Allografting

Retrospective study of alemtuzumab vs ATG-based conditioning without irradiation for unrelated and matched sibling donor transplants in acquired severe aplastic anemia: a study from the British Society for Blood and Marrow Transplantation

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Abstract

This retrospective national study compared the use of alemtuzumab-based conditioning regimens for hematopoietic SCT (HSCT) in acquired severe aplastic anemia with antithymocyte globulin (ATG)-based regimens. One hundred patients received alemtuzumab and 55 ATG-based regimens. A matched sibling donor (MSD) was used in 87 (56%), matched unrelated donor (MUD) in 60 (39%) and other related or mismatched unrelated donor (UD) in 8 (5%) patients. Engraftment failure occurred in 9% of the alemtuzumab group and 11% of the ATG group. Five-year OS was 90% for the alemtuzumab and 79% for the ATG groups, P=0.11. For UD HSCT, OS of patients was better when using alemtuzumab (88%) compared with ATG (57%), P=0.026, although smaller numbers of patients received ATG. Similar outcomes for MSD HSCT using alemtuzumab or ATG were seen (91% vs 85%, respectively, P=0.562). A lower risk of chronic GVHD (cGVHD) was observed in the alemtuzumab group (11% vs 26%, P=0.031). On multivariate analysis, use of BM as stem cell source was associated with better OS and EFS, and less acute and cGVHD; young age was associated with better EFS and lower risk of graft failure. This large study confirms successful avoidance of irradiation in the conditioning regimens for MUD HSCT patients.

Introduction

Long-term OS of patients transplanted for acquired aplastic anemia (SAA) using matched sibling donors (MSD) is excellent but is age dependent. For children, survival approaches 90% but for patients aged >50 years, survival is 45–50%.1, 2 Graft rejection occurs in 5–10% of patients. Standard conditioning for patients aged <30–40 years uses CY 200 mg/kg with antithymocyte globulin (ATG) and CsA with MTX as post-graft immune suppression.3, 4, 5, 6, 7, 8, 9 Outcomes following matched unrelated donor (MUD) hematopoietic SCT (HSCT) for SAA show survival in excess of 75%, and for some subgroups >80%, and a graft rejection rate of 15–17%.10, 11, 12, 13, 14, 15, 16, 17 Fludarabine in combination with lower-dose CY and ATG, and low-dose TBI (2–3 Gy) for adults, is now most commonly used as conditioning regimen for MUD HSCT.12 This regimen is also considered for older MSD HSCT.10

Chronic GVHD (cGVHD) remains a problem for 30–50% of patients, and this impacts not only on survival but also on quality of life after HSCT.8, 18 Risk factors for cGVHD include older age, previous acute GVHD (aGVHD) and PBSC source.19, 20

Alemtuzumab, a CD52 MoAb, has been evaluated in a multicenter retrospective study in 50 patients receiving a MSD or MUD transplant for SAA.21 When used with fludarabine and low-dose CY (FCC), 2-year OS was 95% for MSD and 83% for unrelated donor (UD) HSCT. Graft rejection occurred in 10% of MSD and 15% of UD HSCT. There was a low incidence of cGVHD (7%). Mixed T-cell chimerism was seen in all patients and persisted following discontinuation of CsA, suggesting the achievement of tolerance.

The aim of this retrospective study was to compare outcomes of 155 SAA patients transplanted with either alemtuzumab-based conditioning regimens or ATG-based regimens, from MSD or MUD, who were reported to the British Society for Blood and Marrow Transplant (BSBMT) Registry between 1999 and 2009.

Patients and methods

Patients

This retrospective study was approved and registered by the BSBMT Clinical Trials Committee. Eligible patients were identified from the BSBMT Data Registry. Consent for data to be registered on the BSBMT Registry for use in activity, outcome and research analysis was obtained at the time of transplantation, in line with European Bone Marrow Transplant Registry directives.

This retrospective study comprised 155 adults and children from 22 centers, receiving a first allograft for acquired SAA between 1999 and 2009 who received either ATG or alemtuzumab as part of the conditioning regimen, and with a minimum of 6 months follow-up. All patients included in this study received alemtuzumab pre-transplant only, and patients who also received alemtuzumab after HSCT were excluded. A total of four patients who received cord blood stem cells were excluded and eight centers declined to participate (accounting for 60 patients). The median follow-up of patients receiving alemtuzumab conditioning was 38 months (range 3–125) and 62 months (range 4–13) for ATG conditioning. The diagnosis of SAA was made according to established definitions.22, 23, 24 Fanconi anemia was excluded by diepoxybutane-stimulated peripheral blood (PB) chromosome breakages. Donor matching was performed for HLA-A, -B, -C, -DRB1 and DQB1 using high-resolution DNA typing. The source of stem cells was either BM, PB or both.

