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Bone Marrow Transplantation (2009) 44, 601–605 & 2009 Macmillan Publishers Limited All rights reserved 0268-3369/09 $32.00

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ORIGINAL ARTICLE

Characteristics and risk factors of oral mucositis after allogeneic stem cell transplantation with FLU/MEL conditioning regimen in context with BU/CY2 S Vokurka, K Steinerova, M Karas and V Koza Department of Haemato-Oncology, University Hospital in Plzen (Pilsen), Plzen (Pilsen), Czech Republic

The fludarabine (FLU)/melphalan (MEL) conditioning regimen containing FLU and high-dose MEL was analyzed in comparison with the BU/CY2 regimen to characterize oral mucositis (OM) and risk factors. OM incidence significantly varied between BU/CY2 and FLU/MEL (100 vs 78%, P ¼ 0.004), but the incidence of severe OM grades 3–4 WHO and kinetics of OM were fully comparable. Patients with OM persisting on day þ 21 had more acute GVHD (68 vs 32%, P ¼ 0.005), which tended to occur earlier than among those without such prolonged OM. Multivariate analysis showed significant dependency of acute GVHD on severity and prolonged duration of OM and significant correlation between OM severity and its prolonged duration. Body surface area-based dosing in the FLU/MEL regimen led to a wide range of MEL doses administered per kilogram body weight (2.5–5.2 mg/kg, median 3.5). In multivariate analysis, MEL dose per kilogram of body weight was found to be a significant predictor of OM incidence and severity. Female gender and lower body mass index were less important variables than the fact that the actual dose of MEL administered per kilogram of body weight was relatively high when the dosage was calculated on the basis of body surface area. Bone Marrow Transplantation (2009) 44, 601–605; doi:10.1038/bmt.2009.66; published online 6 April 2009 Keywords: oral mucositis; melphalan; stem cell transplantation; toxicity; graft-versus-host disease

Introduction Allo-SCT is a very important treatment modality in patients with hematological malignancies. The BU and CY-containing regimen, BU/CY2, is a standard and well-established transplant protocol. The fludarabine (FLU)/melphalan (MEL) regimen, usually comprising FLU (total dose

Correspondence: Dr S Vokurka, Department of Haemato-Oncology, University Hospital, Alej Svobody 80, Plzen (Pilsen) 304 60, Czech Republic. E-mail: [email protected] Received 31 October 2008; revised 4 February 2009; accepted 6 February 2009; published online 6 April 2009

125–150 mg/m2) and MEL (total dose 140–180 mg/m2), also seems to be effective and is accompanied by a minimum of fatal toxic complications.1–5 Significant oral mucositis (OM) has been observed with the FLU/MEL protocol,2,5 but the detailed characteristics are lacking, whereas other endpoints (that is, engraftment, major organ toxicity, time-to-progression and GVHD) have usually been well defined. Oral mucositis associated with pain, reduced oral intake, infections and negative overall impact reaches up to 100% incidence in an SCT setting.6,7 Although a better understanding of OM pathogenesis has led to new therapeutic options and pharmacogenomic and pharmacogenetic studies are essential,8 there still remains the need for clinical observations. Studying the characteristics and individual risk factors of OM in widely used conditioning regimens can help find toxicity-reducing approaches, high-risk patients and candidates for new therapeutic agents. This observational study was conducted to characterize OM and risk factors in patients after FLU/MEL conditioning regimen in comparison with the BU/CY2 regimen.

Patients and methods Patients transplanted with allogeneic stem cells after BU/CY2 and FLU/MEL conditioning regimens were prospectively observed during the period January 2005 to December 2007 in our transplant center. The BU/CY2 consisted of BU 4 mg/kg p.o. or 3.2 mg/kg i.v. in divided doses daily for 4 days (total dose 16 mg/kg) and CY 60 mg/ kg once daily i.v. for 2 days (total dose 120 mg/kg). The FLU/MEL consisted of FLU 30 mg/m2 i.v. once daily for 4 days (total dose 120 mg/m2) and MEL 140 mg/m2 i.v. once daily one day before transplantation. The body surface area (BSA) was determined by means of calculations using the Du Bois formula.22 Patients signed informed consent.

Oral care Daily oral care started on the first day of the conditioning. Mouthwashes and gargling were carried out four times a day. Standard solutions with normal saline, chlorhexidine, benzydamine or salvia were offered to patients according to their preference. Dental cleaning was carried out with soft toothbrushes at least twice daily; in case of gum bleeding or pain, only solutions were recommended. Removable

Oral mucositis in FLU/MEL and BU/CY2 allo-SCT S Vokurka et al

602

dentures had to be removed during mouth rinses, at night and in the presence of OM. Amiphostine, palifermin and cryotherapy were not used for OM prevention at that time.

