Severe mucositis is associated with reduced survival after autologous stem cell transplantation for lymphoid malignancies

Authors

  • S. R. Fanning,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • L. Rybicki,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • M. Kalaycio,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • S. Andresen,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • E. Kuczkowski,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • B. Pohlman,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • R. Sobecks,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • J. Sweetenham,

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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  • B. Bolwell

    1. Department of Hematology and Medical Oncology, and Department of Quantitative Health Sciences, Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH, USA
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Brian J. Bolwell, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Desk R32, Cleveland, OH 44195, USA.
E-mail: bolwelb@ccf.org

Summary

Mucositis is a known complication of autologous stem cell transplantation (ASCT). This study retrospectively reviewed 191 patients with lymphoid malignancies undergoing ASCT following a uniform mobilising regimen of etoposide (VP-16)/granulocyte colony-stimulating factor and a uniform high-dose preparative regimen of busulfan/cyclophosphamide/VP-16. Eighty-seven patients experienced severe mucositis (modified Oral Mucositis Assessment Scale ≥1). Patient characteristics compared between mucositis groups were balanced according to disease status, prior exposure to radiation therapy, time from radiation therapy and actual body weight. Log-rank analysis revealed that severe mucositis was associated with inferior overall survival (P = 0·002). A 12-month landmark analysis showed this difference in survival occurred within 1 year post-transplant. Multivariate analysis of all-cause mortality showed lower pretransplant albumin and severe mucositis to be significant risk factors. Multivariate analysis for relapse mortality revealed severe mucositis to be a risk factor (P = 0·047), while lower pretransplant albumin was significant for non-relapse mortality (NRM; P = 0·009). Kaplan–Meier estimates of survival based on relapse and NRM were significantly worse for patients with severe mucositis. Reduced pretransplant forced expiratory volume in 1 s (FEV1) and carbon monoxide (CO) diffusing capacity (DLCO) were also associated with severe mucositis. Our data suggest that studies of new treatment strategies for mucositis should include relapse and survival endpoints and that pretransplant factors, such as FEV1 and DLCO may be useful to risk-stratify patients entered onto such trials.

Mucositis, defined as the disruption of function and/or integrity of the gastrointestinal mucosa, is a frequent complication of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT). The dysfunction caused by mucositis has been associated with an increased risk of infection, need for total parenteral nutrition, intravenous pain control and lengthened hospital stays with increased economic burden (Sezer et al, 2000; Sonis et al, 2001; Bolwell et al, 2002). The pathophysiology leading to mucositis has been well described (Sonis, 2004) and leads to acute therapy-related toxicity that not only affects patient quality of life, but also interferes with the ability to deliver uncompromised chemotherapy and/or radiation therapy regimens. Increased 100-d mortality risk and treatment-related mortality post-ASCT have been observed among patients with more severe mucositis (Rapoport et al, 1999; Sonis et al, 2001). These data are difficult to interpret, however, due to patient populations that have been heterogeneous in terms of both mobilising and high-dose preparative regimens. Few, if any, studies have examined the long-term consequences of mucositis after ASCT.

This study retrospectively identified 191 patients with relapsed lymphoid malignancies who underwent ASCT following a uniform mobilising and preparative regimen within our institution from 2000 to 2005. We examined the relationship between the severity of oral mucositis, as determined by the modified Oral Mucositis Assessment Scale (mOMAS) (Sonis et al, 1999) shown in Table I, and several clinical variables assessed among our ASCT patients.

Table I.   Modified Oral Mucositis Assessment Scale (mOMAS) tool.
Anatomical siteOral examination mOMAS score
Any ulceration? (0–1)Degree of erythema (0–1)
  1. Average ulceration score = total of all site ulceration scores/number of evaluable sites.

  2. Average erythema score = total of all site erythema scores/number of evaluable sites.

  3. Modified OMAS score is the sum of average ulceration score and average erythema score.

Maxillary labial mucosaNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Mandibular labial mucosaNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Right buccal mucosaNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Left buccal mucosaNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Right lateral and ventral tongueNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Left lateral and ventral tongueNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Floor of mouth and lingual frenumNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)
Soft palate and faucesNo (0)None (0)
Yes (1)Mild to moderate (0·5)
Severe (1)

