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Peripheral blood stem cells Patients with acute lymphoblastic leukaemia allografted with a matched unrelated donor may have a lower survival with a peripheral blood stem cell graft compared to bone marrow L Garderet1,2,3, M Labopin1,2,3, NC Gorin1,2,3, E Polge1,2,3, L Fouillard1,2,3, GE Ehninger4, O Ringden5, J Finke6, S Tura7 and F Frassoni8 1 Centre International Greffes AP-HP, Institut des Cordeliers, Paris, France; 2Centre de recherches sur la the´rapie cellulaire de l’Association Claude Bernard et Equipe d’accueil EA 1638, Universite´ Paris 6, Paris, France; 3Service d’He´matologie, Hoˆpital Saint Antoine AP-HP, Paris, France; 4Medizin Klinik I, Universitatsklinikum Dresden, Dresden, Germany; 5Centre for Allogeneic Stem Cell Transplantation, Huddinge University Hospital, Huddinge/Sweden; 6Department of Medicine-Hematology, University of Freiburg, Freiburg, Germany; 7Institute of Hematology and Medical Oncology Seragnoli, San Orsola Hospital, Bologna, Italy; and 8 Department of Hematology, San Martino Hospital, Genova, Italy

Summary: We analysed data for 213 patients with ALL and AML who received either peripheral blood stem cells (PBSC) (n ¼ 74) or bone marrow (BM) (n ¼ 139) from an HLAmatched unrelated donor (EBMT acute leukaemia registry; January 1994 to January 1999). The two groups of patients (by cell source) were comparable with respect to age, sex, disease status, year at transplant and graft T cell depletion. Engraftment was achieved in about 90% regardless of stem cell source or leukaemia type. Kinetics of neutrophil and platelet recovery, similar for both sources in ALL patients, were faster for PBSC in AML patients. The incidence of acute graft-versus-host disease was similar for both sources in AML patients, but higher for PBSC in ALL patients (74 vs 54%, P ¼ 0.05). The 1year probability of chronic graft-versus-host disease was 40 and 45% (P ¼ 0.66) in ALL patients compared to 49 and 35% (P ¼ 0.13) in AML patients (PBSC vs BM). In AML patients, none of the following differed significantly with cell source: transplant-related mortality, relapse incidence, leukaemia-free survival and overall survival. In ALL patients, the transplant-related mortality for PBSC vs BM was 61 vs 47% (P ¼ 0.13), the relapse incidence was 47 vs 39% (P ¼ 0.17), the leukaemia-free survival was 21 vs 32% (P ¼ 0.04) and the overall survival was 24 vs 34% (P ¼ 0.04). These data suggest that the short-term outcome of allogeneic PBSC is not significantly different from that of BM in AML patients who underwent a transplant from a matched unrelated donor but, conversely, that survival with PBSC may be decreased in ALL patients. In conclusion, the source of transplant cells needs to be evaluated by disease, especially when dealing with unrelated donors.

Correspondence: Dr L Garderet, Service d’He´matologie; Hoˆpital Saint Antoine AP-HP, 184 rue du Faubourg Saint Antoine, Paris Cedex 12 75571, France Received 10 April 2002; accepted 30 July 2002

Bone Marrow Transplantation (2003) 31, 23–29. doi:10.1038/sj.bmt.1703778 Keywords: acute leukaemia; allogeneic transplantation; peripheral blood stem cells; unrelated donor

Haematopoietic cells reside in the bone marrow (BM) and can be mobilized in large numbers in the blood by the administration of granulocyte colony-stimulating factor (G-CSF, filgrastim). Apheresis products are now widely used instead of BM for autologous transplantation1 because they avoid the need for general anaesthesia of the donor, are easier to collect and induce faster recovery of haematopoiesis. These favourable results with autologous cells have prompted the evaluation of allogeneic peripheralblood cell transplantation.2–4 Several retrospective studies and most prospective randomized trials, including the recent one from the European Group for Blood and Marrow Transplantation (EBMT), have shown a faster kinetics of engraftment with peripheral blood stem cells (PBSC) but a higher incidence and severity of chronic graftversus-host-disease (cGVHD) in patients allografted with an identical sibling donor.5–7 Most studies have shown no difference in the incidence and severity of acute graftversus-host disease (aGVHD), with the exception of the EBMT study in a total of 350 patients with acute leukaemia in complete remission, and chronic myeloid leukaemia in chronic phase where the incidence and severity of aGVHD were found to be increased following PBSC transplantation.7 Contrasting with these studies, the Seattle group reported no difference in incidence and severity of either acute or chronic GVHD between recipients of allo PBSC or BM from genoidentical donors in 172 patients with various haematological malignancies, not restricted to acute leukaemia.8 In all studies, whatever the results for GVHD, leukaemia-free survival (LFS) and overall survival (OS) were similar. While considerable information exists on PBSC allografting with HLA identical sibling donors, only a few

