This retrospective study assessed the outcome of 576 adult acute lymphoblastic leukemia patients aged ≥ 45 years, and who received a reduced-intensity conditioning (RIC; n = 127) or myeloablative conditioning (MAC; n = 449) allogeneic stem cell transplantation (allo-SCT) from a human leukocyte antigen-identical sibling while in complete remission. With a median follow-up of 16 months, at 2 years, the cumulative incidences of nonrelapse mortality and relapse incidence were 29% ± 2% (MAC) versus 21% ± 5% (RIC; P = .03), and 31% ± 2% (MAC) versus 47% ± 5% (RIC; P < .001), respectively. In a multivariate analysis, nonrelapse mortality was decreased in RIC recipients (P = .0001, hazard ratio [HR] = 1.98) whereas it was associated with higher relapse rate (P = .03, HR = 0.59). At 2 years, LFS was 38% ± 3% (MAC) versus 32% ± 6% (RIC; P = .07). In multivariate analysis, the type of conditioning regimen (RIC vs. MAC) was not significantly associated with leukemia-free survival (P = .23, HR = 0.84). Despite the need for randomized trials, we conclude that RIC allo-SCT from a human leukocyte antigen-identical donor is a potential therapeutic option for acute lymphoblastic leukemia patients aged ≥ 45 years in complete remission and not eligible for MAC allo-SCT.

Acute lymphoblastic leukemia (ALL) accounts for approximately 15% to 20% of all adult acute leukemias.1  Although 80% to 90% of adult patients with ALL succeed in achieving complete remission (CR), most of them will relapse and die of their disease.2  Among adults with ALL, long-term leukemia-free survival (LFS) rates of 30% to 40% have been obtained with the use of chemotherapy, compared with 45% to 75% with the use of conventional myeloablative conditioning (MAC) allogeneic stem cell transplantation (allo-SCT).3,,,7  The latter favorable effect is likely due to a reduced risk of relapse, especially in patients in first CR. However, nonrelapse mortality (NRM) may counterbalance that favorable overall outcome observed after MAC allo-SCT in elderly patients and patients with comorbidities. Thus, the use of reduced intensity conditioning (RIC) before allo-SCT may offer hitherto unavailable opportunities to obtain a graft-versus-leukemia effect without the toxicities of intense preparative regimens. We report herein a retrospective comparative study which assessed the outcomes of 576 adult (age at transplantation ≥ 45 years) patients with ALL who underwent allo-SCT in CR with a human leukocyte antigen (HLA)–identical sibling donor, and analyzed according to the type of conditioning received before allo-SCT (RIC vs MAC).

Study design and data collection

This was a retrospective multicenter analysis. Data of adult ALL patients receiving RIC or MAC allo-SCT were provided by the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT) group. EBMT registry is a voluntary working group of more than 450 transplant centers, participants of which are required once a year to report all consecutive stem cell transplantations and follow-up. The Acute Leukemia Working Party of the EBMT group approved this study.

Criteria of selection

The study included ALL patients receiving first RIC or MAC allo-SCT in first or second CR from an HLA-identical related donor, who (1) were aged ≥ 45 years at time of transplant; (2) were transplanted between 1997 and 2007; (3) had received a MAC regimen (standard high-dose radio- or chemotherapy) or a RIC regimen defined as the use of fludarabine associated with low-dose total body irradiation (TBI; ≤ 6 Gy) or busulfan (total dose ≤ 8 mg/kg), or other immunosuppressive or chemotherapeutic drugs such as melphalan or cyclophosphamide8 ; or (4) were patients whose clinical data on outcomes were adequate. A total of 576 allo-SCT recipients from 186 transplant centers met these eligibility criteria.

