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Increased fecal primary bile acids in multiple myeloma with engraftment syndrome diarrhea after stem cell transplant

Bone Marrow Transplantation volume 54, pages 1898–1907 (2019)Cite this article

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Abstract

Autologous stem cell transplant (ASCT) for multiple myeloma (MM) is associated with diarrhea during the peri-transplant period. We aimed to appraise mechanisms of peri-ASCT diarrhea in a prospective, longitudinal study of patients with MM. We compared by repeated measures (RM)-ANOVA daily bowel movements (BMs) and consistency [7-point Bristol Stool Form Scale (BSFS)], fecal calprotectin (intestinal inflammation), 13C-mannitol excretion in urine 0–2 h (small intestinal permeability), fasting serum C4 (bile acid synthesis) and total and primary bile acid in stool samples during baseline, peri-transplant period (Days 5–7 after stem cell infusion), and after hematological recovery post-ASCT. The 12 (5F, 7M) patients’ median age was 61 y (IQR 54.8–63.3). All participants reported increased BMs (increase of 2 and 1 per day with and without engraftment syndrome, respectively). There were no significant increases in serum C4, total fecal bile acids, or intestinal permeability. Relative to patients without engraftment syndrome, four participants with engraftment syndrome had looser stool consistency (mean 2.6 points higher BSFS compared to without engraftment syndrome), increased primary fecal bile acids relative to baseline (>33 µmol/L vs. 6 µmol/L without engraftment syndrome), and increased fecal calprotectin compared to baseline (313 μg/mL vs. 35.6 μg/mL without engraftment syndrome; p = 0.06). Engraftment syndrome post-ASCT is associated with increased fecal primary bile acids.

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References

  1. D’Souza A, Lee S, Zhu X, Pasquini M. Current use and trends in hematopoietic cell transplantation in the United States. Biol Blood Marrow Transpl. 2017;23:1417–21.

    Article  Google Scholar 

  2. Gay F, Oliva S, Petrucci MT, Conticello C, Catalano L, Corradini P, et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16:1617–29.

    Article  CAS  Google Scholar 

  3. Attal M, Lauwers-Cances V, Hulin C, Leleu X, Caillot D, Escoffre M, et al. Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma. N Engl J Med. 2017;376:1311–20.

    Article  CAS  Google Scholar 

  4. McCarthy PL Jr., Hahn T, Hassebroek A, Bredeson C, Gajewski J, Hale G, et al. Trends in use of and survival after autologous hematopoietic cell transplantation in North America, 1995–2005: significant improvement in survival for lymphoma and myeloma during a period of increasing recipient age. Biol Blood Marrow Transpl. 2013;19:1116–23.

    Article  Google Scholar 

  5. McCarthy PL Jr, La W. Stem cell transplantation. Past, present, and future. In Buchsel PC, editor. Stem Cell Transplantation: A Clinical Textbook. 1st edn. Pittsburgh, PA, USA: Oncology Nursing Society; 2000, pp. 22–36.

  6. Tomblyn M, Gordon L, Singhal S, Tallman M, Williams S, Winter J, et al. Rarity of toxigenic Clostridium difficile infections after hematopoietic stem cell transplantation: implications for symptomatic management of diarrhea. Bone Marrow Transpl. 2002;30:517–9.

    Article  CAS  Google Scholar 

  7. Spitzer TR. Engraftment syndrome: double-edged sword of hematopoietic cell transplants. Bone Marrow Transpl. 2015;50:469–75.

    Article  CAS  Google Scholar 

  8. Jo JC, Kang BW, Jang G, Sym SJ, Lee SS, Koo JE, et al. BEAC or BEAM high-dose chemotherapy followed by autologous stem cell transplantation in non-Hodgkin’s lymphoma patients: comparative analysis of efficacy and toxicity. Ann Hematol. 2008;87:43–8.

    Article  CAS  Google Scholar 

  9. Sharma A, Kayal S, Iqbal S, Malik PS, Raina V. Comparison of BEAM vs. LEAM regimen in autologous transplant for lymphoma at AIIMS. SpringerPlus. 2013;2:489.

    Article  Google Scholar 

  10. Joshi NM, Hassan S, Jasani P, Dixon S, Cavenagh JD, Oakervee HE, et al. Bile acid malabsorption in patients with graft-versus-host disease of the gastrointestinal tract. Br J Haematol. 2012;157:403–7.