Other supportive care Patients were hospitalized in high efficiency particulate airfilter air-conditioned single rooms and protective isolation nursing was applied. Erythrocyte and plt transfusions were leukodepleted and irradiated to 25 Gy. Filgrastim 5 mg/kg/day was administered from day þ 1 post-transplant in BU/CY2 (not in patients with acute myeloid leukemia) and from day þ 5 in FLU/MEL to support engraftment. GVHD disease prophylaxis consisted of CYA since day –1 and MTX 10 mg/m2 i.v. on day þ 1 (15 mg/m2 in BU/CY2 on that day), þ 3 and þ 6 with rescue leucovorine. In BU/ CY2, anti-thymocyte globulin (ATG-Fresenius, Fresenius Biotech, Gra¨felfing, Germany) 5 mg/kg i.v. once daily for 3 days (total dose 15 mg/kg) was administered in unrelated or HLA non-identical donor transplantation. Infectious disease prophylaxis consisted of antibacterial chinolons covering the conditioning till hematopoietic engraftment. Afterward, amoxicilin-clavulanate or cefuroxim, and trimethoprim-sulfomethoxazol were supplied during the immunosuppressive treatment. In addition, fluconazole or itraconazole (in 4.9% of patients) and acyclovir were given as antifungal and antiviral prophylaxis since the start of conditioning. Pre-emptive therapy with ganciclovir was used in CMV infections. Monitoring and assessment Monitoring of the oral cavity (lips, buccal area, tongue and palate) started on the first day of the conditioning and covered the whole inpatient stay. OM was assessed using the WHO grading system (grade 0 absent; 1 pain and erythema; 2 defects and can eat solids; 3 defects and liquid diet only; 4 alimentation not possible because of OM). The number of days with total parenteral nutrition was not recorded. GVHD was assessed using the National Institutes of Health24 criteria accepted by the European Group for Blood and Marrow Transplantation.25 Overall grading of acute GVHD was assessed by the Glucksberg system26 with grades 0–4. Histological verification was not routinely carried out. Statistics Basic statistical univariate analyses were carried out using Statistica software (GraphPad InStat, GraphPad Software Inc., San Diego, CA, USA) with the Mann–Whitney, Fisher and t-tests. The P values compared the presence and absence of characteristics and P values o0.05 were considered as indicating statistically significant differences. Stepwise logistic regression was used for multivariate analysis.

Results A total of 101 patients after allo-SCT with the BU/CY2 (n ¼ 30) and FLU/MEL (n ¼ 71) conditioning regimens were included and evaluated—see Table 1 for more details. In general, OM and severe OM grade 3–4 affected 85/101 (84%) and 40/101 (40%) patients. The complication Bone Marrow Transplantation

manifested on median day þ 5 (2–13) after transplant, persisted for 12 (1–34) days and resolved on day þ 17 (9–37) No significant difference was observed between HLA-matched (n ¼ 40) vs -mismatched (n ¼ 22) unrelated donors with respect to OM incidence (87% vs 86%), time to engraftment (on day þ 14 (11–34) vs þ 15 (9–20) after transplant) and acute GVHD incidence (42 vs 41%). Coincidence of OM and acute GVHD occurring at the same time was observed in 50% (11/22) of the patients with OM persisting on day þ 21 and later. In patients with such prolonged OM, the overall incidence of acute GVHD was significantly higher compared with patients without such prolonged OM (68 vs 32%, P ¼ 0.005), and it tended to occur earlier (20 (15–158) vs 31 (10–140), P ¼ 0.18). Logistic regression showed significant dependency of acute GVHD on the severity and prolonged duration of OM (P ¼ 0.044, P ¼ 0.005). Pearson’s and Spearman’s correlation coefficients confirmed a significant correlation between OM severity and its prolonged duration (Po0.001). Stepwise logistic regression was used to analyze the correlation of possible predictors of incidence and the severity of OM in the whole group of patients. The conditioning regimens (BU/CY2 vs FLU/MEL) were found to be the only independent significant predictors for OM incidence and severity (P ¼ 0.0001). No significant effect was observed within this cohort of patients with respect to age (median 53 (20–68) years), gender, body mass index (BMI) (median 26 (14–42 kg/m2)), donor–patient HLA identity, type of graft, content of CD34 þ cells in graft, MTX dose (median 57 (20–81 mg)), filgrastim administration (median 8 (0–19) days), bilirubin levels (median 12 (6–52 mmol/l)), creatinine clearance (median 1.6 (0.4–3.3 ml/s)), number of days since last chemotherapy (median 74 (19–1320) days), history of OM, presence of oral prosthesis or diabetes. The incidence of OM was significantly lower in FLU/ MEL compared with BU/CY2: 78 vs 100% (P ¼ 0.004). Incidence of severe OM grades 3–4 and kinetics of OM were comparable (P40.05) without significant differences: 38 vs 43%, OM onset on day þ 6 (2–10) vs þ 5 (2–13), duration 12 (1–34) vs 11 (2–31) days, resolution on day þ 18 (9–37) vs þ 16 (9–35) after transplant. See Figures 1 and 2. FLU/MEL patients were further analyzed for individual risk factors (see Table 2) and no significant correlations were observed between OM and age, history of earlier OM, patient–donor HLA identity, creatinine clearance, MTX dose and filgrastim administration. OM presented significantly more in women, in patients with lower BMI and in patients with MEL dose X3.5 mg/kg. MEL dose per kilogram of body weight ranged widely in this cohort of patients (2.5–5.2 mg/kg, median 3.5). In multivariate logistic regression analysis, only a higher MEL dose per kilogram of body weight remained a significant predictor of OM and severe OM (P ¼ 0.0083, P ¼ 0.0086).

