From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
LYMPHOID NEOPLASIA
Outcome of relapsed adult lymphoblastic leukemia depends on response to
salvage chemotherapy, prognostic factors, and performance of stem cell
transplantation
Nicola Gökbuget,1 Daniel Stanze,1 Joachim Beck,2 Helmut Diedrich,3 Heinz-August Horst,4 Andreas Hüttmann,5
Guido Kobbe,6 Karl-Anton Kreuzer,7 Lothar Leimer,8 Albrecht Reichle,9 Markus Schaich,10 Stefan Schwartz,11 Hubert Serve,1
Michael Starck,12 Matthias Stelljes,13 Reingard Stuhlmann,14 Andreas Viardot,15 Knut Wendelin,16 Mathias Freund,17 and
Dieter Hoelzer,1 on behalf of the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia
1Department
of Medicine II, Goethe University Hospital, Frankfurt, Germany; 2University Medicine, Mainz, Germany; 3Department of Hematology, Hemostasis,
Oncology, and Stem Cell Transplantation, Medical School Hannover, Hannover, Germany; 4University Hospital Schleswig Holstein, Campus Kiel, Kiel, Germany;
5University Hospital, Essen, Germany; 6University Hospital, Düsseldorf, Germany; 7University at Cologne, Cologne, Germany; 8Robert Bosch Hospital, Stuttgart,
Germany; 9University Hospital, Regensburg, Germany; 10Department of Medicine I, University Hospital, Dresden, Germany; 11University Hospital Charité,
Campus Benjamin-Franklin, Berlin, Germany; 12Hospital Schwabing, München, Germany; 13Department of Medicine, Hematology, and Oncology, University
Hospital, Münster, Germany; 14Asklepios Hospital St Georg, Hamburg, Germany; 15Department of Internal Medicine III, University Hospital, Ulm, Germany;
16Klinikum Nürnberg, Nord, Germany; and 17University Hospital, Rostock, Germany
Despite improvements in first-line therapies, published results on the treatment
of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still
poor. The aim of the present retrospective
analysis of the German Multicenter Study
Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55)
experiencing their first relapse (406 vs
141 shorter or longer than 18 months
from diagnosis) were evaluated. The aim
of salvage therapy was to achieve a complete remission (CR) with subsequent a
stem cell transplantation (SCT). The CR rate
(assessed in Philadelphia chromosome–
and BCR-ABL–negative ALL without CNS
involvement) after the first salvage in
relapse after chemotherapy (n ⴝ 224) was
42%. After failure of first salvage (n ⴝ 82),
the CR rate after second salvage was
33%. In relapse after SCT (n ⴝ 48) the CR
rate after first salvage was 23%. The median overall survival after relapse was
8.4 months and survival was 24% at
3 years. Prognostic factors for survival
were relapse localization, response to
salvage, performance of SCT, and age.
Overall survival appeared superior compared with previously published studies,
likely because of the high rate of SCT in
the present study (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. The study is
registered at www.clinicaltrials.gov as
NCT00199056 and NCT00198991. (Blood.
2012;120(10):2032-2041)
Introduction
Treatment results for adult acute lymphoblastic leukemia (ALL) have
improved considerably in the past decades: complete remission (CR)
rates have increased to 85%-90% and overall survival (OS) rates to
40%-50%.1,2 Optimized risk stratification, the integration of stem cell
transplantation (SCT), refined chemotherapy, the use of targeted therapies, and optimized supportive care, have all been important developments. However, despite all of these improvements in first-line therapies, at least one-third of standard-risk (SR) patients and up to two-thirds
of high-risk (HR) patients eventually experience relapse, which is still a
major therapeutic challenge. Several retrospective trials have demonstrated that remission rates after first salvage therapy range from
31%-44%.3-6 Clinical trials with newly registered drugs such as nelarabine or clofarabine in patients who were mostly refractory to first
salvage have reported CR rates of 20%-23%.7-9 This is consistent with a
retrospective analysis from the MD Anderson Cancer Center showing
an 18% response rate in patients who underwent second salvage.10 In
particular, patients with early relapse during intensive chemotherapy
appear to be highly resistant to any chemotherapy approach. The
reported OS rates after relapse, including outcomes after subsequent
SCT, were 5%-8%.3-6 Allogeneic SCT is the only curative approach, but
it has been performed in less than 50% of ALL patients.3-6 Furthermore,
limited data are available on the response to salvage therapy during
different stages of disease and in different subtypes of ALL.
