Quality of life assessment in patients undergoing reduced ... - Nature

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Quality of life assessment in patients undergoing reduced intensity conditioning allogeneic as compared to autologous transplantation: results of a prospective study M Dı´ ez-Campelo1, JA Pe´rez-Simoń1, JR Gonza´lez-Porras1, JM Garcı´ a-Cecilia2, M Salinero1, MD Caballero1, MC Can˜izo1, EM Ocio1 and JF San Miguel1 1

Servicio de Hematologıá, Hospital Universitario de Salamanca, Paseo de San Vicente, s/n, Salamanca, Spain; and 2Statistic’s Department, Faculty of Psychology, Segovia, Spain

Summary: The aim was to analyze quality-of-life (QOL) during the first year post transplant in 47 patients undergoing reduced-intensity conditioning (RIC) allotransplantation, and to compare these with a similar subgroup of patients receiving autologous stem cell transplantation (ASCT). We used self-reported questionnaires. Each answer scored from 0 (not at all) to 4 (very much), with higher scores indicating worse functioning. Mean value of physical categories among RIC transplants ranged between 1.23 and 0.77 indicating that patients scored very low for physical symptoms. Patients undergoing ASCT had higher scores in questionnaires performed early after transplant and then gradually improved (Po0.001). Overall, when we compared physical functioning scores, allo-RIC did significantly better (P ¼ 0.049). Nevertheless, while allo-RIC scores were significantly better for the first three questionnaires, ASCT patients did better in the last two questionnaires. These findings are in accordance with the toxicities observed in both subgroups which are lower in the RIC group early after transplant. No significant differences were observed between either subgroup for any of the functional, social/ family, psychological distress and satisfaction with doctor/nurse relationship items. We have observed similar QOL among patients undergoing RIC-allo as compared to ASCT although GVHD remains an important ‘event’ in QOL. Bone Marrow Transplantation (2004) 34, 729–738. doi:10.1038/sj.bmt.1704646 Published online 6 September 2004 Keywords: quality of life; QOL; reduced intensity conditioning; nonmyeloablative; allogeneic transplant

Correspondence: Dr M Dı´ ez-Campelo, Servicio de Hematologı´ a, Hospital Universitario de Salamanca, Paseo de San Vicente, s/n, 37007 Salamanca, Spain; E-mail: [email protected] Received 2 March 2004; accepted 2 June 2004 Published online 6 September 2004

Patients’ preferences are increasingly being considered in decision-making regarding treatment options, so that currently, no option should be pressed on patients without providing information about the potential benefits and harm.1,2 While choosing the best treatment option based on adequate evidence is possible for different diseases,3,4 risk groups of patients5 or disease status,6 evidence regarding outcome cannot always be offered.2 In particular, considerations concerning outcome must take into account more than just patient survival. Moreover, even when there is sufficient evidence in terms of survival, issues regarding the long-term side-effects of intensive therapies are of tremendous importance for patients and their relatives,7 especially when treatment options include aggressive therapeutic approaches. Unfortunately, although several studies have evaluated quality of life (QOL) of SCT recipients in recent years, information remains inconclusive. In this sense, while some authors have reported good physical and functional recovery after SCT,8,7,9–11 other studies have described important functional impairments such as fatigue, psychological distress and sexual dysfunction.12,13 In addition, most of these studies are crosssectional, and other, longitudinal studies analyzing post transplant QOL over time are required.14 Finally, previous cross-sectional studies have shown that QOL might be impaired after allogeneic transplantation more significantly than in autologous especially in the case of severe chronic graft versus host disease,14–18 although as yet, there have been no longitudinal studies comparing QOL after autologous and allogeneic transplantation. In an effort to reduce the morbidity and mortality associated with allogeneic transplantation, several groups have recently developed nonmyeloblative or reduced intensity conditioning regimens (RIC) designed to be immunosuppressive rather than myeloablative in order to reduce the toxicity associated with high-dose chemotherapy, while maintaining the therapeutic effect of the procedure through a graft versus leukemia reaction.19,20 These RIC transplants have extended the use of allogeneic transplantation to patients with a high risk of transplantrelated mortality (TRM) due to age or other concurrent medical conditions.20

QOL in RIC allogeneic transplantation M Dıéz-Campelo et al

730

In the present study, for the first time, QOL was analyzed during the first year post transplant in patients undergoing RIC allogeneic transplantation, and we compared this cohort of patients with a similar group of patients receiving autologous SCT (ASCT) in the same institution during the same period of time. By definition, in our institution, patients with a suitable donor undergo RIC only in the event of advanced age or concurrent medical condition which increases the risk of morbidity and/or mortality after conventional myeloablative conditioning (CMC) regimen. For this reason, we did not compare RIC vs CMC since pretransplant characteristics of both subgroups of patients are significantly different, thus hampering any conclusion regarding comparison of QOL after transplantation. For this reason, we chose to compare RIC patients with a similar group of patients without a suitable donor undergoing ASCT. Moreover, ASCT is considered a procedure associated with a low morbidity and mortality thus making this subset of patients an interesting group to compare with RIC in terms of QOL. For this purpose, we used selfreported questionnaires21 that patients completed at different time-points after transplant. Questionnaires meet requirements of validity, sensitivity and reliability for assessment of various issues such as physical, functional, psychological and social domains based on the FACTBMT questionnaire.22–25