Discussion A total of 101 patients treated with allo-SCT were included and evaluated within this prospective observation.


603 Table 1

Characteristics of patients in the FLU/MEL vs BU/CY2 conditioning regimens

Characteristics

FLU/MEL

BU/CY2

P value

n Age (years), median Gender: males

71 56 (23–68) 51%

30 35 (20–55) 57%

— o0.0001 NS

30/71 (42%) 5 8 5 6 7 3 5 2 57/71 (80%) 25/71 14/71 71/71 (100%) 0 4.95 (1.6–15.2) 1.5 (0.4–3.0) 13 (6–52) 51 (0–72) 0.6 (0–1.1) 8 (5–13) 13 (0–26)

17/30 (56%) 8 1 1 1 0 2 0 0 22/30 (73%) 15/30 8/30 20/30 (66%) 10/30 5.05 (2.2–22.8) 1.8 (0.7–3.3) 11 (6–38) 64 (0–81) 0.9 (0–1.3) 9 (0–19) 15 (11–34)

—

Diagnosis: AML ALL NHL CLL MDS MM CML HL OMF HLA identical donor Matched unrelated Mismatched unrelated Peripheral stem cells graft BM graft Median CD34+ cells in graft ( 106/kg ) Median creatinine clearance (ml/s) Median bilirubin levels (mmol/l) Median MTX total dose (mg) Dose per kilogram body weight (mg) Median number of days with G-CSF filgrastim Granulocytes X1 109/l on the day after transplant

NS o0.0001 NS NS NS o0.0001 0.0006 NS 0.0007

Abbreviations: FLU ¼ fludarabine; HL ¼ Hodgkin’s lymphoma; MDS ¼ myelodysplastic syndrome; MEL ¼ melphalan; MM ¼ multiple myeloma; NHL ¼ non Hodgkin’s lymphoma; OMF ¼ osteomyelofibrosis.

50 FLU/MEL

40 22

20

17

20

23

FLU/MEL

50 25

10 10

4

0

0

0 0

Bu/CY2

75

28

Bu/CY2

%

%

30

100

40

36

1

2

3

4

WHO grade

0

5

10

15

20 Day

25

30

35

40

Figure 1 Incidence of maximum WHO grade of oral mucositis in FLU/

Figure 2 Incidence of oral mucositis on individual day after transplant

MEL and BU/CY2 conditioning regimens. WHO, World Health Organization; FLU, fludarabine; MEL, melphalan.

(0 ¼ day of SCT) in FLU/MEL and BU/CY2 conditioning regimens. FLU, fludarabine; MEL, melphalan.

FLU/MEL and BU/CY2 patients were compared to better reflect the less known oral toxicity of FLU/MEL. The two groups were well balanced with the exception of age, type of transplanted graft, MTX dose and time of granulopoiesis engraftment. These differences mostly respected the individual nature and character of the conditioning regimens (FLU/MEL preferred for older patients) and probably had no effect on results—based on our statistical analyses. Although OM was statistically significantly lower in FLU/MEL compared with BU/CY2, the clinical significance of 78% incidence in FLU/MEL is of a very high importance. Moreover, the duration of OM and incidence of grades 3–4 WHO were fully comparable. Patients with OM persisting on day þ 21 and later had more acute GVHD (68 vs 32%, P ¼ 0.005), which tended to occur earlier than among those without such prolonged OM, and in half of the patients with OM persisting on day

