Quality of life Long-term outcome and quality of life of patients ... - Nature

Bone Marrow Transplantation (2002) 30, 619–626  2002 Nature Publishing Group All rights reserved 0268–3369/02 $25.00 www.nature.com/bmt

Quality of life 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 N Worel1,2, D Biener1, P Kalhs1, M Mitterbauer1, F Keil1, A Schulenburg1, P Ho¨cker2, K Dieckmann3, G Fischer2, A Rosenmayr2, W Linkesch1, W Hinterberger1, K Lechner1 and HT Greinix1 1

Department of Medicine I, Bone Marrow Transplantation Unit, University of Vienna, Austria; 2Department of Blood Group Serology and Transfusion Medicine, University of Vienna, Austria; and 3Department of Radiotherapy, University of Vienna, Austria

Summary: We assessed long-term outcome in 155 patients who had undergone an allogeneic/syngeneic stem cell transplant (SCT) and were in complete remission for more than 2 years after transplant. Probability of late transplantrelated mortality was 6%, and affected only patients with chronic graft-versus-host disease (cGVHD). Thirteen percent of patients experienced relapse. Overall survival projected at 10 and 15 years was 83% and 76%, respectively. Secondary malignancies occurred in two patients, 7.5 and 11 years after SCT. Three female and four male patients parented children 19 to 84 months after SCT. Quality of life (QoL) was assessed in a cross-sectional study by the means of a 30-item questionnaire (QLQ-C30) of the EORTC. The questionnaire was sent to 127 patients remaining alive and answered by 106 patients. Seventy-three percent reported a good to very good QoL within 5 years after SCT and 78% after this time point. However, patients with cGVHD had significant impairment of physical, role and social functioning and only 60% of them were fit for work. These results from long-term survivors show that high cure rates with good to very good QoL can be achieved by allogeneic or syngeneic SCT. Bone Marrow Transplantation (2002) 30, 619–626. doi:10.1038/sj.bmt.1703677 Keywords: allogeneic SCT; long-term outcome; quality of life

Allogeneic bone marrow or peripheral blood stem cell transplantation (SCT) is able to cure a variety of malignant and nonmalignant diseases.1–6 Disease-free survival (DFS) rates and probability of relapse after SCT differ and are influenced by disease stage and response to conventionalCorrespondence: Dr HT Greinix, AKH Wien, Klinik fuer Innere Medizin I/Knochenmarktransplantation, Waehringer Guertel 18-20, A-1090 Vienna, Austria Received 12 September 2001; accepted 13 June 2002

dose therapy prior to SCT, stem cell graft manipulation and occurrence of graft-versus-host disease (GVHD).7 Despite improvements in myeloablative conditioning regimens8,9 and supportive care including use of new generation broadspectrum antibiotics, antiviral and antifungal drugs,10–12 human leukocyte antigen (HLA)-typing and donor selection,13 and prevention and treatment of GVHD,14,15 transplant-related complications have remained a major problem of SCT. In contrast to autograft patients, treatment-related deaths after allogeneic SCT are observed not only in the early phase after SCT but also in later years, especially in patients with chronic GVHD not responding to immunosuppression.16,17 Recently, an increased rate of secondary malignancies has been reported 1.4 to 221 months after allogeneic or syngeneic SCT.18,19 Thus, lifelong monitoring of patients after SCT seems advisable. To date a few assessments on quality of life (QoL) in long-term SCT survivors have been reported.20– 22 Issues of the long-term side-effects of intensive therapies, return to prior activities and reconstitution of normal levels of functioning are of tremendous importance for patients and their relatives in the decision-making process leading to admittance for or refusal of SCT. We therefore retrospectively analyzed the long-term outcome of 155 adult patients who were alive and in continuous complete remission (CCR) more than 2 years after allogeneic stem cell transplantation for various hematological and oncological diseases. Patients were assessed for late toxicity and risk of relapse. Furthermore, we sent a QoL questionnaire to 127 patients still alive at the time of our survey. One hundred and six patients answered and a cross-sectional assessment of their QoL was performed.

