Allografting

Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML

Abstract

We report a retrospective analysis of 128 consecutive patients with high-risk myelodysplastic syndrome (MDS) and AML who received an alemtuzumab-based reduced-intensity conditioning hematopoietic SCT (RIC HSCT). The median recipient age was 53 years (range 21–72 years). A total of 49 (38%) recipients had a sibling donor and 79 (62%) had a volunteer-unrelated donor. The hematopoietic cell transplantation-specific comorbidity index (HCT-CI) was assigned to all patients with a score of 0 in 40 (31%), of 1–2 in 45 (35%) and 3 in 43 (34%) patients. The 3-year non-relapse mortality (NRM) was 31%, disease-free survival (DFS) was 41% and overall survival (OS) was 46%. The 3-year NRM for patients with a HCT-CI score of 0, 1–2 or 3 was 16, 24 and 42%, respectively. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1–2) and 24 and 32% (score 3), respectively. On multivariate analysis, HCT-CI was an independent variable affecting 3-year NRM, DFS and OS (P-value=0.04, 0.01 and <0.01, respectively). Although the disease stage at the time of transplant was an additional independent predictive variable on transplant outcomes, recipient age (>/<50 years) did not have a significant predictive impact. In MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of stratifying patients with a high risk of inferior transplant outcomes.

Introduction

Allogeneic hematopoietic SCT (allo-HSCT) offers a potentially curative option for patients with poor-risk myelodysplastic syndrome (MDS) and AML. The majority of patients with AML and MDS are older, and many present with associated comorbidity rendering them ineligible for myeloablative approaches. More recently, a significant reduction in regimen-related toxicity and non-relapse mortality (NRM) with reduced-intensity conditioning (RIC) regimens has enabled allogeneic transplantation to be extended to this group of patients.1, 2, 3, 4, 5, 6 Despite these advances, transplant-related morbidity and mortality, particularly in elderly patients with advanced disease, remain significant.

There is a need to improve the characterization of patient- and transplant-specific variables that potentially predict outcome to improve survival after allo-HSCT.7, 8, 9, 10, 11, 12, 13, 14, 15, 16 Recent literature has indicated that performance status of transplant recipients, rather than recipient age per se, may be a better indicator of the ability of a patient to tolerate allo-HSCT. The Charlson comorbidity index, adapted for HSCT, has been shown to predict NRM in patients receiving allogeneic HSCT. In the setting of HLA-matched sibling allo-HSCT, it has been shown that a high Charlson comorbidity index correlates with inferior outcomes in patients receiving either myeloablative or non-myeloablative allo-HSCT.17 This association was also observed in recipients of unrelated donor transplants regardless of regimen intensity.18 Sorror et al. have reported on the utility of a hematopoietic cell transplantation-specific comorbidity index (HCT-CI). In a validation study with 1055 recipients of T-cell-replete myeloablative or non-myeloablative allogeneic transplantation, the HCT-CI was shown to correlate with both NRM and overall survival (OS).19 More recently, the same group has shown in a risk stratification-based study that the use of disease risk status together with the HCT-CI provided improved prognostic delineation of patients with AML or MDS receiving allogeneic HSCT. In particular, in patients with high-risk disease MDS or AML undergoing RIC HSCT, patients with an HCT-CI of 3 had a 2-year OS of only 29%.20

Various groups have used in vivo T-cell depletion with either alemtuzumab (Campath-1H) or anti-thymocyte globulin to lower the incidence of both acute GVHD (aGVHD) and chronic GVHD (cGVHD)6, 21, 22, 23, 24, 25 with the aim of reducing NRM.

There are presently limited data available on the utility of the HCT-CI in the setting of T-cell-depleted RIC HSCT, and it remains unclear as to whether the HCT-CI has a similar prognostic utility in this setting. Herein, we report a retrospective analysis of 128 consecutive patients with high-risk MDS and AML who received T-cell-depleted RIC allo-HSCT from sibling and volunteer donors to determine the predictive value of the HCT-CI on overall transplant outcomes.

Patients and methods

Patients

We performed a single-center analysis of 128 consecutive patients with poor-risk MDS and AML treated between 1999 and 2005. The median recipient age was 53 years (range 21–72 years). The diagnostic criteria were defined according to the World Health Organization classification.26 All patients had advanced disease as defined by MDS (RAEB I or II) or AML (CR2 or greater). Cytogenetic risk was assigned to MDS patients in accordance with the international prognostic scoring system and to AML patients according to the UK MRC AML risk stratification.27, 28 Poor-risk cytogenetics were identified in 27% of patients. The median number of cycles of chemotherapy administered pretransplant was 3 (range 1–9) for the AML group and 2 (range 0–9) for the MDS group.