Patients and transplant procedures

Differences between patients, disease, and transplant-related factors according to conditioning regimen are given in Table 1. As per EBMT centers practice for allo-SCT in ALL, patients were eligible to receive a MAC regimen if they were aged under 50 or 55 years and did not have significant comorbidities that precluded the use of high-dose radio- or chemotherapy (n = 362). In addition, 87 patients who were aged > 55 years received a MAC regimen because they did not have significant comorbidities and were judged as “fit” to receive high-dose therapy. In the RIC group, 110 patients (87%) received a RIC regimen mainly because of age ≥ 50 years irrespective of the presence or absence of significant comorbidities. The remaining 17 patients (13%) who received a RIC regimen were aged < 50 years but had one or more comorbidities or specific reasons that precluded the use of high-dose therapy (see details in Table 1). The majority of the patients in the RIC group (91%) received peripheral blood stem cells compared with 66% in the MAC group. For graft-versus-host disease (GVHD) prevention, 81% of the patients in the MAC group received the classical cyclosporine A (CsA) plus methotrexate combination, while patients in the RIC group received either, CsA alone (27%), CsA plus mycophenolate mofetil (36%) or CsA plus methotrexate (37%). Four hundred ninety-six (86%) patients were transplanted in first CR, while the remaining patients were transplanted in second CR (n = 80). The median follow-up was 16 months (range, 1-119) months.

Statistical analysis

The probabilities of overall survival (OS), LFS, relapse incidence (RI), and NRM were the primary study end points. LFS was defined as survival without evidence of relapse or progression. LFS and OS were calculated using the Kaplan-Meier estimate. RI, NRM, as well as the probabilities of acute and chronic GVHD were calculated using cumulative incidence (CI) in a competing risks setting, with death in remission treated as a competing event to relapse.9  Univariate analyses were done with the use of log-rank test for OS and LFS while the Gray test was applied for RI and NRM. Patient-, disease-, and transplant-related variables of the 2 groups were compared, using the χ2 statistic for categorical and the Mann-Whitney test for continuous variables. Multivariate analyses were performed using Cox proportional hazards model including chronic GVDH as a time-dependent variable. Factors differing in term of distribution between the 2 groups and factors associated with a P value less than < .10 by univariate analysis were included in the final model. For all prognostic analyses, continuous variables were categorized and the median was used as a cutoff point. All tests are 2-sided. The type I error rate was fixed at 0.05 for determination of factors associated with time to event outcomes. Statistical analyses were performed with SPSS 15.0 (SPSS Inc) and Splus 6.1 (MathSoft Inc) software packages.

In the total population at 2 years after allo-SCT, OS and LFS were 46% ± 2% and 37% ± 2% respectively. The CIs of grade 2-4 acute and chronic GVHD were 26% ± 3% and 34% ± 3%, respectively, comparable between both MAC and RIC groups (P = .16 and P = .37, respectively). The overall RI and NRM were 34% ± 3%, and 29% ± 3%, respectively. LFS, NRM, RI, and OS according to the type of conditioning regimen are shown in Figure 1. At 2 years, the nonadjusted CI of NRM was 31% ± 2% (MAC) versus 21% ± 4% (RIC; P = .03). The nonadjusted CI of RI at 2 years was 31% ± 2% (MAC) versus 47% ± 5% (RIC; P < .001). At 2 years, there was a trend toward improved LFS in the MAC group: 38% ± 3% (MAC) versus 32% ± 5% (RIC; P = .07). However, OS was similar: 45% ± 3% (MAC) versus 48% ± 5% (RIC; P = .56). In the Philadelphia-positive subgroup of patients (n = 145), the results were 47% ± 5% for OS, 33% ± 5% for LFS, 40% ± 5% for RI, and 27% ± 4% for NRM in the MAC group, versus 40% ± 9% for OS, 34% ± 8% for LFS, 49% ± 9% for RI, and 17% ± 7% for NRM in the RIC group. In patients transplanted in CR1, the results were 48% ± 3% for OS, 40% ± 3% for LFS, 28% ± 2% for RI, and 32% ± 2% for NRM in the MAC group versus 51% ± 6% for OS, 35% ± 5% for LFS, 48% ± 5% for RI, and 17% ± 4% for NRM in the RIC group. In patients transplanted in second CR, the results were 24% ± 7% and 33% ± 11% for OS, 18% ± 6% and 20% ± 10% for LFS, 54% ± 7% and 43% ± 12% for RI, and 28% ± 7% and 38% ± 12% for NRM, in the MAC and RIC groups, respectively. In the MAC group, the incidences of NRM were 23% ± 3%, 38% ± 3%, and 46% ± 18 in the 45 to 50 (n = 218), 50 to 60 (n = 214), and > 60 years (n = 17) age categories, respectively (P = .007). In the RIC group, the incidences of NRM were 14% ± 2% (2 events), 22% ± 5%, and 20% ± 8% in the 45 to 50 (n = 16), 50 to 60 (n = 75), and > 60 years (n = 36) age categories (P = not significant [NS]). In the same age categories, LFS and OS at 2 years were 41% ± 4%, 35% ± 4%, 14% ± 12%, and 50% ± 4%, 40% ± 4%, and 41% ± 15% in the MAC group, respectively. Similarly, LFS and OS at 2 years were 65% ± 13% (4 events), 28% ± 6%, 25% ± 8%, and 79% ± 11% (5 events), 48% ± 7%, and 32% ± 9% in the RIC group, respectively (nonadjusted comparisons for LFS and OS between MAC and RIC within the above age categories were all statistically NS). In a multivariate analysis, adjusting for patient-, disease- and transplant related-factors that were different in both groups, RI was increased in RIC recipients (P = .0001, HR = 1.98); however the use of RIC was associated with lower NRM (P = .03, HR = 0.59). Other factors associated with increased relapse were absence of chronic GVHD and patients transplanted in second CR, whereas other factors associated with decreased NRM were patients younger than 50 years old and male donor. In multivariate analysis for OS, type of conditioning was not associated with OS (RIC vs. MAC: P = .23, HR = 1.21); other factors such as elderly patients (age > 50 years: P = .008, HR = 0.69), disease status at transplant (second CR: P = .001, HR = 0.59), and a female donor to a male recipient (P = .005, HR = 0.68) were factors associated with a decreased OS. In multivariate analysis for LFS, type of conditioning was not associated with LFS (RIC vs MAC: P = .23, HR = 0.84); other factors such as absence of chronic GVHD (P = .01, HR = 0.62), elderly patients (age > 50 years: P = .016, HR = 0.75), disease status at transplant (second CR: P = .004, HR = 0.64), and a female donor to a male recipient (P = .045, HR = 0.77) were factors associated with a decreased LFS.