Patients and methods Patients Between January 1999 and January 2003, 47 out of 60 patients at our institution undergoing an RIC peripheral blood stem cell (PBSC) transplant (allo-RIC) from an HLA identical sibling, gave their consent to participate in this study. Patients gave written informed consent for inclusion in the protocol, which was approved by all local ethical review boards and the Spanish Drug Agency (protocol 990151). Eligibility criteria for entry into this RIC included patients with a myeloid or lymphoid malignancy potentially treatable with an allogeneic transplant, who were 45 years old or more and/or who were at high risk of transplantrelated mortality (TRM) according to their pretransplant evaluation.24–27 Patient characteristics are shown in Table 1. Disease phase at transplant was categorized as early, low risk (acute leukemia or poor-risk myelodysplasia in first complete remission, first chronic–phase CML, lymphoid malignancy in first remission), intermediate (acute leukemia or myelodysplasia in second or more complete remission, second chronic or accelerated-phase CML, lymphoid malignancy in second or more remission, untreated standard-risk myelodysplasia) and advanced, high risk (refractory or relapsed acute leukemia or myelodysplasia, blastic-phase CML, refractory or relapsed lymphoid malignancy and all second transplants). Donors were sexmatched in 51% cases and mismatched in 49%. Two RIC regimens based on fludarabine 150 mg/m2 plus melphalan 140 mg/m2 or fludarabine 150 mg/m2 plus busulfan 10 mg/m2 were used, the former regimen recommended for lymphoid and the latter for myeloid maligBone Marrow Transplantation

Table 1

Patient characteristics

Median age (range) Diagnosis AML ALL CML MDS NHL HD Breast cancer MM CLL Amyloidosis Disease status Low risk Intermediate risk High risk

Autologous transplant N ¼ 70

RIC allogeneic transplant N ¼ 47

P

55 (19–70)

52 (16–65)

0.45

5 1 0 2 27 7 6 18 3 1

37 (53%) 30 (43%) 3 (4%)

10 2 5 5 6 4 0 11 1 0

13 (28%) 24 (51%) 10 (21%)

0.002

0.001

nancies.20 GVHD prophylaxis consisted of cyclosporine A (CsA) plus short-course methotrexate (MTX). Acute and chronic GVHD were graded by established criteria.26 In addition, 70 out of 95 patients receiving autologous stem cell transplant (ASCT) during the same period who gave their consent to enter the study were included. Only patients to be monitored at our institution after the procedure were invited to enter the QOL study. Patient characteristics are shown in Table 1. In all, 37 patients received BEAM27 as the conditioning regimen. Other regimens used were: busulfan plus melphalan (eight patients), cyclophosfamide plus carboplatin plus thiotepa (six patients), melphalan (11 patients), busulfan plus cyclophosfamide (seven patients) and Cy plus TBI (one patient).28,29 Patients receiving RIC and ASCT received a mean of 2 vs 3 lines of chemotherapy prior to transplantation. While no significant differences were observed between the two groups in terms of median age, patients undergoing alloRIC had a more advanced disease status as compared to those undergoing ASCT (21 vs 4% high-risk patients, respectively; Po0.001). In addition, significant differences were observed in terms of diagnosis (P ¼ 0.002, Table 1).

Quality of life assessment Informed consent was required for the prospective QOL study. All eligible patients received the questionnaires on days þ 7, þ 14, þ 21, þ 90, þ 180, þ 270 and þ 360 post transplant. Questionnaires included 55 items divided into six domains assessing physical and functional environment, social/family well-being and psychological distress and satisfaction with the doctor/patient and nursery/patient relationship. Each answer was evaluated from 0 (not at all) to 4 (very much) with higher scores indicating worst functioning except for the items related to functional wellbeing and relationships (social and family well-being and patient/nurse or patient/doctor relationship) where higher scores indicate a better functioning. The questionnaire was based on FACT-BMT (version 3),22–25 including additional items regarding graft-versus-host-disease symptoms.


731

Statistical analysis In order to perform a longitudinal assessment of QOL during the first year after transplant, patients received the questionnaires at seven time points, as previously specified. For cross-sectional comparisons between values obtained at the different time points, univariate ANOVA tests were performed. For longitudinal comparisons, an intrasubject model (time) was defined in order to guarantee equivalence between groups, thereby configuring a mixed factorial or split-plot model30,31 in which the variability attributed to individual characteristics was eliminated by the maximum blocking design.32 As a statistical model for the General Model Line, a two-way, Measurement Repeated Multiple Analysis (MR-MANOVA two way) was performed to compare the differences between both subgroups in terms of mean values considering the whole period analyzed, since the theoretical conditions (independence, normality, homoscedasticity, covariant equality and sphericity) were met and because the possible significance of the intrasubject factor (time) was sought in combination with the different Inter-subject factors. All factors which significantly influenced QOL on univariate analysis were included in a multivariate analysis. Since the variables ‘type of transplant’ and ‘graft versus host disease’ are mutually exclusive (where ‘type of transplant’ ¼ ‘autologous’, GVHD does not apply), a multivariate analysis was performed including ‘type of transplant,’ but excluding GVHD and then a second multivariate analysis was performed which included GVHD but not the type of transplant. As far as the validation of the questionnaire was concerned, items other than those already included in FACT-BMT, were selected and subjected to the Internal Validity of the Construct once the conditions necessary for the use of a Factorial Analysis were in place (sphericity test: P ¼ 0.000 and KMO ¼ 710). After confirming that the factors did not correlate between each other the Principal Components extraction method with Equamax rotation. In the last solution after rotation, three groups of variables were found which included items such as saturations superior to 0.515, which would account for the 61.483% total variability observed in the questionnaire. This led us to conclude that the Structural Validity of the scale had been sufficiently proven.