    Article  CAS  Google Scholar 

  11. Gupta A, Muls AC, Lalji A, Thomas K, Watson L, Shaw C, et al. Outcomes from treating bile acid malabsorption using a multidisciplinary approach. Support Care Cancer. 2015;23:2881–90.

    Article  Google Scholar 

  12. Hofmann AF, Small DM. Detergent properties of bile salts: correlation with physiological function. Ann Rev Med. 1967;18:333–76.

    Article  CAS  Google Scholar 

  13. Camilleri M. Physiological underpinnings of irritable bowel syndrome: neurohormonal mechanisms. J Physiol. 2014;592:2967–80.

    Article  CAS  Google Scholar 

  14. Hofmann AF. The syndrome of ileal disease and the broken enterohepatic circulation: cholerheic enteropathy. Gastroenterology. 1967;52:752–7.

    Article  CAS  Google Scholar 

  15. Wedlake L, A’Hern R, Russell D, Thomas K, Walters JR, Andreyev HJ. Systematic review: the prevalence of idiopathic bile acid malabsorption as diagnosed by SeHCAT scanning in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharm Ther. 2009;30:707–17.

    Article  CAS  Google Scholar 

  16. Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48.

    Article  Google Scholar 

  17. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol. 1997;32:920–4.

    Article  CAS  Google Scholar 

  18. Walters JR, Johnston IM, Nolan JD, Vassie C, Pruzanski ME, Shapiro DA. The response of patients with bile acid diarrhoea to the farnesoid X receptor agonist obeticholic acid. Aliment Pharm Ther. 2015;41:54–64.

    Article  CAS  Google Scholar 

  19. Grover M, Camilleri M, Hines J, Burton D, Ryks M, Wadhwa A, et al. 13C mannitol as a novel biomarker for measurement of intestinal permeability. Neurogastroenterol Motil. 2016;28:1114–9.

    Article  CAS  Google Scholar 

  20. Lostia AM, Lionetto L, Principessa L, Evangelisti M, Gamba A, Villa MP, et al. A liquid chromatography/mass spectrometry method for the evaluation of intestinal permeability. Clin Biochem. 2008;41:887–92.

    Article  CAS  Google Scholar 

  21. Rao AS, Camilleri M, Eckert DJ, Busciglio I, Burton DD, Ryks M, et al. Urine sugars for in vivo gut permeability: validation and comparisons in irritable bowel syndrome-diarrhea and controls. Am J Physiol. 2011;301:G919–28.

    CAS  Google Scholar 

  22. Metafuni E, Giammarco S, De Ritis DG, Rossi M, De Michele T, Zuppi C, et al. Fecal but not serum calprotectin is a potential marker of GVHD after stem cell transplantation. Ann Hematol. 2017;96:929–33.

    Article  CAS  Google Scholar 

  23. Hod K, Sperber AD, Ron Y, Boaz M, Dickman R, Berliner S, et al. A double-blind, placebo-controlled study to assess the effect of a probiotic mixture on symptoms and inflammatory markers in women with diarrhea-predominant IBS. Neurogastroenterol Motil. 2017;29. https://doi.org/10.1111/nmo.13037.

    Article  Google Scholar 

  24. Galman C, Arvidsson I, Angelin B, Rudling M. Monitoring hepatic cholesterol 7alpha-hydroxylase activity by assay of the stable bile acid intermediate 7alpha-hydroxy-4-cholesten-3-one in peripheral blood. J Lipid Res. 2003;44:859–66.

    Article  CAS  Google Scholar 

  25. Camilleri M, Nadeau A, Tremaine WJ, Lamsam J, Burton D, Odunsi S, et al. Measurement of serum 7alpha-hydroxy-4-cholesten-3-one (or 7alphaC4), a surrogate test for bile acid malabsorption in health, ileal disease and irritable bowel syndrome using liquid chromatography-tandem mass spectrometry. Neurogastroenterol Motil. 2009;21:734–e43.

    Article  CAS  Google Scholar 

  26. Donato LJ, Lueke A, Kenyon SM, Meeusen JW, Camilleri M. Description of analytical method and clinical utility of measuring serum 7-alpha-hydroxy-4-cholesten-3-one (7aC4) by mass spectrometry. Clin Biochem. 2018;52:106–11.

