glucan, a dietary supplement, stimulates hematopoietic progenitor cell differentiation, granulocyte colony-stimulating factor production, and recovery of peripheral blood leukocytes after bone marrow injury. This phase II trial examined the effects of Maitake on innate immune function in MDS.

Methods

Myelodysplastic syndromes patients with International Prognostic Scoring System Low- and Intermediate-1-risk disease received oral Maitake extract at 3 mg/kg twice daily for 12 weeks. Primary endpoints included neutrophil count and function tested as endogenous or stimulated neutrophil production of reactive oxygen species (ROS) by flow cytometry compared with age-matched healthy controls (HC). ROS activators were Escherichia coli, phorbol ester, and the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (fMLP). Complete blood counts, chemistry panels, iron studies, and monocyte function were evaluated.

Results

Of 21 patients enrolled, 18 completed the study and were evaluable. Maitake increased endogenous (basal) neutrophil (p = 0.005) and monocyte function (p = 0.021). Pre-treatment monocyte response to E. coli was reduced in MDS patients compared with HC (p = 0.002) and increased (p = 0.0004) after treatment. fMLP-stimulated ROS production response also increased (p = 0.03). Asymptomatic eosinophilia occurred in 4 patients (p = 0.014). Other changes in albumin, hemoglobin, and total protein were not clinically relevant.

Conclusions

Maitake was well tolerated. Enhanced in vitro neutrophil and monocyte function following treatment demonstrate that Maitake has beneficial immunomodulatory potential in MDS. Further study is warranted.

Toma A, Fenaux P, Dreyfus F, Cordonnier C (2012) Infections in myelodysplastic syndromes. Haematologica 97:1459–1470. doi:10.3324/haematol.2012.063420 PubMedCentralPubMedCrossRef

Dayyani F, Conley AP, Strom SS et al (2010) Cause of death in patients with lower-risk myelodysplastic syndrome. Cancer 116:2174–2179. doi:10.1002/cncr.24984 PubMedCentralPubMed

Cunningham I, MacCallum SJ, Nicholls MD, Byth K, Hewson JW, Arnold B, Motum PI, Mulligan SP, Crane GG (1995) The myelodysplastic syndromes: an analysis of prognostic factors in 226 cases from a single institution. Br J Haematol 90:602–606PubMedCrossRef

Kako S, Nakasone H, Endo H et al (2012) Clinical course of patients with aplastic anemia or myelodysplastic syndrome associated with persistent neutropenia. Hematol Oncol 30:82–88. doi:10.1002/hon.1001 PubMedCrossRef

Boogaerts MA, Nelissen V, Roelant C, Goossens W (1983) Blood neutrophil function in primary myelodysplastic syndromes. Br J Haematol 55:217–227PubMedCrossRef

Ricevuti G, Mazzone A, Pasotti D, Fossati G, Mazzucchelli I, Notario A (1993) The role of integrins in granulocyte dysfunction in myelodysplastic syndrome. Leuk Res 17:609–619PubMedCrossRef

Fianchi L, Leone G, Posteraro B, Sanguinetti M, Guidi F, Valentini CG, Voso MT, Pagano L (2012) Impaired bactericidal and fungicidal activities of neutrophils in patients with myelodysplastic syndrome. Leuk Res 36:331–333. doi:10.1016/j.leukres.2011.11.012 PubMedCrossRef

Fuhler GM, Knol GJ, Drayer AL, Vellenga E (2005) Impaired interleukin-8- and GROalpha-induced phosphorylation of extracellular signal-regulated kinase result in decreased migration of neutrophils from patients with myelodysplasia. J Leukoc Biol 77:257–266. doi:10.1189/jlb.0504306 PubMedCrossRef

Fuhler GM, Drayer AL, Olthof SG, Schuringa JJ, Coffer PJ, Vellenga E (2008) Reduced activation of protein kinase B, Rac, and F-actin polymerization contributes to an impairment of stromal cell derived factor-1 induced migration of CD34+ cells from patients with myelodysplasia. Blood 111:359–368. doi:10.1182/blood-2006-11-060632 PubMedCrossRef

10.

Ohsaka A, Kitagawa S, Yuo A, Motoyoshi K, Furusawa S, Miura Y, Takaku F, Saito M (1993) Effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor on respiratory burst activity of neutrophils in patients with myelodysplastic syndromes. Clin Exp Immunol 91:308–313PubMedCentralPubMedCrossRef

11.

Nakaseko C, Asai T, Wakita H, Oh H, Saito Y (1996) Signalling defect in FMLP-induced neutrophil respiratory burst in myelodysplastic syndromes. Br J Haematol 95:482–488PubMedCrossRef

12.

Prodan M, Tulissi P, Perticarari S, Presani G, Franzin F, Pussini E, Pozzato G (1995) Flow cytometric assay for the evaluation of phagocytosis and oxidative burst of polymorphonuclear leukocytes and monocytes in myelodysplastic disorders. Haematologica 80:212–218PubMed

13.