Results Overall outcome Although the number of CD34 þ cells infused did not significantly differ between either subgroup (2.3278.95 and 4.3872.41 s.d. 106 CD34 þ cells/kg for ASCT and alloRIC, respectively; P ¼ 0.53), granulocyte engraftment was significantly faster among patients receiving autologous transplantation (Table 2). Both subgroups also differed regarding fever episodes (100 and 64% of patients receiving ASCT and RIC allogeneic transplant developed any fever episode, Po0.001) and finally, patients receiving ASCT had significantly more mucositis and nausea/vomiting as

Table 2

Transplant characteristics

CD34 cells infused Median (range) Days to reacha 4500 granulocytes 420 000 platelets

Autologous transplant N ¼ 70

RIC allogeneic transplant N ¼ 47

P

2.32 (1.2–8.38)

4.38 (1.2–13.2)

0.53

11 (9–17) 12 (11–28)

64%

o0.001 0.12 o0.001

Fever Days of fever Mean (s.d.)

4 (2.6)

5 (7.6)

0.35

Toxicity Mucositis 0–1 Mucositis 3–4 Nausea/vomiting 0–1 Nausea/vomiting 3–4 Diarrhea 3–4

73.10% 40.40% 38.50% 15.40% 5.70%

41.30% 21.70% 21.30% 8.50% 6.40%

0.0001 0.03 0.05 0.23 0.87

a

100%

15 (6–23) 13 (0–23)

Median (range).

compared to patients receiving allo-RIC (Table 2). No other severe toxicities were observed in either of the two groups. With a median follow-up of 281 days (range: 21–2196 days) 17 patients have died and 17 have relapsed. Projected event-free survival (EFS) at 3 years is 51% for patients undergoing RIC allogeneic transplant and 54% for those receiving autologous transplantation and relapse rates did not significantly differ between either subgroup (21 vs 13%, ptns). Among allo-RIC patients acute graft versus host disease (aGVHD) appeared at a median of 35 days (range: 10–125) and an overall cumulative incidence was 42% (11% grades III–IV). Chronic GVHD flared at a median of 168 days (104–420) with overall cumulative incidence of 66%. All patients included in this study who developed aGVHD had extensive cGVHD.

Quality of life assessment (QOL) Physical functioning categories. Regarding physical functioning categories, 13 items were analyzed. Mean values of physical categories among RIC allogeneic transplants ranged between 1.23 and 0.77, which indicates that, overall, patients scored very low for physical symptoms. As observed in Figure 1, mean values did not significantly change during the year post transplant (P ¼ 0.34) in this subset of patients since scores were low even on the questionnaires performed very early after transplant in contrast to patients undergoing ASCT who had higher scores on questionnaires performed on days þ 7 to þ 28 and then gradually improved mean QOL scores at subsequent controls (scores ranging from 1.63 to 0.51, Po0.001). Overall, when we compared mean physical functioning scores during the first year after transplant between allo-RIC and ASCT patients, the former group did significantly better (Figure 1n, P ¼ 0.049). Nevertheless, it should be noted that while allo-RIC scores were better for the first three controls performed early after transplant, Bone Marrow Transplantation


732

a

b

c

3

3

3

P = 0.016

0

1

2

3

4

P = 0.78

5

6

7

0

1

2

3

4

5

6

7

0

d

1

2

3

e

3

P=0.04

3

P = 0.006

4

5

6

7

0

1

2

3

4

P = 0.6

5

6

0

7

1

2

3

4

5

6

7

4

5

6

7

Days after transplant

g

f

h

3

3

1

2

3

4

5

6

7

0

1

2

3

4

3

P = 0.19

5

6

7

j

3

P = 0.086

P = 0.15

0

i

3

0

2

3

4

P = 0.33

5

6

7

0

1

2

3

P = 0.83

4

5

6

0

7

1

2

3


k 3

l 3

P = 0.049

m 3

P = 0.006

n

3

P = 0.049

P = 0.001

Autologous RIC allogeneic 0

1

2

3

4

5

6

7

0

1

2

3

4

5

6

7

0

1 2

3

4

5

6

7

0

1

2

3

4

5

6

7


Figure 1

Scores of physical well-being categories along the first year post transplant. (a) Lack of energy (V1); (b) shortness of breath (V2); (c) need of rest (V3); (d) nausea (V4); (e) uncompliance of family duties due to physical limitations (V5); (f) pain (V6); (g) pain interferes in daily activities (V7); (h) any symptom related to therapy (V8); (i) I feel sick (V9); (j) I need to stay in the bed (V10); (k) itching (V11); (l) any ocular disturbances (V12); (m) any disturbances in mouth (V13); (n) evolution of the mean score of all categories. Days after transplant: (1) day þ 7 after infusion; (2) day þ 14; (3) day þ 28; (4) day þ 90; (5) day þ 180; (6) day þ 270; (7) day þ 365.

