Allogeneic stem cell transplantation in the myelodysplastic

syndromes: interim results of outcome following

reduced-intensity conditioning compared with

standard preparative regimens

Jane E. Parker,1

Tariq Shafi,1

Antonio Pagliuca,1

Aleksandar Mijovic,1

Stephen Devereux,1

Mike Potter,2

H. Grant Prentice,2

Mamta Garg,3

John A. Yin,3

Jenny Byrne,4

Nigel H. Russell4

and Ghulam J. Mufti1 1Department of Haematological Medicine, Guy’s, King’s, Thomas’ School of Medicine,

2Department of Haematology, Royal Free and University College Medical School, London, 3University Department of

Haematology, Manchester Royal Infirmary, Manchester, 4Division of Haematology, School of Clinical and

Laboratory Sciences, University of Nottingham, Nottingham, UK

Received 6 November 2001; accepted for publication 4 April 2002

Summary. Conventional allogeneic stem cell transplanta-tion (SCT) for myelodysplastic syndrome (MDS) is associatedwith excessive procedure-related mortality. The outcomefollowing volunteer-unrelated donor (VUD) or siblingallogeneic SCT was therefore evaluated in 23 MDS patientsconditioned with reduced-intensity regimens (fludarabine/busulphan/Campath-1H) because of advanced age (48vs 37 years, P ¼ 0Æ002) and/or co-morbidity (19 vs 3,P < 0Æ0001) which precluded conventional transplanta-tion, and compared with 29 treated with standard protocols[busulphan/cyclophosphamide (Bu/Cy); Bu/Cy/total-bodyirradiation/Campath-1G]. Graft-versus-host disease (GVHD)prophylaxis comprised of cyclosporine/methotrexate. Onehundred per cent donor engraftment (variable numbertandem repeat analysis/cytogenetics/fluorescence in situhybridization) was achieved in 18/19 (95%) evaluablepatients receiving reduced-intensity regimens, although six(32%) have subsequently shown mixed chimaerism.Reduced-intensity conditioning was associated with signifi-cantly reduced duration of aplasia, less mucositis, fever,antibiotic, analgesia, parenteral nutrition use, less acute

and chronic GVHD, and lower early procedure-relatedmortality [two (9%) vs nine (31%), P < 0Æ05]. Six patientsrelapsed (two standard, four reduced-intensity) and two(reduced-intensity) experienced late graft failure. The 2 yearactuarial overall/disease-free survival (OS/DFS) was48/39% in the reduced-intensity arm and 44/44% in thestandard group. The 2 year non-relapse mortality was 31%and 50% respectively. In VUD recipients, OS was superior inthe reduced-intensity arm (49% vs 34%). Predictors of DFSincluded good/intermediate-risk karyotype, low/intermedi-ate-1 International Prognostic Scoring system score, humanleucocyte antigen compatibility and attainment of completeremission. Our data demonstrates that VUD or siblingallogeneic SCT following reduced-intensity conditioning isfeasible in high-risk MDS patients considered unsuitable forstandard transplantation and is associated with comparable3Æ5 year DFS to those receiving conventional regimens.

Keywords: MDS, MDS-AML, allogeneic stem cell trans-plantation, reduced-intensity conditioning, Campath-1H.

The myelodysplastic syndromes (MDS) are clonal stem celldisorders characterized by ineffective and dysplastic hae-mopoiesis. The natural history is variable, with approx-

imately 50% of patients dying from cytopenic com-plications and 30% undergoing leukaemic transformation(Mufti & Galton, 1986; Greenberg et al, 1997). Growthfactors and differentiation-inducing agents have been usedin low-risk disease, with little evidence of prolongation orimprovement in quality of survival (Aul et al, 1993;Greenberg et al, 1993; Wijermans et al, 2000). In high-risk cases, response to intensive chemotherapy is inferior tothat observed in de novo acute myeloid leukaemia (AML),

Correspondence: Professor Ghulam J. Mufti, The Department of

Haematological Medicine, Guy’s, King’s, Thomas’ School of Medi-cine, Denmark Hill Campus, Bessemer Road, London SE5 8RX, UK.

