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Conditioning

Impact of pre-transplant co-morbidities on outcome after alemtuzumab-based reduced intensity conditioning allo-SCT in elderly patients: A British Society of Blood and Marrow Transplantation study

Abstract

The advent of reduced intensity conditioning (RIC) regimens has permitted the extension of allo-SCT to selected patients into their eighth decade but GVHD remains a major cause of morbidity and mortality. Alemtuzumab is increasingly used to reduce the risk of severe GVHD, but there are concerns that T-cell depletion may compromise outcome particularly in older patients. We therefore studied the impact of pre-transplant factors on the outcome of 187 patients with a haematological malignancy over the age of 60 transplanted using an alemtuzumab-based RIC regimen of whom co-morbidity scoring was possible in 169. Of the patients, 120 had a haematopoietic cell transplantation co-morbidity index (HCT-CI) of 0 or 1 and 49 had a score of 2 or more. The 5-year OS was 33%. In multivariable analysis, OS was determined by co-morbidity score (P=0.001) and disease status at transplant (P=0.004) but not by patient age. Non-relapse mortality was determined by co-morbidity score (P=0.001). Two-year OS for patients with a HCT-CI of 0–1 was 59 versus 6% for patients with a higher score. Alemtuzumab-based RIC allografts can be delivered safely in patients aged over 60 but co-morbidity scoring is mandatory to identify patients who will benefit.

Introduction

The demonstration that reduced intensity conditioning (RIC) regimens permit the delivery of a GVL effect with a marked reduction in transplant-related toxicity has permitted the extension of allogeneic transplantation to older adults in whom this potentially curative treatment modality was previously precluded.1, 2, 3, 4 A major factor limiting the utilisation of RIC regimens in this population has been the substantial risk of GVHD in patients who receive a T-replete stem cell inoculum and consequently there is increasing use of in vivo T-cell depletion using alemtuzumab or anti-thymocyte globulin (ATG).5,6,7,8 However, in vivo T-cell depletion is associated with delayed immune reconstitution, which may result in an increased risk of infectious death and disease relapse.9,10 This has led to concerns that any benefits accruing from the utilisation of alemtuzumab or ATG may be offset by an increased risk of both non-relapse mortality (NRM) and disease recurrence particularly in older patients. There is therefore an urgent requirement to identify, with greater precision, the tolerability of RIC regimens incorporating in vivo T-cell depletion in older patients with particular reference to factors determining long-term outcome.

The development of a weighted scoring system, the haematopoietic cell transplantation co-morbidity index (HCT-CI), which captures multiple-organ co-morbidities, has been shown to provide a robust guide to transplant toxicity and survival in younger adults undergoing allo-SCT using either a myeloablative or RIC regimen.11,12 Recently, it has been shown that such a scoring system also accurately predicts the outcome in patients transplanted using an alemtuzumab-based RIC regimen.13,14 However, to date, there have been no studies of the utility of co-morbidity scoring on predicting outcome after a T-cell depleted allograft in older patients. We therefore studied patient and donor factors predicting outcome in patients over the age of 60 undergoing allo-SCT using an alemtuzumab-based preparative regimen with the aim of identifying factors predicting survival and transplant toxicity.

Patients and methods

In this retrospective study, we examined factors predicting outcome in 187 patients with haematological malignancies who underwent an alemtuzumab-based RIC allograft for a haematological malignancy at participating centres (Table 1). The median age of the patients was 62.7 years (range 60.0–72.8). Forty-five patients were aged 65–69 and five patients were aged 70–72. Sixty-two patients received a graft from a sibling donor and 125 from an adult unrelated donor. One hundred and sixty-eight patients were transplanted using GCSF-stimulated PBSC, 18 using cells collected from a BM harvest and one using PBSC and BM collected from the same donor. The HCT-CI index was assessed in all patients pre-transplant but insufficient data were available for its accurate calculation in 18 patients.

Table 1 Characteristics of study population

Transplant regimens and GVHD prophylaxis

Patients over the age of 60 who were transplanted in transplant centres, which routinely utilised alemtuzumab-based RIC regimens including combinations of fludarabine and melphalan (Flu/Mel),15 fludarabine and Bu (Flu/Bu),16 BCNU, BEAM17 and fludarabine and Cy (Flu/Cy) (Table 1)18 were studied. GVHD prophylaxis consisted of CYA (5 mg/kg) commenced pre-transplant and subsequently dose-adjusted to achieve therapeutic levels. Alemtuzumab was administered pre-transplant according to the relevant conditioning regimen over a period of 2–5 days in total doses ranging from 30 to 100 mg. Patients received aciclovir, co-trimoxazole and anti-fungal prophylaxis according to institutional policies. Acute and chronic GVHD were classified according to published criteria.19

Statistical analysis

OS and PFS were estimated by the Kaplan–Meier method. Univariable and multivariable survival comparisons and hazard ratios (HR) were estimated from Cox regression models.20 NRM and relapse rate (RR) were calculated by competing risks analysis. Relapse was the competing risk for NRM, whereas death in remission was the competing risk for RR. Univariable and multivariable models were calculated by the method of Fine and Gray.21,22 The HCT-CI index was calculated for each patient, and treated as a continuous variable for the purposes of these survival analyses.11 Patient age and sex, diagnosis, disease status, patient/donor CMV, CD34+ stem cell dose and HCT-CI index score were analysed for their association with NRM, relapse risk, OS and PFS using univariable analyses. All factors significant for any outcome in the univariable analysis in addition to age were included in the multivariable model.