Conditioning regimen

The RIC regimen consisted of fludarabine (150 mg/m2 i.v. in divided doses over 5 days from days −9 to −5), BU (8 mg/kg orally over 2 days on days −3 and −2) and alemtuzumab (100 mg i.v. over 5 days from day −8 to −4) (FBC) in 95 patients, FBC with i.v. BU (6.4 mg/kg i.v. over 2 days) in 32 patients, and fludarabine (150 mg/m2 i.v. over 5 days), melphalan (140 mg/m2 i.v.) and alemtuzumab (100 mg i.v. over 5 days) (FMC) in 1 patient. CYA was administered for GVHD prophylaxis, commenced at day −1 and tapered from day +56 in the absence of GVHD. The indication for RIC included age >50 years (n=84), invasive pulmonary aspergillosis within 3 months of transplant (n=24), impaired organ function (n=43), earlier autologous HSCT (n=6) and iron overload (n=1). In total, 30 patients had more than one relative contraindication for myeloablative conditioning.

All donor–recipient pairs were matched for HLA-A, -B, -C, -DRB1 and DQB1 by high-resolution allelic testing. A sibling donor was used in 49 (38%) and volunteer-unrelated donor (VUD) in 79 (62%) transplants, with a 1 Ag mismatch donor in 29 patients (17 HLA class 1 mismatch and 12 HLA class 2 mismatch). A further five patients received stem cells from a two Ag mismatch donor. PBSCs were administered to 95 (74%) patients. Standard nursing care and post-transplant prophylaxis were administered as described earlier.6

Comorbidity score

The HCT-CI was used to assign a pretransplant comorbidity score to all patients.19 A score of 0 was identified in 40 (31%), score 1 in 23 (18%), score 2 in 22 (17%) and 3 in 43 (34%) patients. The most frequent comorbidities identified were a reduction in pulmonary diffusion capacity <80% (n=46) or cardiac ejection fraction <50% (n=14), infection requiring treatment after day 0 (n=20), ischemic heart disease (n=2), arrhythmia (n=2), renal dysfunction (n=2) and other comorbidity (n=12).

Statistical analysis

Differences between patient groups were evaluated using the χ2-test for categorical data, and the Mann–Whitney test for continuous data. OS and relapse-free survival curves were estimated by the Kaplan–Meier method in the entire study population and in univariate analysis (the log-rank test was used to compare survival curves between different subgroups).

To calculate relapse incidence, NRM and the incidence of aGVHD and cGVHD, a competing risk model was used. In each case, death (before the event under study) was used as the competing event (NRM was therefore derived from the relapse-competing risk analysis). The effect of any possible risk factor on either relapse or NRM was still estimated by using a Cox model where relapse was treated as a censoring event for the end point ‘death’ and vice versa.

The Cox proportional hazards model was used to assess the independent effect of age, sex, disease group (MDS vs AML), HCT-CI (0 vs 1–2 vs 3), cytogenetic risk, disease status at time of transplant (CR vs active disease), donor type (sibling vs VUD), HLA disparity, source of stem cells (PBSC vs BM), as well as stem cell dose on transplant outcomes. On multivariate analysis, independent variables with P>0.1 were sequentially excluded from the model. The P-value was set at P<0.05 for statistical significance.

Results

Engraftment

Neutrophil and plt engraftment were defined as neutrophils >0.5 × 109 per liter on the first two consecutive days and plts >20 × 109 per liter for 5 days without transfusions. The median time to neutrophil and plt engraftment was 13 days (range 8–57 days) and 18 days (range 0–121 days), respectively. Primary graft failure was identified in 4 (3%) patients.

NRM

There were 33 deaths attributable to NRM. The cumulative incidence of NRM at 1 and 3 years was 25 and 31%, respectively. NRM was caused by to GVHD in 4 patients, bacterial infection in 13, viral infection in 11, multiorgan failure in 2, veno-occlusive disease of the liver in 1 and by other causes in 2 patients.