Figure 1

Survival probabilities. (A) LFS according to conditioning regimen; (B) NRM according to conditioning regimen; (C) relapse incidence according to conditioning regimen; (D) OS according to conditioning regimen. MAC: plain curve; RIC: dashed curve. x-axis: years after transplantation; y-axis: percent outcome.

Figure 1

Survival probabilities. (A) LFS according to conditioning regimen; (B) NRM according to conditioning regimen; (C) relapse incidence according to conditioning regimen; (D) OS according to conditioning regimen. MAC: plain curve; RIC: dashed curve. x-axis: years after transplantation; y-axis: percent outcome.

Close modal

The role of allo-SCT in adult ALL is still controversial.4,10,12  In addition, ALL encompasses a group of chemosensitive diseases, raising concerns that significant reduction of the intensity of the preparative regimen before allo-SCT may have a negative impact on long-term leukemic control as it has been already shown in other settings.13,14  Very few data are available analyzing RIC allo-SCT for patients with ALL.15,,18  Results of this registry analysis suggest that RIC regimens may reduce NRM rate after allo-SCT for adult ALL compared with standard MAC regimens, but with a higher risk of disease relapse and no statistically significant impact on LFS. In another word, there is an apparent trade off, including lower NRM with RIC, but a higher rate of relapse. It is also notable that the RIC patients did not do significantly worse than the MAC patients, although LFS tended to be lower. However, OS, likely the most important outcome for an individual patient, was strictly comparable between both groups.

In the MAC regimens groups (high-dose TBI versus high-dose chemotherapy alone), LFS, NRM, and relapse incidence were: 40 ± 3 versus 28 ± 6 (P = .06), 31 ± 3 versus 30 ± 5 (P = .98), and 28 ± 3 versus 42 ± 6 (P = .04), respectively. On the other hand, although RIC regimens were heterogeneous, there were no statistically significant differences in NRM and relapse incidences for the different RIC categories (NRM: 18% ± 8%, 23% ± 9%, and 23% ± 9% [P = NS]; relapse: 48% ± 9%, 55% ± 11%, and 45% ± 12% [P = NS] in the low-dose TBI-based RIC, fludarabine-busulfan, and fludarabine-melphalan RIC regimens, respectively).

