Peripheral Blood Stem Cells Fewer relapses and increased ... - Nature

Bone Marrow Transplantation (2003) 32, 257–264 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00

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Peripheral Blood Stem Cells Fewer relapses and increased chronic GVHD in patients transplanted with blood stem cells: a 5-year follow-up in a single centre study D Heldal1, L Brinch1, G Tjnnfjord1, BG Solheim2, T Egeland2, D Albrechtsen3, G Aamodt4 and SA Evensen1 1 Medical Department, Rikshospitalet University Hospital, 0027 Oslo, Norway; 2Institute of Immunology, Rikshospitalet University Hospital, 0027 Oslo, Norway; 3Department of Surgery, Rikshospitalet University Hospital, 0027 Oslo, Norway; and 4Section of Biostatistics, Rikshospitalet University Hospital, 0027 Oslo, Norway

Summary: A total of 61 consecutive adult patients with haematological malignancies with an HLA-identical or one antigenmismatched haploidentical family donor were randomised to allogeneic transplantation with blood stem cells (BSC) or bone marrow (BM). The median observation time was 5 years. Apart from engraftment parameters and acute graft-versus-host disease (GVHD), transplant-related mortality (TRM), incidence and severity of chronic GVHD, relapse, leukaemia-free survival (LFS) and overall survival (OS) were recorded. In the BSC and BM group, respectively, TRM was 8/30 and 4/30 (P ¼ 0.405), the incidence of chronic GVHD was 15/26 and 11/30 (P ¼ 0.138), extensive chronic GVHD was 10/26 and 4/30 (P ¼ 0.034), and relapse one and 10 patients (P ¼ 0.007). In log-rank test restricted to the cases allografted from HLA-identical donors, the difference remained significant with regard to relapse incidence (P ¼ 0.039), but not extensive chronic GVHD (P ¼ 0.072). No difference in LFS and OS was observed. In conclusion, our study strongly indicates an enhanced graft-versus-leukaemia effect in BSC recipients, which is not expressed in increased survival. The increased chronic GVHD in these patients may contribute, but the relation is complex and not yet understood. Bone Marrow Transplantation (2003) 32, 257–264. doi:10.1038/sj.bmt.1704127 stem cell allografting; relapse; chronic Keywords: GVHD

Randomised1–8 and nonrandomised9 trials have shown a significantly shorter period of aplasia using blood stem cells (BSC) compared to bone marrow (BM) in allogeneic stem cell transplantation, and BSC allografts reduce the requirements for platelets and antibiotics.6

Correspondence: Dr D Heldal, Medical Department, Rikshospitalet, Oslo, 0027, Norway Received 18 July 2002; accepted 17 January 2003

Despite a high number of T lymphocytes in BSC allografts, there is little evidence of an increased incidence of acute GVHD. This could be because of the modulation of T cell cytokine expression towards a Th-2/Tc-2 (noncytotoxic) phenotype with anti-inflammatory functions induced by G-CSF.10,11 However, the results are not fully consistent since one of the largest studies revealed a significantly higher incidence of acute GVHD, possibly explained by the omission of the methotrexate dose on day +11.1 There are indications that BSC allografts are more likely to reduce TRM. A Canadian randomised study showed a significant reduction in nonrelapse mortality at 30 months in the BSC group compared to BM.7 Furthermore, a nonrandomised, retrospective study showed a significant difference in 1-year TRM in favour of BSC allografting in advanced leukaemia.9 Several retrospective and nonrandomised studies indicate that the incidence of chronic GVHD might be increased after BSC allografting.12–17 Two randomised studies showed a significantly higher overall incidence of chronic GVHD and, in particular, extensive chronic GVHD in BSC-transplanted patients,18,19 in contrast to larger randomised studies.1,20 On the other hand, currently there is no evidence that an increased incidence of chronic GVHD causes a higher late mortality rate. Analyses of the impact on long-term quality of life are lacking. It is well established that the occurrence of GVHD and GVL is strongly correlated. 21 Given an increased incidence of chronic GVHD following BSC allografting, a reduced relapse rate in patients may be anticipated. This notion is supported by one prospective randomised trial in CML,22 and by a few nonrandomised studies.23–25 Several authors have reviewed the available randomised studies.26–30 They conclude that a longer follow-up is required to establish the role of BSC allografts in terms of long-term haematopoietic reconstitution, chronic GVHD, late transplant-related mortality (TRM), relapse rate and overall survival (OS). We present the results of a 5-year follow-up of the first single centre prospective randomised trial comparing BSC and BM allogeneic transplantation, with special attention to chronic GVHD, TRM, relapse rate, leukaemia-free survival (LFS) and OS.