In the present study, we analyzed data from a large series of adult
patients with relapsed ALL who had been recruited into the consecutive
German Multicenter Study Group for Adult ALL (GMALL) studies
06/99 and 07/03 for de novo ALL. In this series, in which a uniform
first-line treatment was applied, the major aim was to analyze response
and outcome data for subtypes of ALL, to identify prognostic factors for
CR and OS, and to evaluate the impact of SCT after relapse. In addition,
the analysis aimed to provide a reference for future trials pertaining to
relapsed ALL, including pivotal trials with new drugs.
Methods
Study eligibility
The retrospective analysis included patients 15-55 years of age with ALL
(patients with mature B-ALL were excluded) who were consecutively
Submitted December 19, 2011; accepted March 18, 2012. Prepublished
online as Blood First Edition paper, April 4, 2012; DOI 10.1182/blood-201112-399287.
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.
The online version of this article contains a data supplement.
© 2012 by The American Society of Hematology
2032
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
treated after first diagnosis within GMALL studies 06/99 and 07/03. A total
of 547 patients with first relapse were included in the analysis. The GMALL
studies were approved by the institutional review board of the University of
Frankfurt (Frankfurt, Germany) and are registered at www.clinicaltrials.gov
as NCT00199056 and NCT00198991. All patients gave written informed
consent in accordance with the Declaration of Helsinki.
First-line treatment
The first-line treatment was risk adapted and based on intensive cyclical
chemotherapy, as described previously.11 During first-line treatment, patients were allocated to risk groups based on conventional prognostic
factors. High-risk factors were WBC above 30 000/␮L at diagnosis in
B-lineage ALL, pro-B-ALL, early or mature T-cell ALL, MLL-AF4/t(4;11)
translocation, or no CR after induction I. Patients with any of these factors
were allocated to the HR group. HR patients and those with Philadelphia
chromosome–positive (Ph⫹) or BCR-ABL–positive ALL were candidates
for allogeneic SCT after achievement of first CR. Myeloablative conditioning was recommended with VP16 and 12 Gy total body irradiation (TBI) for
sibling and cyclophosphamide and 12 Gy TBI for matched unrelated SCT.
The remaining patients were allocated to the SR group.
Patient cohorts
Different cohorts of patients were defined for the purpose of analysis. Based
on first-line treatment, patients who relapsed during or after chemotherapy
were analyzed separately from those patients who relapsed after SCT.
Salvage therapy was different for patients with CNS involvement (intrathecal therapy), isolated extramedullary involvement, and Ph⫹/BCR-ABL⫹
ALL (tyrosine kinase inhibitors). Therefore, these 3 patient groups were
excluded from the analysis of response to salvage therapy. The first and
second approaches to salvage therapy were analyzed separately. The
analysis of prognostic factors was focused on patients with relapse during
or after chemotherapy without Ph⫹/BCR-ABL⫹ ALL without isolated
extramedullary involvement and without CNS involvement to exclude
confounding factors and to provide reference data in a well-defined patient
population. Time to relapse, an important potential prognostic feature, was
stratified at 18 months duration of first remission based on the results from a
previous GMALL relapse trial.12 Patients with a remission duration shorter or
longer than 18 months were categorized as early or late relapse, respectively.
Relapse treatment and data collection
Patients who relapsed after treatment in the initial study were followed, but
the choice of salvage therapy was left to the discretion of the treating
physicians. Limited data on therapy after relapse and performance of
allogeneic SCT were collected, but the survival data were always recorded.
The choice of relapse treatment was mainly influenced by the duration
of the first remission based on published data on its prognostic impact12 and
on immunophenotype. In B-precursor ALL, the most frequently used
regimens for early relapse were consolidation protocol I (high-dose
cytarabine, high-dose methotrexate, etoposide, vindesine, and dexamethasone) or FLAG-IDA (high-dose cytarabine, fludarabine, and idarubicin).