Patients and methods Patients Between November 1978 and May 1998, 307 patients with acute leukemia (AL, n = 131), chronic myeloid leukemia (CML, n = 96), multiple myeloma (MM, n = 9), myelodysplastic syndrome (MDS, n = 12), non-Hodgkin’s lym-

Long-term outcome after allogeneic SCT N Worel et al

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phoma (NHL, n = 29), severe aplastic anemia (SAA, n = 24), paroxysmal nocturnal hemoglobinuria (PNH, n = 2), osteomyelofibrosis (OMF, n = 2), Hodgkin’s disease (n = 1) and testicular cancer (n = 1) underwent SCT at our institution. Stem cell donors were identical twins (n = 8), HLAidentical siblings (n = 239), one-antigen (n = 1) or twoantigen (n = 1) mismatched family members, HLAidentical unrelated donors (n = 45), one-antigen (n = 10) or two-antigen (n = 3) mismatched unrelated donors. Patients were categorized as standard risk if they had acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) in first complete remission (CR1), CML in first chronic phase (CP1), NHL in first partial remission (PR1) or testicular cancer. All others were categorized as high risk. One hundred and seventy-eight patients were assigned to the high risk and 129 to the low risk group. During the first 2 years after SCT, 152 patients died, either due to relapse (n = 65 including 51 patients categorized as high risk) or transplant-related complications (n = 87 including 54 patients in the high risk group). One hundred and fifty-five patients remained disease-free for 2 or more years after SCT and are subjects of the present analysis. Their pre-transplant characteristics are shown in Table 1. Written informed consent was obtained from all patients. Data were analyzed as of 15 March 2001. The conditioning regimens used for transplantation were those given at our institution during the time period patients were transplanted. The majority of patients received total body irradiation (TBI, 12–13.2 Gy) and cyclophosphamide Table 1

Characteristics of patients in long-term study

Patients (n) Male/female Median age (range) years Diagnosis at SCT ALL/AML CML MM MDS NHL SAA Testicular cancer Risk group Standard risk High risk Conditioning regimen TBI/No TBI GVHD prophylaxis MTX alone MTX+CsA CsA alone/CsA+MP Donor and stem cell source Syngenic BM/PBSC HLA-identical related BM/PBSC HLA-mismatched related BM HLA-identical unrelated BM HLA-mismatched unrelated BM

155 86/69 34 (17–57) 9/43 56 5 7 15 19 1 82 73 124/31 21 115 8/5 5/1 115/9 1 15 9

n = number; ALL = acute lymphoblastic leukemia; AML = acute myeloid leukemia; CML = chronic myeloid leukemia; MM = multiple myeloma; MDS = myelodysplastic syndrome; NHL = non-Hodgkin’s lymphoma; SAA = severe aplastic anemia; TBI = total body irradiation; GVHD = graft-versus-host disease; MTX = methotrexate; CsA = cyclosporine A; MP = methylprednisone; BM = bone marrow; PBSC = peripheral blood stem cells; HLA = human leukocyte antigen. Bone Marrow Transplantation

(CY, total dose 120 mg/kg b.w.). TBI was given as single dose until 1989 and then fractionated with lung shielding to prevent lung irradiation with more than 10 Gy. Patients with SAA received CY (total dose 200 mg/kg b.w.) with or without TBI and in 11 cases additionally buffy coat cell infusions from days 1 to 4 after SCT. One patient with SAA received CY and antithymocyte globulin. Eleven patients with CML were prepared with busulfan (16 mg/kg b.w. over 4 days) and CY (total dose 120 mg/kg b.w.).9 Supportive care Patients were hospitalized in isolation rooms with laminar air-flow or reverse isolation. They received antimicrobial prophylaxis with nonabsorbable antibiotics and Pneumocystis carinii prophylaxis with cotrimoxazole. For cytomegalovirus (CMV) prophylaxis patients received CMVhyperimmunoglobulin until 1993 and thereafter acyclovir as described.12 Pre-emptive gancyclovir was given in cases of CMV reactivation as tested by pp65 antigenemia assay or polymerase chain reaction, in recent years. Packed red blood cells (RBC) were given to maintain hemoglobin concentrations above 8.0 g/dl and single donor platelet transfusions from CMV-negative donors to keep platelet counts above 20 ⫻ 109/l. All blood products were leukocyte depleted and irradiated with 30 Gy. GVHD prophylaxis, diagnosis and therapy For GVHD prophylaxis, methotrexate (MTX) alone was given to 21 patients, cyclosporine A (CsA) and methylprednisone to five and CsA alone to eight patients. Since 1987 the majority of patients (n = 115) have received CsA and MTX according to the Seattle protocol.15 CsA levels were monitored by a monoclonal radioimmunoassay and a level of 200 to 250 ng/ml was considered optimal. Tapering of CsA started after day 100 if no signs of GVHD were present and CsA was discontinued around day 180. The clinical diagnosis of GVHD was confirmed by appropriate biopsies and clinically graded as 0 to IV by the criteria for acute GVHD, and as none, limited or extensive for chronic GVHD.23,24 Treatment of acute GVHD was started in patients presenting with grades II or more and consisted of corticosteroids (2 mg/kg b.w. per day). In patients resistant to steroid treatment antithymocyte globulin or extracorporeal photochemotherapy (ECP) was administered.14 Patients with chronic GVHD were mostly treated with CsA and corticosteroids (1 mg/kg b.w.) as described.25 Assessment of long-term sequelae Patients 2 years beyond SCT were seen in the outpatient clinic every 6 months for the first 3 years and yearly thereafter, had a physical examination and blood drawn to check peripheral blood cell counts, their immunologic status, liver, kidney, thyroid and gonadal function. In females, gynecologic examinations were performed every 6 months. If appropriate, radiologic and histologic evaluations were then undertaken. Patients were asked to come lifelong once a year to our outpatient clinic.