E-mail: ghulam.mufti@kcl.ac.uk

British Journal of Haematology, 2002, 119, 144–154

144 � 2002 Blackwell Publishing Ltd

with most patients relapsing within 12 months of achiev-ing complete remission (CR) (De Witte et al, 1995). Todate, allogeneic stem cell transplantation (SCT) followingstandard conditioning is the only curative option in MDS(Anderson et al, 1993, 1996; Sutton et al, 1996; Arnoldet al, 1998). The elderly nature of most patients, frequentco-morbidity and the lack of a human leucocyte antigen(HLA)-compatible sibling, however, limits use of thistreatment modality as a result of unacceptable procedure-related mortality (Keating et al, 1996). Reduced-intensityimmunosuppressive conditioning, which utilizes immuno-logical mechanisms to secure donor cell engraftment andleukaemia cell abrogation (Giralt et al, 1997) is associatedwith considerably lower toxicity and should broaden theapplication of allogeneic SCT in MDS. We present apreliminary comparison of outcome following allogeneicSCT in MDS patients conditioned with standard protocolsand those receiving reduced-intensity regimens, comprisingfludarabine, busulphan and Campath-1H (FBC).

MATERIALS AND METHODS

PatientsBetween December 1993 and November 2000, 52 MDSpatients underwent allogeneic SCT at four UK transplantcentres. Patients were considered for transplantation if theyhad > 5% bone marrow (BM) blasts and/or potentially life-threatening cytopenias, and had a suitable donor. twenty-nine patients were conditioned with standard protocols and23 with reduced-intensity regimens (Tables I and II). A fullexplanation of the transplant procedure was given andinformed consent obtained. The reduced-intensity protocolswere approved by the Local Ethics Committee.

Therapy prior to transplantationPatients were given remission-induction chemotherapy ifthey had: > 10% BM blasts or 5–10% blasts plus interme-diate/poor-risk cytogenetics. Eligible patients (27/30)received one to four courses of chemotherapy prior totransplantation; 15 (56%) achieved CR (< 5% BM blasts/normalization of peripheral counts and karyotype). Ninepatients (33%) attained a partial remission (PR) (> 5% BMblasts but ‡ 50% reduction in blast percentage/cytogeneticabnormalities or < 5% blasts with persisting cytopenias/cytogenetic abnormalities), two (7%) were refractory tochemotherapy (< 50% reduction in BM blast percentage/cytogenetic abnormalities) and one failed to regenerate. Attransplantation, 13 patients remained in continuing CR,seven were transplanted in relapse or with progressivedisease, and the remainder had stable disease.

Donor characteristicsSerological- and molecular-based tissue typing for HLA classI (A, B, C) was undertaken on patient and donor samplesusing sequence-specific oligonucleotide probe (SSOP) andsequence-specific primer (SSP) methods. For some samplesprocessed prior to 2000, only serological class I typing wasperformed. HLA class II (DR and DQ) high-resolution typingwas achieved through both SSOP and SSP methods using

commercially available reagents (Biotest ELPHA for Class I;Dynal Reli for class II SSOP; Dynal Allset for SSP).

Twenty-five patients received stem cells from siblingdonors, of which 24 were HLA identical. Two patientsunderwent transplantation using a one antigen-mis-matched alternative family donor (AFD) and 25 fromvolunteer-unrelated donors (VUD). Of these, 15 (60%)VUD were matched at HLA A, B, C, DRB1 and DQB1, sixwere mismatched at one, and four at two antigen loci.Twenty-five (48%) donor-recipient pairs were sex mis-matched, while cytomegalovirus (CMV) sero-positivity inrecipient and/or donor was detected in 37 (71%) cases. In13 (25%) patients, SC were harvested peripherally (PBSC),following granulocyte colony stimulating factor (G-CSF;filgrastim, 10 lg/kg · 5) priming. In the remaining cases,bone marrow was used as the source of stem cells.