patients undergoing autologous transplant did better in the last two questionnaires performed on days þ 270 and þ 365, so that both curves crossed around day þ 180, which coincides with the median day of cGVHD flare. More specifically, in the early post transplant period, patients undergoing ASCT had worse scores regarding lack of energy, need for rest, nausea, pain or symptoms related to therapy as specified in Figure 1a, c, d, f, g and h. This is in accordance with post transplant toxicities specified in Table 2. Although scores decreased significantly later questionnaires for ASCT patients, overall, significant differences persisted in favor of allo-RIC patients in the longitudinal comparison during the first year post transplant regarding lack of energy, need of rest and nausea. By contrast, upon analyzing variables related to GVHD symptoms such as itching, ocular or mouth disturbances, we observed that, except for an initial benefit in mouth disturbances after allo-RIC, scores were Bone Marrow Transplantation

significantly higher after day þ 180 among patients receiving RIC allogeneic transplant (Figure 1k, l, m). Finally, on day þ 365, 9.5% of patients receiving alloRIC, as compared to 5.5% among ASCT patients (P ¼ 0.54), scored ‘quite a bit or very much’ to the item ‘I have shortness of breath,’ while 32.3% of allo-RIC vs 59.1% of ASCT patients (P ¼ 0.01) scored ‘quite a bit or very much’ to the item ‘I need to rest’. Other variables with significant influence on mean physical well-being are summarized in Table 3. Fever, mucositis and nausea/vomiting influenced physical wellbeing on days þ 7, þ 14 or þ 28, while none of them had an impact after that time-point in cross-sectional analysis. Nevertheless, mucositis and nausea/vomiting did influence the overall physical well-being during the first year post transplant as assessed by longitudinal analysis (Table 3 and Figure 2a, b). In addition, as shown in Figure 2c and d, aGVHD adversely affects QOL in the cross-sectional


733 Variables with significant influence on physical well-being during the first year post transplant

Table 3


P long

+7

P

+14

P

+28

P

+90

P

+180

P

+270

P

+360

P

Fever Yes No

1.49 1.06

0.032

1.47 1

0.023

1.04 0.94

0.53

0.73 0.82

0.56

0.61 0.85

0.14

0.76 0.77

0.96

0.67 0.71

0.84

0.065

Mucositis Grades 0–1 Grades 2–4

1.3 1.6

0.06

1.18 1.49

0.04

0.9 1.13

0.09

0.75 0.76

0.93

0.68 0.65

0.85 0.58

0.12

0.77 0.57

0.14

0.008

Nausea/vomiting Grades 0–1 Grades 2–4

1.29 1.85

0.001

1.25 1.59

0.037

0.87 1.38

0.001

0.77 0.74

0.86

0.7 0.45

0.19

0.73 0.8

0.77

0.69 0.47

0.25

0.034

aGVHD Yes No

1.23 1.18

0.85

1.9 1.1

0.27

1.22 0.99

0.27

1.14 0.64

0.01

1.04 0.75

0.31

1.17 0.75

0.17

0.61 0.86

0.38

0.004

cGVHDa Yes No

1.55 1.07

0.1

1.08 1.22

0.68

0.89 1.15

0.24

0.88 0.81

0.74

1.16 0.58

0.01

1.25 0.61

0.01

1.53 0.52

0.024

0.77

86

P long refers to differences between auto and RIC along the year post transplant. P-value in each time-point refers to differences observed between mean values in that specific day post transplant. a P ¼ 0.032 when we compared results from day X+90. Bold type indicates statistically significant values (lower than 0.05).

a

b

4

P = 0.008

0

c

1

2

3

4

4

P = 0.034

5

6


7

0

d

4

4

1

2

3

4

P = 0.004

5

6

7

Days after trasnplant

Yes

0

1

2

3

4

P = 0.032

5

6


7

0

1

2

3

4

5

6

7


No

Figure 2 Mean physical well-being along the first year post transplant according to the development of mucositis grades 1,2 (a); nausea/vomiting grades 1,2 (b); acute graft versus host disease (c) and chronic graft versus host disease (d). Days after transplant: (1) day þ 7 after transplant; (2) day þ 14; (3) day þ 28; (4) day þ 90; (5) day þ 180; (6) day þ 270; (7) day þ 365.

analysis performed on the first four controls after transplant, while cGVHD had an unfavorable impact on QOL from day þ 180 and onwards. In the longitudinal analysis, GVHD significantly influenced QOL during the first year post transplant. All variables which significantly affected physical functioning on univariate longitudinal analysis were included in a multivariate analysis and mucositis plus type of transplant were the only variables which had a significant impact on physical well-being in the longitudinal analysis (P ¼ 0.0003 for both). By contrast, when we excluded type of transplant and included GVHD, this was the only variable which retained statistical significance in multivariate analysis (P ¼ 0.018).

Functional well-being categories. Eight items were included for evaluating functional well-being (see Appendix A). No significant differences were observed between either subgroup for any of the functional well-being items. Mean value of functional categories ranged between 2.03 and 2.52 among allo-RIC patients during the first year post transplant and between 2.04 and 2.75 among ASCT patients, so that in both groups mean scores slowly improved over the year post transplant. Nevertheless, 14.3% of allo-RIC and 26.3% of ASCT patients still had problems sleeping in the control performed on day þ 365 (P ¼ 0.29), while 38 vs 57.9% of allo-RIC and ASCT patients scored ‘quite a bit or very much’ to the item ‘I’m able to work’ (P ¼ 0.17). Bone Marrow Transplantation


734 Table 4

Variables with significant influence on mean functional well-being during the first year post transplant Day +7

Day +14

Day +28

Day +90

Day +180

Day +270

Day +365

P long

Mean

P

Mean

P

Mean

P

Mean

P

Mean

P

Mean

P

Mean

P

aGVHDa No Yes

2.06 2.07

0.96

1.94 2.1

0.56

2.23 2.02

0.4

2.2 2.57

0.07

2.3 2.46

0.59

2.22 2.36

0.73

2.78 2.37

0.4

0.036

cGVHDb No Yes

1.69 2.28

0.09

2.13 2.11

0.9

2.15 2.21

0.8

2.39 2.44

0.8

2.17 2.6

0.1

1.88 2.6

0.02

2.2 2.79

0.14

0.05

P ¼ 0.036 upon comparing QOL from day o/ ¼ +90. P ¼ 0.02 when we compared results up to day +90. Bold type indicates statistically significant values (lower than 0.05).

a

b

Regarding variables which could influence mean functional well-being, only GVHD, both acute and chronic, had an adverse impact on functional well-being during the first year post transplant (Table 4).

were scored 3 or higher and no differences were observed between ASCT or allo-RIC patients. Scores did not significantly change during the year post transplant.