CLAEG (high-dose cytarabine, etoposide, and cladribine; supplemental
Table 1, available on the Blood Web site; see the Supplemental Materials
link at the top of the online article) and nelarabine were most frequently
used in T-lineage ALL. The most frequently used regimen for late relapse
was a repetition of standard induction. For allogeneic SCT, a myeloablative
conditioning regimen based on TBI was recommended, but details of
regimens were not collected.
CR after salvage therapy was defined according to conventional criteria
with a BM blast count below 5% and no peripheral blast cells or
extramedullary manifestations. Recovery of peripheral blood counts may
not have been reached in all cases, particularly if patients received SCT
shortly after achievement of a marrow CR. Death during relapse therapy
and failure to respond to relapse therapy were summarized as “failure.”
Statistical analysis
All patients were registered at the GMALL Study Center, where statistical
analysis was performed with SAS Version 8.02 for PC. For all analyses,
OUTCOME OF RELAPSED ADULT LYMPHOBLASTIC LEUKEMIA
2033
P ⱕ .05 was considered statistically significant. Statistical analysis was
mainly descriptive. Data are presented in tables, with percentage proportions for categorical variables and medians for continuous variables.
Statistical comparisons were performed with the ␹2 test for categorical
variables and with the Wilcoxon test for continuous variables. The survival
analysis was based on the Kaplan-Meier method. The survival time after
relapse was calculated from the time point of relapse until death or the last
follow-up. The median observation time in patients surviving after relapse
was 23 months. Survival rates are given as probabilities of survival at 3 or
5 years, with a 95% confidence interval. The log-rank test was used to
compare survival curves. Multivariate analysis was performed with the Cox
logistical regression.
Results
Patients and patient characteristics
A total of 547 patients with first relapse were evaluable. The
median age was 33 years (range, 15-55); 393 patients (72%) had
B-lineage ALL; 150 (28%) had T-lineage ALL; and 94 patients had
Ph⫹ ALL (17%). The median time to relapse was 162 days (range,
19-2838 days). A total of 432 (79%) patients had an early relapse,
and 115 (21%) had a late relapse. The majority of patients (92%)
had BM involvement at relapse; 6% had CNS involvement with or
without other involvement, and 6% experienced isolated extramedullary relapse (Table 1).
A total of 378 patients (69%) relapsed during or after first-line
chemotherapy, whereas 169 patients (31%) relapsed after SCT
performed during the first CR. A significantly higher proportion of
patients with relapse after SCT had high-risk features because SCT
was predominantly performed in HR or Ph⫹ patients (Table 1). This
included patients with high-risk immunophenotypes such as pro-BALL (11% vs 5%) or early T-ALL (20% vs 3%; P ⬍ .0001), and
patients allocated to the HR or very-high-risk group (92% vs 32%;
P ⬍ .0001) for first-line treatment. The time to relapse was
significantly shorter in patients who relapsed after SCT compared
with those who relapsed during or after chemotherapy (122 vs
288 days; P ⬍ .0001). Few patients experienced late relapse after
SCT compared with chemotherapy (3% vs 29%; P ⬍ .0001).
Response to salvage therapy
The response to salvage therapy was analyzed in patients with
evaluable information about salvage type and who did not have
CNS involvement, isolated extramedullary involvement, or Ph⫹ ALL.
Data are reported separately for the first and second salvage approaches
and for relapse after chemotherapy and relapse after SCT.
Response to first salvage in relapse during or after chemotherapy. A total of 224 patients were evaluable; 160 (71%) had
early relapse and 64 (29%) had late relapse. The overall CR rate
was 42% after first salvage, 36% for early relapse, and 58% for late
relapse (P ⫽ .003). The overall CR rate after first salvage was 46%
for B-precursor ALL and 34% for T-ALL (P ⬎ .05). The CR rate
was significantly lower for early relapse compared with late relapse
(39% vs 64%; P ⫽ .003) in B-precursor ALL, whereas the difference
was not significant in T-ALL (30% vs 42%; P ⬎ .05). Because of
these differences and the fact that different salvage regimens were
preferred, B-precursor and T-ALL were analyzed separately.