Preparative regimensStandard conditioning. Eighteen sibling allografts were

conditioned with busulphan (16 mg/kg), cyclophosphamide(200 mg/kg), while AFD and nine VUD recipients receivedsmaller busulphan (4 mg/kg) and cyclophosphamide(120 mg/kg) doses in combination with total-body irradi-ation (TBI), 1440 cGy and Campath-1G (10 mg i.v., d )5to d +5) (Table IA).

Reduced-intensity conditioning. Twenty-three patients(seven sibling, 16 VUD) were treated with reduced-intensityregimens, comprising fludarabine (150 mg/m2), busulphan(8 mg/kg), Campath-1H (20 mg i.v., d )5 to )1) (FBC)(Table 1B). In two patients transplanted in relapse, thebusulphan dose was increased to 16 mg/kg to maximizetumour cell elimination. Campath-1G [rat anti-CD52monoclonal antibody (IgG2b mAb)] and )1H (humanizedanti-CD52 IgG1 mAb), which lyse human T lymphocytesthrough Fc receptor binding (Hale et al, 1983) were kindlysupplied by Professors Geoff Hale and Hermann Waldmann,Therapeutic Antibody Centre, Oxford, UK.

GVHD prophylaxisCyclosporin A was commenced 24 h prior to SC infusionand doses adjusted to maintain trough levels between 100and 200 lg/l. Following reduced-intensity conditioning,cyclosporin A was stopped at d +100, provided there wasfull donor engraftment and no GVHD. All patients addi-tionally received intravenous methotrexate (MTX) followingtransplantation at varying doses, depending on the type ofconditioning (Bu/Cy: 15 mg/m2 on d +1, then 10 mg/m2,d +3, +6, +11; Bu/Cy/TBI: 8 mg/m2, d +2, +4, +8, +12;FBC 10 mg/m2, d +1, +3, +6). Methotrexate doses wereomitted in the presence of severe mucositis. In vitro T-celldepletion prior to SC infusion was performed in one case(PBSC from DRB1 mismatched AFD).

Supportive carePatients were treated in rooms with HEPA filtration, andreceived gut sterilization with oral colistin and neomycin.Antifungal prophylaxis with fluconazole or itraconazole wasadministered to all patients, while CMV-positive patientsand those receiving SC from CMV-positive donors were

Standard vs Reduced-intensity Allogeneic SCT in MDS 145

� 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 144–154

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Standard vs Reduced-intensity Allogeneic SCT in MDS 147

� 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 144–154

additionally given intravenous acyclovir, 500 mg/m2, t.d.s.All blood products were irradiated for at least 3 months pre-and 1 year post transplantation and were CMV compatible.Empirical intravenous antibiotics, amphotericin, ganciclovirand total parenteral nutrition (TPN) were administered asrequired. G-CSF (filgrastim), 300 lg/d, was commenced 7 dfollowing SC infusion and continued until neutrophilswere > 1Æ0 · 109/l for 3 d consecutively. Nebulized pen-tamidine (300 mg monthly) administered for pneumocystispneumonia (PCP) prophylaxis during transplantation waschanged to septrin (two tablets b.i.d. · 3/week) uponsustained haemopoietic recovery (neutrophils > 1Æ0 · 109/l;platelets > 100 · 109/l).

EngraftmentNeutrophil engraftment was defined as the first of 3 dconsecutively of a neutrophil count ‡ 0Æ5 · 109/l andplatelet engraftment as the first of 7 d consecutively of anunsupported platelet count ‡ 20 · 109/l. Chimaerism stud-ies for sex-mismatched donor/recipient pairs were per-formed using fluorescence in situ hybridization (FISH). Forsex-matched transplants, chimaerism was assessed byvariable number of tandem repeats (VNTR)/short tandem

repeats (STR) analysis. Before January 2000, this wascarried out by whole-blood polymerase chain reaction (PCR)DNA amplification of two highly polymorphic regions(region I and region II) of the von Willebrand factor geneas previously described (van Amstel & Reitsma, 1990). Afterthis date, a commercial kit (Powerplex 1Æ2, Promega,London, UK) was used, which amplifies short tandemrepeats within nine different gene loci.