For evaluation of QoL, patients received a questionnaire (QLQ-C30) created by the European organization for research and treatment of cancer (EORTC) quality of life study group, which is a multidimensional, cancer-specific and cross-culturally tested 30-item questionnaire to assess self-reported QoL.26 This questionnaire was chosen to make our data comparable to other European studies published on SCT patients.27 The 30-item questionnaire is composed of scales evaluating global quality of life, physical, role, emotional, cognitive and social function. Three symptom scales evaluate nausea/vomiting, pain and fatigue, while five single items assess dyspnea, diarrhea, appetite loss, sleep disturbances and constipation. The response categories are either dichotomous as yes or no, with four categories: ‘not at all’, ‘a little’, ‘quite a bit’ or ‘very much’, or as a modified visual analogue scale going from 1 to 7. All scores were linearly transformed to a 0 to 100 scale. Higher scores on the functioning scales and the global quality of life scale indicate better functioning, while higher scores on the symptom scales reflect more problems. For the analysis, results on the global quality of life were summarized in very poor (0–20), poor (21–40), intermediate (41–60), good (61–80) and very good (81–100). Symptom scales were summarized as none to slight (0–29), moderate (30–69) and severe (70–100). Additionally, patients were asked if they were fit for work, irrespective of their having a job or not. In October 2000, questionnaires on QoL after SCT were sent to those 127 patients alive at the time of our survey. One hundred and six of 127 patients (83%) responded and were included in our analysis of QoL. Forty-five percent of these are women and 55% men. Eighty-one percent had a related and 19% an unrelated stem cell donor. In 37 patients (35%) SCT was 2–5 years ago whereas 69 (65%) were more than 5 years after SCT. Statistical methods Overall survival, transplant-related mortality and relapse rates were estimated using the method of Kaplan and Meier. Comparisons were based on the generalized Wilcoxon and the log-rank test. Comparisons of global quality of life, physical, role and social functioning between patients with or without chronic GVHD were based on the Mann–Whitney U test. A P value ⬍0.05 was considered to indicate statistical significance.

Results Chronic GVHD and late transplant-related mortality Six patients received syngeneic stem cell grafts. Of 149 patients transplanted with stem cells from sibling or unrelated donors 35 patients (23%) experienced limited and 46 (31%) extensive chronic GVHD at some time after SCT. One of these patients developed severe bronchiolitis obliterans and is in very good condition 2 years after doublelung transplantation.28 Eight patients with extensive chronic GVHD were receiving immunosuppressive treatment with

CsA (n = 3), CsA and steroids (n = 1), FK506 (n = 1), FK506 and steroids (n = 1), mycophenolate mophetil (n = 1) and azathioprine (n = 1) at the last contact, whereas in 31 patients chronic GVHD has resolved. Two patients with extensive chronic GVHD died of bronchiolitis obliterans and another three (one with limited chronic GVHD), of multi-organ failure due to severe infection 36, 41 and 55 months after SCT. One patient with SAA who had experienced extensive chronic GVHD with ulcerating lesions of the skin and who had received long-lasting immunosuppressive treatment developed an anaplastic squamous cell carcinoma of the skin 11 years after SCT and died 6 months later despite surgical intervention.29 One patient developed hepatitis B and C about 6 months after SCT and died of hepatic failure 16 years after SCT. Probability of late TRM for all patients projected at 10 and 15 years is 4% and 6%, as shown in Figure 1. Late TRM at 10 and 15 years is significantly different in patients with or without chronic GVHD (5% and 12% vs 0%, P = 0.013). Probability of secondary malignancies projected at 10 and 15 years is 1% and 4%, respectively.