Early relapses in patients with B-precursor ALL were most
frequently treated with the consolidation I regimen or with
FLAG-IDA and CR could be obtained in 29% and 42%, respectively. This difference was not statistically significant. Early T-ALL
relapse patients were most frequently treated with CLAEG,
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
2034
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
GÖKBUGET et al
Table 1. Clinical characteristics
Relapse during/
after chemotherapy
Characteristic
n*
Relapse after SCT
378
P
Total
169
547
Age†
Median age, y
32
⬎ .05
34
33
15-25
129 (34%)
50 (30%)
179 (33%)
26-45
173 (46%)
84 (50%)
257 (47%)
46-55
76 (20%)
35 (20%)
111 (20%)
Male
242 (64%)
101 (60%)
Female
136 (36%)
68 (40%)
⬍ 30 000
250 (69%)
100 (62%)
⬎ 30 000
113 (31%)
61 (38%)
Sex
⬎ .05
343 (63%)
204 (37%)
WBCs/␮L†
⬎ .05
350 (67%)
174 (33%)
Immunophenotype†
Pro-B
Pre-B/c
18 (5%)
18 (11%)
253 (67%)
104 (62%)
⬍ .0001
36 (7%)
357 (66%)
Early T
12 (3%)
33 (20%)
45 (8%)
Mature T
16 (4%)
11 (7%)
27 (5%)
Thymic
77 (20%)
1 (1%)
78 (14%)
Risk group†
Standard
⬍ .0001
258 (68%)
14 (8%)
High
87 (23%)
94 (56%)
181 (33%)
272 (50%)
Very high (Ph⫹)
33 (9%)
61 (36%)
94 (17%)
Time from diagnosis to relapse, mo
⬍ .0001
Median (range, d)
288 (22-2838)
122 (19-666)
⬍ 18
268 (71%)
164 (97%)
432 (79%)
162 (19-2838)
⬎ 18
110 (29%)
5 (3%)
115 (21%)
317 (89%)
111 (85%)
12 (3%)
6 (5%)
7 (2%)
4 (3%)
11 (2%)
22 (6%)
10 (7%)
32 (6%)
Site of relapse
BM only ⫾ other
BM ⫾ CNS ⫾ other
Isolated CNS
Isolated other extramedullary‡
⬎ .05
428 (88%)
18 (4%)
*Total number of patients may vary for the different subgroups depending on the number of patients with evaluable data.
†At first diagnosis.
‡Locations of extramedullary involvement were: mediastinum (n ⫽ 6), testis (n ⫽ 5), lymph nodes (n ⫽ 5), breast (n ⫽ 4), skin (n ⫽ 4), bone (n ⫽ 3), kidney (n ⫽ 2), liver
(n ⫽ 2), nasopharynx/tonsils (n ⫽ 2), pleura/pericardium (n ⫽ 2), prostate (n ⫽ 1), paravertebral (n ⫽ 1), epidural (n ⫽ 1), parotis (n ⫽ 1), retina (n ⫽ 1), and lung (n ⫽ 1).
Table 2. Response to first salvage therapy in patients with relapse during/after chemotherapy
Total
n
CR
224
95 (42%)*
160
58 (36%)
Consolidation I
47
FLAG-IDA
39
CLAEG
16
Early relapse
B-lineage
T-lineage
n
CR
P†
159
73 (46%)*
⬎ .05
114
44 (39%)
13 (28%)
38
11 (29%)
9
2
16 (41%)
38
16 (42%)
1
0
3 (19%)
0
0
16
P†
⬎ .05
n
CR
65
22 (34%)*
P†
46
14 (30%)
⬎ .05
3 (19%)
Standard induction
9
3
8
2
1
1
HDAC ⫾ Mitox
9
4
5
2
4
2
HDMTX
7
3
3
1
4
2
8
4
7
2
4
2
Other chemotherapy
15
6 (40%)
SCT in relapse‡
18
10 (56%)
Late relapse
64
37 (58%)
CLAEG
9
Standard induction
SCT in relapse
FLAG-IDA
30
1
15
⬍ .0001
14
8 (57%)
45
29 (64%)
.0003
2
27 (90%)
1
4 (27%)
27
1
14
24 (88%)
19
8 (42%)
9
2
3
3
1
0
0
4 (29%)
1
0
HDAC ⫾ Mitox
1
0
1
0
0
0
Other
8
3
2
0
6
3
Patients with evaluable information on the type of salvage therapy, without CNS involvement and with Ph/BCR-ABL–negative ALL.