Acute lymphoblastic leukaemia L Garderet et al

24

patients have been reported who received PBSC from unrelated donors.9–12 Furthermore, there is presently no guideline regarding the preferred source of stem cells (PBSC or BM) from unrelated volunteer donors, and for each procedure the source is usually selected by the centre of harvest rather than the centre that actually does the transplant.13,14 The major risk when selecting PBSC over marrow concerns the higher number of T cells infused and the increased risk of acute and/or chronic GVHD.15 This risk may be of a greater magnitude with unrelated volunteer donors than with identical siblings. Indeed, the risk of GVHD has been shown to be considerably increased over marrow for a one HLA antigen mismatch, when using unrelated donors.16,17 In order to address this question, we analysed results of primary allogeneic PBSC transplantation from matched unrelated donors performed from 1994 to 1999, as reported to the EBMT. We compared the results according to leukaemia type with those obtained after matched unrelated allogeneic bone marrow transplantation (BMT).

status at transplant, patient age, year of transplant, and whether or not the graft was T cell depleted. The characteristics of the two groups, for both acute myeloid and lymphoid patients, are detailed in Table 1. The median follow-up was 18 months (PBSC, range, 1–36 months) and 25 months (BM, 1–60) in AML patients and 16 months (PBSC, 1–50) and 23 months (BM, 1–49) in ALL patients.

Donor/recipient cytomegalovirus (CMV) status and HLA matching Table 1 provides details concerning CMV status of donors and recipients. In most cases, either the recipient or the donor was CMV positive prior to transplantation. There was no difference according to stem cell source. HLA typing was done by serology for class I and high-resolution typing for class II. All donor–recipient pairs were HLA-A, B and DRB1 identical.

Engraftment evaluation Neutrophil engraftment was defined as an absolute neutrophil count (ANC) greater than 0.5 109/l occurring on the first of three consecutive days. Platelet engraftment was defined as the first day with a platelet count greater than 50 109/l without further need for platelet transfusions.

Patients and methods Patients All patients were transplanted for acute leukaemia (myeloid and lymphoid) between January 1994 and January 1999, and were reported to the registry of the Acute Leukaemia Working Party (ALWP) of the EBMT. The data for 74 patients (adults and children) who received G-CSFmobilized PBSC from a matched unrelated donor as their first allotransplant for acute leukaemia were analysed and compared with data for a historical control group comprising 139 matched unrelated marrow transplants computer-matched for the following variables: disease

Table 1

End points The study end points were acute and chronic GVHD, treatment-related mortality (TRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS). Incidence and time of onset of GVHD were evaluated in patients with evidence of engraftment who, after transplantation, survived at least 21 days (aGVHD) or 90 days (cGVHD). Acute aGVHD was graded according to

Patient and donor characteristics ALL

Number of patients Patient age Children Adult>16 years Median (range) Gender Patient female Donor female Phase of disease 1st complete remission 2nd and 3rd complete remission Other Cytomegalovirus serology Recipient +/ Donor +/ T depletion No Yes Total body irradiation No Yes Follow-up (months)

Bone Marrow Transplantation

PBSC

BM

36

66

15 (42%) 21 (58%) 18 (5–66)

28 (42%) 38 (57%) 17 (1–50)

9 (25%) 10 (29%)

28 (42%) 27 (41%)

7 (19%) 19 (53%) 10 (28%)

12 (18%) 35 (53%) 19 (29%)

15/16 15/15

AML P

PBSC

BM

38

73

3 (8%) 35 (92%) 36 (1–55)

6 (8%) 67 (92%) 33 (1–52)