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Relapse Nineteen (13%) patients (ALL n = 1, AML n = 6, CML n = 8, NHL n = 2, MM n = 2) experienced relapse 24 to 142 months after SCT. Probability of relapse beyond 2 years after allogeneic stem cell grafting projected at 10 and 15 years is 13% and 16% for the whole cohort, 16% and 16% for patients with AML and 16% and 23% for patients with CML, respectively. In AML patients the latest relapse occurred 6.6 and in CML patients 12 years after SCT, respectively, as shown in Figure 2. After recurrence of disease, patients were given conventional chemotherapy (ALL n = 1, AML n = 2, CML n = 3, MM n = 1, NHL n = 2), second allogeneic stem cell transplantation (AML n = 2, CML n = 1), second syngenic transplantation followed by third SCT from an unrelated donor (CML n = 1) or donor leukocyte infusions (DLI) (AML n = 2, CML n = 3, MM n = 1). Eight of nine patients receiving conventional chemotherapy for treatment of relapse died due to disease whereas one patient with MM 50 Probability of TRM (%)

Evaluation of quality of life

40 30 20

cGvHD (n = 81) all patients (n = 155)

P = 0.013

10

no cGVHD (n = 74)

0

5

10 15 Time after SCT (years)

20

Figure 1 Probability of transplant-related mortality in patients in continuous complete remission more than 2 years after stem cell transplantation. The thick line indicates all patients (n = 155). The thin line indicates patients who experienced chronic GVHD (n = 81), the dashed line indicates patients without chronic GVHD (n = 74). Bone Marrow Transplantation


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Overall survival

100

CML (n = 56)

Probability (%)

80

all patients (n = 155)

60

AML (n = 43)

40 Relapse 20

5

CML (n = 56) AML (n = 43) all patients (n = 155)

10 15 Time after SCT (years)

20

Figure 2 Probability of overall survival and relapse in patients in continuous complete remission more than two years after stem cell transplantation. The upper part shows the probability of overall survival. The thick line indicates all patients (n = 155). The thin line indicates patients transplanted for CML (n = 56) and the dashed line indicates patients transplanted for AML (n = 43). The lower part shows the probability of relapse. The thick line indicates all patients (n = 155). The thin line indicates patients transplanted for CML (n = 56) and the dashed line indicates patients transplanted for AML (n = 43).

is still alive with disease 5 years after relapse. Three of four patients given another SCT died between 25 and 31 days later of transplant-associated complications and one patient with CML is currently in molecular remission 41 months after 2nd SCT.30 Following treatment with DLI, three patients (AML n = 2, CML n = 1) responded transiently. Currently, three (CML n = 2, MM n = 1) are alive with disease 7, 35 and 48 months after DLI infusion, respectively. Overall survival and long-term sequelae After a median observation time of 6 years (range, 2–18.5 years), 127 of 155 patients (82%) are currently alive. Six patients were lost to follow-up 6 to 14 years after SCT, 14 died of relapse, seven of transplant-related causes and one patient died of myocardial infarction 15 years after SCT. Overall survival projected at 10 and 15 years is 83% and 76% for the whole cohort, 77% and 58% for patients with AML and 80% and 80% for patients with CML (Figure 2). Two patients (1.3%) developed secondary malignancies. One patient with AML in CR1 had received TBI at a dose of 12 Gy and CY (120 mg/kg b.w.) as conditioning therapy and developed an anaplastic squamous cell cancer of the lip 7.5 years after SCT. After surgical resection and local irradiation he has been disease-free for 26 months. Another patient died from anaplastic squamous cell cancer 12 years after SCT, as described above. Pregnancies Three female and four male patients parented children 19 to 84 months after SCT as shown in Table 2. Delivery by caesarean section was necessary in one patient with vaginal sclerosis caused by chronic GVHD whereas six deliveries were uneventful. Three newborns showed peri- and postpartal problems: one required blood exchange because of maternal–fetal rhesus incompatibility, one had persistence Bone Marrow Transplantation

Table 2

Pregnancies after SCT

Age at SCT in years/Sex

Disease

Conditioning regimen

SCT– Pregnancy (months)

No. of pregnancies/ Live birth

SAA SAA SAA SAA SAA CML NHL

CY CY CY CY CY+TBI (3 Gy) BU/CY CY+TBI (13.2 Gy)