One major limitation in this type of analysis is that the patient populations are fundamentally different. Patients received a MAC regimen unless they were elderly or had major comorbidities. Thus, the RIC patients were older (6 years older) or had comorbidities precluding the use of MAC. Thus, the most relevant question would be whether RIC in older patients produces an acceptable outcome. However, despite the latter limitations, this analysis contains some promising findings, since it was focused on patients aged ≥ 45. Indeed, those patients who received RIC are likely to have serious comorbidities, which led the transplantation center to choose RIC instead of MAC.19  In fact, age older than 45 to 50 years is widely accepted as a major prognostic variable for increased NRM after allo-SCT.20  In addition, toxicity of the intensive chemotherapy used in ALL to achieve initial or subsequent remission before transplant can compromise a patient's ability to tolerate a MAC regimen. Unfortunately, it was not possible to provide the details of the prior chemotherapy used in these patients and assess the impact of this parameter on outcome. Obviously, any comparison between RIC and MAC may be influenced by a selection bias. However, to adjust for differences between patients selected for RIC or MAC, we had enough patients in this study to perform a multivariate analysis and adjust for differences between the 2 groups. Moreover, we focused on those patients in CR and who received allo-SCT from an HLA-identical donor. With these considerations in mind, these results are encouraging in this subgroup of ALL patients aged ≥ 45, especially in term of OS. Moreover, in the RIC group, LFS in patients aged ≥ 60 years was 25% ± 8% at 2 years comparing favorably with results of chemotherapy alone in elderly ALL,1  and further highlighting the overall benefit of RIC allo-SCT in elderly ALL.18  However one should bear in mind that the value of allo-SCT versus chemotherapy is definitely among the key issues that need to be further assessed. Indeed, given the increasingly improved results and safety of chemotherapy alone, the comparison of transplant versus chemotherapy at different age groups warrants some well designed and rigorous prospective trials because the current study suggests that the results of the RIC allo-SCT approach look promising versus chemotherapy alternatives for those ALL patients aged > 45 years.

The use of preemptive donor leukocyte infusion immediately after RIC allo-SCT may be also expected to be beneficial, especially in patients with a positive residual disease,21  but this could not be assessed in this cohort. In addition, amplification of the graft-versus-leukemia effect may be one way to reduce the rate of relapse.22  Post-RIC allo-SCT maintenance therapy (eg, tyrosine kinase inhibitors) may also succeed in eradicating residual leukemic cells.23  Monoclonal antibodies directed against antigens expressed by leukemic cells (anti-CD20/22/33) may be also less toxic and more efficient than chemotherapy.24  Despite the need for prospective randomized studies with analyses based on the intention–to–treat principle, we conclude that RIC allo-SCT from an HLA-identical donor is a feasible and potential therapeutic option for ALL patients aged ≥ 45 in CR and not eligible for MAC allo-SCT.

The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

We thank E. Polge and B. Samey from the office of the Acute Leukemia Working Party of EBMT.

Contribution: M.M., M.L., and V.R. conceived and designed the study, provided administrative support, performed data analysis and interpretation, and revised the manuscript; M.M. and V.R. arranged financial support; M.M., L.V., A.G., G.S., J.E., R.T., A.N., and V.R. provided study materials or patients; M.L. collected and assembled data and conducted statistical analyses; M.M. wrote the manuscript; and M.M., M.L., L.V., A.G., G.S., J.E., R.T., A.N., and V.R provided final manuscript approval.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Mohamad Mohty, Service d'Hématologie Clinique, CHU Hôtel-Dieu, Université de Nantes and Inserm U892, Place Alexis Ricordeau, F-44093 Nantes, France; e-mail: mohamad.mohty@univ-nantes.fr.