SC source and relapse/chronic GVHD D Heldal et al

258 Table 1

Subjects and methods

Patient characteristics BSC (n=30)

Median age, years (range) 39 (15–52) Recipient/donor sex Male/female 9 Diagnosis CML 1. chronic phase 12 AML 1. complete remission 8 AML 2. complete remission 2 AML 1. early relapse 1 Sec. AML, 1. complete remission 1 Sec. AML, 1. early relapse 0 ALL 1. complete remission 0 ALL 2. complete remission 2 ALL 2. early relapse 1 MDS 1 a PMF 2 Delayed response to induction treatment 1 Unfavourable cytogenetics in AL 7 5, 7 Trisomy 11, t(3;3) ALL with t(9;22) Complex karyotype 3q abnormalities No patients with X1 risk criterion(s)b CMV serostatus Rec neg/don neg 1 ag HLA mismatch MTX 3 dosesc Median follow-up, years (range)

2 1 1 0 0 0 11 3 5 4 5.41 (3.38–8)

BM (n=30) 45 (18–55) 4 13 5 0 6 0 1 2 3 0 0 0 5 0 0 0 2 1 1 13 4 1 3 5.46 (3.47–7.89)

a

Primary myelofibrosis. Risk of relapse. c Omission of methotrexate on day +11. b

Table 2 Age 52 42 40 32 52 20 31 15 52 50 42 51 29 49 18 52 35 52 23 39 54 45 31 50

Definitions TRM is defined as treatment-related death, irrespective of the time after transplantation. Relapse of acute leukaemia shall mean extramedullary leukaemia and/or more than 5% blasts in a BM smear with normal cellularity. In patients with CML, relapse is defined as cytogenetic relapse. A positive bcr–abl-PCR is not considered as relapse. LFS is measured as the number of days from transplantation until death or the first manifestation of relapse. OS is measured as the number of days from transplantation until death.

Patients From June 1994 until February 1999, 61 patients were randomised to either transplantation with BSC or BM, 31 and 30 patients, respectively. One patient in the BSC group was excluded. The results from this trial were first published in 2000.6 Patient characteristics are summarised in Table 1. The following criteria of risk of relapse were used: an unfavourable cytogenetic profile,31,32 the need for additional induction treatment defined as delayed response to induction therapy, and finally, patients with acute leukaemia beyond one CR, MDS and secondary AML defined as advanced disease at the time of transplantation. The number of patients with one risk factor or more is showed in Table 1, while Table 2 describes the risk factor in question for each individual patient. Three patients had

Patients with risk factor(s) with regard to relapse Gender male/female (M/F) M M F M M M M M F M M F M M M F M F F F F M M M

a

Diagnosisa

Cytogentics

Response to induction

Status at tx

Other risk factors

AML M1 ALL L1, pre B AML M2 AML M4 MDS/RAEB(t) ALL L2 AML M4 AML M2 AML M2 ALL L2 AML ALL L2, pre B ALL L1, pre B AML M6 ALL ALL AML M3 AML M2 AML M2 AML M4 AML M5 ALL L2 AML M7 AML M2

Unknown Unknown Monosomy 7 Inv(16) Negative Negative Del 18 Trisomy 11, t(3;3) Monosomy 7 Negative Monosomy 5, 7 t(9;22) Negative Unknown Unknown Unknown t(15;17),(8;16) Negative t(8;21), del 9,11 t(3;11) t(2;3), t(23;27) t(9;22) Complex karyotype Clonal loss of X chromosome

Ab A A A A A A A Delayed A A A Delayed A A A Delayed Delayed A A A A Delayed Delayed

2.CRc 2.CR 1.CR 1.CR 1.CR 2.CR 2.CR 1.ERe 1.CR 2.ER 1.CR 2.CR 1.CR 1.ER 2.CR 2.CR 1.CR 1.ER 1.ER 1.ER 1.ER 1.CR 1.ER 1.ER