Study protocols

The choice of conditioning regimen was based on national and European guidelines. Patients transplanted from MSD received CY 200 mg/kg with either ATG or alemtuzumab (SANOFI-Genzyme, Cambridge, MA, USA). Dose of alemtuzumab given was available for 91/103 patients. The median total dose administered was 50 mg (range 3.6–100, equivalent to 0.96 mg/kg (range 0.1–10)). All patients received alemtuzumab pre-transplant. Patients who also received alemtuzumab after HSCT were not included in this study. Rabbit ATG (Thymoglobuline, SANOFI-Genzyme) was most frequently used; the median total dose was 11.25 mg/kg (range 1.1–90). Post-graft immune suppression comprised CsA and MTX for ATG-based regimens, and CsA alone for alemtuzumab -based regimens. MUD HSCT regimen comprised fludarabine 30 mg/m2 for 4 days, CY 300 mg/m2 for 4 days and either ATG or alemtuzumab. For eight patients who received a mismatched (9/10 Ag matched) UD HSCT, 2 Gy TBI was added to the conditioning regimen. Post-graft immune suppression was as for MSD HSCT. Centers transplanting older patients from MSD had the option of using the above fludarabine-based regimen instead of CY 200 mg/kg. CsA was administered and monitored as previously described. aGVHD and cGVHD were assessed using standard criteria. Supportive care was administered according to individual centre practice, and all patients were screened for CMV at least weekly using CMV antigenemia or PCR-based assay. Lineage-specific chimerism was documented in 46 patients and unfractionated blood or marrow in 51 patients.

See Supplementary File for definitions of engraftment and chimerism and details of statistical analysis.

Results

Patient characteristics

Patient characteristics are summarized in Table 1. The median age of the 155 patients was 20 years (range 1.5–67.5). Of these, 59 (38%) patients were children (<18 years of age). Twenty-two patients were aged >40 years and 10 patients were >50 years. Figure 1 summarizes details of the transplant conditioning, donor and stem cell source. Eighty seven patients received a transplant from a MSD, 62 from a MUD, two from a mismatched UD and six from an alternative related donor. Alemtuzumab-based conditioning was used in 100 patients and ATG-based regimen in 55 patients. Source of stem cells was BM in 108 (70%) patients, PB in 39 (25%) and BM plus PB in 8 (5%). Before HSCT, in the alemtuzumab group, 11 (26%) MSD patients received immunosuppressive therapy with ATG (6 received one course and 2 received two courses) compared with 46 MUD patients (88%; 33 received one course, 11 two courses and 2 three courses). In the ATG group, 10 (24%) patients received ATG before HSCT, all with one course, and three MUD patients received one course, and one each received two and three courses of ATG, respectively. CY 200 mg/kg conditioning was used more often with ATG-based regimens and fludarabine-based regimen with alemtuzumab. ATG was used more frequently for MSD HSCT and alemtuzumab was used more frequently for MUD HSCT.

Table 1 Patient characteristics
Figure 1
figure1

Summary of transplants according to donor type, conditioning regimen and source of stem cells. MSD=matched sibling donor; MUD=matched unrelated donor.

Engraftment

Failure of engraftment (primary and secondary) occurred in 9% of the alemtuzumab group (4/45, 9% for MSD and 5/54, 9% for UD) and in 11% of the ATG group (6/47, 13% for MSD and 0/7 for UD). Median time to neutrophil and platelet engraftment was the same between the two groups (see Table 2). In three patients, cause of death included rejection, one of them on day +72, the other two on day +102 and +427. It was not possible to ascertain if other patients experienced late graft failure and subsequently recovered. At day +100, full donor chimerism occurred in 58% of the alemtuzumab group and 66% the ATG group (P=0.237), and mixed donor chimerism in 39% and 31%, respectively. At last follow-up, full donor chimerism occurred in 54% of the alemtuzumab group and 71% of the ATG group; and mixed donor chimerism occurred in 43% and 29%, respectively. For children (age <18 years), incidence of graft failure was 0% for MSD compared with 17% for adults (P=0.011) and 3% for MUD HSCT compared with 17% for adults (P=0.195). There was no significant difference in graft failure among children using alemtuzumab or ATG.