Statistical analysisRelapse was defined as the re-emergence of prior morpho-logical abnormalities and/or recipient karyotype. Non-relapse mortality (NRM) was defined as death withoutevidence of disease, during conditioning or following SCinfusion. Death from relapse or non-relapse causes was usedto determine overall survival (OS), while time to relapse wasutilized to calculate disease-free survival (DFS). The Mann–Whitney, Kruskal–Wallis, chi-square and Fisher’s Exact Testwere used for comparison of clinical and laboratorycharacteristics. Relapse, NRM, and survival estimates andcurves were obtained by the method of Kaplan and Meier. Inall statistical calculations, a P value < 0Æ05 was consideredsignificant.

Table II. Clinical characteristics of MDS patients: reduced-intensity vs standard conditioning.

Variable

Conditioning

P-valueReduced-intensity Standard

Number 23 29

Diagnosis RA 6 (26%) 12 (41%) n/sRAEB 6 (26%) 8 (28%)

RAEB-t 1 (4Æ5%) 2 (7%)

MDS-AML 6 (26%) 6 (21%)

t-MDS/AML 4 (17Æ5%) 1 (3%)Recipient age (years) Median 48 37 < 0Æ001

(range) (25–63) (18–59)

age VUD recipients (years) Median 47Æ5 27 0Æ001

(range) (25–59) (18–43)age sib recipients (years) Median 48 42Æ5 n/s

(range) (41–63) (23–57)

Sex Male 10 (44%) 12 (41%) n/s

Female 13 (56%) 17 (59%) n/sTime to transplant (months) Median 16 10 n/s

(range) (3–41) (2Æ5–36)

Co-morbidity 19 (83%) 3 (10%) < 0Æ0001Cytogenetics Good-risk 6 (27%) 13 (45%) n/s

Intermediate-risk 8 (36Æ5%) 7 (24%)

Poor-risk 8 (36Æ5%) 9 (31%)

IPSS risk group Low/INT-1 5 (22%) 12 (41%) n/sINT-2 10 (43%) 7 (24%)

High 8 (35%) 10 (35%)

Induction chemotherapy 11 (48%) 16 (55%) n/s

CR attainment 7 (63%) 8 (50%) n/sDisease status at transplant CR 5 (22%) 8 (27Æ5%) n/s

PR/stable 13 (57%) 19 (65Æ5%)

Relapse/NR/progressive 5 (21%) 2 (7%)

VUD, volunteer unrelated donor; IPSS, International Prognostic Scoring System; CR, complete remission; PR, partialremission; NR, no response.

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RESULTS

Patient and transplant characteristicsEighteen patients had refractory anaemia (RA), 14 RA withexcess blasts (RAEB), three RAEB in transformation (RAEB-t),12 AML secondary to MDS (MDS-AML) and five therapy-related MDS/AML (t-MDS/AML). There were 22 men and 30women. Median age at transplantation was 43 years (range18–63). Patients receiving reduced-intensity protocols weresignificantly older [median 48 years (range 25–63) vsmedian 37 years (range 18–59), P < 0Æ001]. Age differenceswere particularly marked in VUD/AFD recipients [reduced-intensity, median 47Æ5 years (range 25–59) vs standard,median 27 years (range 18–43), P ¼ 0Æ001]. An intermedi-ate-2/high-risk International Prognostic Scoring system(IPSS) score (Greenberg et al, 1997) was more commonlyobserved in the reduced-intensity group [18 (78%) vs 17(59%), n/s] and a higher percentage of patients weretransplanted in relapse [five (21%) vs two (7%), n/s].Significant co-morbidity was also more frequent [19 (83%)vs three (10%), P < 0Æ0001], three patients having pre-viously undergone autologous SC transplantation and fourwith angioinvasive pulmonary aspergillosis at the time oftransplant. Eight had multiple pathologies (Table II). Patientstreated with reduced-intensity regimens more frequentlyreceived SC from unrelated donors [16 (70%) vs nine (31%),P ¼ 0Æ01]. In all other respects, donor/recipient character-istics were similar between the two groups (Table III).

