Bone Marrow Transplantation (2006) 38, 501–506 & 2006 Nature Publishing Group All rights reserved 0268-3369/06 $30.00 www.nature.com/bmt
ORIGINAL ARTICLE Oral mucositis in myeloma patients undergoing melphalan-based autologous stem cell transplantation: incidence, riskfactors and a severity predictive model
ML Grazziutti, L Dong, MH Miceli, SG Krishna, E Kiwan, N Syed, A Fassas, F van Rhee, H Klaus, BBarlogieand EJ Anaissie
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, USA
Melphalan-based autologous stem cell transplant (Mel- remission rates, event-free and overall survival with ASCT) is a standard therapy for multiple myeloma, but is high-dose melphalan and autologous stem cell transplant associated with severe oral mucositis (OM). To identify (Mel-ASCT) compared to low-dose melphalan and predictors for severe OM, we studied 381 consecutive prednisone.1,2 This improved response is further enhanced newly diagnosed myeloma patients who received Mel- when tandem Mel-ASCT is applied, suggesting that higher ASCT. Melphalan was given at 200 mg/m2 body surface melphalan doses would be desirable if well tolerated. The area (BSA), reduced to 140 mg/m2 for serum creatinine dose-limiting toxicity of melphalan is oral mucositis (OM), 43 mg/dl. Potential covariates included demographics, which can be severe,3 especially in patients with renal pre-transplant serum albumin and renal and liver function failure (melphalan is excreted by the kidneys). High-dose tests, and mg/kg melphalan dose received. The BSA melphalan as a single agent is considered as one of the most dosing resulted in a wide range of melphalan doses given mucotoxic conditioning regimens.4 The pain of OM is the (2.4–6.2 mg/kg). OM developed in 75% of patients and single most bothersome symptom after ASCT,5 and OM is was severe in 21%. Predictors of severe OM in multiple associated with prolonged hospitalization and increased logistic regression analyses were high serum creatinine cost of care,6–10 often resulting in dose reduction or (odds ratio (OR) ¼ 1.581; 95% confidence interval (CI): interruption of therapy with a negative impact on cancer 1.080–2.313; P ¼ 0.018) and high mg/kg melphalan outcome.11 OM also acts as an entry portal for serious (OR ¼ 1.595; 95% CI: 1.065–2.389; P ¼ 0.023). An OM infections.6,12 Other negative consequences of OM include prediction model was developed based on these variables. dysgeusia, difficulty speaking and receiving nutrition, We concluded that BSA dosing of melphalan results in hydration and oral medications.9 Opiates, the agents of wide variations in the mg/kg dose, and that patients with choice for controlling OM pain, may result in various renal dysfunction who are scheduled to receive a high mg/ adverse events.13 kg melphalan dose have the greatest risk for severe OM Despite the critical role of Mel-ASCT in the therapy of following Mel-ASCT. Pharmacogenomic and pharmaco- myeloma, the risk factors for OM, the dose-limiting toxicity kinetic studies are needed to better understand inter- of Mel-ASCT, have not been identified. We sought to patient variability of melphalan exposure and toxicity. identify the risk factors for melphalan-induced OM among Bone Marrow Transplantation (2006) 38, 501–506. 381 consecutive myeloma patients undergoing Mel-ASCT. doi:10.1038/sj.bmt.1705471 Keywords: mucositis; melphalan; autologous stem cell transplantation; myeloma Patients and methods