Zabernigg A, Hilbe W, Eisterer W, Greil R, Ludescher C, Thaler J (1997) Cytokine priming of the granulocyte respiratory burst in myelodysplastic syndromes. Leuk Lymphoma 27:137–143. doi:10.3109/10428199709068280 PubMed

14.

Verhoef G, Boogaerts M (1991) In vivo administration of granulocyte-macrophage colony stimulating factor enhances neutrophil function in patients with myelodysplastic syndromes. Br J Haematol 79:177–184PubMedCrossRef

15.

van de Peppel RJ, Dekkers OM, von dem Borne PA, de Boer MG (2014) Relapsed and secondary disease drive the risk profile for invasive aspergillosis prior to stem cell transplantation in patients with acute myeloid leukemia or myelodysplastic syndrome. Med Mycol 52:699–705. doi:10.1093/mmy/myu036 PubMedCrossRef

16.

Steensma DP (2011) Hematopoietic growth factors in myelodysplastic syndromes. Semin Oncol 38:635–647. doi:10.1053/j.seminoncol.2011.04.014 PubMedCrossRef

17.

Lin H, de Stanchina E, Zhou XK et al (2010) Maitake beta-glucan promotes recovery of leukocytes and myeloid cell function in peripheral blood from paclitaxel hematotoxicity. Cancer Immunol Immunother 59:885–897. doi:10.1007/s00262-009-0815-3 PubMedCentralPubMedCrossRef

18.

Lin H, Cheung SW, Nesin M, Cassileth BR, Cunningham-Rundles S (2007) Enhancement of umbilical cord blood cell hematopoiesis by Maitake beta-glucan is mediated by granulocyte colony-stimulating factor production. Clin Vaccine Immunol 14:21–27PubMedCentralPubMedCrossRef

19.

Nanba H, Hamaguchi A, Kuroda H (1987) The chemical structure of an antitumor polysaccharide in fruit bodies of Grifola frondosa (Maitake). Chem Pharm Bull (Tokyo) 35:1162–1168CrossRef

20.

Masuda Y, Murata Y, Hayashi M, Nanba H (2008) Inhibitory effect of MD-Fraction on tumor metastasis: involvement of NK cell activation and suppression of intercellular adhesion molecule (ICAM)-1 expression in lung vascular endothelial cells. Biol Pharm Bull 31:1104–1108PubMedCrossRef

21.

Masuda Y, Inoue M, Miyata A, Mizuno S, Nanba H (2009) Maitake beta-glucan enhances therapeutic effect and reduces myelosupression and nephrotoxicity of cisplatin in mice. Int Immunopharmacol 9:620–626PubMedCrossRef

22.

Lin H, She YH, Cassileth BR, Sirotnak F, Cunningham Rundles S (2004) Maitake beta-glucan MD-fraction enhances bone marrow colony formation and reduces doxorubicin toxicity in vitro. Int Immunopharmacol 4:91–99PubMedCrossRef

23.

Ito K, Masuda Y, Yamasaki Y, Yokota Y, Nanba H (2009) Maitake beta-glucan enhances granulopoiesis and mobilization of granulocytes by increasing G-CSF production and modulating CXCR4/SDF-1 expression. Int Immunopharmacol 9:1189–1196. doi:10.1016/j.intimp.2009.06.007 PubMedCrossRef

24.

Lin H, De Stanchina E, Zhou XK, She Y, Hoang D, Cheung SW, Cassileth B, Cunningham-Rundles S (2009) Maitake beta-glucan enhances umbilical cord blood stem cell transplantation in the NOD/SCID mouse. Exp Biol Med (Maywood) 234:342–353CrossRef

25.

Deng G, Lin H, Seidman A et al (2009) A phase I/II trial of a polysaccharide extract from Grifola frondosa (Maitake mushroom) in breast cancer patients: immunological effects. J Cancer Res Clin Oncol 135:1215–1221. doi:10.1007/s00432-009-0562-z PubMedCentralPubMedCrossRef

26.

Swerdlow SH, International Agency for Research on Cancer, World Health Organization (2008) WHO classification of tumours of haematopoietic and lymphoid tissues. International Agency for Research on Cancer and World Health Organization, Lyon, France

27.

Vardiman JW, Thiele J, Arber DA et al (2009) The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114:937–951. doi:10.1182/blood-2009-03-209262 PubMedCrossRef

28.

Cheson BD, Greenberg PL, Bennett JM et al (2006) Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 108:419–425. doi:10.1182/blood-2005-10-4149 PubMedCrossRef

29.

Machova E, Bystricky S (2013) Antioxidant capacities of mannans and glucans are related to their susceptibility of free radical degradation. Int J Biol Macromol 61:308–311. doi:10.1016/j.ijbiomac.2013.07.016 PubMedCrossRef

30.