— — — Extrad — — — — — — Secf — — — — — — — — — Sec — — —

According to the FAB classification. Adequate. c Complete remission. d Extramedullary leukaemia. e Early relapse. f Secondary AML. b

Bone Marrow Transplantation

Stem cell source BSC BSC BSC BSC BSC BSC BSC BSC BSC BSC BSC BM BM BM BM BM BM BM BM BM BM BM BM BM


259 Median number of nucleated cells, CD34+ and T cells

TNC ( 108/kg rec. bwa) (range) CD34+( 106/kg rec. bw) (range) CD3+( 108/kg rec. bw) (range) a

BSC

BM

P

9.35 (3.9–15.2) n=28 3.1 (1.8–7.7) n=30 2.1 (0.6–4.4) n=27

3.25 (2.1–8.2) n=30 2.3 (0.7–4.6) n=19 0.43 (0.1–4.5) n=18

o0.001 0.005 o0.001

Recipient body weight.

1.0

Probability of extensive chr. GVHD

Table 3 infused

_____ BM 0.8

_ _ _ _ BSC

0.6

0.4

0.2

0.0 0

favourable cytogenetics, one in the BSC group (inv(16)) and two in the BM group (inv(16) and t(15;17), respectively). The remaining patients had normal cytogenetics or minor abnormalities associated with intermediate risk of relapse. In each treatment group, there were three patients with unknown cytogenetics.

2

4

6

8

Years Figure 1 Cumulative incidence of extensive chronic GVHD in patients transplanted with BSC or BM, excluding the HLA mismatched.

Study design and statistical analysis Harvest procedures The harvest procedures have been described previously.6,33 A minimum of 2 106 CD34+ cells/kg recipient body weight (bw) was required for BSC transplantation, and a minimum of 2 108 nucleated cells (TNC)/kg recipient bw was required for BM transplantation. Graft characteristics are presented in Table 3.34

Conditioning and GVHD prophylaxis All patients were conditioned with busulphan (16 mg/kg) and cyclophosphamide (120 mg/kg) as described.7 Intrathecal methotrexate (MTX) 12 mg/day was given to patients with AML (FAB classification M4/M5) or ALL on days 8 and 4 and four times after transplantation. TBI, CNS radiation and T cell depletion were not parts of the conditioning regimen in any patient. GVHD prophylaxis consisted of cyclosporin A (CsA) from day 1 and tapered from day+180 unless there were clinical signs of chronic GVHD. In addition, MTX was administered i.v. 15 mg/m2 on day+1 and 10 mg/m2 on days +3,+6 and +11 providing there were no signs of serious liver toxicity. Acute GVHD was graded continuously according to the Glucksberg criteria.35 Chronic GVHD was classified as described by Shulman et al.36

Supportive care Supportive care consisted of prophylactic administration of acyclovir from day 2 until day +28. The patients were given co-trimoxazol (TMS) for 2 weeks and until day 4. When neutrophils exceeded 1.0 109/l and platelets 50 109/l, TMS was given as pneumocystis carinii prophylaxis until day +180, or longer if immunosuppressive treatment for chronic GVHD was given. Patients were not given G-CSF post transplant.

The 61 patients were stratified according to age, but not to HLA mismatch, stage of the disease or other prognostic factors. Subsequently, they were randomised in blocks of six, three for each type of cell harvest. We applied parametric methods (t-tests) to compare different groups. Categorical data were analysed with w2 tests or Fisher’s exact tests. Competing risk outcomes such as chronic extensive GVHD and relapse were visualised with cumulative incidence curves.37 Survival data were visualised with Kaplan–Meier survival curves.38 Comparisons of survival were performed with log-rank tests. Cox models were used to study the effect of several variables on extensive chronic GVHD and relapse. Two-sided P-values less than 0.05 were considered as statistically significant. The algorithms in SPSS 10.0 (SPSS, Chicago, IL, USA) and Splus (Insightful, Seattle, WA, USA) were used to perform the statistical analysis. Written informed consent was obtained according to protocols approved by the Regional Committee for Medical Research Ethics, Southern Norway (REC II).