1
Pui
CH
Evans
WE
Treatment of acute lymphoblastic leukemia.
N Engl J Med
2006
354
2
166
178
2
Rowe
JM
Buck
G
Burnett
AK
et al
Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993.
Blood
2005
106
12
3760
3767
3
Hunault
M
Harousseau
JL
Delain
M
et al
Better outcome of adult acute lymphoblastic leukemia after early genoidentical allogeneic bone marrow transplantation (BMT) than after late high-dose therapy and autologous BMT: a GOELAMS trial.
Blood
2004
104
10
3028
3037
4
Thomas
X
Boiron
JM
Huguet
F
et al
Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial.
J Clin Oncol
2004
22
20
4075
4086
5
Goldstone
AH
Richards
SM
Lazarus
HM
et al
In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993).
Blood
2008
111
4
1827
1833
6
Cornelissen
JJ
van der Holt
B
Verhoef
GE
et al
Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison.
Blood
2009
113
6
1375
1382
7
Tomblyn
MB
Arora
M
Baker
KS
et al
Myeloablative hematopoietic cell transplantation for acute lymphoblastic leukemia: analysis of graft sources and long-term outcome.
J Clin Oncol
2009
27
22
3634
3641
8
Aoudjhane
M
Labopin
M
Gorin
NC
et al
Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT).
Leukemia
2005
19
12
2304
2312
9
Gooley
TA
Leisenring
W
Crowley
J
Storer
BE
Estimation of failure probabilities in the presence of competing risks: new representations of old estimators.
Stat Med
1999
18
6
695
706
10
Sebban
C
Lepage
E
Vernant
JP
et al
Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia.
J Clin Oncol
1994
12
12
2580
2587
11
Hahn
T
Wall
D
Camitta
B
et al
The role of cytotoxic therapy with hematopoietic stem cell transplantation in the therapy of acute lymphoblastic leukemia in adults: an evidence-based review.
Biol Blood Marrow Transplant
2006
12
1
1
30
12
Ribera
JM
Oriol
A
Bethencourt
C
et al
Comparison of intensive chemotherapy. allogeneic or autologous stem cell transplantation as post-remission treatment for adult patients with high-risk acute lymphoblastic leukemia. Results of the PETHEMA ALL-93 trial.
Haematologica
2005
90
10
1346
1356
13
Martino
R
Iacobelli
S
Brand
R
et al
Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes.
Blood
2006
108
3
836
846
14
Shimoni
A
Hardan
I
Shem-Tov
N
et al
Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.
Leukemia
2006
20
2
322
328
15
Mohty
M
Labopin
M
Tabrizzi
R
et al
Reduced intensity conditioning allogeneic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a retrospective study from the European Group for Blood and Marrow Transplantation.
Haematologica
2008
93
2
303
306
16
Cho
BS
Lee
S
Kim
YJ
et al
Reduced-intensity conditioning allogeneic stem cell transplantation is a potential therapeutic approach for adults with high-risk acute lymphoblastic leukemia in remission: results of a prospective phase 2 study.
Leukemia
2009
23
10
1763
1770
17
Bachanova
V
Verneris
MR
DeFor
T
Brunstein
CG
Weisdorf
DJ
Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation.
Blood
2009
113
13
2902
2905
18
Marks
DI
Wang
T
Perez
WS
et al
The outcome of full-intensity and reduced-intensity conditioning matched sibling or unrelated donor transplantation in adults with Philadelphia chromosome negative acute lymphoblastic leukemia in first and second complete remission.
Blood
2010
116
3
366
374
19
Sorror
ML
Maris
MB
Storb
R
et al
Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT.
Blood
2005
106
8
2912
2919
20
Meijer
E
Cornelissen
JJ
Allogeneic stem cell transplantation in acute myeloid leukemia in first or subsequent remission: weighing prognostic markers predicting relapse and risk factors for non-relapse mortality.
Semin Oncol
2008
35
4
449
457
21
Matsue
K
Tabayashi
T
Yamada
K
Takeuchi
M
Eradication of residual bcr-abl-positive clones by inducing graft-versus-host disease after allogeneic stem cell transplantation in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.
Bone Marrow Transplant
2002
29
1
63
66
22
Slavin
S
Immunotherapy of cancer with alloreactive lymphocytes.
Lancet Oncol
2001
2
8
491
498
23
Wassmann
B
Pfeifer
H
Stadler
M
et al
Early molecular response to posttransplantation imatinib determines outcome in MRD+ Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL).
Blood
2005
106
2
458
463
24
Jandula
BM
Nomdedeu
J
Marin
P
Vivancos
P
Rituximab can be useful as treatment for minimal residual disease in bcr-abl-positive acute lymphoblastic leukemia.
Bone Marrow Transplant
2001
27
2
225
227
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