Study design The study population consisted of adult patients with newly Introduction diagnosed multiple myeloma cared for at the Myeloma Institute for Research and Treatment (MIRT) between The importance of melphalan dose intensity for patients October 1998 and December 2002. All patients were with multiple myeloma is supported by the increase in enrolled in our study UARK 98-026 (Total Therapy II) protocol.14 Medical records of the first 381 consecutive patients undergoing their first Mel-ASCT were reviewed with approval from the Institutional Review Board. One Correspondence: Dr EJ Anaissie, Myeloma Institute for Research and patient who received 100 mg/m2 of melphalan was excluded Therapy, University of Arkansas for Medical Sciences, 4301 West Markham, Slot 816, Little Rock, AR 72205, USA. from this analysis. The Total Therapy II protocol consists E-mail: [email protected] of four phases. Induction with four cycles of chemotherapy: Received 7 March 2006; revised 23 June 2006; accepted 4 July 2006 (1) VAD (days 1–4): vincristine 0.5 mg/day, doxorubicin Mucositis risk factors after melphalan transplant ML Grazziutti et al 502 10 mg/m2/day and dexamethasone 40 mg/day (days 1–4, CTCv20_4-30-992.pdf) in which Grade 0 ¼ no mucositis; 9–12 and 17–20); (2) DCEP (days 1–4): dexamethasone Grade 1 ¼ painless ulcers, erythema or mild soreness in the 40 mg/day, cyclophosphamide 400 mg/m2/day, etoposide absence of lesions; Grade 2 ¼ painful erythema, edema 40 mg/m2/day and cisplatin 15 mg/m2/day; (3) CAD (days or ulcers but can eat and swallow; Grade 3 ¼ painful 1–4): cyclophosphamide 750 mg/m2/day, doxorubicin erythema, edema or ulcers requiring intravenous hydration 15 mg/m2/day and dexamethasone 40 mg/day, followed by and Grade 4 ¼ severe ulceration or requires parenteral or collection of peripheral stem cell and (4) a second cycle of enteral nutritional support or prophylactic endotracheal DCEP. Following induction, patients received tandem intubation. Grade 3 and 4 are considered severe mucositis. ASCT with melphalan 200 mg/m2 of body surface area (BSA) for patients with serum creatinine o3 mg/dl and reduced to 140 mg/m2 for patients with serum creatinine Risk factors 43 mg/dl. Melphalan was administered in one dose on Pre-ASCT variables including age, gender, race, weight, day À1 of ASCT. The consolidation phase was given for BSA, BMI, renal and liver function tests, serum albumin a year and was followed by maintenance therapy with and melphalan dose received (in mg/kg) response to dexamethasone and alpha interferon. induction chemotherapy and thalidomide allocation at At study enrollment, patients were randomized to receive enrollment. thalidomide or no thalidomide 400 mg/day through the Pre-ASCT data refer to those obtained immediately induction phase. Thalidomide was withheld 1 week before before the infusion of melphalan. Mel-ASCT and resumed during the post transplant consolidation and maintenance phases. All patients received antimicrobial prophylaxis consist- Statistical analysis ing of acyclovir, fluconazole and a fluoroquinolone Analysis of the risk factors for severe OM was performed (levofloxacin or gatifloxacin) throughout the period of with SAS 9.1 (SAS Institute Inc., Cary, NC, USA). Binary neutropenia. During the ASCT period, patients used logistic regression analysis was used to assess the relation prophylactic Biotene mouthwash (lysozyme, lactoferrin, between pre-determined variables and risk for severe glucose oxidase and lactoperoxidase) up to five times a day mucositis. Gender and race were analyzed as categorical and the Magic Mouthwash Solution (lidocaine solution, variables. All other variables were analyzed as continuous diphenhydramine hydrochloride and aluminum hydroxide variables. Risk factors for severe OM were evaluated by suspension) up to five times a day if signs or symptoms of univariate logistic regression analysis and variables with OM were present. Patients were evaluated every other day P-value p0.25 were entered into multiple logistic regres- or more often if clinically indicated by the ASCT team, sion analysis by stepwise selection to identify independent until engraftment, and longer if clinically indicated. risk factors. The identification of independent risk factors allowed the development of the best-fitted predictive model for severe mucositis. Significance level was chosen as Melphalan dosing Pp0.05. The melphalan dose given was calculated according to the Mosteller’s formula of BSA15 as follows: rffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi Results heightðcmÞÂweightðkgÞ BSAðm2Þ¼ 3600 Patient