HDAC indicates high-dose cytarabine; HDMTX, high-dose methotrexate; and Mitox, mitoxantrone.
*No percentage was calculated in subgroups with total number of cases less than 10.
†␹2 test.
‡Patients received SCT as their salvage treatment; and CR rate indicates the remission rate after SCT.
⬎ .05
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
OUTCOME OF RELAPSED ADULT LYMPHOBLASTIC LEUKEMIA
2035
Table 3. Response to second salvage therapy in patients with relapse during/after chemotherapy
Total
FLAG-IDA
CLAEG
Nelarabine
B-lineage
n
CR
n
CR
82
27 (33%)*
P
48
12 (25%)*
10
2 (20%)
⬎ .05
9
4
16
1
T-lineage
n
CR
P
34
15 (44%)*
⬎ .05
1
1
0
0
4
8 (50%)
0
0
16
1
8 (50%)
HDAC ⫾ Mitox
4
0
1
0
SCT in relapse†
26
8 (31%)
22
7 (32%)
4
1
Other
22
8 (36%)
14
4 (29%)
8
4
0
3
P
⬎ .05
1
Patients with evaluable information about the type of salvage therapy, without CNS involvement and with Ph/BCR-ABL–negative ALL.
HDAC indicates high-dose cytarabine; and Mitox, mitoxantrone.
*No percentage was calculated in subgroups with total number of cases less than 10.
†Patients received SCT as their first salvage treatment; and CR rate indicates the remission rate after SCT.
Prognostic factors
resulting in a 19% CR rate. For late relapse in B-precursor ALL, the
most frequently used regimens were the GMALL standard induction regimen and FLAG-IDA. GMALL standard induction therapy
induced a significantly higher CR rate (88% vs 29%; P ⬍ .0001).
In late relapse of T-ALL, the most frequent regimen was CLAEG,
which induced a 22% CR rate (Table 2).
Response to second salvage in relapse during or after chemotherapy. In patients failing to achieve CR after first salvage, data
for the response to second salvage therapy were available for
82 patients. The overall CR rate was 33% after second salvage,
25% in B-lineage ALL, and 44% in T-ALL (P ⫽ .07; Table 3).
Response to first salvage in relapse after SCT. For 48 patients
who had received allogeneic SCT in first remission, data for the
response to first salvage therapy in relapse after SCT were
available. The overall CR rate was 25%. The most frequently used
regimens in B-precursor ALL were FLAG-IDA and repeated
induction (29% vs 40% CR rate; P ⬎ .05). In T-ALL, nelarabine
induced CRs in 3 of 8 patients (Table 4).
The prognostic factors for outcomes after relapse were analyzed in
patients with relapse during or after chemotherapy and without
CNS involvement, isolated extramedullary involvement, or Ph⫹
ALL.
Prognostic factors for CR. CR after first salvage was influenced by age, with CR rates decreasing from 53% in patients
25 years of age or younger to 37% in patients older than 25 years
(P ⫽ .02). CR rates were also significantly different for patients
with early and late relapse (36% vs 58%; P ⫽ .003). Other factors
had no significant impact on CR (Table 5).
Prognostic factors for survival after relapse. Survival 3 years
after relapse was influenced by various factors. It significantly
decreased with increasing age, from 38% ⫾ 5% for patients
15-25 years of age to 28% ⫾ 4% for patients 26-45 years of age to
12% ⫾ 5% for patients 46-55 years of age (P ⬍ .0001; Figure 2A).