Table 2 Outcomes

GVHD

Overall incidence of aGVHD was similar between the alemtuzumab and ATG cohorts (29% vs 24%, P=0.569), although aGVHD was more severe in the ATG cohort: (alemtuzumab grade I–II 89%, grade III–IV 11% vs ATG grade I–II 69% and 31%, grade III–IV 31%, P=0.179). cGVHD occurred in 10 patients (11% of evaluable patients) of the alemtuzumab group, of whom seven were limited and three were extensive. There was a trend for a higher incidence of cGVHD using ATG regimens, affecting 13 (26% evaluable) patients, P=0.126, and more extensive cGVHD (P=0.031); see Table 2.

aGVHD was observed more often in patients who received PB stem cells compared with patients receiving BM stem cells. There was no difference in aGVHD between PB and BM for alemtuzumab, but aGvHD was significantly lower for ATG BM when compared with PB. (alemtuzumab group, 38% vs 27%, P=0.538, and ATG group, 64% vs 14%, P=0.004). There was no difference in the incidence of cGVHD between BM and PB in the alemtuzumab group (13% vs 10%, P=0.907), but significantly less cGvHD with BM in the ATG group (15% vs 67%, P=0.002).

Overall survival

Actuarial OS at 5 years was 90% for the alemtuzumab group and 79% for ATG group, P=0.11; see Figure 2a. For MSD HSCT, 5-year OS using alemtuzumab was 91% compared with 85% using ATG (P=0.562); see Figure 2b. For UD HSCT, 5-year OS was significantly better using alemtuzumab (88%) compared with ATG (57%), P=0.0266; see Figure 2c.

Figure 2
figure2

OS of patients comparing Alemtuzumab with ATG conditioning (a) for all patients; (b) for HLA-matched sibling donor HSCT; and (c) for matched unrelated donor HSCT).

Of the variables assessed for impact on OS, Karnofsky score (80%), stem cell dose (total nucleated cell (TNC) and CD34+ cell dose), CMV, ABO and M/F matching had no significant effect. In contrast, age, stem cell source and time from diagnosis to HSCT did significantly impact OS. Patients aged < 40 years had a significantly better OS than those patients aged >40 years (OS: 87% vs 75%, P=0.0426). Ten patients were aged >50 years with OS of 90% (see Figures 3a and b), of whom nine received alemtuzumab and one ATG conditioning. Amongt the pediatric cohort, 5-year OS was 97% for MSD and 88% for UD HSCT (P=0.267). OS was identical whether using alemtuzumab or ATG for pediatric transplants (93%), (see Figure 3c). For alemtuzumab conditioning, use of BM resulted in better OS (97%) compared with PB (70%), P=0.0001 (see Table 3), and there was no significant difference between stem cell source for ATG conditioning (OS 84%). OS was significantly better for patients transplanted <3 months from diagnosis to HSCT compared with patients transplanted >3 months from diagnosis, P=0.018, although this likely reflects the difference between MSD and MUD transplants. In contrast, a time period of <12 months from diagnosis to HSCT compared with >12 months had no impact on OS.

Figure 3
figure3

Effect of young age on OS. Panel a compares patients aged <40years, 40–50 years and >50 years of age; panel b compares matched sibling with MUD HSCT in children (age <18years); panel c compares Alemtuzumab with ATG-based conditioning in children.

Table 3 Effect of stem cell source and dose

Risk factors affecting outcomes

Results of multivariate analyses for factors related to outcomes are shown in Table 4. Use of BM was a significant factor for improved OS (Hazard ratio (HR): 5.62, P=0.001), EFS (HR: 3.93, P=0.001) and lower risk of aGVHD and cGVHD (HR: 3.96, P=0.003 and HR: 3.00, P=0.047, respectively). Younger age (<18 years) was associated with improved EFS (HR: 2.87, P=0.043) and lower risk of graft failure (HR: 12.63, P=0.018).

Table 4 Multivariate analysis for survival

Cause of death

In the ATG group, 11/55 (20%) patients died and 10/100 (10%) patients died in the alemtuzumab group. In the ATG group, deaths were because of infection in four patients (fungal in two, viral in one and unspecified in one), multi-organ failure in two, GVHD in three (one with bronchiolitis, one with interstitial pneumonitis with infection and rejection), EBV post transplant lymphoproliferative disorder (PTLD) in one and one of unknown cause. In the alemtuzumab group, deaths were due to multi-organ failure in three (all with infection), GVHD in three (one with intra-abdominal hemorrhage, one with infection and multi-organ failure), infection in two (one with rejection) and two of unknown cause. Because of worse survival with PB compared with BM as stem cell source, we examined the causes of death in those patients who received PB or BM (see Table 5). For patients receiving BM alone, 4/8 deaths (50%) were due to infection, either alone or with GVHD, compared with 9/12 (75%) with PB alone, although the difference was NS (P=0.356). There were no other differences in the cause of death between the two stem cell sources.

