Introduction

Conventional high-dose TBI-containing conditioning regimens for allogeneic hematopoietic SCT (alloHSCT) have a high non-relapse mortality (NRM) in adults with high-risk myelodysplastic syndromes (MDS) and AML above the age of 45–50 years.^{1, 2, 3} In an effort to reduce NRM, several groups have developed reduced-intensity conditioning (RIC) regimens,^{4, 5, 6, 7, 8, 9, 10, 11} which lead to engraftment of donor lymphoid and hematopoietic stem cells without the non-hematologic toxicities of traditional myeloablative transplants.^{4, 5, 6, 7, 8, 9, 10, 11, 12, 13} However, experience with RIC alloHSCT in AML and high-risk MDS is limited. We have reported previously that RIC followed by allogeneic PBSCT after a homogeneous RIC regimen produces high rates of engraftment with tolerable toxicity and acceptable outcomes in a heterogeneous group of patients with myeloid malignancies.^{12, 13} On the basis of these data, we started a prospective trial in which adult patients with poor-risk AML and MDS in an early disease status and with an HLA-identical sibling were assigned to receive a conventional or an RIC regimen based solely on patient age. The outcomes of both conditioning strategies, with a specific emphasis on NRM, were compared in the 74 adults who received the assigned conditioning strategy, as well as in all patients with an HLA-identical sibling on the basis of intention to treat (ITT).¹⁴

Patients and methods

Patient selection

Between 1998 and December 2005, all consecutive adult patients with 'poor-prognosis' AML or MDS in an 'early disease' status and with an HLA-identical sibling were programmed to receive an allogeneic PBSCT within this study. Early disease status was defined as AML or refractory anemia with excess blast (RAEB) type 2 (blasts in BM at diagnosis 10%) in CR-1 after chemotherapy¹⁵ and untreated RAEB type 1.

'Poor-prognosis' AML and RAEB type 2 were defined as one or more of the following: (1) poor-risk cytogenetics;¹⁴ (2) CR-1 was obtained only after two cycles of intensive induction therapy; and/or (3) presence of flt-3 internal tandem duplication or MLL rearrangement in molecular analysis.¹⁶ Poor-prognosis RAEB type 1 was defined by an international prognostic score intermediate-2 or high.¹⁷

During the study period, 40 consecutive patients 50 years of age or younger were assigned to receive the conventional high-dose conditioning regimen, while 47 patients above the age of 50 were assigned to receive the RIC regimen. However, five (13%) and eight (17%) patients from each transplant group, respectively, did not reach the assigned therapy because of disease progression (n=10) or death during intensification chemotherapy (n=3). Thus, the number of patients who received the assigned therapy was 35 and 39, respectively. Patients gave written informed consent for inclusion in the protocols, which were approved by all local ethical review boards and the Spanish Drug Agency. The characteristics and outcomes of the 74 study subjects are shown in Table 1.

Table 1 - Patient characteristics and transplant outcomes (% in parentheses).

Full table

Conditioning regimens and supportive care

A homogeneous transplant protocol was used in each study (or age) group. Young patients (those with 50 years of age or younger) were conditioned with cyclophosphamide plus TBI, and PBSC underwent CD34+-positive cell selection^{15, 18} (CTCD34+ transplant group), while the RIC regimen used in elderly patients (more than 50 years of age) consisted of fludarabine plus busulphan^{12, 13} (10 mg/kg) (FB-RIC transplant group). GVHD prophylaxis consisted of cyclosporine A alone or in combination with short-course methotrexate in each group, respectively.

Statistical analysis

The biological features of unselected groups of young and elderly patients with AML and high-risk MDS are expected to differ, especially since all consecutive patients were included. These biological differences have an impact on the risk of relapse and disease-free survival (DFS), which may not be apparent in small patient subgroups, and a detailed statistical risk factor analysis for these outcomes would be unreliable. NRM, however, is strongly linked to age. Consequently, the current analysis focuses on NRM in each transplant group as well as in the entire cohort.