Survival was also significantly poorer in patients with early relapse
compared with later relapse (22% ⫾ 3% vs 43% ⫾ 6%; P ⬍ .0001;
Figure 2B). Different cutoff points for time to relapse were
analyzed, and all showed significant differences, with CR rates and
survival rates decreasing with shorter remission duration and
increasing with longer remission duration (supplemental Table
5A). The patient’s risk group at the time of first diagnosis also
influenced OS, whereas sex, WBC count, and ALL subtype were
not significantly correlated with outcome (Table 5).
Response to salvage therapy as a prognostic factor was analyzed in subsets of patients for whom data were available. OS was
47% ⫾ 6% for patients with CR after first salvage, compared with
13% ⫾ 3% for failure patients (P ⬍ .0001; Figure 3A). For
B-precursor ALL, survival was 46% ⫾ 6% when CR was achieved
Overall outcome after relapse
The median OS in 547 relapse patients was 8.6 months, with a
survival probability of 24% ⫾ 2% at 3 years (supplemental Figure
1A). The median survival after relapse during or after chemotherapy compared with relapse after SCT was 10 months versus
5.8 months, and the probability of survival was 28% ⫾ 3% versus
15% ⫾ 3% at 3 years (P ⬍ .0001; Figure 1). Patients with BM
relapse with or without additional relapse localizations had an OS
of 23% ⫾ 2% at 3 years compared with patients with CNS
involvement (27% ⫾ 10%) and patients with other isolated extramedullary relapses (47% ⫾ 10%; P ⫽ .02 for the 3 groups;
supplemental Figure 1B).
Table 4. Response to first salvage therapy in patients with relapse after SCT
Total
B-lineage
T-lineage
n
CR
n
CR
n
CR
48
11 (23%)*
P
24
6 (25%)*
P
24
5 (21%)*
P
FLAG-IDA
14
4 (29%)
⬎ .05
10
4 (40%)
⬎ .05
4
0
⬎ .05
Induction
10
4 (40%)
4
2
6
2
CLAEG
3
0
3
0
Nelarabine
8
3
8
3
HDAC ⫾ Mitox
1
0
Other
9
0
2nd SCT in relapse†
3
0
8
0
1
0
1
0
3
0
Patients with evaluable information about the type of salvage therapy, without CNS involvement and with Ph/BCR-ABL–negative ALL.
HDAC indicates high-dose cytarabine; and Mitox, mitoxantrone.
*No percentage was calculated in subgroups with total number of cases less than 10.
†Patient received SCT as their first salvage treatment; and CR rate indicates the remission rate after SCT.
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
2036
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
GÖKBUGET et al
Figure 1. Survival in patients with relapsed ALL according to
first-line therapy. Relapse during or after chemotherapy, n ⫽ 378
(solid line), 28% ⫾ 3% after 3 years, 25% ⫾ 3% after 5 years;
median 10 months; relapse after SCT, n ⫽ 169 (dashed line),
15% ⫾ 3% after 3 and 5 years, median 5.8 months (P ⬍ .0001).
after first salvage, compared with 8% ⫾ 3% for failure patients
(P ⬍ .0001). For T-ALL, survival rates were 50% ⫾ 11% and
21% ⫾ 6% (P ⫽ .003), respectively (supplemental Figure 3C).
In patients with failure after first salvage, OS was 35% ⫾ 9%
when CR was achieved after second salvage and 8% ⫾ 4% for
failure cases (P ⫽ .0003; Figure 3B). For B-precursor ALL,
survival was 36% ⫾ 14% when CR was achieved after second
salvage, compared with 3% ⫾ 3% in failure cases (P ⫽ .001). For
T-ALL, the corresponding survival rates were 33% ⫾ 12% and
16% ⫾ 8% (P ⬎ .05), respectively (supplemental Figure 3D).