Results Chronic GVHD and morbidity In total, 26 patients in the BSC arm and 30 patients in the BM arm were evaluable for chronic GVHD, having survived 3 months. The number of patients developing chronic GVHD was 15 in the BSC group (57.7 %) and 11 (36.7 %) in the BM group (P ¼ 0.138). Extensive chronic GVHD was found in 10 (38.5 %) and four patients (13.3 %), respectively (P ¼ 0.034). However, a log-rank test restricted to the cases allografted from HLA-identical donors did not show any significant difference between the groups (P ¼ 0.072), and the corresponding cumulative incidence curves are shown in Figure 1. A multivariate analysis of factors affecting extensive chronic GVHD showed that HLA mismatch was the most important factor Bone Marrow Transplantation


260 Table 4

Extensive chronic GVHD. Characteristics of BSC recipients

Patients Age (years) Sex match (rec/don)a Diagnosis HLA identical (y/n) CD34+ 106/kg rec. bw CD3+ 108/kg rec. bw No of MTX inj Acute GVHD (grade) OBd (y/n) Alive (y/n)

1

2

3

4

5

6

7

8

9

10

33 M/M CML No 3.2 2.3 4 I Yes Yes

16 M/F CML Yes 3.8 1 4 I No Yes

27 M/F CML No 4.7 2.6 4 0 Yes Yes

39 M/F CML Yes 2.4 2 4 III No No

52 F/F CML Yes 3.8 2.6 4 I No Yes

32 M/M AML Yes 3.1 3.3 4 0 No Yes

20 M/F ALL Yes 2.7 2.1 3 0 Yes Yes

15 M/M AML No 2.3 1.7 3 III Yes No

42 M/M Sec AMLb Yes 2.2 1.7 4 0 No No

43 F/F PMFc Yes 4.4 2.2 4 0 No Yes

a

Recipient/donor: M=male F=female. Secondary AML. c Primary myelofibrosis. d Obliterative bronchiolitis. b

Extensive chronic GVHD. Characteristics of BM recipi-

Patients Age Sex match (rec/don) Diagnosis HLA identical CD34+ 106/kg rec. bw CD3+ 108/kg rec. bw No of MTX inj Ac GVHD (grade) OBa (y/n) Alive (y/n) a

1.0 ______ BM

1

2

3

4

50 M/M CML Yes 1.4 0.32 4 0 No Yes

52 F/M ALL No 3.5 3.5 3 II Yes No

41 M/F CML Yes 0.72 0.45 4 II No No

45 F/F AML Yes – – 4 0 No No

Obliterative bronchiolitis.

_ _ _ _ BSC

0.8

Probability of TRM

Table 5 ents

0.6

0.4

0.2

0.0 0

2

4

6

8

Years

(P ¼ 0.032) followed by the source of stem cells. Other risk factors such as male recipient with female donor, age, CMV status, CD34+ and CD3+ cell count had no significant influence. At 3 years post transplant, 12 patients suffered from chronic GVHD in the BSC group, two patients had died because of GVHD-related complications and in one patient GVHD had resolved. In the BM group, seven patients suffered from chronic GVHD, two patients had died because of chronic GVHD and two patients had recovered completely. One of these patients died of obliterative bronchiolitis after 4 years. No patient developed chronic GVHD after 3 years. At the last follow-up at 4 years post transplant, GVHD had resolved in another patient in the BSC group. Among the BSC recipients, there were 10 patients with extensive GVHD. Four of them had obliterative bronchiolitis, and three of these patients had an HLA-mismatched donor. In the BM group, only four patients had extensive GVHD, one of whom suffered from obliterative bronchiolitis. This patient was the only recipient of an HLAmismatched allograft in the BM group. A detailed characterisation of the patients with extensive chronic GVHD is presented in Tables 4 and 5. In patients with limited chronic GVHD, CsA was continued and gradually tapered. In some cases of extensive chronic GVHD, the condition required steroids and other immunosuppressive agents. Patients with obliterative Bone Marrow Transplantation

Figure 2 Time to TRM for patients transplanted with BSC or BM.

bronchiolitis were, in addition, given cimetidine without any convincing effect. Among the BSC recipients, one patient has developed cancer of the breast 5 years post transplant. In the BM group, there were two cases of secondary malignancy. One developed basocellular carcinoma of the skin, another, Epstein–Barr virus associated non-Hodgkin’s lymphoma. A third patient acquired a probable malignant melanoma in the choroidea. Prior to the outbreak of secondary cancer they all had chronic GVHD, except for the patient with the eye condition. Hypothyroidism developing after stem cell transplantation has not been diagnosed in any of the patients.