20 (54%) 19 (51%)

31 (43%) 31 (43%)

0.99

8 (21%) 11 (29%) 19 (50%)

16 (22%) 21 (29%) 36 (49%)

0.99

35/24 23/31

0.32 0.51

19/11 14/17

41/26 20/42

0.84 0.22

30 (83%) 6 (17%)

60 (91%) 6 (9%)

0.26

34 (90%) 4 (10%)

67 (92%) 6 (8%)

0.69

10 (29%) 24 (71%) 16 (1–50)

9 (14%) 57 (86%) 23 (1–49)

0.06

16 (44%) 20 (56%) 18 (1–36)

18 (25%) 55 (75%) 25 (1–60)

0.04

0.94

P

0.95


standard criteria.18 Outcome data were compiled from the date of transplantation through the date of death or last contact. TRM was defined as death with no evidence of disease. To evaluate relapse rate, patients dying either from the direct toxicity of the procedure or from any cause unrelated to leukaemia were censored. LFS was defined as survival without evidence of relapse, the event under study being death or relapse. Patients were censored at the time of relapse or last follow-up.

cumulative incidence of aGVHD grade II–IV at 100 days did not differ significantly between the two sources of stem cells. We observed the same results for the cumulative incidence in grade III–IV aGVHD, which were 18% in both groups of AML patients and 19% in ALL patients. The 1-year probability of cGVHD was slightly higher with PBSC than BM transplants in AML patients (49 vs 35%, P ¼ 0.13) but similar in ALL patients (40 vs 45%, P ¼ 0.66).

Statistical analysis

Transplant-related mortality, RI and survival

Statistical differences between subgroups were determined using the w2 test or Fisher’s exact test for categorical variables. All P values are two-sided. LFS, RI, TRM and OS were also estimated by the product limit method.19 A series of several characteristics of patients and grafts were studied for a possible impact on LFS, RI, TRM and OS, by using the proportional hazard model.20 All variables with a probable association (Po0.2) with relapse, LFS, TRM or OS were included in the Cox proportional hazard model. Then, stepwise fitting procedures were used with a cut-off level of 0.05 significance for inclusion of terms in the models. All analyses were performed with the SPSS computer program (SPSS, Chicago, IL, USA).

The relative risk of treatment failure differed according to leukaemia type. It was identical with blood and BM cells in AML patients (38 vs 40%, P ¼ 0.92, Figure 1a) while slightly higher for blood cells in ALL patients (61 vs 47%, P ¼ 0.13, Figure 1b). The relapse incidence rate did not differ statistically according to the stem cell origin and leukaemia type. However, in both leukaemias the RI was higher with PBSC (Figure 2a and b). The 2-year probability of LFS in patients with AML was similar regardless of cell source (Figure 3a). However, LFS was significantly lower with blood cell transplants (21 vs 32%, P ¼ 0.04, Figure 3b). Overall survival was also different depending upon whether patients had acute lymphoid or myeloid leukaemia: no difference existed in AML patients (Figure 4a) but ALL patients had a significantly lower OS if they received a PBSC graft (P ¼ 0.04, Figure 4b). Thus, the use of blood stem cells rather than bone marrow decreased LFS and OS in patients with acute lymphoid leukaemia.

Results Engraftment (PBSC vs BM) Neutrophil engraftment occurred in 92 vs 93% of AML patients and 88 vs 89% of ALL patients. Recovery was significantly faster with PBSC than BM in AML patients: median time to engraftment was 16 vs 19 days (P ¼ 0.05) for neutrophils and 21 vs 41 days (P ¼ 0.005) for platelets. In contrast, there was no difference in speed of recovery in ALL patients (16 vs 19 days (P ¼ 0.94) for neutrophils; 37 vs 33 days (P ¼ 0.24) for platelets) (data not shown).

Acute and chronic GVHD The incidence and grading of acute and chronic GVHD in the two groups are shown in Table 2. aGVHD was similar in both groups of AML patients (62 vs 63%) but slightly higher after PBSC than BM transplants in ALL patients (74 vs 54%, P ¼ 0.05). However, for all patients, the Table 2

25

Multivariate analysis for TRM, RI, and survival In multivariate analyses, cell source and disease status at transplant were significant factors for RI, LFS and OS (Table 3). The only significant factor for RI was disease status. ALL patients had a reduced survival when PBSC were used and if they were not in complete remission at transplant. In AML patients, the source of stem cells did not influence survival.