    Article  CAS  Google Scholar 

  27. Shin A, Camilleri M, Vijayvargiya P, Busciglio I, Burton D, Ryks M, et al. Bowel functions, fecal unconjugated primary and secondary bile acids, and colonic transit in patients with irritable bowel syndrome. Clin Gastroenterol Hepatol. 2013;11:1270–5. e1

    Article  CAS  Google Scholar 

  28. Camilleri M, Acosta A, Busciglio I, Boldingh A, Dyer RB, Zinsmeister AR, et al. Effect of colesevelam on fecal bile acids and bowel functions in diarrhea-predominant irritable bowel syndrome. Aliment Pharm Ther. 2015;41:438–48.

    Article  CAS  Google Scholar 

  29. Gordillo C, Parmar S, Blanco M, Delille EM, Assal A, Mapara MY, et al. Gastrointestinal toxicity of high-dose melphalan in autologous stem-cell transplantation: identification of risk factors and a benchmark for experimental therapies. Blood. 2017;130(Suppl 1):5464.

    Google Scholar 

  30. Hammami MB, Talkin R, Al-Taee AM, Schoen MW, Goyal SD, Lai JP. Autologous graft-versus-host disease of the gastrointestinal tract in patients with multiple myeloma and hematopoietic stem cell transplantation. Gastroenterol Res. 2018;11:52–57.

    Article  Google Scholar 

  31. Rapoport AP, Stadtmauer EA, Aqui N, Vogl D, Chew A, Fang HB, et al. Rapid immune recovery and GVHD-like engraftment syndrome following adoptive transfer of costimulated autologous T cells. Clin Cancer Res. 2009;15:4499–507.

    Article  CAS  Google Scholar 

  32. Shidham VB, Chang C-C, Shidham G, Ghazala F, Lindholm PF, Kampalath B, et al. Colon biopsies for evaluation of acute graft-versus-host disease (A-GVHD) in allogeneic bone marrow transplant patients. BMC Gastroenterol. 2003;3:5.

    Article  Google Scholar 

  33. Hall AG, Tilby MJ. Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies. Blood Rev. 1992;6:163–73.

    Article  CAS  Google Scholar 

  34. Weber D, Frauenschlager K, Ghimire S, Peter K, Panzer I, Hiergeist A, et al. The association between acute graft-versus-host disease and antimicrobial peptide expression in the gastrointestinal tract after allogeneic stem cell transplantation. PloS ONE. 2017;12:e0185265.

    Article  Google Scholar 

  35. Pawlyn C, Khan MS, Muls A, Sriskandarajah P, Kaiser MF, Davies FE, et al. Lenalidomide-induced diarrhea in patients with myeloma is caused by bile acid malabsorption that responds to treatment. Blood. 2014;124:2467–8.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors thank Mrs. Cindy Stanislav for excellent secretarial assistance.

Funding

This study was supported by a grant to Dr. MC from Fondation Dr. Corinne Schuler.

Author contributions

WG and MC—co-principal investigators, patient care, authorship of manuscript. PV—authorship of manuscript. DB—database management. WR, AT—study coordination, patient recruitment. AL—lab measurements of serum C4 and total and individual fecal bile acids LD—laboratory supervision, authorship of manuscript. WJH and TM—protocol development.

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Authors and Affiliations

  1. Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Mayo Clinic, Rochester, MN, USA

    Priya Vijayvargiya, Duane Burton & Michael Camilleri

  2. Division of Hematology, Mayo Clinic, Rochester, MN, USA

    Wilson Gonsalves, William J. Hogan & Teresa Miceli

  3. Division of Medicine Clinical Trials Unit, Mayo Clinic, Rochester, MN, USA

    William Rossini & Ann Taylor

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Alan Lueke & Leslie Donato

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  1. Priya Vijayvargiya
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Correspondence to Michael Camilleri.

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Vijayvargiya, P., Gonsalves, W., Burton, D. et al. Increased fecal primary bile acids in multiple myeloma with engraftment syndrome diarrhea after stem cell transplant. Bone Marrow Transplant 54, 1898–1907 (2019). https://doi.org/10.1038/s41409-019-0581-6

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