TRM A total of 30 patients in each group were evaluable. In the BSC group, eight patients (26.7%) died of treatmentrelated conditions, four (13.3%) in the BM group. The probability of TRM is shown in Figure 2. The difference between the groups is not statistically significant (P ¼ 0.405). The causes of transplant-related death until August 1999 have been published in a previous paper.7 Since then four patients have died of treatment-related conditions, three in BSC treatment arm. A male patient died 472 days after transplantation of chronic GVHD and


opportunistic infections, another male patient died after 626 days of chronic GVHD including obliterative bronchiolitis. He was transplanted with an HLA-mismatched donor. Furthermore, a male patient died of chronic GVHD and secondary graft failure 4 years after transplantation. Finally, a female recipient of an HLA-mismatched BM allograft died 4 years after transplantation of obliterative bronchiolitis.

In the BM group 10 patients relapsed, eight of these were considered as high risk for relapse (Table 6). Among the 13 patients with high-risk leukaemia, three patients have developed chronic GVHD. Two of the relapsed patients had CML classified to represent standard risk. One of these patients received donor lymphocyte infusions (DLI) in combination with interferon. At last follow-up he was in complete haematological, cytogenetic and molecular remission. The other patient had positive bcr/abl transcripts by nested-PCR all the time since transplantation. At 5 years post transplant, she relapsed cytogenetically and is now treated with DLI. A female patient with ALL in second remission relapsed 2 years post transplant. She obtained complete haematological remission, which lasted 2 years after reinduction with cytotoxic agents. A male patient transplanted with AML in early first relapse was treated with DLI unsuccessfully when he relapsed after 4 months. None of the relapsed patients developed chronic GVHD. Except for the two patients with CML, all the relapsed patients have died. Finally, a patient with CML transplanted in the first chronic phase had a molecular relapse with a positive bcr–abl-PCR at 3 years post transplant, but is still in cytogenetic and haematological remission without any treatment. This patient is not counted among the relapses in the BM group. The Kaplan–Meier survival curve for LFS is shown in Figure 4. The difference between the groups was not

Relapse, LFS and OS The cumulative incidence curves for relapse are shown in Figure 3. The difference between the groups is statistically significant (P ¼ 0.007). A log-rank test restricted to the cases allografted from HLA-identical donors shows significantly reduced relapse rate among the BSC allografted (P ¼ 0.039). A multivariate analysis of factors affecting relapse showed that high-risk disease was the only factor associated with significantly increased relapse incidence (P ¼ 0.005) in addition to the stem cell source. In the BSC group, only one male patient relapsed (Table 6). His AML was classified to represent standard risk. He had a chromosome 2 abnormality not considered unfavourable. He did not develop chronic GVHD. Among the 11 patients with high-risk leukaemia, five patients have developed chronic GVHD.

261

Probability of leukaemia-free survival

1.0

Probability of relapse

0.8 _____ BM

0.6

_ _ _ _ BSC

0.4

0.2

0.0 0

2

4

6

8

1.0

0.8

0.6

0.4

_ _ _ _ BSC

0.2

0.0

Years

______ BM

0

2

4

6

8

Years Figure 3 Cumulative incidence of relapse in patients transplanted with Figure 4 LFS for patients transplanted with BSC or BM.

BSC or BM.

Table 6

Characteristics of relapsed patients associated with risk criteria

Patients Diagnosis LFS (days) Stem cell source Delayed resp.b Stagec Cytogenetics All-round risk

1 AML 131 BSC No 1.CR Interf Standj

2 ALL 740 BM No 2.CR Unfavg High

3 ALL 185 BM Yes 1.CR Inter High

4 CML 1044+ BM – 1.Cphd Inter Stand

a

f

b

g

Secondary AML. Delayed response to induction treatment: Yes/No. c Stage of disease at the time of transplantation. d First chronic phase. e First early relapse.