Early toxicityThe onset of marrow aplasia was significantly delayedfollowing reduced-intensity conditioning compared withstandard protocols (median 9 d (range 5–14) vs median19 d (range 3–22), P ¼ 0Æ003). Twenty-four (77%)patients who received standard conditioning developed

severe (Bearman grade II–III) mucositis, with 15 (52%)requiring TPN and 20 (69%) requiring systemic opiates. Incontrast, mucositis was minimal in all but one patienttreated with reduced-intensity regimens (P < 0Æ0001).Reduced-intensity conditioning was additionally associatedwith significantly shorter duration of neutropenia, fewerdays of fever, lower systemic antibiotic and amphotericinuse, and reduced blood and platelet transfusion require-ments (Table IV).

EngraftmentThree unrelated donor recipients (12%) experienced primarygraft failure: two (12Æ5%) VUD recipients undergoingreduced-intensity conditioning and one (11%) treated withstandard regimens. Failure to engraft was also noted in onepatient receiving SC from AFD. In the remaining cases,median time to neutrophil and platelet regeneration was17 d (range 13–30) and 21 d (range 9–104) respectively.Time to neutrophil recovery was reduced following reduced-intensity conditioning compared with standard protocols(median 16 d (range 14–24) vs median 21 d (range 13–30),P ¼ 0Æ05). Platelet regeneration showed no differencebetween the two groups.

Eighteen out of 19 evaluable patients undergoingreduced-intensity conditioning achieved 100% donorengraftment (VNTR/FISH analysis) at d 30 post transplant.Six patients (32%) have subsequently shown mixed chima-erism and two VUD recipients (12Æ5%) have experiencedgraft rejection at d +90 and d +99, following SC trans-plantation.

Post-transplant complicationsComplications arose in 12 (52%) patients conditioned withreduced-intensity protocols compared with 23 (79%)receiving standard regimens. Complications secondary to

Table III. Transplant characteristics: reduced-intensity vs standard conditioning.

Variable

Conditioning

P-valueReduced-intensity Standard

Number 23 29Donor source Sibling 7 (30%) 18 (62%) n/s

VUD 16 (70%) 9 (31%) 0Æ03

AFD 0 (0%) 2 (7%) n/s

Donor age (years) Median 40 37 n/s(range) (25–63) (18–59)

Donor sex Male 15 (65%) 12 (41%) n/s

Female 8 (35%) 17 (59%) n/s

Sex mismatch 11 (48%) 14 (48%) n/sCMV seropositivity* 18 (78%) 19 (66%) n/s

Source stem cells BM 18 (78%) 21 (72%) n/s

PB 5 (22%) 8 (28%) n/sHLA mismatch 6 (26%) 7 (24%) n/s

*Recipient and/or donor.

CMV, cytomegalovirus; VUD, volunteer unrelated donor; AFD, alternative family donor;

BM, bone marrow; PB peripheral blood.

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immunosuppression were the major post-transplant eventsin the reduced-intensity arm, with CMV reactivationoccurring in five of 18 (28%) patients previously exposedto CMV and three patients succumbing to viraemia (CMV,one; respiratory syncytial virus (RSV), one; adenovirus,one). One female developed Epstein–Barr virus (EBV)-positive small bowel lymphoma 6 months followingreduced-intensity therapy. In contrast, hepatic veno-occlu-sive disease (VOD) was the most frequent complicationfollowing standard therapy, occurring in nine patients(31%) (Table V). There were 11 early (before d +100)procedure-related deaths: nine (31%) in the standard armand two (7%) in the reduced-intensity group (P < 0Æ05).

GVHDAcute and chronic GVHD were defined and scored accord-ing to established criteria (Glucksberg et al, 1974; Schul-man et al, 1980). Fifty-one patients were evaluable for thedevelopment of acute GVHD (survival > 14 d post trans-plant). Acute GVHD grade II and above was evident in fourof 23 patients (17%) undergoing reduced-intensity condi-tioning compared with 16/28 (55%) receiving standard

protocols (P ¼ 0Æ004). Fifteen of 41 patients (37%) alive100 d post transplant developed chronic GVHD, three of 20patients (15%) in the reduced-intensity arm and 12/21(57%) conditioned with standard regimens (P ¼ 0Æ01)(Table V).