On univariate analysis (Table 1), both disease status at transplant and HCT-CI significantly influenced the NRM. An advanced disease status was associated with an inferior NRM when compared with early disease status (3-year TRM: 50 vs 28%, P<0.01). The 3-year NRM for patients with an HCT-CI score of 0, 1–2 or 3 was 16, 24 and 42%, respectively (Figure 1a). However, although patients with an HCT-CI score of 3 had a significantly worse NRM (P=0.02) when compared with those with an HCT-CI score of 0, there was no significant difference in the NRM between patients with a score of 1–2 and those with either an HCT-CI score of 0 (P=0.33) or a score 3 (P=0.11). In addition, recipient age, donor source (sibling vs VUD) and the presence of HLA disparity had no influence on NRM.

Table 1 Univariate analysis of factors affecting outcome following RIC allo-HSCT
Figure 1
figure1

Stacked cumulative incidence curves from a competing risk model with ‘Relapse’ and ‘Death’ as competing risks, with the study population sub-stratified according to an HCT-CI score of 0 (a) vs 1–2 (b) vs 3 (c). NRM, non-relapse mortality.

On multivariate analysis (Table 2), disease status at transplant and HCT-CI were independent variables predicting NRM. The hazard ratio (HR) for NRM was 2.70 (95% CI 1.25–5.83, P=0.01) for those with advanced disease at the time of transplant when compared with those with early disease. When compared with patients with an HCT-CI of 0, the HR was 1.72 (95% CI 0.64–4.67) for those with an HCT-CI of 1–2 and 3.18 (95% CI 1.24–8.17) for those with an HCT-CI 3.

Table 2 Multivariate analysis of factors affecting outcome after RIC allo-HSCT

GVHD

The cumulative incidence of Grade II–IV aGVHD was 30%, with the specific incidence of grade IV as 2%. Patients surviving at least 100 days post transplant were analyzed for cGVHD. The cumulative incidence of chronic limited GVHD at 3 years was 23%, with an incidence of chronic extensive GVHD of 15%. There was no correlation between the HCT-CI score and GVHD.

OS and DFS

The median follow-up of the study group was 2.8 years (range 0.5–6.1 years). The 3-year disease-free survival (DFS) was 41% and OS was 46%. The 3-year DFS and OS by HCT-CI was 58 and 69% (score 0), 39 and 39% (score 1–2), and 24 and 32% (score 3), respectively. Figure 1 shows the effect of HCT-CI on DFS and OS, respectively. Patients with HCT-CI scores of 1–2 and 3 had a significantly inferior OS to patients with an HCT-CI score of 0 (P<0.01, P<0.01, respectively). However, there was no statistically significant difference in OS between HCT-CI scores 1–2 and 3 (P=0.52). A similar association was seen in DFS (score 0 vs 1–2, P=0.03), (score 0 vs 3, P<0.01) and (score 1–2 vs 3, P=0.35).

On multivariate analysis, HCT-CI was an independent variable affecting both DFS and OS (P=0.01 and P<0.01, respectively). Advanced disease at the time of transplant also showed an adverse effect on OS in the multivariate model (HR: 1.96, 95% CI 1.08–3.56; P=0.03). Advanced recipient age (> 50 years) did not have a significant influence on DFS (HR 1.55, 95% CI 0.92–2.61; P=0.10) and had only a borderline significant influence on OS (HR 1.78, 95% CI 1.00–3.14; P=0.05) in the multivariate analysis.

Discussion

The use of RIC regimens and improved supportive care has enabled allogeneic HSCT to be carried out in older patients with comorbidities. Regardless of the intensity of conditioning or the variation in transplant regimens used, only modest differences in OS have been reported.29, 30, 31, 32 Additional improvements in transplant outcomes may, however, be achieved through identification of prognostic variables and improved patient selection. Reduced-intensity regimens are frequently used in patients with comorbidities. However, formal analysis of these comorbidities on transplant outcome is rarely performed.19, 21, 33 The HCT-CI was specifically developed for use in recipients of HSCT whereby it showed an improved predictive value in identifying patients receiving myeloablative and non-myeloablative HSCT who had a subsequent inferior NRM and survival.19 There is, however, a lack of data on the use of comorbidity scores in the T-cell-depleted allo-HSCT setting.