5 ALL 97 BM No 2.CR Unknh High

6 AML 242 BM Yes 1.rele Inter High

7 AML 167 BM No 1.rel Favi High

Intermediate risk of relapse. Unfavourable. h Unknown cytogenetics. i Favourable with regard to risk of relapse. j Standard

8 sAML 148 BM No 1.rel Unfav High

a

9

10

11

AML 91 BM Yes 1.rel Unfav High

AML 129 BM Yes 1.rel Inter High

CML 1867+ BM – 1.Cph Inter Stand

+alive.



262

significant (P ¼ 0.35), and with regard to OS the difference was not found significantly better among BSC recipients compared to BM (P ¼ 0.617).

Discussion This long-term follow-up supports previous reports that there is a significantly higher incidence of extensive chronic GVHD among recipients of BSC as compared to BM.12–19 Our patient population has an unequal distribution of HLA-mismatched pairs that in part explains the difference. This is disclosed by the log-rank test where the HLAmismatched pairs were excluded. There are also more male recipients with a female donor in the BSC group. This is regarded as an important risk factor for chronic GVHD,39,40 but is not supported by the multivariate analysis of our data. In the BSC group there are nine male recipients with a female donor, of whom four developed chronic GVHD. Seven of 13 male recipients with a male donor developed chronic GVHD. Older age of the recipient is an independent risk factor for chronic GVHD.40 In our cohort the BSC patients are slightly younger than BM recipients, which possibly could reduce the risk. Some authors suggest an association between low number of CD34+ cell number with higher T cell number in the graft and chronic GVHD.26 Other authors state that a CD34+ cell dose below 8 106/kg recipient bw is associated with a decreased risk of developing clinical extensive chronic GVHD, compared to higher doses.41 Our BSC patients received a median of 3.1 106/kg recipient bw, which was sufficient for an early engraftment, but the effect on GVHD is uncertain. We conclude that the heterogeneity between the treatment groups and the small number of patients reduces the power of statistical analysis related to extensive chronic GVHD, even if the trend is clear. Supportive evidence comes from the multivariate analysis of our data, which showed that the stem cell source is the most important predictor for developing extensive chronic GVHD next to HLA mismatch. It has been suggested that the strongest predicting factor for secondary malignancies is chronic GVHD.42 Since BSC allografting is associated with more chronic GVHD, one would expect a higher incidence of secondary malignant neoplasm among the recipients of BSC. This notion is not supported by our study. A longer follow-up may change this picture. Does more extensive chronic GVHD lead to higher TRM in recipients of BSC? Randomised studies do not support this hypothesis. On the contrary, many studies show a trend towards a lower TRM in recipients of BSC allografts, and one randomised study shows a significantly reduced TRM in the BSC group.7 One retrospective study shows significantly lower 1-year TRM after BSC transplants in patients with advanced leukaemia, probably because of the rapid engraftment reducing the risk for severe infections and haemorrhages.9 Our study shows no significant difference between BSC and BM allografting. However, the study was not designed to address this question. The higher incidence of chronic GVHD may have a negative Bone Marrow Transplantation