Non-relapse mortality and disease relapse were calculated using cumulative incidence estimates. Univaried Cox regression was used for univaried analyses, and variables with a P0.1 were included in multivariate Cox regression analyses, while the probabilities of DFS and overall survival (OS) were estimated using Kaplan–Meier product-limit estimates. Variables analyzed for their impact on outcomes included the hematopoietic cell transplant (HCT)-comorbidity index, cytogenetics risk group, disease type (AML and RAEB type 2 or RAEB type 1), acute GVHD 2–4, chronic GVHD, patient age, CD34+ cell dose infused, sex mismatch, origin of AML-MDS (de novo vs therapy-related AML-MDS vs secondary AML) and patient's CMV serostatus.

All outcomes were measured from the date of transplantation, except for the ITT analysis, which was done from the date that a patient who fulfilled the criteria for an alloHSCT was found to have an HLA-identical sibling donor.^{19, 21}

Results

All patients had initial donor-derived hematological recovery. The number of days with neutrophils below 0.5 10⁹/l and platelets below 20 10⁹/l were shorter in the FB-RIC with respect to the CTCD34+ group (15 vs 8 days for neutrophils and 14 vs 4 days for platelets, respectively; P<0.05 for both comparisons). Using DNA-based chimerism testing in peripheral blood,²² the proportion of patients who had complete donor chimerism in T cells on days +90, +180 and +360 was higher in the FB-RIC group (Table 1).

The day +100 cumulative incidence of acute GVHD (grades 2–4) was 18% (95% confidence interval (CI), 6–30%) for CTCD34+ and 21% (95% CI, 14–28%) for FB-RIC groups (P=0.8). The cumulative incidence of chronic GVHD (cGVHD) at 4 years was 32 and 71%, respectively (P<0.01).

NRM and other post transplant outcomes

The median follow-up for survivors was around 4 years as of 30 March 2007. The transplant group had no impact on any outcome at 4 years post transplant. Table 1 shows in detail the 4-year incidence of relapse, DFS and OS (including the ITT analysis for DFS and OS).

Results of univariate and multivariate analyses of NRM (primary end point of the study) are shown in detail in Table 2. The 4-year incidence of NRM was 20 and 19% in the FB-RIC and CTCD34+ group, respectively (P=0.8). Multivariate analysis was done in the whole patient population, while only univariate analyses were done separately in each transplant group due to the small sample sizes. Of note, a high HCT-comorbidity showed a strong deleterious impact in both patient groups (Figure 1).

Figure 1.

Incidence of non-relapse mortality (NRM) (a) in the CTCD34+ group by the hematopoietic cell transplantation-comorbidity index (HCT-CI); the 4-year NRM in patients with an HCT-CI 3 and <3 was 65 and 10%, respectively (P=0.01). (b) In the FB-RIC group, the 4-year NRM was 45 and 7%, respectively (P=0.04).

Full figure and legend (30K)

Table 2 - Summary of the results of risk factor analyses for non-relapse mortality.

Full table

In multivariate analysis, only not developing cGVHD (hazard ratio 5.8, 95% CI 1.6–24, P=0.04) had an independent impact on relapse (10% incidence in patients with and 38% in patients without cGVHD, P=0.01). For OS and DFS, in multivariate analysis, the only variables that showed an impact were not developing cGVHD (hazard ratio 3.6, 95% CI 1.2–20, P=0.02 for OS; hazard ratio 5.3, 95% CI 1.2-29, P=0.02 for DFS) and a high HCT-comorbidity index (P=0.05 for OS and P=0.06 for DFS), while a trend was found for male recipient with a female donor (P=0.06 for OS and P=0.08 for DFS).

Only two variables clearly had an opposite impact on post transplant outcomes in the univariate analyses done separately in each transplant group: (i) patient age (<42 vs 42 years) had an impact on NRM, OS and DFS only in the CTCD34+ group (Figure 2a); while (ii) the dose of CD34+ cells/kg infused (6 10⁶ vs <6 10⁶/kg) had an impact on survival only in the FB-RIC group (Figure 2b).

Figure 2.

Probability of disease-free survival (DFS) (a) in the CTCD34+ group by patient age; the 4-year DFS in patients 42 and <42 years old was 37 (95% confidence interval (CI), 19–55%) and 64% (95% CI, 49–79%), respectively (P=0.08). (b) In the FB-RIC group, the 4-year DFS in patients who received a CD34+ cell dose in the graft 6 10⁶ and >6 10⁶/kg was 42 (95% CI, 19–65%) and 72% (95% CI, 55–89%), respectively (P=0.05).