37 19 81 34, 52 94 63, 84 32

1/1 1/1 1/0a 2/2 1/0b 2/2 1/1c

27/F 23/F 17/F 22/M 26/M 24/M 31/M

SCT = stem cell transplantation; F = female; M = male; No. = number; SAA = severe aplastic anemia; CML = chronic myeloid leukemia; NHL = non-Hodgkin’s lymphoma; CY = cyclophosphamide; BU = busulfan; TBI = total body irradiation. a Abortion in the 25th week of gestation. b Interruption for personal reasons. c Artificial insemination.

of the fetal circulation which was surgically corrected and one suffered from prolonged newborn jaundice which resolved without treatment.31 The neonatal course of the other four children was uneventful and the offspring are alive and well. Quality of life The mean global QoL was good (mean group score 73.2; s.d. 23.5). Fifty percent of all patients enjoyed a very good global QoL (score 81–100), 26% had a good (score 61– 80), 14% an intermediate (score 41–60), 6% a poor (score 21–40) and 4% a very poor (score ⬍21) global QoL as shown in Figure 3a. More detailed analyses revealed distinct differences in global QoL dependent on the time elapsed since SCT. Whereas 2 to 5 years after SCT 73% of patients had a good to very good global QoL, this was reported from 79% of patients more than 5 years after SCT as shown in Figure 3b and c. Within the functioning subscales, role, emotional and social functioning were the most obviously impaired as shown in Figure 4. Patients more than 5 years after SCT reported better role, cognitive and social functioning compared to patients 2 to 5 years after SCT. Eighteen percent of all patients reported no or minimal physical complaints, whereas 25% suffered severely from at least one symptom and another 7.5% from three or more symptoms. Fatigue, dyspnoea and sleep disturbances were the most frequently reported symptoms as shown in Figure 5. At the time of our survey 74% of all participants were fit for professional work. Fifty-three of 106 (50%) had developed chronic GVHD at some time after SCT. There was no statistical difference in global QoL between patients with and without chronic GVHD (mean score 71 ⫾ 22 s.d. vs 76⫾ 25 s.d.). Compared to patients never experiencing chronic GVHD means of physical, role and social functioning were significantly lower (P ⬍ 0.05) whereas no difference in emotional and cognitive functioning between those two groups was observed (Table 3). Patients in the chronic GVHD group reported significantly more fatigue, pain and constipation

Percentage of patients (%)


70 a

50

50 26

30 14 10

4

6

70 b

25 years after SCT

35

38

30 8

85 85 86 80

16

76

80 69

72 74 71

RF

EF

80

82 75

71

74 66

60 40 20 0

50

10

623

100

All patients

Mean scores of functioning scales



PF

CF

SF

Figure 4 Mean scores of functioning scales in long-term survivors after allogeneic stem cell transplantation. PF, physical functioning; RF, role functioning; EF, emotional functioning; CF, cognitive functioning; SF, social functioning. White bars indicate all patients, light gray bars indicate patients 2 to 5 years after SCT and dark gray bars indicate patients more than 5 years after SCT. Numbers above bars indicate mean scores.

3

70 c

>5 years after SCT 57

50

30

10

Score

91 84 96

Pain

66 62 68

Fatigue

50 49 51

Dyspnea

59 57 61

Diarrhea

81 76 84

13 6 16 8 12 4

Loss of appetite

87 87 87

10 3 13 9 4

Sleep disturbances

45 49 44

Constipation

83 84 83

22 1

7

13

very poor

poor

intermediate

good

very good

(020)

(2140)

(4160)

(6180)

(81100)

Figure 3 Global quality of life of long-term survivors after stem cell transplantation. The bars on the left side indicate percentage of patients with very poor (QoL ⬍21) and poor (QoL 21–40) global quality of life, bars in the middle indicate patients with intermediate (QoL 41–60) and bars on the right indicate patients with good (QoL 61–80) and very good (QoL 81–100) global quality of life. (a) shows the global quality of life of all patients, (b) of patients 2 to 5 years after SCT and (c) of patients more than 5 years after SCT. Numbers above bars indicate percentage of patients.