In the multivariate analysis of prognostic factors for survival,
3 prognostic factors with significant effects in the univariate
Table 5. Prognostic factors for achievement of CR and survival
Total n
CR*
224
94(42%)
141
59(42%)
83
36(43%)
15-25
75
40(53%)
26-45
109
41(38%)
46-55
49
14(35%)
⬍ 30 000
146
68(47%)
⬎ 30 000
72
25(35%)
164
74(45%)
60
21(35%)
B-lineage
159
73(46%)
T-lineage
65
22(34%)
150
72(48%)
9
1(11%)
Total
P
n
Survival†
291
29% ⫾ 3%
P
Sex
Male
Female
⬎ .05
181
30% ⫾ 4%
110
26% ⫾ 5%
.06
107
38% ⫾ 5%
.02§
129
28% ⫾ 4%
55
12% ⫾ 5%
⬎ .05
Age, y
⬍ .0001
WBCs/␮L‡
⬎ .05
201
29% ⫾ 4%
81
28% ⫾ 5%
⬎ .05
Risk group‡
Standard
High
⬎ .05
217
32% ⫾ 4%
74
20% ⫾ 5%
.01
Subtype
⬎ .05
215
29% ⫾ 3%
76
30% ⫾ 6%
201
31% ⫾ 4%
⬎ .05
Subtype (detail)
C/pre-B
Pro B
⬎ .05
14
9
3(33%)
11
9% ⫾ 9%
Mature T
11
2(18%)
12
17% ⫾ 11%
Thymic T
44
17(39%)
52
38% ⫾ 7%
⬍ 18
160
58(36%)
200
22% ⫾ 3%
⬎ 18
64
37(58%)
91
43% ⫾ 6%
Early T
⬎ .05
0%
Time to relapse, mo
.003
⬍ .0001
Response to first salvage
95
47% ⫾ 6%
129
13% ⫾ 3%
CR
27
35% ⫾ 9%
No CR
55
8% ⫾ 4%
CR
No CR
⬍ .0001
Response to second salvage‡
Patients with relapse during or after chemotherapy and without Ph⫹/BCR-ABL⫹ ALL or CNS involvement.
*CR rates were calculated for 224 patients with data on their response to first salvage therapy.
†Survival rates are shown as probability of survival ⫾ SD at 3 years.
‡At first diagnosis.
§CR rates in patients younger and older than 25 years: 53% versus 37%, respectively.
¶Calculated for 82 patients with data on their response to second salvage therapy.
.0003
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
OUTCOME OF RELAPSED ADULT LYMPHOBLASTIC LEUKEMIA
2037
Figure 2. OS in 291 patients with relapse during or after
chemotherapy, no Phⴙ ALL, and no CNS involvement for whom
data were available. (A) OS according to age: 15-25 years of age,
n ⫽ 107 (solid line), 38% ⫾ 2% after 3 years, median 14.4 months;
26-45 years of age, n ⫽ 129 (short dashed line), 28% ⫾ 4% after
3 years, median 28.5 months; and 46-55 years of age, n ⫽ 55 (long
dashed line), 12% ⫾ 5% after 3 years, median 6.1 months
(P ⬍ .0001). (B) OS according to time to relapse: ⬍ 18 months,
n ⫽ 200 (solid line), 22% ⫾ 3% after 3 years, median 8.3 months;
⬎ 18 months, n ⫽ 91 (dashed line), 43% ⫾ 6% after 3 years,
median 19.7 months (P ⬍ .0001).
analysis (Table 5) were entered: age, time to relapse, and response
to first salvage. In the 224 patients for whom data on all 3 factors
were available, age (hazard ratio ⫽ 1.421; P ⫽ .004) and response
to first salvage (hazard ratio ⫽ 3.186; P ⬍ .0001) remained statistically significant.
SCT after relapse
Performance of SCT. Data on the performance of SCT were
missing for 24 of the 224 patients for whom data on response to
first salvage therapy were available. Further, this analysis was
restricted to patients with relapse during or after chemotherapy and
without CNS involvement, isolated extramedullary involvement,
or Ph⫹ ALL, so the performance of SCT after relapse was analyzed
in 200 patients. Overall, 75% (n ⫽ 149) of patients received SCT,
of whom 32% were in CR after first salvage, 10% were in CR after
later salvage, and 31% without CR (Table 6). A higher number of
T-ALL patients received SCT in CR after later salvage compared
with B-lineage ALL patients (25% vs 5%; P ⫽ .0003). Sixty-five of
the 93 patients with CR after first salvage received SCT during a
continuous first CR (70%). Overall, 86 of 93 patients with CR after
first salvage received SCT in any phase of disease after salvage,
compared with 63 of 107 patients with failure after first salvage
(92% vs 59%; P ⬍ .0001).