Full figure and legend (30K)

In keeping with previous observations, all early post transplant extrahematological toxicities were milder in the FB-RIC group, leading to fewer days of hospitalization in the first 30 days after transplant for supportive care, mainly due to gastrointestinal toxicity (median 9 vs 20 days in the FB-RIC and CTCD34+ group, respectively; P<0.02). However, the median number of readmissions after day +30 and up to 1 year post transplant was higher in the FB-RIC group (3 (range: 0–6) vs 1 (range: 0–4) readmission, respectively; P<0.05), mostly due to severe infections and/or gastrointestinal GVHD (details not shown).

The proportion of surviving patients with a Karnofsky score of 90% in the CTCD34+ vs the FB-RIC groups was 50 vs 30%, respectively, at 1 year, 75 vs 40% at 2 years and 90 vs 60% at 4 years.

Discussion

Elderly age has been considered a major risk factor for failure of a conventional myeloablative alloHSCT, attributed mainly to a high early post transplant conditioning-related NRM. The results obtained from this single-center prospective study suggest that the negative impact of elderly age on the outcome of alloHSCT for patients with early-status AML and MDS can be reduced with an RIC protocol. We believe that the main strength of this study is the prospective 'age-randomized' nature of the trial. In the context of a single-center consecutive patient cohort, 'age randomization' can be a suitable way of comparing two transplant strategies, while eliminating potentially unknown selection biases.²¹ In addition, we analyzed survival according to the ITT principle to avoid misleading interpretations and biased treatment effects,¹⁹ since reasonable doubts have arisen as to the true impact of RIC allo-HSCT to elderly patients due to the various biases that lead to selection of only very fit older patients.^{23, 24, 25} The similar 4-year OS and DFS in this ITT analysis suggest that RIC alloHSCT may be proposed for elderly patients with AML/MDS. Other strengths of this study are the inclusion only of patients with very poor-risk AML/MDS, the relatively long median follow-up of 4 years and the homogeneous donor type, stem cell source and conditioning regimen used in each cohort.

On the other hand, the main weakness of the current study is the small sample sizes, and, as previously highlighted, the age-dependent differences in the biological characteristics of AML and high-risk MDS. Because of these differences, only the statistical analyses of NRM are shown. In addition, many centers would disagree with the conventional high-dose conditioning chosen for young patients and the RIC strategy chosen for elderly patients; it should be stressed, however, that these strategies showed good outcomes in each age group in our previous single-arm studies, and this prompted us to choose them and keep them homogeneous throughout the study. The trend for increased NRM in the CTCD34+ group in the patients with an age near 50 and the relatively low NRM in the FB-RIC group suggest that our goals may have been met. Interestingly, the higher NRM in patients with a high HCT-comorbidity index in both age groups (Figure 1) is in line with previous observations, confirming that comorbidities, and not simply age alone, may help identify proper candidates for RIC regimens.²⁰

In summary, these single-center results suggest that in this disease setting, the expected high NRM in elderly patients can be reduced with an RIC regimen, leading to equivalent survival when compared to young patients receiving a myeloablative alloPBSCT from an HLA-identical sibling. Our study was not powered to identify the impact of the type of conditioning on other outcomes, and for this purpose, a larger multicenter protocol is ongoing.

Notes

Specific contribution(s) of each coauthor: RM: conceived and executed the research reported in the paper, the integrity and data analysis, was involved in patient care and wrote the various versions of the manuscript. In addition, he also had the task of data management and statistical analyses. DV: collaborated in patient care, data management and the statistical analyses. All other co-authors contributed in the conception and execution of the research reported in the paper and in-patient care, and participated in writing or interpreting relevant parts of the manuscript.

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Acknowledgements

This study was performed in the setting of the CETLAM cooperative group (Grupo Cooperativo para el Estudio y Tratamiento de las Leucemias Agudas y Mielodisplasias, protocols CET-LAM-99 and CET-LAM-2003), in part with grants C03/010 and 603/008 from the Instituto de Salud Carlos III and two grants from Fundació d'Investigació Sant Pau and Fundació 'La Caixa' (Barcelona, Spain).