impact on late TRM among the BSC patients. Longer follow-up studies are needed. As the presence of chronic GVHD is strongly associated with increased GVL-effect, it has been expected that BSC allografting would reduce the relapse rate compared to BM.43,44 The randomised trials are presenting diverging results and are therefore not conclusive. One small randomised study showed a significantly lower risk of relapse in BSC recipients.5 Other studies show a trend towards lower relapse rate after BSC allografting only in patients with advanced leukaemia.8,9 In two randomised studies with patients in early-stage leukaemia, the LFS was identical in the two groups.1,4 Our study shows a significantly lower relapse incidence in BSC recipients. Patients considered high-risk are equally distributed between the groups. Among the 11 high-risk patients in the BSC group, there were five patients with chronic GVHD and no relapse occurred. In the BM group, the corresponding numbers were 13 and three, and eight patients relapsed. These data support the hypothesis that an enhanced GVL effect is provided by BSC allografts, an effect that may exist without clinically overt chronic GVHD.45 The slightly higher number of high-risk patients in the BM group cannot fully explain the difference between the groups, and for this reason, the stem cell source seems to be a crucial factor. Nevertheless, the study did not show any statistically significant difference between the groups regarding LFS, which could be explained by the relatively higher TRM (eight patients in the BSC group vs four in the BM group) annulling the lower relapse mortality in the BSC group. With regard to OS, BSC recipients with advanced leukaemia appeared to have a benefit over BM as shown in the large retrospective IBMTR/EBMT study.9 In the Canadian randomised trial, there was a significant difference in OS at 30 months favouring patients randomised to BSC allografting.7 Our trial does not reveal any significant difference between the BSC and BM recipients. Higher incidence of chronic GVHD implies more morbidity with a higher risk of late TRM among BSC patients. On the other hand, reduced relapse rate has an opposite effect on survival. Longer follow-up of our and patients from other randomised studies is necessary to assess this key end point. Regarding donors, previous studies of safety and complaints have shown that BSC harvest is the best method of collecting stem cells providing no unexpected long-term detrimental consequences will emerge.33,46,47 In addition, BSC allografting is at least cost equivalent to allogeneic BM transplantation as suggested in a Canadian and a French trial.48,4 Thus, the choice of stem cell source should mainly depend on what is regarded as most favourable to the recipient. The relatively high incidence of extensive chronic GVHD is an important reservation against the uncritical use of BSC in allogeneic sibling donor transplantation, at least in low-risk and standard risk patients. Several of the BSC recipients with standard-risk leukaemia in our study developed chronic GVHD. They were probably not in need of this potentially mutilating condition to evade relapse. It is our opinion that at the present time, BSC should be reserved for patients with advanced disease. An alternative approach to improve the


effect of BSC is to selectively strengthen the immunosuppressive treatment in patients with standard-risk leukaemia. However, this may reduce the beneficial GVL-effect. Other pharmacotherapeutic approaches are investigated.49 Graft engineering by some kind of T cell depletion and/or CD34+ selection is another approach. Humanised CD52 antibodies have been used with encouraging results.50 Recently, it has been suggested that a higher number of mesenchymal cells in the graft could facilitate engraftment and prevent GVHD.51,52 In conclusion, long-term follow-up of our patients shows a trend towards increased incidence of extensive chronic GVHD, resulting in increased, but so far not statistically significant higher TRM in patients allografted with BSC compared to BM. On the other hand, BSC transplantation seems to result in a stronger GVL effect with a subsequent reduced relapse rate, but without a significant impact on the leukaemia-free survival and the OS. Patients with highrisk leukaemia may nevertheless have benefit from the use of BSC, while BM may give the most favourable outcome for patients with low- and standard-risk leukaemia. The clinical practice in our centre has been changed accordingly and implemented since year 2000.

263 8

9

10

11

12

13

14

Acknowledgements This study was supported by Bergliot and Sigurd Skaugen’s ‘Fond til bekjempelse av kreft’. We also thank the nurses and administrative personnel at Section of Haematology, Medical Department, Rikshospitalet University Hospital, Oslo for their excellent cooperation and patient care, Lill Anny Gunnes Grseth for CD 34+ cell and T-lymphocyte enumeration and Ellen Finsberg for graphs.

References 1 Schmitz N, Beksac M, Hasenclever D et al. Transplantation of mobilized peripheral blood cells to HLA-identical siblings with standard-risk leukaemia. Blood 2002; 100: 761–767. 2 Vigorito AC, Azevedo WM, Marques JF et al. A randomised, prospective comparison of allogeneic bone marrow and peripheral blood progenitor cell transplantation in the treatment of haematological malignancies. Bone Marrow Transplant 1998; 22: 1145–1151. 3 Mahmoud HK, Fahmy OA, Kamel A et al. Peripheral blood vs bone marrow as a source for allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 1999; 24: 355–358. 4 Blaise D, Kuentz M, Fortanier C et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukaemia: a report from the Socie´te´ Française de Greffe de Moelle. J Clin Oncol 2000; 18: 537–546. 5 Powles R, Mehta J, Kulkarni S et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000; 355: 1231–1237. 6 Heldal D, Tjnnfjord G, Brinch L et al. A randomised study of allogeneic transplantation with stem cells from blood or bone marrow. Bone Marrow Transplant 2000; 25: 1129–1136. 7 Couban S, Simpson DR, Barnett MJ et al. A randomized multicenter comparison of bone marrow and peripheral blood

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