(P ⬍ 0.05). Only 60% of patients who had developed chronic GVHD were fit for professional work. Discussion The purpose of this study was to evaluate the long-term outcome of patients given allogeneic or syngeneic SCT for various hematological and oncological diseases at a single transplant center. We observed that in patients who are in CR for more than 2 years after SCT the probability of overall survival is 83% at 10 and 76% at 15 years after SCT which is comparable with other reports.16,17 In a European Group for Blood and Marrow Transplantation (EBMT) study on long-term outcome of patients with acute leukemia – alive and disease-free 2 years after bone marrow transplantation – an event-free survival of 82% after 9

7 2 all 16 25 yrs after SCT 13 >5 yrs after SCT

Nausea and vomiting

0

28 35 25

6 3 7

41 38 42

9 13 7 34 32 35

7 11 4

43 43 42

12 8 14 13 4 13 3 13 4

20 40 60 80 Percentage of patients (%)

100

Figure 5 Physical complaints in long-term survivors after stem cell transplantation. Upper bars indicate percentage of all patients, bars in the middle patients 2 to 5 years after SCT and lower bars patients more than 5 years after SCT. Left white parts indicate percentage of patients with none to slight complaints (left side), light grey parts patients with moderate complaints (middle) and dark grey parts patients with severe complaints (right side). Numbers in bars indicate percentage of patients. Bone Marrow Transplantation


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years, regardless of the subtype of leukemia, stage of disease at transplant and stem cell source, was reported.16 Whereas in our study overall survival of CML patients was 80% both after 10 and 15 years, a further decline in overall survival was observed in patients with acute leukemia over time. This finding is most likely due to small patient numbers. The major cause of death in our study was late recurrence of malignant disease which was observed in 13% of our patients, with the latest occurring 12 years after SCT for CML. In patients with acute leukemia, the latest relapse was seen 6.6 years after SCT, which is similar to previous reports.16,17,32 Thus, disease-free survival does not reach a stable plateau and long-term monitoring especially in patients with molecular disease markers, eg CML is warranted. This would allow early administration of salvage therapy including DLI, where in CML patients complete remissions were achieved in 82% of patients in cytogenetic relapse and in 78% of those in hematologic relapse.33 In our study population investigated 2 years after SCT and in CR, occurrence of acute or chronic GVHD had no influence on risk for relapse which confirms results previously reported.16 The probability of late TRM in our study of 6% at 15 years compares favorably with previous reports.17 Only chronic GVHD had a statistically significant impact (P = 0.013) on transplant-related mortality in our patients, leading to late deaths due to obstructive and restrictive lung disease or severe opportunistic infection. Recently, it was demonstrated that the presence of chronic GVHD requiring immunosuppressive therapy 2 years after SCT identifies a group of patients at high risk for non-relapse death.17 The incidence of secondary cancers in our study was low at 1.3% after a median follow-up of 73 months (range, 27.6– 222 months), which compares favorably with other reports.18,19 Curtis et al19 reported a significantly higher risk of new solid tumors with 2.2% at 10 and 6.7% at 15 years after SCT. There, chronic GVHD and male sex were strongly linked with an excess risk of squamous cell cancer of the buccal cavity and skin. In our study, the only secondary cancers observed were affecting skin and oral mucosa of patients with extensive chronic GVHD. All these findings thus strongly support the need for lifelong surveillance of patients after SCT. In our survey, pregnancies occurred in three patients and four partners of patients who had undergone SCT. So far, only a minority of patients given TBI containing conditionTable 3 Mean scores of functioning scales in patients with and without chronic GVHD Chronic GVHD group (n = 53) mean (s.d.) Physical functioning Role functioning Emotional functioning Cognitive functioning Social functioning

81 67 71 79 62

(24) (34) (26) (25) (37)

Without GVHD (n = 53) mean (s.d.) 90 85 73 80 81

(19) (26) (25) (28) (27)

P-value

⬍0.05 ⬍0.05 NS NS ⬍0.05

GVHD = graft-versus-host disease; s.d. = standard deviation; NS = not significant. Bone Marrow Transplantation

