Abstract
Gastrointestinal side effects are the dose-limiting toxicity of high-dose melphalan (HDM) in autologous hematopoietic stem-cell transplantation, but there are limited contemporary data on the incidence and severity of gastrointestinal toxicity associated with this regimen. We retrospectively studied 100 consecutive patients who received HDM alone or in combination with other conditioning agents. Patients had a median age of 56 (range 20–73); underlying diseases were myeloma (42%), lymphoma (42%), or amyloidosis (16%) and melphalan dosages were 200 (40%), 140 (59%), or 100 mg/m2 (1%). Ninety-seven percent of patients experienced diarrhea with a range of 1–18 bowel movements per day, 88% developed nausea, and 60% experienced vomiting. Abdominal CT scans rarely altered patient management, but stool studies were useful in identifying a treatable infectious source. Grade ≥ 2 diarrhea was associated with longer duration of diarrhea, longer length of stay, worse hypoalbuminemia, higher use of antibiotics, abdominal imaging, electrolyte repletions, and anti-diarrheal agents. Risk factors for severe diarrhea were female sex, melphalan dose, age > 50, creatinine clearance < 60 ml/min, and having a plasma cell neoplasm as opposed to lymphoma. Female sex was also associated with more severe nausea and vomiting. In summary, diarrhea remains an important toxicity of HDM and novel therapies for chemotherapy-induced diarrhea for patients undergoing stem-cell transplantation are needed. Grade 2 or higher diarrhea is associated with significant clinical consequences and should be used as the primary endpoint in prospective clinical trials.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data are available upon request from the corresponding author.
References
Lazarus HM, Herzig RH, Graham-Pole J, Wolff SN, Phillips GL, Strandjord S, Hurd D, Forman W, Gordon EM, Coccia P (1983) Intensive melphalan chemotherapy and cryopreserved autologous bone marrow transplantation for the treatment of refractory cancer. J Clin Oncol 1:359–367
Cibeira MT, Sanchorawala V, Seldin DC, Quillen K, Berk JL, Dember LM, Segal A, Ruberg F, Meier-Ewert H, Andrea NT, Sloan JM, Finn KT, Doros G, Blade J, Skinner M (2011) Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients. Blood 118:4346–4352
Philip T, Guglielmi C, Hagenbeek A et al (1995) Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non Hodgkin’s lymphoma. N Engl J Med 333:1995–1545
Linch DC, Winfield D, Goldstone AH et al (1993) Dose intensification with autologous bone-marrow transplantation in relapsed and resistant Hodgkin’s disease: results of a BNLI randomised trial. Lancet 341:1051–1054
Lazarus HM, Phillips GL, Herzig RH, Hurd DD, Wolff SN, Herzig GP (2008) High-dose melphalan and the development of hematopoietic stem-cell transplantation: 25 years later. J Clin Oncol 26:2240–2243
Lilleby K, Garcia P, Gooley T, McDonnnell P, Taber R, Holmberg L, Maloney DG, Press OW, Bensinger W (2006) A prospective, randomized study of cryotherapy during administration of high-dose melphalan to decrease the severity and duration of oral mucositis in patients with multiple myeloma undergoing autologous peripheral blood stem cell transplant. Bone Marrow Transplant 37:1031–1035
Blijlevens N, Schwenkglenks M, Bacon P, D'Addio A, Einsele H, Maertens J, Niederwieser D, Rabitsch W, Roosaar A, Ruutu T, Schouten H, Stone R, Vokurka S, Quinn B, McCann S, European Blood and Marrow Transplantation Mucositis Advisory Group (2008) Prospective oral mucositis audit: oral mucositis in patients receiving high-dose melphalan or BEAM conditioning chemotherapy–European Blood and Marrow Transplantation Mucositis Advisory Group. J Clin Oncol 26:1519–1525