Table 5 Causes of death according to stem cell source

Discussion

In this national retrospective study, we have confirmed the continued improvement in outcomes of patients transplanted for acquired SAA during the last decade, with 5-year OS of 87% for MSD and 85% for MUD transplants. A major point to emphasize from this large study is that those patients transplanted from MUDs received a conditioning regimen that avoided irradiation as was previously reported in smaller studies.21, 25, 26 Irradiation is not justified for sibling donor HSCT for aplastic anemia (AA), but for UD HSCT, irradiation is included to reduce the risk of graft rejection. However, irradiation increases the risk of GVHD, interstitial pneumonitis and second malignancies, and impairs fertility; for children, irradiation increases the risk of delayed growth and development and thyroid abnormalities.27, 28, 29, 30, 31 A dose-finding study of TBI for UD HSCT in AA established that 2 Gy was sufficient to improve engraftment and with the lowest risk of pneumonitis,13 but data are lacking concerning other complications with this dose of irradiation.

The use of alemtuzumab instead of ATG as part of the conditioning regimen was associated with significantly improved OS for MUD HSCT, although the number of patients transplanted using ATG was small, reflecting the more frequent use of alemtuzumab for UD HSCT among UK transplant centers. For MSD HSCT, there was no difference in OS whether alemtuzumab or ATG was used. Alemtuzumab was associated with a lower rate of cGVHD compared with ATG, although on multivariate analysis this did not impact on survival. This confirms previous reports of a low incidence of cGVHD after alemtuzumab conditioning for SAA HSCT, which represents a major improvement over time. Reduction in cGVHD is of major importance, as cGVHD affects quality of life after HSCT. Use of non-irradiation-based conditioning regimens for MSD HSCT reduces the risk of long-term complications of second tumors, reduced growth and development in children, and cataracts, as well as reduces the risk of GVHD.31

This study also emphasizes the excellent survival of children transplanted for SAA, with 97% of MSD and 90% of MUD transplants surviving. Compared with adults, the risk of graft failure was significantly lower in children transplanted from MSD, with a trend (NS) for less graft failure following UD HSCT. Similar outcomes of MSD and MUD HSCT in children have resulted in MUD HSCT being considered up front in children with SAA who lack a MSD.15, 32, 33

Transplantation is less straightforward in older patients. For patients aged >40 years, OS of 50–65% have been reported from Center for International Blood and Marrow Transplant Research (CIBMTR) and Seattle, respectively.34, 35 Because of concern about toxicity from high-dose CY in older patients, particularly cardiotoxicity, alternative conditioning regimens using a lower dose of CY with fludarabine and ATG have been proposed.7 Recent data from European Blood and Marrow Transplant Severe Aplastic Anemia Working Party (EBMT SAAWP) have shown that OS of patients aged 40–50 years is similar to those aged 30–40 years, resulting in the proposal for first-line MSD HSCT in patients with SAA aged <50 years (A Bacigalupo, on behalf of EBMT, 2010, unpublished data). The retrospective study using alemtuzumab with fludarabine and low-dose CY showed 70% 2-year OS for 12 patients aged >50 years.21 We show that among 10 patients aged >50 years, OS was 82%, six of whom received MUD transplants.

Use of PBSC as a source of stem cells for transplantation in SAA patients who have received ATG-based conditioning is associated with a higher risk of cGVHD and worse OS.8, 9, 36 In this study, PBSC were used alone or in combination with BM in 33% of patients in the alemtuzumab group and 13% in the ATG group. Use of PBSC resulted in worse OS in the alemtuzumab group and a trend for worse OS in the ATG group. The reason for worse OS with PBSC is not clear. Alemtuzumab resulted in less cGVHD than with ATG, and graft rejection rate was similar between the two groups. Use of alemtuzumab may override the effect of stem cell source on cGVHD, as there was no difference in the incidence of cGVHD when using BM or PBSC among the group receiving alemtuzumab. Infection was the most common cause of death among all patients, but numbers were not significantly different between the two groups. The study was too small to compare the effect of PBSC and BM among MSD and MUD transplants separately. Although we showed better OS for MUD HSCT using alemtuzumab compared with ATG, the number of patients transplanted with ATG comprised only 11%. Larger numbers of patients are needed to assess this further. A potential major concern using BM for UD HSCT has been the poor quality of BM harvests from some harvest centers, resulting in low stem cell dose, further resulting in a higher risk of graft rejection; hence the use by some centers of PBSC for MUD HSCT with alemtuzumab to ensure an adequate stem cell dose and without increasing the risk of cGVHD. However, the goal should be to improve the quality of BM harvesting at centers.