Discussion There is currently considerable information on the respective value of BM and PBSC as sources of stem cells for

Incidence and severity of acute and chronic GVHD ALL

Acute GVHD No Yes Grade I II III IV Grade II–IV 1-year probability of chronic GVHD

AML

PBSC (36)

BM (66)

P

PBSC (38)

BM (73)

P

9 (26%) 26 (74%)

28 (46%) 33 (54%)

0.05

13 (38%) 21 (62%)

27 (37%) 46 (63%)

0.9

12 7 5 2 39% N=18 40715

8 12 7 6 38% N=42 4578

6 8 4 3 39% N=21 49712

13 19 5 8 44% N=44 3578

NS 0.66

NS 0.13



26

Transplant-related mortality

AML patients

1.0 AML patients

0.8

0.4

40 ± 6%

BM (n =73)

38 ± 10%

PBSC (n=38)

0.2

Relapse incidence

0.8

0.6

0.0

b

a

1.0

0.6 46 ± 11% 0.4

30 ± 7%

PBSC (n=38) BM (n=73)

0.2 P =0.92 0

1.0

12 24 Months after transplant

36

P =0.23

0.0 0

b

ALL patients

1.0


36

ALL patients

0.8 0.8 0.6

61 ± 9%

PBSC (n =36)

47 ± 7%

BM (n=66)

0.4 0.2

0


PBSC (n=36) 0.6 47 ± 13% 39 ± 8%

0.4

36

0.0

P =0.17 0

Figure 1 Transplant-related mortality of patients grafted with PBSC or BM from unrelated donors: (a) AML (PBSC vs BM, P ¼ 0.92); (b) ALL (PBSC vs BM, P ¼ 0.13).

allogeneic transplantation using an HLA identical family donor.2–8,21 Several retrospective cohort studies as well as several multicentric randomized studies have concluded equivalence of the two stem cell sources in terms of diseasefree and overall survival, despite an increased incidence of cGVHD in most studies including the one from EBMT,7 and an increased incidence and severity of aGVHD with PBSC. A more pronounced graft-versus-leukaemia effect (GVL) has been credited to PBSC transplantation, somehow compensating for the increase in GVHD and TRM with PBSC.22,23 This GVHD increase is attributed to the larger number of T cells administered (one more log)24 and also to a higher immunological reactivity of peripheral blood over marrow T cells.25 Decreasing donor/recipient tissue compatibility might result in important outcome differences when using PBSC over marrow as a stem cell source. With unrelated donors, the Idar–Oberstein group, on a total of 74 patients, found a similar incidence of severe aGVHD with PBSC and BM from HLA-matched unrelated donors but a higher one with PBSC in cases of HLA mismatch.11,12 Currently, in fact, there is limited information on which source to select when undertaking family mismatched and unrelated transplants. Therefore, the present study from the EBMT registry addressed the question precisely in patients transplanted using unrelated donors. Bone Marrow Transplantation

BM (n=66)

0.2

P= 0.13

0.0

Relapse incidence

Transplant-related mortality

a


36

Figure 2

Relapse incidence of patients grafted with PBSC or BM from unrelated donors: (a) AML (PBSC vs BM, P ¼ 0.23); (b) ALL (PBSC vs BM, P ¼ 0.17).

This study has confirmed that PBSC from unrelated HLA-A, -B, -DR fully matched donors can be safely administered as an alternative to BM. Patients with AML receiving PBSC tended to have faster engraftment of neutrophils and platelets than the BM controls. The speed of recovery did not differ in ALL patients according to stem cell source. There was no difference in acute or chronic GVHD between AML patients receiving PBSC or BM, but the incidence of aGVHD was slightly higher in ALL patients receiving PBSC. The results of the previously published retrospective and prospective randomized trials have combined several categories of diseases. As demonstration examples with HLA identical family donors, the Seattle team has included acute and chronic leukaemias, myelodysplastic syndromes, lymphomas and myelomas.8 The EBMT study7 has included patients with acute leukaemia in CR and with chronic myeloid leukaemia in chronic phase. In all studies, the number of patients with ALL has been small, and while the conclusion that the outcome was similar with PBSC and BM is well established as a whole, the question of whether differences might exist for different diseases has not been raised, and indeed there is very limited information regarding ALL specifically.