Grazziutti M, Dong L, Miceli M et al (2006) Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, risk factors and a severity predictive model. Bone Marrow Transplant 38:501–506
Sweiss K, Patel S, Culos K, Oh A, Rondelli D, Patel P (2016) Melphalan 200 mg/m2 in patients with renal impairment is associated with increased short-term toxicity but improved response and longer treatment-free survival. Bone Marrow Transplant 51:1337–1341
Sirohi B, Powles R, Kulkarni S, Rudin C, Saso R, Rigg A, Horton C, Singhal S, Mehta J, Treleaven J (2001) Glomerular filtration rate prior to high-dose melphalan 200 mg/m2 as a surrogate marker of outcome in patients with myeloma. Br J Cancer 85:325–332
Bashir Q, Shah N, Parmar S, Wei W, Rondon G, Weber DM, Wang M, Orlowski RZ, Thomas SK, Shah J, Qureshi SR, Dinh YT, Popat U, Anderlini P, Hosing C, Giralt S, Champlin RE, Qazilbash MH (2012) Feasibility of autologous hematopoietic stem cell transplant in patients aged ≥70 years with multiple myeloma. Leuk Lymphoma 53:118–122
Jantunen E, Kuittinen T, Penttilä K, Lehtonen P, Mahlamäki E, Nousiainen T (2006) High-dose melphalan (200 mg/m2) supported by autologous stem cell transplantation is safe and effective in elderly (≥65 years) myeloma patients: comparison with younger patients treated on the same protocol. Bone Marrow Transplant 37:917–922
Mougenot P, Pinguet F, Fabbro M et al (2004) Population pharmokinetics of melphalan, infused over a 24-hour period, in patients with advanced malignancies. Cancer Chemother Pharmacol 53:503–512
Selby PJ, McElwain TJ, Nandi AC et al (1987) Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol 66:55–62
Nath CE, Shaw PJ, Trotman J, Zeng L, Duffull SB, Hegarty G, McLachlan AJ, Gurney H, Kerridge I, Kwan YL, Presgrave P, Tiley C, Joshua D, Earl J (2010) Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy. Br J Clin Pharmacol 69:484–497
Palumbo A, Bringhen S, Bruno B, Falcone AP, Liberati AM, Grasso M, Ria R, Pisani F, Cangialosi C, Caravita T, Levi A, Meloni G, Nozza A, Pregno P, Gabbas A, Callea V, Rizzo M, Annino L, de Stefano V, Musto P, Baldi I, Cavallo F, Petrucci MT, Massaia M, Boccadoro M (2010) Melphalan 200 mg/m2 versus melphalan 100 mg/m2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study. Blood 115:1873–1879
McElwain TJ, Powles RL (1983) High-dose intravenous melphalan for plasma-cell leukemia and myeloma. Lancet 322:822–824
Bensinger WI, Becker PS, Gooley TA, Chauncey TR, Maloney DG, Gopal AK, Green DJ, Press OW, Lill M, Ifthikharuddin JJ, Vescio R, Holmberg LA, Phillips GL (2016) A randomized study of melphalan 200 mg/m2 vs. 280 mg/m2 as a preparative regimen for patients with multiple myeloma undergoing auto-SCT. Bone Marrow Transplant 51:67–71
Malek E, Gupta V, Creger R et al (2018) Amifostine reduces gastro-intestinal toxicity after autologous transplantation for multiple myeloma. Leuk Lymphoma 59:1–8
Funding
R.R is supported by grant R01HL14342 from the National Institues of Health and grant CA180898 from the U.S. Department of Defense.
Author information
Authors and Affiliations
Contributions
All authors contributed to data analysis and review of the manuscript.
Corresponding author
Ethics declarations
Ethics approval
The retrospective study was approved with waiver of informed consent by the Institutional Review Board at Columbia University Irving Medical Center.
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gordillo, C.A., Parmar, S., Blanco, M. et al. Gastrointestinal toxicity of high-dose melphalan in autologous hematopoietic stem cell transplantation: identification of risk factors and a benchmark for experimental therapies. Ann Hematol 100, 1863–1870 (2021). https://doi.org/10.1007/s00277-020-04378-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00277-020-04378-8