Patients and methods

Patient characteristics

One hundred and ninety-one patients who underwent ASCT at the Cleveland Clinic Foundation for relapsed lymphoid malignancy between May 2000 and February 2005 were retrospectively identified. All patients had been treated with a uniform mobilisation regimen that comprised etoposide and granulocyte colony-stimulating factor (G-CSF), as well as a uniform high-dose preparative regimen of busulfan/cyclophosphamide/etoposide (Bu/Cy/VP). All patients were in either complete (CR) or partial remission (PR) at the time of transplant. All treatments were administered under Institutional Review Board approved protocols. The median age was 52 years; 124 patients (65%) were male. Diagnosis and clinical characteristics are shown in Table II. Of the 155 patients with non-Hodgkin lymphoma, 85 (55%) had diffuse large B cell lymphoma, 32 (21%) follicular, 22 (14%) mantle cell and 16 (10%) other.

Table II.   Patient characteristics.
Variable (%)All patients (191)mOMAS < 1 (104)mOMAS ≥ 1 (87)P-value
  1. mOMAS, modified Oral Mucositis Assessment Scale; ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; DLCO, carbon monoxide (CO) diffusing capacity (DL).

Age (years), median (range)52 (16–77)51 (16–77)54 (19–75)0·30
Gender, male64·960·670·10·17
Race, White93·293·393·10·96
Primary diagnosis
 Non-Hodgkin lymphoma81·281·180·5 
 Hodgkin disease18·818·319·50·82
ECOG performance status
 065·471·657·8 
 134·628·442·20·051
Actual body weight (kg), median (range)85·1 (30·5–191·4)84·8 (40·3–146·9)85·4 (30·5–191·4)0·87
Ideal body weight (kg), median (range)68·6 (33·2–112·7)67·2 (33·2–86·8)71·4 (43·1–112·7)0·024
Albumin (pretransplant), median (range)3·4 (2·0–4·6)3·5 (2·0–4·6)3·4 (2·6–4·4)0·024
FEV1, % predicted (pretransplant) per 10% increase92 (36–141)94 (55–134)88 (36–141)0·037
DLCO, % predicted (pretransplant) per 10% increase82 (45–133)86 (45–133)76 (45–130)0·035
Disease status at transplant
 Complete remission26·727·925·3 
 Partial remission73·372·174·70·69
Number of prior chemotherapy regimens
 1–270·276·063·2 
 >229·824·036·80·06
Prior radiation therapy, yes29·330·827·60·63
Months from pretransplant radiation to transplant, median (range)18·6 (1·8–241·0)22·2 (3·1–241·0)17·4 (1·8–207·3)0·69
Lactate dehydrogenase >22031·927·936·80·19
CD34+ dose, ×106/kg, median (range)8·49 (2·01–44·32)8·39 (2·17–44·32)8·98 (2·01–40·88)0·59

Peripheral blood progenitor cell mobilising regimen

All patients received a uniform mobilising regimen consisting of etoposide 2 g/m2 based on adjusted ideal body weight [(actual body weight − ideal body weight)/4 + ideal body weight] with G-CSF (10 μg/kg/d s.c.). Leucopheresis was initiated once white blood cell (WBC) recovery was >1 × 109/l.

Preparative regimen

All patients received a uniform preparative regimen of busulfan 14 mg/kg, cyclophosphamide 120 mg/kg and etoposide 60 mg/kg (based on adjusted ideal body weight).

Supportive care

Patients were hospitalised for the delivery of chemotherapy and discharged after haematological recovery occurred. Platelet and red blood cell (RBC) transfusions were administered when the platelet count was <15 000 × 109/l or haemoglobin <8·5 g/dl respectively. All blood products were irradiated before infusion. Broad-spectrum antibiotics were administered for febrile neutropenic episodes. Narcotics, either oral or intravenous, were used as needed for analgesia. The prophylactic oral regimen included either nystatin solution or a clotrimazole troche four times daily and chlorhexidine gluconate 0·12% mouthwash three times daily. All patients received G-CSF, initiated 5 d after stem cell infusion and continued until absolute neutrophil count >500 × 109/l. Acyclovir prophylaxis was initiated upon hospital admission in all patients.

Mucositis assessment

We used the mOMAS to evaluate oral mucositis. This grading scale focuses on the anatomical changes to the oral mucosa and toxicity is based upon a composite score of 18 different assessments. Patients were assessed daily for the first 12 d of conditioning, thereafter every Monday, Wednesday and Friday. Eight regions of the oral cavity were evaluated for erythema and ulceration/pseudomembranes: the maxillary labial mucosa, the mandibular labial mucosa, the right buccal mucosa, the left buccal mucosa, the right lateral and ventral tongue, the left lateral and ventral tongue, the floor of the mouth and lingual frenum, and the soft palate and fauces. All clinical examinations were performed by two physician assistants of the inpatient transplant service.