ing experiences recovery of gonadal function.34 Furthermore, an increased rate of spontaneous abortion in patients receiving TBI-containing conditioning regimens and a higher risk for pre-term labor and delivery of low birth weight (1.36 to 2.24 kg) infants has been reported.34 In view of the excellent long-term results of SCT including high overall survival rates, cryopreservation of gonadal cells prior to SCT should be offered to younger patients to allow parenthood after SCT. The mean global quality of life of our patients is good and comparable with results observed in a Norwegian study in patients 1 year after SCT.21 As in other reports we found a better QoL beyond 5 years after SCT with 79% of patients having a good to very good global QoL compared to 73%, 2 to 5 years after SCT.22 Whether this is an actual improvement over time or results from drop out of patients with more serious health impairment cannot be answered due to the cross-sectional design of our study, but does need to be evaluated by a long-term prospective study. Physical, role and social functioning scores in our long-term survivors were lower when compaired to a normal population analyzed by Hjermstad et al21 Our results are in agreement with findings reported by Hjermstad et al.21 and Sutherland et al20 who used a different questionnaire in comparing SCT patients with a normal population. In our study physical, role and social functioning scores were significantly lower in patients experiencing chronic GVHD compared to patients without chronic GVHD. This observation has also been reported in a prospective longitudinal study by Syrjala et al35 where patients with more severe chronic GVHD had an impaired physical and psychosocial recovery at 1 year after SCT. Knowing about the deficits in these functional scales after SCT should have direct clinical implications for counseling of patients and their relatives. Realistic information from the staff about the often lengthy rehabilitation periods before resumption of prior activities is important. Knowing what to expect might help patients to reduce their frustration about shortcomings in the fulfilment of working and social roles.36 Fatigue, dyspnea and sleep disturbances were the most frequently reported symptoms in our study. This is in agreement with other reports in long-term transplant survivors and prohibitive for normal functioning.20,21,27,35 Fatigue and dyspnea decreased in patients more than 5 years after SCT. In patients with chronic GVHD significantly more fatigue, pain and constipation were observed. Seventy-four percent of patients are fit for work which is encouraging and comparable with recently reported findings.37 In conclusion, in patients who are disease-free 2 years after SCT, the probability of cure is high and the prospects of long-term survival with good quality of life are excellent. There is still a substantial percentage of patients whose QoL is lower than would be desirable and symptoms like fatigue and sleep disturbances are, at least in moderate form, frequent among long-term survivors. Larger prospective studies with longer follow-ups are warranted to address the various aspects of QoL after SCT and appropriate psychological support should be available for these patients. Since deaths can occur years later after allogeneic SCT due to relapse, chronic GVHD, or secondary malig-


nancies lifelong monitoring of these patients in the outpatient clinic is warranted. Acknowledgements We thank the nurses, fellows and house staff and the medical technicians of our stem cell transplant program, Department of Blood Group Serology and Transfusion Medicine and Department for Radiotherapy and the physicians who referred patients to our unit.

References 1 O’Donnell MR, Nademanee AP, Snyder DS et al. Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes. J Clin Oncol 1987; 5: 1822–1826. 2 Gahrton G, Tura S, Ljungman P et al. Allogeneic bone marrow transplantation in multiple myeloma. New Engl J Med 1991; 325: 1267–1273. 3 Clift RA, Appelbaum FR, Thomas ED. Treatment of chronic myeloid leukemia by bone marrow transplantation. Blood 1993; 82: 1954–1956. 4 Zittoun RA, Mandelli F, Willemze R et al. Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. New Engl J Med 1995; 332: 217–223. 5 Passweg JR, Socie´ G, Hinterberger W et al. Bone marrow transplantation for severe aplastic anemia: has outcome improved? Blood 1997; 90: 858–864. 6 de Witte T, Hermans J, Vossen J et al. Haematopoietic stem cell transplantation for patients with myelodysplastic syndromes and secondary acute myeloid leukemias: a report on behalf of the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 2000; 110: 620–630. 7 Goldman JM, Gale RP, Horowitz MM et al. Bone marrow transplantation for chronic myelogenous leukemia in chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 1988; 108: 806–814. 8 Appelbaum FR. The influence of total dose, fractionation, dose rate, and distribution of total body irradiation on bone marrow transplantation. Semin Oncol 1993; 20 (Suppl. 4): 3–10. 9 Tutschka PJ. Use of busulfan containing chemotherapy for conditioning patients with leukemia for bone marrow allografting. Bone Marrow Transplant 1993; 12 (Suppl. 1): 34–36. 10 Boeckh M, Bowden RA, Gooley T et al. Successful modification of a pp65 antigenemia based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients. Blood 1999; 93: 1781–1782. 11 Roy V, Ochs L, Weisdorf D. Late infections following allogeneic bone marrow transplantation: suggested strategies for prophylaxis. Leuk Lymphoma 1997; 26: 1–15. 12 Winston DJ, Gale RP. Prevention and treatment of cytomegalovirus infection and disease after bone marrow transplantation in the 1990s. Bone Marrow Transplant 1991; 8: 7–11. 13 Fischer GF, Fae´ I, Petrasek M, Moser S. A combination of two distinct in vitro amplification procedures for DNA typing of HLA-DRB and -DQB1 alleles. Vox Sang 1995; 69: 328– 335. 14 Greinix HT, Volc-Platzer B, Knobler RM. Extracorporeal photochemotherapy in the treatment of severe graft-versushost disease. Leuk Lymphoma 2000; 36: 425–434.