characteristics Three hundred and eighty-one consecutive newly diagnosed The actual body weight (ABW) was used for patients adult myeloma patients were evaluated. The M component whose weight was 60 kg, whereas calculated body weight p of 56% of the patients was IgG, followed by IgA (24%), (CBW) was utilized for patients weighing 460 kg. CBW free light chains only (16%), non-secretory (3%) and IgD was derived from ideal body weight (IBW) according to the (1%). Pre-transplant characteristics analyzed as potential formula: CBW (ABW IBW) 0.4 IBW. The following ¼ À Â þ risk factors are shown in Tables 1 and 2. All patients formula for calculating IBW was used: IBW 50 kg ¼ þ engrafted after Mel-ASCT. Forty-six patients (12%) 2.3 (inches 60) for men and IBW 45.5 kg 2.3 Â À ¼ þ Â received prophylactic colony-stimulating factors (granulo- (inches 60) for women. The body mass index (BMI) was À cyte or granulocyte-macrophage) that did not affect calculated as ABW (in kg) divided by height squared mucositis severity (data not shown). (in meters).16
Mucositis assessment Melphalan dose OM that developed after the first Mel-ASCT was evaluated Melphalan (200 mg/m2) was given to 350 patients whereas for this study. The follow-up period included days 0–60 31 patients received a dose of 140 mg/m2. When calculated (day 0: day of infusion of stem cells). according to the patient’s ABW, the mean7s.d. mg/kg Medical records were reviewed by two research nurses melphalan dose received was 4.670.67. Melphalan doses in with extensive training and experience in the evaluation of mg/kg were inversely proportional to patients’ weight and mucositis. Peak OM was graded according to the Common BMI (Figure 1). The mean and range melphalan mg/kg Toxicity Criteria from the National Cancer Institute CTC dose was 3.4 (range 2.4–4.3) and 4.8 (range 2.9–6.2) for Version 2.0, 30 April 1999 (http://ctep.cancer.gov/forms/ patients receiving 140 and 200 mg/m2, respectively.
Bone Marrow Transplantation Mucositis risk factors after melphalan transplant ML Grazziutti et al 503 Incidence and risk factors for OM serum creatinine and alkaline phosphatase (Table 2). The OM was present in 75% of the patients and was severe in predictive variables for severe OM in the multiple logistic 21%. Of interest, 25% of the patients remained mucositis- regression analyses were higher serum creatinine (odds free regardless of the melphalan mg/kg dose (Figure 2) and ratio (OR) ¼ 1.581; 95% confidence interval (CI): 1.080– of the serum creatinine level (data not shown). 2.313; P ¼ 0.018) and higher mg/kg melphalan dose Univariate analysis identified three potential risk factors for severe OM: higher mg/kg melphalan dose and higher
7
Table 1 Pre-transplant characteristics of 381 myeloma patients undergoing high-dose melphalan and ASCT 6
Continuous variables Mean7s.d. Median (range) 5 Age 55.7179.52 55.97 (30–76) Weight (kg) 79.2717.12 78 (41–160) 7 4 BMI 27.29 4.95 26.59 (17.36–55) MELMG/ KG BSA 1.8470.19 1.86 (1.27–2.44) Creatinine (mg/dl) 0.9870.61 0.9 (0.4–6.3) Albumin (mg/dl) 4.1970.44 4.2 (2.4–5.2) 3 Alkaline phosphatase (IU/l) 70.5728.27 65 (27–303) Melphalan (mg/kg) 4.6570.67 4.69 (2.41–6.21) 2 Categorical variables Number Percentage 40 50 60 70 80 90 100 110 120 130 140 150 160 WT_KG +++ ◊◊ ◊ Male 235 38 WTGROUP*** NORMAL OBESE OVERWT Caucasiana 343 90 Figure 1 Distribution of mg/kg melphalan dose and actual weight for Thalidomide arm 189 49 patients receiving melphalan at 200 mg/m2 of BSA. Patients are grouped as Good response to induction 325 85 normal weight, obese or overweight according to their BMI. Patients of normal weight received larger mg/kg doses of melphalan than overweight Abbreviations: ASCT ¼ autologous stem cell transplant; BMI ¼ body mass or obese patients. MELMG/KG: melphalan in mg/kg. WT_KG: weight in index; BSA ¼ body surface area. kg. WTGROUP: groups by weight according to BMI as defined by World aOther race: African-American (28) other (10). Health Organization criteria. OVERWT: overweight.