Results

Transplant outcomes

The 1-year estimate of OS for the whole group was 56% (48–63%) and 33% (23–43%) at 5 years. The PFS at 1 year was 50% (42–57%) and 27% (18–37%) at 5 years. Ninety-two (49%) patients are alive of whom 81 remain in continuous remission after a median follow-up of 24 months (range 2–90). Fifty-eight patients died because of transplant-related complications. The NRM in the first year posttransplant was 26%. The main causes of NRM were infectious complications (n=22) and GvHD (n=22). Of the patients, 39% developed grade I–II acute GVHD and 13% grade III–IV acute GVHD.

Fifty-two patients relapsed after transplant. The RR at 1 year was 24% (18–31%) and 37% at 5 years (28–45%). Thirty-seven patients died as a consequence of disease recurrence and four of transplant-related causes. Eleven patients are alive post relapse. Four patients received DLI of whom three are still alive at a range of 16–30 months post DLI. One patient received a second transplant, and is still alive 46 months after the second allograft.

Predictors of outcome

The results of a univariable analysis of factors impacting on OS, NRM and relapse risk are summarised in Table 2. On multivariable analysis, disease status at transplant (HR 1.49; 95% confidence interval (CI) 1.13–1.95 P=0.004) and HCT-CI index (HR 1.77; 95% CI 1.52–2.10 P= 0.001) influenced OS (Table 3). Specifically, patients who had a HCT-CI index of 0 or 1 experienced a statistically significantly improved survival compared with those a HCT-CI index of 2 or greater: 2-year OS 59% (95% CI 49–69%) compared with 6% (95% CI, 1–17%) (P=0001) (Figure 1). On multivariable analysis, NRM was influenced by HCT-CI score (HR 1.87; CI 1.56–2.22 P=0.001) but no other factors were of significance (Figure 2). Alemtuzumab dose did not impact outcome. No factors were shown to correlate with RR on univariable or multivariable analysis.

Table 2 Univariable analysis of pre-transplant factors determining survival, relapse and non-relapse mortality
Table 3 Multivariable analysis of pre-transplant factors determining survival, relapse and non-relapse mortality
Figure 1
figure1

OS according to pre-transplant HCT-CI.

Figure 2
figure2

Non-relapse mortality according to pre-transplant HCT-CI.

Discussion

An increasing number of older adults are undergoing allo-SCT, many using an alemtuzumab-based RIC. This is the first study to examine predictors of outcome in this challenging patient group. Our data confirm the important impact of the HCT-CI on patient outcome, which has been previously demonstrated in younger patients but, in contrast to previous studies, we observed an exceptionally poor tolerance of more than one co-morbidity in this older population. Thus, although broadly equivalent outcomes to those reported in younger patients are observed in the presence of an HCT-CI of 0 or 1, TRM rises abruptly in older patients with an HCT-CI score of 2 or more resulting in a markedly reduced OS. On the basis of these data, older patients, with an HCT-CI of greater than 1, should only be considered for an allogeneic transplant using an alemtuzumab-based RIC regimen, in their current formulation, after careful deliberation. Importantly our data confirm that patient age itself should not itself be considered a barrier to the safe delivery of a potentially curative allograft in patients with a low HCT-CI. Supporting the thesis that biological age, as manifest by co-morbidity status, rather than chronological age is the critical determinant of transplant outcome, we observed no impact of age within the group of patients we studied. The observation that the other key determinant of outcome after a RIC allograft is disease status has been reported in a number of previous reports.17,23 Taken together, with the profoundly adverse impact of multiple co-morbidities on transplant outcome, our data allow the identification of a population of older patients with active disease in whom allogeneic transplantation is very unlikely to deliver a survival benefit. As a consequence, these data now inform clinical practice at the reporting centres and patients with a HCT-CI of greater than 1 are only transplanted in exceptional circumstances or according to an investigational protocol.

The extent to which the use of alemtuzumab as a component of the conditioning regimen contributes to the marked impact of the HCT-CI on transplant outcome is unclear. Further studies in this age group, in patients transplanted using differing preparative regimens and forms of T-cell depletion, are now warranted. One previous, smaller study reported no impact of the HCT-CI on outcome but included patients transplanted using a range of preparative regimens and degrees of T-cell depletion, which complicated interpretation,24 and a separate study performed in patients over the age of 60 transplanted using a non-alemtuzumab-based regimen identified an impact of co-morbidities as determined by the less precise Karnovsky score.25 To date, other studies addressing the impact of HCT-CI status on outcome post transplant have not specifically focussed on elderly patients and it will be of interest to observe whether the marked impact of co-morbidities on outcome is also observed in patients transplanted using a T-cell replete protocol. Transplantation of a higher dose of CD34+ cells has been reported to be correlated with improved immune reconstitution and it is of interest that there was no impact of stem cell dose on outcome in the patient population studied.26

This study confirms that alemtuzumab-based RIC allografts can be delivered safely in patients above the age of 60 with a low rate of GVHD. Furthermore, these data demonstrate that co-morbidity scoring is mandatory in older patients considered for a RIC allograft to identify those with an acceptable procedure-related toxicity. Novel strategies that permit the safe delivery of allogeneic transplants in older patients with significant co-morbidities are urgently required.

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Acknowledgements

The hard work of the data managers at the contributing transplant centres is gratefully acknowledged. The work of the BSBMT registry was originally supported by a grant from Leukaemia and Lymphoma Research which is gratefully acknowledged.

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Correspondence to C Craddock.

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Nikolousis, E., Nagra, S., Pearce, R. et al. Impact of pre-transplant co-morbidities on outcome after alemtuzumab-based reduced intensity conditioning allo-SCT in elderly patients: A British Society of Blood and Marrow Transplantation study. Bone Marrow Transplant 50, 82–86 (2015). https://doi.org/10.1038/bmt.2014.215

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