Data from these clinical examinations were used to calculate an OMAS score for each patient at each assessment. In the OMAS system, erythema of the oral cavity is assessed as none, mild, moderate or severe, and patients were also evaluated for the presence of ulcers or pseudomembranes. The mOMAS score is the sum of the average ulceration score and average erythema score. The maximal mOMAS score was used for this analysis, and a mOMAS score ≥1 was considered to be consistent with severe mucositis.

Statistical analysis

Categorical variables are summarised overall and by mOMAS score as frequency counts and percentages; variables were compared between mOMAS groups using the chi-squared test. Continuous variables are summarised as the median and range and compared between mOMAS groups using either the t-test or Wilcoxon rank sum test. The Kaplan–Meier method was used to estimate survival, relapse mortality and non-relapse mortality (NRM); the log-rank test was used to compare these outcomes between mOMAS groups. A 12-month landmark analysis was used to assess an impression that survival differences between mOMAS groups were a result of early deaths. Patients who died within 12 months of ASCT or who had <12 months of follow-up were excluded from the landmark analysis. Survival was calculated for the remaining patients and compared between mOMAS groups using the log-rank test. Cox proportional hazards analysis was used to identify univariate and multivariate risk factors for all-cause mortality, relapse mortality and NRM. All variables described in Table II were analysed as possible risk factors in univariate analysis. Because the main objective was to determine whether mOMAS was associated with outcomes after adjusting for other variables, the multivariate model for each outcome included mOMAS and any variable that was both prognostic for outcome at P < 0·10 and which differed between mOMAS groups at P < 0·10. Therefore, the multivariate model for all-cause mortality was adjusted for performance status, albumin, carbon monoxide (CO) diffusing capacity (DLCO) and number of prior chemotherapy regimens. The model for relapse mortality was adjusted for albumin and number of prior chemotherapy regimens. Ideally, the model for NRM would be adjusted for performance status, albumin and DLCO; however, only 20 patients died due to non-relapse causes therefore only two variables should be included in a multivariate model. Three multivariate models for NRM were therefore examined: each included mOMAS with one additional adjustment variable. Analyses of all-cause and relapse mortality did not pose such problems, as there were 58 total deaths, 38 due to relapse. Analyses were performed using sas® software (SAS Institute, Inc., Cary, NC, USA). All statistical tests were two-sided, and P < 0·05 was used to indicate statistical significance.

Results

Mucositis was common among this patient population. Eighty-seven patients (46%) had a mOMAS score of ≥1. Patients with severe mucositis had a statistically significant greater ideal body weight, lower pretransplant albumin, lower DLCO and lower forced expiratory volume (FEV) (Table II); otherwise, the mucositis groups were otherwise balanced with respect to patient characteristics. We also examined left ventricular ejection fraction, serum creatinine, aspartate transaminase and total bilirubin, which are pretransplant comorbidities that might be associated with mucositis, but found no significant differences between mOMAS groups (P > 0·2; results not shown). Although there was no difference in the time to neutrophil or platelet engraftment, patients with severe mucositis (mOMAS ≥ 1) had a longer hospital stay (23 vs. 21 d, P < 0·001).

Mucositis was associated with an adverse overall survival. Figure 1 shows Kaplan–Meier estimates of survival and reveals that the group with more severe mucositis had an inferior overall survival compared with the less severe mucositis group (P = 0·002). Overall survival for the less severe mucositis group was 85%, 78%, 73% and 62% at 1, 2, 3 and 4 years post-ASCT compared with 64%, 54%, 52% and 47% for the more severe mOMAS group respectively. There were 15 relapse events in the mOMAS <1 group, compared with 23 in those with mOMAS ≥ 1 (P = 0·015; log-rank test). Analysis of cause of death among all patients is shown in Table III. The most common cause of NRM was pulmonary toxicity.

Figure 1.

 Kaplan–Meier curve of survival according to severity of mucositis.

Table III.   Cause of death.
 All patientsmOMAS < 1mOMAS ≥ 1
  1. ARDS, adult respiratory distress syndrome; ILD, interstitial lung disease; aGVHD, acute graft-versus-host disease; CNS, central nervous system; mOMAS, modified Oral Mucositis Assessment Scale.