Social/family well-being and psychological distress categories. In total, 14 items divided into two domains were used to assess social/family well-being and psychological distress. Within the former domain, high scores (ie, better well-being for social and family items) were obtained for all questions (see Appendix A) even in the first controls performed early after transplantation, with mean scores ranging from 2.7 and 2.7 for ASCT and from 2.58 to 2.64 for allo-RIC in day þ 7 on day þ 365, respectively (P ¼ 0.29). In addition, no significant changes in mean scores were observed for these items during the year following transplant. By contrast, sexual well-being had low scores, ranging from 0.5 in the fist questionnaire to 2.2 in the questionnaire performed on day þ 365 (P ¼ 0.001). In fact, this was the only item which significantly improved during the first year post transplant. Finally, no significant differences were observed between ASCT and allo-RIC for any of these items. Regarding psychological distress, seven items addressing symptoms of depression (see Appendix A) were evaluated. No significant differences were observed between patients undergoing ASCT or allo-RIC either in terms of depression or anxiety. Scores were low for depression and they did not significantly alter over the year post transplant. In this sense, 0–13% of allo-RIC and 4.3–23% of ASCT patients answered ‘quite a bit or very much’ to items related to depression in the first questionnaire (day þ 7) as compared to 5–5.6% of allo-RIC and 9–13.6% of ASCT patients in the questionnaire performed on day þ 365 (P40.63). Concerning symptoms of anxiety, again scores did not significantly alter during the year post transplant. Nevertheless, mean scores were slightly higher than those observed for depression with 22.6–45.2% of allo-RIC and 19–34.4% of ASCT patients who answered ‘quite a bit or very much’ to items related to anxiety in the first questionnaire (day þ 7) as compared to 26.3–44.4% of allo-RIC and 9.1–42.9% of ASCT patients in the questionnaire performed on day þ 365 (P40.14).

Discussion

Doctor/patient and nurse/patient relationship. As far as relationship with doctors and nurses is concerned, all items Bone Marrow Transplantation

Although allogeneic transplantation is the best treatment modality for patients diagnosed with poor prognostic acute leukemias or advanced stage hematological malignancies,1,3,4 its efficacy has been hampered by significant morbidity and mortality related to the procedure (TRM).33 Even with the chance of being cured, some questions remain crucial for these patients: Does the time gained have sufficient quality? Is curative therapy with a high mortality or persistent morbidity worth it? The answer to these questions should contribute to providing patients with better information regarding quality of life which would be of great use for patients and their physicians in standardizing practice regarding the decision-making process. Moreover, this information should be available to the patients and their relatives in order for them to choose the most appropriate treatment option.2 With this goal in mind, in 1999, we developed a questionnaire based on FACT-BMT,22–25 including additional items regarding graft-versus-host-disease symptoms. The questionnaire was validated as previously described. We designed a prospective longitudinal study in order to evaluate the QOL among patients undergoing reduced intensity conditioning allogeneic transplantation and compared these results to those obtained among patients receiving ASCT. RIC transplants have been developed to be immunosuppressive rather than myeloablative,19,20 in an effort to reduce the high mortality rate reported after conventional allogeneic transplantation in patients of advanced age or with comorbid pretransplantation conditions.34 Moreover, in addition to a lower TRM, in standard clinical practice it has been observed that there is a significant improvement in QOL after RIC allogeneic transplantation although no study has been reported to date far evaluating the impact of this procedure on QOL of these patients. On the other hand, according to previous studies, age may adversely affect QOL after transplant and, since most candidates receiving RIC allogeneic transplantation are of advanced age or have a concurrent medical condition, QOL assessment could be impaired.35 In addition, since this procedure


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may reduce TRM in patients with a poor performance status, a higher subset of these patients may survive after transplant thus adversely affecting overall QOL. Although it would be reasonable to argue that the optimal comparison in terms of QOL would have been to compare patients undergoing RIC vs conventional myeloablative conditioning (CMC) allogeneic transplantation, in our institution, patients with a suitable donor undergo RIC only in the event of advanced age or a comorbid medical condition which increases the risk of morbidity and/or mortality after conventional transplantation. For this reason, by definition pretransplant characteristics of both subgroups of patients are significantly different. An alternative was to compare RIC patients with a similar group of patients without a suitable donor undergoing ASCT in the same period of time. As a matter of fact, although some characteristics at transplant differ between the two subgroups, none of these variables represented a contraindication to receiving one or the other option and, furthermore, none of them significantly affected QOL on univariate analysis. In addition, this comparison would allow us to address the impact on QOL of the immune reactions inherent to the allogeneic transplant with low toxicity related to the chemotherapy in the RIC setting vs the side effects of the high doses of chemotherapy used in the autologous setting. Finally, ASCT is considered a procedure, which induces a low morbidity and mortality thus making this subset of patients an interesting group to compare with RIC in terms of QOL. To the best our knowledge, the present study is the first of its kind to focus on QOL assessment after RIC allogeneic transplantation. Moreover, so far, there have been no longitudinal studies comparing QOL after autologous or allogeneic transplant especially during the first year after transplant,12,36 although cross-sectional studies have shown impaired QOL among patients receiving allogeneic as compared to those receiving autologous transplants mostly due to graft versus host disease-related symptoms.14–18 In the present study, both subgroups of patients receiving either autologous or RIC allogeneic transplants had a similar median age although, as expected, diagnosis and disease status at transplant significantly differed between subgroups. Interestingly, when we compared physical well-being items, those patients receiving an RIC allogeneic transplant had a significantly better QOL during the first year post transplant, thus showing the favorable impact of RIC transplant on morbidity. Nevertheless, it should be noted that, in the current study, among seven questionnaires, four were completed before day þ 180 and only two after that date, so that the higher number of questionnaires completed during the first 6 months after transplant may have increased their weight in the overall comparison even though scores were better among patients receiving ASCT in the questionnaires performed after that date. Not unexpectedly, items concerning high-dose chemotherapy-related toxicity such as nausea and vomiting, lack of energy or need to rest had significantly better scores in the allo-RIC group than in the ASCT group. By contrast, symptoms related to acute graft versus host disease significantly hampered QOL among patients receiving RIC allogeneic transplants in the early