Table 2 Risk factors for severe OM (grades 3 and 4) in 381 myeloma patients undergoing Mel-ASCT: Univariate analysis
Variable No mucositis or non-severe (grades 0, 1 and 2): 301 patients (79%) Severe mucositis (grades 3 and 4): 80 patients (21%)
Continuous n Mean Median s.d. Minimum Maximum n Mean Median s.d. Minimum Maximum P-value
Age 301 56 56.22 9.42 30.27 76.84 80 54.8 55.3 9.9 34.49 73.2 0.321 Weight 301 79.8 79 17.59 45 160 80 77.1 75.5 15.13 41 123 0.222 BMI 301 27.4 26.65 4.98 17.36 55.03 80 27 26.35 4.83 18.76 42.3 0.500 BSA 301 1.85 1.87 0.19 1.39 2.44 80 1.82 1.84 0.17 1.27 2.26 0.334 Serum creatinine 301 0.95 0.9 0.58 0.4 6.3 80 1.09 0.9 0.71 0.5 5.8 0.077 (mg/dl) Albumin (mg/dl) 301 4.19 4.2 0.44 2.4 5.1 80 4.2 4.2 0.43 2.8 5.2 0.773 Alkaline phosphatase 295 69.2 64 26.52 27 213 80 75.2 70 33.72 31 303 0.103 (IU/l) Melphalan (mg/kg) 301 4.61 4.68 0.69 2.41 6.08 80 4.77 4.74 0.59 3.27 6.21 0.067
Categorical Frequency Percent Frequency Percent
Sex F 113 77 33 23 0.544 M 188 80 47 20
Race Caucasian 270 79 73 21 0.681 Other 31 82 7 18
Thalidomide Yes 154 81 35 19 0.239 No 147 77 45 23
Response to induction Yes 259 80 66 20 0.426 No 42 75 14 25
Abbreviations: BMI ¼ body mass index; BSA ¼ body surface area; Mel-ASCT ¼ melphalan-based autologous stem cell transplant; OM ¼ oral mucositis.
Bone Marrow Transplantation Mucositis risk factors after melphalan transplant ML Grazziutti et al 504 Table 3 Risk factors for severe OM (grades 3 and 4) in 381 myeloma patients undergoing Mel-ASCT: Multiple logistic regression analysis
Analysis of maximum likelihood estimates OR estimates
Parameter Estimate Standard error w2 P-value OR 95% CI
Intercept À3.9594 1.0630 13.8741 0.0002 Serum creatinine 0.4579 0.1942 5.5610 0.0184 1.581 1.080–2.133 Melphalan (mg/kg) 0.4671 0.2060 5.1403 0.0234 1.595 1.065–2.389
Abbreviations: CI ¼ confidence interval; Mel-ASCT ¼ melphalan-based autologous stem cell transplant; OM ¼ oral mucositis; OR ¼ odds ratio.
Oral mucositis by melphalan mg/kg dose OM, in agreement with prior reports by us and others,3,18–21 and that a quarter of the patients remained mucositis-free 68% 70% G0(n =94) GI&II(n =207) GIII&IV(n =80) despite receiving higher mg/kg doses of melphalan and/or 57% having higher serum creatinine. 60% 52% Our new finding of a wide variation in mg/kg melphalan 50% given and the correlation between severe OM and higher mg/kg of melphalan suggest that BSA dosing may not be 40% the optimal method for dosing melphalan. In a study 30% 24% 26% 24% 24% conducted in dogs with cancer, melphalan was adminis-
Percent 2 17% tered at various mg/m using a BSA formula. Dispropor- 20% tionately greater myelosuppression was observed in small 10% 4% dogs (P ¼ 0.016) leading the investigators to conclude that although both BSA and weight were significantly correlated 0% 2.4
Bone Marrow Transplantation Mucositis risk factors after melphalan transplant ML Grazziutti et al 505 mucoprotective agents. Of interest, a quarter of our 2 Giralt S, Bensinger W, Goodman M, Podoloff D, Eary J, patients did not develop severe OM even when given Wendt R et al. 166Ho-DOTMP plus melphalan followed by higher mg/kg melphalan doses, suggesting that genetic peripheral blood stem cell transplantation in patients with polymorphisms in melphalan metabolism40 and/or response multiple myeloma: results of two phase 1/2 trials. Blood 2003; to inflammation41,42 could be responsible for the variable 102: 2684–2691. individual susceptibility to mucositis. This is reflected by 3 Barlogie B, Jagannath S, Desikan KR, Mattox S, Vesole D, Siegel D et al. Total therapy with tandem transplants for newly the receiver operated characteristic of 0.61, that is, the two diagnosed multiple myeloma. Blood 