Non-relapse mortalityTwenty patients (38%) died from non-relapse causes between14 d and 17Æ3 months post transplant [reduced-intensity, six(26%); standard, 14 (48%), not significant (n/s)]. The 2 yearactuarial non-relapse mortality was 31% in the reduced-intensity arm, with death primarily due to the delayedoccurrence of opportunistic infections. In contrast, GVHDrepresented the major cause of death in patients receivingstandard protocols, resulting in 2 year non-relapse mortalityrates of 50% (Fig 1).

RelapseSix patients (11Æ5%) have relapsed between 1Æ5 and14 months post transplant. Four patients (17%) receivingreduced-intensity conditioning have relapsed comparedwith two (7%) in the standard arm (n/s), giving 2 year

Table IV. Toxicity profile/supportive care: reduced-intensity vs standard conditioning.

Variable

Conditioning

P-valueReduced-intensity Standard

Number 23 29

Onset of neutropenia* Median 19 9 0Æ003(range) (3–22) (5–14)

Duration of neutropenia* Median 8 23 < 0Æ0001

(range) (4–48) (10–31)

Mucositis grade II–III 1 (4%) 24 (77%) < 0Æ0001Onset mucositis* Median 19 12 < 0Æ0001

(range) (13–26) (10–19)

TPN 1 (4%) 15 (52%) < 0Æ0001

systemic opiates 1 (4%) 20 (69%) < 0Æ0001Days of fever (‡ 38�C) Median 1 7Æ5 < 0Æ0001

(range) (0–9) (2–21)

Days of systemic antibiotics Median 8 27 < 0Æ0001

(range) (0–21) (11–56)Systemic amphotericin 4 (17%) 17 (59%) 0Æ002

Blood requirements Median 9 13 0Æ003

(units packed cells) (range) (2–44) (2–38)Platelet requirements Median 7Æ5 17 0Æ006

(adult pools) (range) (2–73) (6–57)

Complications 12 (52%) 23 (79%) 0Æ02

Primary graft failure 3 (18%) 2 (7%) n/sEarly death� 2 (9%) 9 (31%) < 0Æ05

CMV reactivation 5/18 (28%) 5/19 (26%) n/s

Hepatic VOD 0 (0%) 9 (31%) 0Æ002

Multiorgan failure 1 (4%) 7 (24%) n/sAcute GVHD (‡ grade II) 4/23 (17%) 16/28 (55%) 0Æ004

Chronic GVHD 3/20 (15%) 12/21 (57%) 0Æ01

*Days from onset of conditioning.

�Before d 100 post transplant.TPN, total parenteral nutrition; CMV, cytomegalovirus; VOD, veno-occlusive disease; GVHD, graft-

versus-host disease.

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actuarial relapse rates of 31% and 11Æ5% respectively (n/s).Two relapsed patients received donor lymphocyte infusions(DLI) and three received re-induction chemotherapy. Onepatient subsequently underwent sibling allogeneic SCtransplantation, following TBI/cyclophosphamide condi-tioning. All patients died of cytopenic complications beforeresponse to therapy could be evaluated.

SurvivalMedian duration of follow-up post transplant was21 months (range 4–86Æ5 months) [standard, median42 months (range 12–86Æ5); reduced-intensity, median10 months (range 4–24)]. Twenty-six (50%) patientsremain alive; 13 (57%) in the reduced-intensity arm and13 (45%) in the standard group (n/s). The 2 year actuarialOS/DFS was 48%/39% following reduced-intensity condi-tioning and 44/44% in patients treated with standard

protocols (Fig 1). In VUD recipients, actuarial OS wassuperior following reduced-intensity conditioning comparedwith standard regimens (49% vs 34%, n/s) while OSfollowing sibling transplantation was similar between thetwo groups (reduced-intensity, 48%; standard, 50%, n/s).Predictors of actuarial DFS (Table IV) included karyotype(P < 0Æ0001), IPSS risk group (P ¼ 0Æ001), HLA compati-bility (P ¼ 0Æ04) and response to induction chemotherapy(P ¼ 0Æ008) (Fig 2), with patients attaining CR achievingDFS rates mirroring RA (CR 54% vs RA 63%).