post transplant period and symptoms related to chronic graft versus host disease adversely affected QOL after day þ 180, which was approximately the median day of cGVHD flare. In fact, items addressing cGVHD symptoms such as itching, ocular or mouth disturbances are variables which significantly contributed to the poorer QOL observed among allo-RIC patients after day þ 180, and thus effected the cross between the curves of ASCT and alloRIC patients at that specific time-point. Although not surprising, this is an important finding since the therapeutic effect of allo-RIC transplantation relies mainly on the graft versus tumor effect and, in this sense, several studies have shown that cGVHD favorably affects event-free survival.37 According to this and other studies,11 cGVHD should also be considered an ‘event’ regarding QOL of patients, so that in the future, more specific targets for the immune response must be explored in order to exploit the graft versus tumor effect without hampering QOL. Quality of life scores were good for most of the items analyzed; the same scores were found for ASCT and RIC patients regarding fuctional environment, social and family well-being, psychological distress and satisfaction with doctor/nurse relationships. Nevertheless, this information should be interpreted with caution since, as has been pointed out,12,38 patients who have suffered a stressful event, such as cancer diagnosis, are grateful for treatment, which would be reflected in their QOL scores. This could be a confusing variable in studies which have compared symptoms of patients receiving bone marrow transplantation with those of healthy controls.39 By contrast, it would not affect either the comparison between ASCT and alloRIC patients or the tendency or evolution of symptoms in patients during the year following transplant. In addition, it should be noted that, as suggested in previous studies, QOL among patients receiving a SCT is especially hampered during the first year post transplant, with improvements observed during the long-term follow-up for most patients at 2 and 5 years after transplantation.7,15 Interestingly, in our study, focusing on QOL during the first year post transplant, most patients gave low scores for fatigue or weakness, which are some of the most common symptoms described among SCT survivors.12,40 More specifically 9.5% of patients receiving allo-RIC scored ‘quite a bit or very much’ to the item ‘I have shortness of breath’ on day þ 365 which is in contrast to previous studies describing 72% of patients who reported distressing levels of fatigue at 20 months post transplant.41 Although in the current study a significant proportion of patients (32.3% of allo-RIC) scored ‘quite a bit or very much’ to the item ‘I need to rest’ these results again compare favorably to previous studies showing that 30% of patients maintained problems with their energy level at 45 months post transplant.40 Other symptoms commonly described after SCT are problems concerning sleep quality and psychological distress.12,40 In this sense, Whedon et al42 have reported moderate-tosevere psychological distress in 93% of patients, while other authors have described symptoms of depression in 33–45% and anxiety in 48% of patients undergoing SCT.43,44 In the current study, 0–13% of patients undergoing RIC allogeneic transplantation showed symptoms of depression during the first year post transplant, which did not Bone Marrow Transplantation


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significantly differ from those patients undergoing autologous transplantation. By contrast, a higher percentage of patients had symptoms of anxiety, ranging from 22.6 to 45.2% among patients receiving allo-RIC and this incidence is similar to that reported in previous studies. In the present study, we have observed a lower adverse impact on QOL of RIC allogeneic as compared to autologous transplantation during the first months after transplant, which is due to a lower incidence of high-dose chemotherapy-related toxicity. By contrast, graft versus host disease remains an important ‘event’ in terms of QOL among patients receiving RIC allogeneic transplant and its effect on QOL becomes evident at 9 months after transplantation. In conclusion, by the first time point in the decision-making process, impairment of QOL does not hamper the allo-RIC approach as compared to autologous transplantation at least in the period analyzed in the current study. Studies analyzing QOL of these patients in the long-term follow-up are warranted.

Acknowledgements To Amelia de Leoń and Inmaculada Garcı´ a-Palomero for their contribution to this study.