We have previously described the impact of the HCT-CI on the outcomes of a cohort of MDS patients (with both high- and low-risk disease) receiving an unrelated donor alemtuzumab-based RIC allo-HSCT,23 with no association between the HCT-CI and NRM and only a borderline association with OS. This study includes 31 patients from the previous report, but focuses on high-risk MDS and AML patients who have received an alemtuzumab-based RIC allo-HSCT from either a sibling or an unrelated donor.

A high HCT-CI score of 2 or more was observed in 51% of our cohort of patients, with the most frequent comorbidities being impairment of the pulmonary or cardiac function at the time of transplant and infection requiring treatment with antimicrobial agents at day 0 of transplant. Although the cohort with an HCT-CI score of 1–2 did not have a significantly inferior NRM when compared with the HCT-CI score 0 patients in our study, an HCT-CI score of 3 correlated with a significantly increased risk of NRM (42% at 3 years), consistent with previously reported analyses of non-T-cell-depleted transplant cohorts.19 This indicates that the HCT-CI identifies a distinct cohort of patients (HCT-CI 3) at the highest risk of transplant-related mortality. Taking into account the substantial treatment-related mortality of this sub-cohort, and in view of the recent emergence of several novel therapeutic agents in the treatment of both MDS and AML, prospective clinical studies are required to reassess the role of allogeneic HSCT in patients with high-risk disease and high comorbidities.

In addition, the HCT-CI was able to distinguish cohorts of patients with HCT-CI scores of 1–2 and 3, who had a significantly inferior DFS and OS when compared with patients with no overt comorbidities (HCT-CI score 0). However, unlike the observations within non-T-cell-depleted allo-HSCT, there was no significant difference in either DFS or OS when comparing recipients with an HCT-CI score of 1–2 and those with a higher score of 3. This suggests that the HCT-CI score is a less specific predictor of disease-free and OS in alemtuzumab-treated patients. These observations could in part be explained by the fact that, owing to the high disease risk of the cohort, there was no significant difference in relapse incidence between any of the HCT-CI subgroups of patients.

The association between older age and inferior outcome is well documented in the literature, in particular with myeloablative conditioning.9, 24, 34, 35, 36 However, a number of recent studies of RIC allo-HSCT have shown age to not be a significant factor affecting outcome.5, 23, 32, 37 In this study, although an advanced recipient age of more than 50 years showed an independent correlation with poorer OS (P=0.05), the use of the HCT-CI seemed to be a much stronger predictor of post-transplant outcomes.

We report a low incidence of grade IV aGVHD (2%) within a cohort of patients in which a high proportion (62%) received VUD stem cells. In addition, the cumulative incidence of limited and extensive cGVHD was low at 23 and 15%, respectively, of the patients. Conversely, within this cohort of patients with advanced disease, alemtuzumab was associated with a higher relapse rate, reported at 38% at 3 years. A high incidence of viral complications has also been reported with the use of T-cell depletion.4, 38 Death due to viral illness occurred in 11 (23%) patients who died as a result of NRM: CMV pneumonitis (n=4), adenovirus (n=3), hepatitis B (n=1) and respiratory virus (n=3).

This study confirms observations from several other studies that disease burden at the time of transplantation is one of the most important predictors of outcome.12, 32, 39, 40, 41 The presence of active disease at the time of transplantation remained the strongest predictor of inferior transplant outcome, indicating that this cohort of patients should be considered for alternative therapeutic strategies. The role of dose-escalated conditioning regimens or sequential chemotherapy followed by RIC HSCT has been investigated by other groups in this context, with promising results.42

In summary, this retrospective analysis shows that in MDS or AML patients with advanced disease receiving alemtuzumab-based RIC HSCT, the HCT-CI provides an important means of identifying patients with a high risk of inferior transplant outcome. New therapeutic strategies need to be developed for patients with high-risk disease and increased comorbidities.

Conflict of interest

The authors declare no conflict of interest.

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Acknowledgements

Wendy Ingram is supported by the Leukaemia Research Fund, UK

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Correspondence to A Pagliuca.

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Lim, Z., Ingram, W., Brand, R. et al. Impact of pretransplant comorbidities on alemtuzumab-based reduced-intensity conditioning allogeneic hematopoietic SCT for patients with high-risk myelodysplastic syndrome and AML. Bone Marrow Transplant 45, 633–639 (2010). https://doi.org/10.1038/bmt.2009.236

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Keywords

  • reduced-intensity conditioning
  • AML
  • comorbidity
  • HCT-CI
  • MDS

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