In this retrospective study, it was not possible to compare the effects of immune reconstitution and infectious complications or formal quality of life assessments between the two conditioning regimens using either ATG or alemtuzumab. This would be important to examine in future studies, along with further evaluation of the impact of alemtuzumab on the long-term outcome of patients transplanted for AA, compared with those receiving ATG in the conditioning regimen.

In conclusion, we show in this national retrospective study excellent outcomes following HSCT for SAA, alemtuzumab results in excellent OS for MUD HSCT, and compared with ATG, a lower rate of cGVHD. For all patients together, the use of PBSC resulted in worse OS and more GVHD. There was less cGVHD with alemtuzumab, and for a disease in which there is no advantage for any GVHD, this is an important property of alemtuzumab, as cGVHD impacts on patients’ quality of life. For UD HSCT, we demonstrated the successful outcome using a non-irradiation-based conditioning regimen. Although this study is restricted by the constraints of being a retrospective study, we feel that prospective trials comparing alemtuzumab with ATG for SAA HSCT are now indicated. Continued improvement in outcomes after HSCT for SAA over time provides the rationale for stimulating further discussions regarding extending the upper age limit for HSCT for not only MSD but also UD.

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Acknowledgements

We would like to thank the data managers and transplant physicians at participating centers for providing data: Dr MBC Koh, data manager S Kukkapalli, St George’s Hospital, London; Dr J Snowden, data managers B Holt and L Scott, Sheffield teaching Hospitals, Sheffield; Dr AJ Vora, data manger J Williams, Sheffield Children’s Hospital, Sheffield; Dr RT Wynn, data manager M Coussons, Royal Manchester Children’s Hospital, Manchester; Professor N Russell, data manager P Nelson, Nottingham University Hospital, Nottingham; Dr B Gibson, Yorkhill Children’s Hospital, data manager G Stewart, Glasgow; Dr M Gilleece, data managers S Hardaker, R Goodall, St James University Hospital, Leeds; Dr D Milligan, data manager W Clay, Heartlands Hospital, Birmingham; Dr P Veys, Great Ormond Street Hospital, London; Dr S Samarasinghe, Great North Children’s Hospital, Newcastle; Dr M McMullin, data manager S Piggott, Belfast City Hospital, Belfast; Prof G Jackson, data manager L McNally, Royal Victoria Infirmary, Newcastle; Dr K Orchard, data manager C Hurlock, Southampton General Hospital, Southampton; Dr A Hunter, data manager R Lewin, Leicester Royal Infirmary, Leicester; Prof C Craddock, data manager J Ward, Queen Elizabeth Hospital, Birmingham; Dr A O’Meara, data managers H Kerrigan and C Cawley, Our Lady’s Hospital for Sick Children, Dublin; Prof J Apperley, data manager F O’Boyle, Hammersmith Hospital, London; Dr K Wilson, data manager S Nicholas, University Hospital of Wales, Cardiff; Dr A Bloor, data manager T Dalton, Christie Hospital, Manchester; Dr P Johnson, data manager A Robertson, Western General Hospital, Edinburgh; Dr S Lawson, data manager J Rogers, Birmingham Children’s Hospital, Birmingham; Dr J dela Fuente, data manager F O’Boyle, St Mary’s Hospital, London; Dr K Thomson, University College Hospital, London.

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Correspondence to J C Marsh.

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Competing interests

JCM held a consultancy with Genzyme from May 2008 to May 2009 and from June 2009 to July 2009. The other authors declare no competing financial interests.

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Authors contribution

JCM, RMP, GC, ZL, GJM, AP contributed to the design of the study. JCM drafted the manuscript. KK and JP were responsible for coordination of data acquisition. JP, KK, MBCK, JAS, AJV, RTW, NR, BG, MG, DM, PV, SS, MM and GC contributed patient data to the study. RMP performed statistical analysis of the data. All authors were responsible for critical review and revision of the manuscript.

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Keywords

  • aplastic anemia
  • alemtuzumab
  • ATG
  • SCT

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