References 1 Woolf SH. Shared decision making: the case for letting patients decide which choice is best. J Fam Pract 1997; 45: 205–208. 2 Silver RT, Woolf SH, Hehlmann R et al. An evidence-based analysis of the effect of busulfan, hydroxyurea, interferon, and allogeneic bone marrow transplantation in treating the chronic phase of chronic myeloid leukaemia: developed for the American Society of Haematology. Blood 1999; 5: 1517–1536. 3 Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukaemia. European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N Engl J Med 1995; 332: 217–223. 4 Sebban C, Lepage E, Vernant JP et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukaemia in first complete remission: a comparative study. French group of therapy of adult acute lymphoblastic leukaemia. J Clin Oncol 1994; 12: 2580–2587. 5 Gianni AM, Bregni M, Siena S et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 18: 1290–1298. 6 Philip T, Guglielmi C, Hagenbeek A et al. Autologous bone marrow transplantation as compared with salvage chemotherapy in relapses of chemotherapy-sensitive non-Hodgkin’s lymphoma. N Engl J Med 1995; 23: 1540–1545. 7 Worel N, Biener D, Kalhs P et al. Long-term outcome and quality of life of patients who are alive and in complete remission more than two years after allogeneic and syngeneic stem cell transplantation. Bone Marrow Transplant 2002; 30: 619–626.

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8 Chao NJ, Tierney K, Bloom JR et al. Dynamic assessment of quality of life after autologous bone marrow transplantation. Blood 1992; 80: 825–830. 9 Hjermstad MJ, Evensen SA, Kvaloy SO et al. Health-related quality of life 1 year after allogeneic or autologous stem-cell transplantation: a prospective study. J Clin Oncol 1999; 17: 706–718. 10 Heinonem H, Volin L, Uutela A et al. Quality of life and factors related to perceived satisfaction with quality of life after allogeneic bone marrow transplantation. Ann Hematol 2001; 80: 137–143. 11 Kiss TL, Abdolell M, Jamal N et al. Long-term medical outcomes and quality of life assessment of patients with chronic myeloid leukemia followed at least 10 years after allogeneic bone marrow transplantation. J Clin Oncol 2002; 20: 2334–2343. 12 Neitzert CS, Ritvo P, Dancey J et al. The psychosocial impact of bone marrow transplantation: a review of the literature. Bone Marrow Transplant 1998; 22: 409–422. 13 Kopp M, Schweigkofler H, Holzner B et al. Time alter bone marrow transplantation as an important variable for quality of life: results of a cross-sectional investigation using two different instruments for quality of life assessment. Ann Hematol 1998; 77: 27–32. 14 Syrjala KL, Chapko MK, Vitaliano PP et al. Recovery alter allogeneic marrow transplantation: prospective study of predictors of long-term physical and psychosocial functioning. Bone Marrow Transplant 1993; 11: 319–327. 15 Zittoun R, Suciu S, Watson M et al. Quality of life in patients with acute myelogenous leukemia in prolonged first complete remission alter bone marrow transplantation (allogeneic or autologous) or chemotherapy: a cross-sectional study of EORTC-GIMEMA AML 84 trial. Bone Marrow Transplant 1997; 20: 307–315. 16 Andrykowski MA, Henslee-Downey PJ, Farral MG. Physical and psychosocial functioning of adult survivors of allogeneic bone marrow transplantation. Bone Marrow Transplant 1989; 4: 75–81. 17 Belec RH. Quality of life: perceptions of long-term survivors of bone marrow transplantation. Oncol Nurs Forum 1992; 19: 31–37. 18 Jenkins PL, Linington A, Whittaker JA. A retrospective study of psychosocial morbidity in bone marrow transplantation recipients. Psychosomatics 1991; 32: 65–71. 19 Slavin S, Nagler A, Naparstek E et al. Nonmyeloablative stem cell transplantation and cell therapy as an alternative to conventional bone marrow transplantation with lethal citoreduction for the treatment of malignant and non malignant hematologic diseases. Blood 1998; 91: 756–763. 20 Martino R, Caballero MD, Canals C et al. Allogeneic peripheral blood stem cell transplantation with reducedintensity conditioning: results of a prospective multicenter study. Br J Haematol 2001; 115: 653–659. 21 Slevin ML, Plant H, Lynch D et al. Who should measure quality of life, the doctor or the patient? Br J Cancer 1998; 57: 109–112. 22 Aaronson NK, Ahmedzai S, Bergman B et al. The European organization for research and treatment of cancer QLQ-C30: a quality of life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376. 23 Kopp M, Schweigkofler H, Holzner B et al. EORTC QLQ-C30 and FACT-BMT for the measurement of quality of life in bone marrow transplant recipients: a comparison. Eur J Hematol 2000; 65: 97–103. 24 Cella DF, Tulsky DS, Gray G et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol 1993; 11: 570–579.