Within first year after transplant (n = 43)
 Relapse28919
 Pulmonary toxicity303
 Multiorgan failure202
 ARDS202
 Sepsis202
 2° malignancy110
 Bacterial infection110
 Advanced ILD101
 Kidney failure110
 Chemo toxicity110
 Unknown110
Death at any time (n = 58)
 Relapse381523
 Pulmonary toxicity303
 Multiorgan failure303
 ARDS202
 2° malignancy211
 Sepsis202
 Bacterial infection110
 Heart failure101
 aGVHD110
 Advanced ILD*101
 CNS bleed110
 Kidney failure110
 Chemo toxicity110
 Unknown110

A survival difference between those with more severe mucositis and those without was found to disappear after 1 year post-transplant. Figure 2 shows a landmark analysis of patients that survived 1 year, where survival was analysed by the two mOMAS groups. As shown, there was no survival difference in the two mOMAS groups, illustrating the fact that the survival difference in the two groups occurred entirely in the first year post-transplant.

Figure 2.

 Kaplan–Meier curve of 12-month landmark survival according to severity of mucositis.

Kaplan–Meier curves of relapse mortality and NRM are shown in Figs 3 and 4 respectively. Both curves showed a statistically significant increase in mortality associated with more severe mucositis.

Figure 3.

 Kaplan–Meier curve of relapse mortality according to severity of mucositis.

Figure 4.

 Kaplan–Meier curve of non-relapse mortality according to severity of mucositis.

Univariate and multivariate risk factors for all-cause mortality, relapse mortality and NRM are shown in Tables IV and V respectively. Multivariate analysis of all-cause mortality revealed both lower pretransplant albumin level and mOMAS ≥ 1 to be significant risk factors. Multivariate analysis showed that only mOMAS ≥1 was associated with greater relapse mortality, while only lower pretransplant albumin level was associated with greater non-relapse survival.

Table IV.   Univariate risk factors for mortality.
VariableHazard ratio95% Confidence intervalP-value
  1. ECOG, Eastern Cooperative Oncology Group; FEV1, forced expiratory volume in 1 s; DLCO, carbon monoxide (CO) diffusing capacity (DL); mOMAS, modified Oral Mucositis Assessment Scale.

All-cause mortality
 ECOG performance status 1/01·801·06–3·040·03
 Albumin (pretransplant) per 0·5 U increase0·580·42–0·800·001
 DLCO, % predicted (pretransplant) per 10% increase0·860·75–0·980·023
 Number of prior chemotherapy regimens >2/1–21·781·04–3·030·034
 Highest mOMAS 1+/<12·331·36–3·990·002
Relapse mortality
 Albumin (pretransplant) per 0·5 U increase0·650·43–0·990·044
 Number of prior chemotherapy regimens >2/1–22·011·04–3·870·037
 Highest mOMAS 1+/<12·231·15–4·340·018
Non-relapse mortality
 Age at transplant per 10 years increase1·480·99–2·220·06
 ECOG performance status 1/02·410·96–6·050·06
 Albumin (pretransplant) per 0·5 U increase0·460·27–0·790·005
 DLCO, % predicted (pretransplant) per 10% increase0·810·64–1·020·07
 Highest mOMAS 1+/<12·521·00–6·320·049
Table V.   Multivariate models for mortality.
VariableHazard ratio95% Confidence intervalP-value
  1. Significant at *P < 0·05.

  2. DLCO, carbon monoxide (CO) diffusing capacity (DL); ECOG, Eastern Cooperative Oncology Group; mOMAS, modified Oral Mucositis Assessment Scale.

Model for all-cause mortality
 Highest mOMAS 1+/<11·831·05–3·190·033*
 ECOG performance status 1/01·390·79–2·440·26
 Albumin (pretransplant) per 0·5 U increase0·620·43–0·910·014*
 DLCO, % predicted per 10% increase0·920·80–1·060·25
 Number of prior chemotherapy regimens >2/1–21·470·85–2·540·17
Model for relapse mortality
 Highest mOMAS 1+/>11·981·01–3·870·047*
 Number of prior chemotherapy regimens >2/1–21·740·90–3·370·10
 Albumin (pretransplant) per 0·5 U increase0·680·43–1·070·09
Model no. 1 for non-relapse mortality
 Highest mOMAS 1+/<12·120·83–5·440·12
 ECOG performance status 1/02·190·87–5·540·10
Model no. 2 for non-relapse mortality
 Highest mOMAS 1+/<12·320·92–5·820·07
 Albumin (pretransplant) per 0·5 U increase0·460·26–0·820·009*
Model no. 3 for non-relapse mortality
 Highest mOMAS 1+/<12·310·91–5·870·08
 DLCO, % predicted per 10% increase0·840·67–1·060·13