27

a

a

1.0

1.0 AML patients

0.8

42 ± 6% 0.4 33 ± 8%

Leukemia-free survival

BM (n=73) PBSC (n =38)

Overall survival

0.6

0.2 0.0 0

b

0.8

P =0.49 12 24 Months after transplant

0

BM (n =73)

38 ± 9%

PBSC (n=38)

P =0.86 12 24 Months after transplant

1.0

36

ALL patients

ALL patients 0.8

0.8 0.6 0.4 0.2 0.0 0

42 ± 6% 0.4

0.0

36

b 1.0

0.6

0.2

Overall survival

Leukemia-free survival

AML patients

32 ± 6%

BM (n=66)

21 ± 7%

PBSC (n =36)

P =0.04

0.4

34 ± 7% 24 ± 7%

0.2

0

36

Figure 3 Leukaemia-free survival of patients grafted with PBSC or BM from unrelated donors: (a) AML (PBSC vs BM, P ¼ 0.49); (b) ALL (PBSC vs BM, P ¼ 0.04).

BM (n =66) PBSC (n=36)

P=0.04

0.0


Table 3

0.6


36

Figure 4 Overall survival of patients grafted with PBSC or BM from unrelated donors: (a) AML (PBSC vs BM, P ¼ 0.86); (b) ALL (PBSC vs BM, P ¼ 0.04).

Multivariate analyses ALL

TRM Adult vs children RI CR at transplant LFS PBSC vs BM CR at transplant Overall survival PBSC vs BM CR at transplant

AML

RR

CI

P

1.97

1.1–3.7

0.04

0.23

0.1–0.5

o0.0001

1.69 0.55

1–2.7 0.35–0.89

0.03 0.05

1.77 0.36

1.1–2.9 0.21–0.6

0.03 o0.0001

RR

CI

P

TRM No factor RI CR at transplant LFS CR at transplant

0.26

0.1–0.6

0.002

0.41

0.25–0.7

0.001

Overall survival CR at transplant

0.41

0.25–0.7

0.001

CR: complete response.

In our retrospective study of the EBMT registry, multivariate analysis indicated that the prognostic value of the source of stem cells (PBSC or BM) differed according to acute leukaemia type. Patients with ALL, but not AML, had a lower LFS and OS following transplant with PBSC than BM. In general, ALL transplantation gives poorer results compared with AML. Observations on GVH disease/GVL as well as reports on delayed lymphocyte

infusion (DLI) available in the past decade have indicated that the GVL effect is less pronounced in patients with ALL than with AML or CML.26 Moreover, nonmyeloablative stem cell transplants, which rely essentially on the GVL effect to control leukaemia, are also less effective in ALL patients.27 Results with PBSC may be worse for ALL patients in the unrelated transplant setting for many reasons, including a slightly higher TRM that is not Bone Marrow Transplantation


28

counterbalanced by the beneficial effect of GVL observed in AML. Differences in graft composition might also explain delayed platelet recovery and reduced LFS and OS in ALL patients allografted with PBSC. Haematopoietic stem cells collected from peripheral blood have higher numbers of nucleated cells, CD34+ cells, CFU-GM, T lymphocytes and NK cells. The absolute and relative differences between PBSC and BM harvests as regards numbers of CD34+ cells and cells with GVHD- and GVL-inducing potential (T cells, NK cells) might explain differences in survival. Unfortunately, missing data as regards numbers of transplanted CD34+ and CD3+ cells in both the PBSC and BM grafts precluded any meaningful statistical comparison of the ALL and AML groups with regard to the quality of the grafts. The present study suggests that the risk of PBSC transplantation may increase with unrelated donor transplants, and focuses on ALL as a possible higher risk disease for whom BM may be preferred. However, the small number of patients in this analysis limits the validity of the study and further observations or even a prospective randomized trial in ALL are needed to strengthen the statistical power.

Acknowledgements

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10

11

12

13

14

15

16

We thank Tiiu Ojasoo for her critical review of the manuscript. 17

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