þ 21 and later the activity of acute GVHD was present at the same time. Multivariate analysis showed significant dependency of acute GVHD on the severity and prolonged duration of OM and simultaneously significant correlation between OM severity and its prolonged duration. All these findings show a close relation of the processes playing roles in the pathogenesis of both OM and acute GVHD, where early occurring GVHD can keep up and prolong the persistence of originally toxic mucositis and severe and prolonged OM increases the risk of acute GVHD incidence after transplant. However, OM persisting beyond day þ 21 was also observed in an autologous transplant setting.16 Unfortunately, from a clinical point of view it is not possible to differentiate precisely between oral acute GVHD and toxic mucosal damage. Melphalan is undoubtedly the major course of oral toxicity in FLU/MEL. The molecule is responsible for Bone Marrow Transplantation


604 Table 2

Oral mucositis after FLU/MEL conditioning regimen and risk factors evaluated by univariate analysis OM present

n Age, median (years) Gender: females vs males Melphalan dose per kg: o3.5 vs X3.5 mg/kg Body mass index, median MTX total dose, median (mg) Number of days with filgrastim after transplant, median Donor–patient HLA identity: yes vs no OM in history: yes vs no Creatinine clearance: o1.5 vs X1.5 ml/s Oral prosthesis: yes vs no

56 89 65 26 51 8 77 85 81 90

55 (23–68) vs 67% vs 88% (14–39) (20–66) (5–13) vs 78% vs 74% vs 74% vs 75%

OM not present

P value

16 55 (30–65) — — 28 (17–43) 60 (41–72) 7 (6–10) — — — —

— NS 0.04 0.03 0.01 NS NS NS NS NS NS

Abbreviations: FLU ¼ fludarabine; MEL ¼ melphalan; OM ¼ oral mucositis.

OM in single-drug high-dose chemotherapy high dose melphalan followed by autologous SCT.9,16,17 No such oral toxicity has been observed in FLU so far. To be objective, it is necessary to mention the possible effect of MTX administered for GVHD prophylaxis and contributing significantly to oral toxicity in allogeneic transplantations.18–20 Though we found a significant difference in MTX dosing between FLU/MEL and BU/CY2, the values of the drug doses were most likely clinically less important within our cohort of patients and we were not able to show any effect on OM characteristics. Owing to the high toxicity of BU/CY2 and the lower number of patients in that group, we focused on FLU/ MEL to search for individual risk factors. We assumed that the age of our patients had no significant effect on OM characteristics. We found no age correlation within the whole transplanted group or within the FLU/MEL patients, and several earlier studies did not find it either or had conflicting results.9–16 As for gender, univariate analysis showed significantly more OM in women, which was also observed in some earlier studies with patients after MEL 200 mg/m2 or BEAM autologous SCT15 or in patients on 5-fluorouracil chemotherapy.21 Lower BMI also presented as a possible risk factor. However, the most important risk phenomenon—observed earlier by Grazziutti et al.23—was the fact that empirical BSA-based dosing of MEL led to a wide range of the drug doses administered per kilogram body weight. Our patients with doses of MEL X3.5 mg/kg had a significantly higher incidence of OM. A higher MEL dose per kilogram of body weight remained the only significant predictor of OM and severe OM in final multivariate analysis. In other words, in patients with the same BSA, those who were taller and slimmer (lower body weight, lower BMI) received a higher MEL dose per kilogram in comparison with those who were smaller and more rotund (higher weight and higher BMI). In addition, it was mostly women who were present within the lower BMI cohort of our patients. In view of these observations and in concordance with the results of multivariate analysis, it is possible to conclude that lower BMI and female gender are apparent risk factors for OM in case of MEL BSA-based dosing, but probably not in MEL body weight-based dosing. To further analyze the effect of gender and other factors, it would be necessary Bone Marrow Transplantation

to ensure an identical per kilogram dosing of MEL and a much larger observation. In conclusion, the conditioning regimen FLU/MEL can be considered highly risky with respect to OM. The major factor influencing OM in FLU/MEL patients is the MEL dose administered per kilogram, which ranges widely in empirical BSA-based dosing. Consequent to this, female gender and lower BMI appear to be only apparent risk factors subordinated to the higher MEL dose given per kilogram of body weight. Female gender and other possible factors are not excluded from playing roles in OM pathogenesis, but to distinguish them would need a much larger observation with MEL dosing being based on body weight. This scheme should lead to more homogeneous dosing and perhaps a reduction of OM incidence and severity if the ‘median’ dose of 3.5 mg/kg was used instead of MEL 140 mg/m2. The effect of such a dosing change on OM and other transplant characteristics should be verified in prospective trials.

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