National Cancer Institute (2009) Common terminology criteria for adverse events (CTCAE) Version 4.0. http://evs.nci.nih.gov/ftp1/CTCAE/About.html. Accessed February 14, 2014

31.

Ballabh P, Simm M, Kumari J, Califano C, Aghai Z, Laborada G, Sison C, Cunningham-Rundles S (2003) Respiratory burst activity in bronchopulmonary dysplasia and changes with dexamethasone. Pediatr Pulmonol 35:392–399PubMedCrossRef

32.

Merkle RK, Poppe I (1994) Carbohydrate composition analysis of glycoconjugates by gas-liquid chromatography/mass spectrometry. Methods Enzymol 230:1–15PubMedCrossRef

33.

Negrin RS, Haeuber DH, Nagler A, Kobayashi Y, Sklar J, Donlon T, Vincent M, Greenberg PL (1990) Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony-stimulating factor. Blood 76:36–43PubMed

34.

Sanz GF, Sanz MA, Vallespi T, Canizo MC, Torrabadella M, Garcia S, Irriguible D, San Miguel JF (1989) Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 74:395–408PubMed

35.

Thompson JA, Gilliland DG, Prchal JT, Bennett JM, Larholt K, Nelson RA, Rose EH, Dugan MH (2000) Effect of recombinant human erythropoietin combined with granulocyte/macrophage colony-stimulating factor in the treatment of patients with myelodysplastic syndrome. GM/EPO MDS study group. Blood 95:1175–1179PubMed

36.

Sekeres MA, Schoonen WM, Kantarjian H, List A, Fryzek J, Paquette R, Maciejewski JP (2008) Characteristics of US patients with myelodysplastic syndromes: results of six cross-sectional physician surveys. J Natl Cancer Inst 100:1542–1551. doi:10.1093/jnci/djn349 PubMedCentralPubMedCrossRef

37.

Soehnlein O, Kenne E, Rotzius P, Eriksson EE, Lindbom L (2008) Neutrophil secretion products regulate anti-bacterial activity in monocytes and macrophages. Clin Exp Immunol 151:139–145. doi:10.1111/j.1365-2249.2007.03532.x PubMedCentralPubMedCrossRef

38.

van Leeuwen HJ, Van Der Tol M, Van Strijp JA, Verhoef J, van Kessel KP (2005) The role of tumour necrosis factor in the kinetics of lipopolysaccharide-mediated neutrophil priming in whole blood. Clin Exp Immunol 140:65–72. doi:10.1111/j.1365-2249.2005.02748.x PubMedCentralPubMedCrossRef

39.

Wu MJ, Cheng TL, Cheng SY, Lian TW, Wang L, Chiou SY (2006) Immunomodulatory properties of Grifola frondosa in submerged culture. J Agric Food Chem 54:2906–2914. doi:10.1021/jf052893q PubMedCrossRef

40.

Ghoti H, Amer J, Winder A, Rachmilewitz E, Fibach E (2007) Oxidative stress in red blood cells, platelets and polymorphonuclear leukocytes from patients with myelodysplastic syndrome. Eur J Haematol 79:463–467. doi:10.1111/j.1600-0609.2007.00972.x PubMedCrossRef

41.

Levy AM, Kita H, Phillips SF, Schkade PA, Dyer PD, Gleich GJ, Dubravec VA (1998) Eosinophilia and gastrointestinal symptoms after ingestion of shiitake mushrooms. J Allergy Clin Immunol 101:613–620. doi:10.1016/S0091-6749(98)70168-X PubMedCrossRef

42.

Wimazal F, Germing U, Kundi M et al (2010) Evaluation of the prognostic significance of eosinophilia and basophilia in a larger cohort of patients with myelodysplastic syndromes. Cancer 116:2372–2381. doi:10.1002/cncr.25036 PubMed

Title: Maitake mushroom extract in myelodysplastic syndromes (MDS): a phase II study
Authors: Kathleen M. Wesa
Susanna Cunningham-Rundles
Virginia M. Klimek
Emily Vertosick
Marci I. Coleton
K. Simon Yeung
Hong Lin
Stephen Nimer
Barrie R. Cassileth
Publication date: 01-02-2015
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 2/2015
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-014-1628-6

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 2/2015

The importance of comparative oncology in translational medicine

Generation of cytotoxic T lymphocytes specific for native or modified peptides derived from the epidermal growth factor receptor pathway substrate 8 antigen

Immune impairments in multiple myeloma bone marrow mesenchymal stromal cells

Benefit of adjuvant interferon alfa-2b (IFN-α) therapy in melanoma patients with high serum MMP-8 levels

CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo

Monocyte-derived dendritic cells reflect the immune functional status of a chromophobe renal cell carcinoma patient: Could it be a general phenomenon?

Keynote webinar | Spotlight on antibody–drug conjugates in cancer