DISCUSSION

All patients with MDS have a reduced life expectancycompared with age- and sex-matched normal controls,regardless of French–American–British subtype (Morel et al,1996). Allogeneic SCT following standard conditioning

Table V. Factors influencing disease-free survival (DFS) post-allogeneic SC transplantation in

MDS.

Variable DFS

Actuarial

DFS (%) P-value

None 24 (46%) 41

Conditioning Reduced-intensity 11 (48%) 44Æ6 n/s

standard 13 (45%) 44

Recipient sex Male 9 (41%) 46 n/sFemale 15 (50%) 35 0Æ08

Diagnosis RA 11 (61%) 63

RAEB 6 (43%) 43RAEB-t 1 (33%) 50

MDS-AML 4 (33%) 0

t-MDS 2 (40%) 20

Co-morbidity Yes 11 (46%) 45 n/sNo 13 (45%) 38

Cytogenetics Good-risk 13 (68%) 66 < 0Æ0001

Intermediate-risk 7 (47%) 47

Poor-risk 3 (18%) 0IPSS risk group Low/INT-1 12 (71%) 74 0Æ001

INT-2 6 (35%) 31

High 6 (33%) 15

Chemotherapy Yes 12 (44%) 30 n/sNo 12 (54Æ5%) 57

CR attainment Yes 10 (67%) 54 n/s

No 2 (13Æ3%) 8Disease status

at transplant

CR 9 (69%) 56 n/s

PR/stable 14 (45%) 40

NR/progressive 1 (14%) 11

Donor source Sibling 13 (52%) 50 n/sVUD 11 (44%) 34

AFD 0 (0%) 0

Donor sex Male 14 (52%) 47 n/s

Female 10 (40%) 39Source SC BM 21 (54%) 49 0Æ01

PB 3 (23%) 19

CMV status* Positive 15 (40Æ5%) 35 n/sNegative 9 (60%) 56

HLA-compatibility Yes 20 (51%) 49 0Æ04

No 4 (31%) 15

*Recipient and/or donor.

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offers long-term disease-free survival in up to 50% cases, butcarries non-relapse mortality rates of 32–48%. Olderpatients, those with comorbid conditions, and recipients ofSC from unrelated donors are particularly at risk as a resultof increased rates of acute GVHD and non-haemopoieticorgan toxicity (Anderson et al, 1993, 1996; Keating et al,1996; Sutton et al, 1996; Arnold et al, 1998). Suchpatients, who comprise the majority of MDS cases, are thusgenerally precluded from undergoing this potentially

Fig 1. Reduced-intensity vs standard conditioning: actuarial non-relapse mortality (NRM) (A), overall survival (OS) and (B) disease-

free survival (DFS) (C) post transplant.

Fig 2. Factors predictive of disease-free survival (DFS) following

allogeneic transplantation in MDS: cytogenetic risk group (A), IPSSrisk group (B), chemotherapy response (C) and donor/recipient HLA

compatibility (D).