1999; 93: 55–65. variables (renal function and melphalan mg/kg dose) could 4 Wardley AM, Jayson GC, Swindell R, Morgenstern GR, predict OM with 61% certainty. Chang J, Bloor R et al. Prospective evaluation of oral Our findings suffer the limitations inherent to retro- mucositis in patients receiving myeloablative conditioning spective studies, including the inability to retrieve accurate regimens and haemopoietic progenitor rescue. Br J Haematol data on pre-existing oral pathology, or on opiate usage for 2000; 110: 292–299. the control of OM pain. We did not evaluate the effect of 5 Bellm LA, Epstein JB, Rose-Ped A, Martin P, Fuchs HJ. mg/kg melphalan dose on event-free and overall survival as Patient reports of complications of bone marrow transplant- the treatment protocol (Total Therapy II) includes four ation. Support Care Cancer 2000; 8: 33–39. cycles of induction chemotherapy, consolidation and 6 O’Brien SN, Blijlevens NM, Mahfouz TH, Anaissie EJ. Infections in patients with hematological cancer: recent maintenance phases, all of which with agents other than developments. Hematology (Am Soc Hematol Educ Program) melphalan. The treatment protocol further randomizes 2003, 438–472. patients to thalidomide or no thalidomide therapy. Of note, 7 Donnelly JP, Blijlevens NM, Verhagen CA. Can anything thalidomide has been shown to have a beneficial effect on be done about oral mucositis? Ann Oncol 2003; 14: 505–507. myeloma outcome,43 including in the current Total 8 Wingard JR, Niehaus CS, Peterson DE, Jones RJ, Piantadosi Therapy II study.44 S, Levin LS et al. Oral mucositis after bone marrow Our findings have several implications. The high rate of transplantation. A marker of treatment toxicity and predictor OM in our patient population highlights the need for of hepatic veno-occlusive disease. Oral Surg Oral Med Oral evaluation of mucoprotective agents, such as keratinocyte Pathol 1991; 72: 419–424. 9 Epstein JB, Schubert MM. Oropharyngeal mucositis in cancer growth factor,45 amifostine20 or interleukin-11.46 In addi- therapy. Review of pathogenesis, diagnosis, and management. tion, the wide variation in the melphalan mg/kg dose Oncology (Huntington) 2003; 17: 1767–1779; discussion 1779– received implies the need to explore modifications of or 1782, 1791–1792. alternatives to BSA dosing for recipients of high-dose 10 Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg melphalan, whether given in the autologous or in the J et al. Oral mucositis and the clinical and economic outcomes allogeneic setting with potentially important implications of hematopoietic stem-cell transplantation. J Clin Oncol 2001; for the development of graft-versus-host disease and other 19: 2201–2205. complications of allogeneic transplantation. Finally, differ- 11 Peterson DE, Cariello A. Mucosal damage: a major risk factor ences in the intensity of induction therapy before Mel- for severe complications after cytotoxic therapy. Semin Oncol ASCT, method of dosage adjustment for BSA (actual vs 2004; 31 (3 Suppl 8): 35–44. ideal or CBW) and mucositis score used (WHO, NCI, 12 Blijlevens NM, Donnelly JP, De Pauw BE. Mucosal barrier injury: biology, pathology, clinical counterparts and OMAS, etc.) should be described in publications addressing consequences of intensive treatment for haematological toxicities of antineoplastic agents as these variables may malignancy: an overview. Bone Marrow Transplant 2000; 25: result in different rates of toxicity including OM. 1269–1278. In conclusion, BSA dosing of melphalan results in wide 13 Coda BA, O’Sullivan B, Donaldson G, Bohl S, Chapman CR, variations in the mg/kg dose of melphalan. Patients Shen DD. 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