15 Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for acute leukemia. New Engl J Med 1986; 314: 729–735. 16 Frassoni F, Labopin M, Gluckman E et al. Are patients with acute leukemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Leukemia 1994; 8: 924–928. 17 Singhal S, Powles R, Treleaven J et al. Long-term outcome of adult acute leukemia patients who are alive and well two years after allogeneic bone marrow transplantation from an HLA-identical sibling. Leuk Lymphoma 1999; 34: 287–294. 18 Deeg HJ, Socie´ G, Schoch G et al. Malignancies after marrow transplantation for aplastic anemia and Fanconi anemia: a joint Seattle and Paris analysis of results in 700 patients. Blood 1996; 87: 386–392. 19 Curtis RE, Rowlings PA, Deeg HJ et al. Solid cancers after bone marrow transplantation. New Engl J Med 1997; 336: 897–904. 20 Sutherland HJ, Fyles GM, Adams G et al. Quality of life following bone marrow transplantation: a comparison of patient reports with population norms. Bone Marrow Transplant 1997; 19: 1129–1136. 21 Hjermstad MJ, Holte H, Evensen SA et al. Do patients who are treated with stem cell transplantation have a health-related quality of life comparable to the general population after 1 year? Bone Marrow Transplant 1999; 24: 911–918. 22 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. 23 Thomas ED, Storb R, Clift RA et al. Bone marrow transplantation. New Engl J Med 1975; 292: 832–843, 895–902. 24 Sullivan KM, Shulman HM, Storb R et al. Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression. Blood 1981; 57: 267–276. 25 Sullivan KM, Witherspoon RP, Storb R et al. Alternating-day cyclosporine and prednisone for treatment of high-risk chronic graft-versus-host disease. Blood 1988; 72: 555–561. 26 Aaronson NK, Ahmedzai S, Bergman B et al. The European Organization for Research and Treatment of Cancer QLQC30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993; 85: 365–376. 27 Bush NE, Haberman M, Donaldson G, Sullivan KM. Quality of life of 125 adults surviving 6–8 years after bone marrow transplantation. Soc Sci Med 1995; 40: 479–490. 28 Rabitsch W, Deviatko E, Keil F et al. Successful lung transplantation for bronchiolitis obliterans after allogeneic marrow transplantation. Transplantation 2001; 71: 1341–1343. 29 Gmeinhart B, Hinterberger W, Greinix HT et al. Anaplastic squamous cell carcinoma (SCC) in a patient with chronic cutaneous graft-versus-host disease (GVHD). Bone Marrow Transplant 1999; 11: 1197–1199. 30 Reiter E, Greinix HT, Keil F et al. Long-term follow-up of patients after related- and unrelated-donor bone marrow transplantation for chronic myelogenous leukemia. Ann Hematol 1999; 78: 507–513. 31 Hinterberger-Fischer M, Kier P, Kalhs P et al. Fertility, pregnancies and offspring complications after bone marrow transplantation. Bone Marrow Transplant 1991; 7: 5–9. 32 Witherspoon R, Flournoy N, Thomas ED et al. Recurrence of acute leukemia more than two years after allogeneic marrow grafting. Exp Hematol 1986; 14: 178–181. 33 Kolb HJ, Schattenberg A, Goldman JM et al. Graft-versusleukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1996; 86: 2041–2050. 34 Sanders JE, Hawley J, Levy W et al. Pregnancies following

625

Bone Marrow Transplantation


626

high-dose cyclophosphamide with or without high-dose busulfan or total-body irradiation and bone marrow transplantation. Blood 1996; 87: 3045–3052. 35 Syrjala KL, Chapko MK, Vitaliano PP et al. Recovery after allogeneic marrow transplantation: prospective study of predictors of long-term physical and psychosocial functioning. Bone Marrow Transplant 1993; 11: 319–327. 36 Andrykowski MA, Brady MJ, Greiner CB et al. ‘Returning

Bone Marrow Transplantation

to normal’ following bone marrow transplantation: outcomes, expectations and informed consent. Bone Marrow Transplant 1995; 15: 573–581. 37 Duell T, Van Lint MT, Ljungman P et al. Health and functional status of long-term survivors of bone marrow transplantation. EBMT working party on late effects and EULEP study group on late effects. European group for blood and marrow transplantation. Ann Intern Med 1997; 126: 184–192.