Discussion

Mucositis is a well-described toxicity among patients receiving chemotherapy and/or radiotherapy and is almost invariable in patients undergoing high-dose therapy and stem cell transplantation. Grade 3/4 mucositis has been shown to occur in up to 98% of patients receiving high-dose chemotherapy (Spielberger et al, 2004). The effects of severe mucositis are numerous and include significant patient discomfort, lengthened hospital stays, additional hospital cost, increased risk of infection and increased mortality. Previous studies have demonstrated an association between the development of severe mucositis and survival after transplantation (Sezer et al, 2000; Sonis et al, 2001), however, interpretation of these data have been limited by the heterogeneous nature of the patients in these series with respect to underlying diagnosis, high dose regimens and source of stem cell rescue. This is the first series to report the association between severe mucositis and survival in a homogeneous population of patients with relapsed lymphoma, treated with the same mobilising regimen and receiving the same high-dose chemotherapy regimen, with consistent supportive care protocols.

This study is also the first to report an association between pretransplant co-morbidity variables, specifically reduced FEV1 and DLCO, and the development of severe mucositis. Many prior studies have investigated the effect of co-morbid conditions on outcomes after stem cell transplantation. Results from these studies have been variable. While performance and disease status at time of transplant predicts postbone marrow transplantation outcome in most series, age and cardiopulmonary status are less clearly predictive (Bearman et al, 1990; Carella et al, 1991; Bierman et al, 1993; Hertenstein et al, 1994; Sweetenham et al, 1994; Cahn et al, 1995; Copelan et al, 1996; Jain et al, 1996; Lazarus & Nugent, 1996; Miller et al, 1996; Kusnierz-Glaz et al, 1997; Sierra et al, 1997; Zangari et al, 1999; Fujimaki et al, 2001; Greinix et al, 2002; Doney et al, 2003) of survival, and have not been reported to be correlated with the incidence of severe mucositis in the peri-transplant period.

Analysis of overall survival in our entire cohort revealed a statistically significant difference between mucositis groups, in favour of those with less severe mucositis (mOMAS <1). The entire survival difference occurred within the first year post-ASCT.

Multivariate analysis revealed that patients with a lower pretransplant albumin level had a higher all-cause and non-relapse mortality compared with those with normal pretransplant albumin levels.

Multivariate analysis showed that severe mucositis was a significant risk factor for relapse mortality. This association of disease relapse and more severe mucositis is a novel finding and is difficult to interpret, especially in view of the relatively low number of relapses in the entire patient series. Further studies of this apparent association, with larger numbers of patients, will be required.

Numerous therapeutic strategies have been evaluated in an effort to prevent or limit the severity of oral mucositis, however, most have fallen short of reducing the incidence of mucositis. These agents include topical antibiotics (Weisdorf et al, 1989), glutamine (Ziegler et al, 1992; Anderson et al, 1998), granulocyte-macrophage colony-stimulating factor (Gordon et al, 1994) and Iseganan, an analogue of protegrin-1 (Giles et al, 2002, 2003). Palifermin, a recombinant human keratinocyte growth factor and member of the family of fibroblast growth factors, is currently the only Food and Drug Administration approved prophylactic treatment available for oral mucositis among patients receiving chemotherapy and/or radiotherapy (Spielberger et al, 2004). The identification of pretransplant risk factors for mucositis will enable the stratification of patients in prospective studies of this and other agents. In this respect, our observation of the predictive value of pulmonary function prior to ASCT may be helpful if confirmed in subsequent series.

In summary, this study demonstrated an association between severe oral mucositis and overall survival in a homogeneous patient population with relapsed lymphoma undergoing high-dose therapy and ASCT according to a single protocol. Reduced pretransplant FEV1 and DLCO were significantly associated with the development of severe mucositis. Multivariate analysis showed that severe mucositis was an independent predictive factor for relapse-mortality, but not for NRM. The cause for this apparent association is unclear and further studies will be required to confirm this observation. However, these data suggest that studies of new treatment strategies for mucositis should include relapse and survival endpoints and that pretransplant factors, such as FEV1 and DLCO, may be useful to risk-stratify patients entered onto such studies.

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