152 J. E. Parker et al

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curative therapy. The feasibility of SCT following reduced-intensity conditioning in patients with haematologicalmalignancies has been demonstrated in a number of studies(Giralt et al, 1997; Slavin et al, 1998). Experience with thistherapeutic modality in MDS, however, is limited. In ourseries, 23 MDS patients received reduced-intensity condi-tioning, comprising fludarabine, which is cytotoxic andimmunosuppressive (Goodman et al, 1995), busulphan andCampath-1H, an anti-CD52 monoclonal antibody effectivein reducing GVHD and procedure-related mortality follow-ing transplantation (Hale et al, 1998). Despite increased ageand co-morbidity that had precluded conventional trans-plantation, allogeneic SCT following reduced-intensity con-ditioning was well tolerated, with only two early deaths.Reduced-intensity regimens were associated with signifi-cantly shorter duration of marrow aplasia, less mucositis,lower intravenous antifungal, antibiotic, opiate andparenteral nutrition use, and reduced transfusion require-ments. As previously documented, the incidence andseverity of both acute and chronic GVHD was also signifi-cantly reduced (Giralt et al, 1997). This may reflect thecapacity of Campath-1H to eliminate recipient/donor T cells.Minimization of endothelial damage and cytokine releasemay also contribute, by creating less of a host environmentthat promotes allorecognition. Whether limiting GVHD willlead to a reduced graft-versus-leukaemia effect is not clear.

Despite the lower procedure-related mortality associatedwith reduced-intensity regimens, estimated overall anddisease-free survival mirrored that observed with standardconditioning, which appeared to be due to a higherincidence of relapse in the former group (17% vs 7%). Thismay, however, reflect the proportionately higher numbersof patients in the reduced-intensity arm with progressive orrefractory disease at transplant and/or having adverseprognostic factors such as poor-risk karyotype/IPSS riskscore. In the group as a whole, as previously documented(Anderson et al, 1996; Sutton et al, 1996; Appelbaum &Anderson, 1998; Nevill et al, 1998), advanced diseasestage, poor-risk cytogenetics, high IPSS score and chemo-resistant disease were associated with a lower probability ofsurvival following allogeneic transplantation.

Sixteen MDS patients undergoing reduced-intensity con-ditioning were transplanted using SCs from unrelateddonors. Actuarial OS in VUD recipients receiving reduced-intensity protocols appeared superior to patients treatedwith standard regimens (49% vs 34%, n/s) despite theincreased age and frequent co-morbidity of the formergroup. The occurrence of primary graft failure or laterejection in four cases (25%), however, is of concern. Theprofound and prolonged immunosuppression and the lack ofGVHD observed following FBC conditioning suggests thatthis may be due to excessive in vivo donor immunesuppression and has lead us to administer Campath-1Hearlier in the course of conditioning (d )9 to )5) insubsequent transplant protocols.

Our data demonstrates that reduced-intensity regimenscan be administered with minimal toxicity in MDS patientsconsidered ineligible for standard transplantation because ofadvanced age or co-morbidity and permits successful

engraftment of sibling or unrelated donor stem cells.Although follow-up duration is short, the comparableactuarial 2 year DFS suggests that allogeneic SCT followingreduced-intensity conditioning may also be associated withdisease elimination in a proportion of cases. Patients mostlikely to benefit are those with low- or intermediate-riskcytogenetics at diagnosis, low or INT-1 IPSS risk score, anHLA-compatible donor and chemosensitive disease. Con-versely, our results suggest that patients with poor-riskcytogenetics/IPSS score at presentation and chemoresistantMDS have a poor outcome following either reduced-inten-sity or standard transplantation. Trials comparing theefficacy of different reduced-intensity protocols shouldidentify the optimal conditioning strategy in MDS anddetermine the minimum immunosuppressive dose requiredfor successful allogeneic SC engraftment. The role of priorinduction chemotherapy and the success of DLI in preven-ting or treating relapse post transplant will also need to beascertained. Comparison of long-term outcome betweenreduced-intensity conditioning and standard regimens willbe required before this approach can be considered inyounger patients who would normally be eligible forstandard conditioning.

ACKNOWLEDGMENTS

We are indebted to Michelle Kenyon (transplant co-ordina-tor nurse), Simon Goodwin (apheresis), Maryam Sekhavat(in vitro culture), Michel Lalloz, Lisa Thompson (VNTR),Barbara Czepulkowski, Stuart Adams (cytogenetics), KeithFishlock, Ann Etches (CD34+ cell enumeration), transplantcentre clinical staff, the Anthony Nolan Bone Marrow Trust,and especially the stem cell donors, without whom thisstudy would not have been possible.

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