737 25 McQuellon RP, Russell GB, Cella DF et al. Quality of life measurement in bone marrow transplantation: development of the Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) scale. Bone Marrow Transplant 1997; 19: 357–368. 26 Przepiorka D, Weisdorf D, Martin P et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828. 27 Caballero MD, Rubio V, Rifoń J et al. BEAM chemotherapy followed by autologous stem cell support in lymphoma patients: analysis of efficacy, toxicity and prognostic factors. Bone Marrow Transplant 1997; 20: 451–458. 28 Sureda A, Arranz R, Iriondo A et al. Autologous stem-cell transplantation for Hodgkin’s disease: results and prognostic factors in 494 patients from the Grupo Espanol de Linfomas/ Transplante Autologo de Medula Osea Spanish Cooperative Group. J Clin Oncol 2001; 19: 1395–1404. 29 Caballero MD, Perez-Simon JA, Iriondo A et al. High-dose therapy in diffuse large cell lymphoma: results and prognostic factors in 452 patients from the GEL-TAMO Spanish Cooperative Group. Ann Oncol 2003; 14: 140–151. 30 Arnau J. Disenõs longitudinales aplicados a las CC.SS. y del comportamiento. Limusa: Me´xico, 1995. 31 Kirk RE. Experimental Design: Procedures for the Behaviorial Sciences, (2nd edn) Brooks/Cole: Monterrey, 1982. 32 Maxwell SE, y Delaney HD. Designing Experiments and Analysis of Data – A Model Comparison Perspective. Wadsworth Publishing Company: Beltmont, 1990. 33 Armitage JO. Bone Marrow Transplantation. N Eng J Med 1994; 330: 827–838. 34 Klingemann HG, Storb R, Fefer A et al. Bone marrow transplantation in patients aged 45 years and older. Blood 1986; 65: 770–776. 35 Chiodi S, Spinelli S, Ravera G et al. Quality of life in 244 recipients of allogeneic bone marrow transplantation. Br J Haematol 2000; 110: 614–619. 36 Hjermstad JR, Kaasa S. Quality of life in adult cancer patients treated with bone marrow transplantation – a review of the literature. Eur J Cancer Care 1995; 31A: 163–173. 37 Pe´rez-Simoń JA, Martino R, Alegre A et al. Chronic but not acute graft versus host disease improves outcome in multiple myeloma patients after nonmyeloablative allogeneic transplantation. Br J Hematol 2003; 121: 104–108. 38 Vickberg S, Duhamel KN, Smith MY et al. Global meaning and psychological adjustment among survivors of bone marrow transplant. Psycho-oncology 2001; 10: 29–39. 39 Andrykowski MA, Greiner CB, Altmaier EM et al. Quality of life following bone marrow transplantation: findings from a multicenter study. Br J Cancer 1995; 71: 1322–1329. 40 Andrykowski MA, Carpenter JS, Greiner CB et al. Energy level and sleep quality following bone marrow transplantation. Bone Marrow Transplant 1997; 20: 669–679. 41 Hann DM, Jacobsen PB, Martin SC et al. Quality of life following bone marrow transplantation for breast cancer: a comparative study. Bone Marrow Transplant 1997; 19: 257– 264. 42 Whedon M, Stearns D, Millis LE. Quality of life of long-term adult survivors of autologous bone marrow transplantation. Oncol Nursing Forum 1995; 22: 1322–1329. 43 McQuellon RP, Craven B, Russell GB et al. Quality of life in breast cancer patients before and after autologous bone marrow transplantation. Bone Marrow Transplant 1996; 18: 579–584. 44 Syrjala KL, Chapko MK, Vitaliano PP et al. Recovering after allogeneic marrow transplantation: prospective study of predictors of long-term physical and psychosocial functioning. Bone Marrow Transplant 1993; 11: 319–327.

Appendix A: English version questionnaire FACT-BMT (version 3) Below is a list of statements that other people with your illness have said are important. By circling one number per line, please indicate how true each statement has been for you during the past 7 days. Physical well-being (not at all, a little bit, some-what, quite a bit, very much) 1 I have a lack of energy. 2 I have nausea. 3 Because of my physical condition, I have trouble meeting the needs of my family. 4 I have pain. 5 I am bothered by side-effects of treatment. 6 I feel sick. 7 I am forced to spend time in bed. 8 Looking at the above 7 questions, how much would you say your Physical Well-Being affects your quality of life? Social/family well-being (not at all, a little bit, some-what, quite a bit, very much) 9 I feel distant from my friends. 10 I get emotional support from my family. 11 I get support from my friends and neighbors. 12 My family has accepted my illness. 13 Family communication about my illness is poor. 14 I feel close to my partner (or the person who is my main support). 15 Have you been sexually active during the past year? No/Yes If yes: I am satisfied with my sex life. 16 Looking at the above seven questions, how much would you say your life Social/Family Well-Being affects your quality of life? Relationship with doctor (not at all, a little bit, some-what, quite a bit, very much) 17 I have confidence in my doctor(s). 18 My doctor is available to answer my questions. 19 Looking at the above two questions, how much would you say your Relationship with the Doctor affects your quality of life? Emotional well-being (not at all, a little bit, some-what, quite a bit, very much) 20 I feel sad. 21 I am proud of how I’m coping with my illness. 22 I am losing hope in the fight against my illness. 23 I feel nervous. 24 I worry about dying. 25 I worry that my condition will get worse. 26 Looking at the above six questions, how much would you say your Emotional Well-Being affects your quality of life? Functional well-being (not at all, a little bit, some-what, quite a bit, very much) 27 I am able to work (include work in home). Bone Marrow Transplantation


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28 29 30 31 32 33 34

My work (include work in home) is fulfilling. I am able to enjoy life. I have accepted my illness. I am sleeping well. I am enjoying the things I usually do for fun. I am content with the quality of my life right now. Looking at the above seven questions, how much would you say your Functional Well-Being affects your quality of life?

Additional concerns (not at all, a little bit, some-what, quite a bit, very much) 35 I am concerned about keeping my job (include work in home). 36 I feel distant from other people. 37 I worry that the transplant will not work. 38 The effects of treatment are worse than I had imagined. 39 I have a good appetite. 40 I like the appearance of my body.

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41 42 43 44 45 46 47

I am able to get around by myself. I get tired easily. I am interested in having sex. I have concerns about my ability to have children. I have confidence in my nurse(s). I regret having the bone marrow transplant. Looking at the above 12 questions, how much would you say these Additional Concerns affect your quality of life?

Additional items regarding GVHD symptoms: 48 Shortness of breath. 49 Need of rest. 50 Itching. 51 Any ocular disturbances. 52 Any disturbances in mouth. 53 Pain had interfered in my daily activity. 54 Fatigue. 55 Cough.