The transplantation rate decreased with increasing age, from
88% of patients 15-25 years of age (n ⫽ 69) to 75% of patients
26-45 years of age (n ⫽ 93) and 47% of patients older than 45 years
of age (n ⫽ 38; P ⬍ .0001 for all 3 groups). The SCT rate was also
significantly lower in patients with early relapse (n ⫽ 143) compared with late relapse (n ⫽ 57; 70% vs 86%; P ⫽ .02).
Outcome according to performance of SCT. No patient
without SCT survived more than 1 year after relapse, compared
with a 38% survival in patients with SCT at any time after first
salvage (P ⬍ .0001; Figure 4A). Survival was significantly better
when SCT was performed during CR after first salvage compared
with SCT during later CR or SCT during relapse (56 ⫾ 7% vs
39 ⫾ 11% vs 20 ⫾ 5%, respectively; P ⬍ .0001; Figure 4B).
Similar results were observed for B- and T-lineage ALL (Table 6).
No significant differences in outcomes were detected between Band T-lineage ALL.
Discussion
The present study involved a large cohort of uniformly pretreated
adult patients with relapsed ALL. In previously published studies,
the long-term OS ranged from 5%-8%.3-6 The median age in these
previous trials was 33-34 years, with age groups ranging between
15 and 81 years. The number of patients older than 55 years was
low in all trials. In our present study, long-term survival was
achieved in 24% of all patients (median age, 33 years) and in 28%
of patients with relapse during or after chemotherapy. These data
show that relapsed adult ALL is not an incurable disease.
One essential aim of this study was to provide data on the
response to salvage therapy and long-term outcomes for welldefined subgroups of relapsed ALL with a focus on patients with
Ph⫺ ALL and without CNS involvement of isolated extramedullary
involvement, or prior SCT. These data, including detailed results in
immunologic subtypes and relapse stages, are helpful for clinical
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
2038
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
GÖKBUGET et al
Figure 3. OS in 224 patients with relapse during or after
chemotherapy, Phⴚ/BCR-ABLⴚ ALL, and no CNS involvement for whom data on salvage therapy were available.
(A) OS according to response to first salvage: CR, n ⫽ 95 (solid
line), 47% ⫾ 6% after 3 years, median 33.3 months; no CR,
n ⫽ 129 (dashed line); 13% ⫾ 3% after 3 years, median
5.8 months (P ⬍ .0001). (B) OS according to response to second
salvage: CR, n ⫽ 27 (solid line), 35% ⫾ 9% after 3 years, median
14.2 months; no CR, n ⫽ 55 (dashed line), 8% ⫾ 4% after
3 years, median 6.6 months (P ⫽ .0003).
decision-making and could also serve as a reference for future trials
exploring experimental drugs for subgroups of ALL.
Prospective studies in relapsed adult ALL have reported CR
rates ranging from 50%-74% for a variety of treatment
regimens.4,13-17 The overall CR rate of 42% for the first salvage
approach in the present study was within the range reported from
other retrospective studies (31%-44%).3-6 Clearly, remission rates
depend on chemotherapy sensitivity, which is lower in early relapse
compared with late relapse and lowest in patients with refractory
disease after the first salvage approach. Oriol et al demonstrated
previously that the CR rate was 38% in patients with a first remission
duration of less than 1 year compared with 63% in patients with a
remission duration longer than 2 years.6 In the present study, the
CR rate in early relapse was 36% compared with 58% in late
relapse. Definitions of early and late relapse were not uniform in
the previously published studies. The most important conclusion is
probably that early relapses during intensive chemotherapy indicate a pronounced resistance to conventional chemotherapy. In
contrast, late relapses may have a completely different biologic
mechanism because they arise during maintenance treatment or
Table 6. Performance and outcome of SCT after relapse
Evaluable
Total (n ⴝ 200)
B-lineage (n ⴝ 144)
T-lineage (n ⴝ 56)
149 (75%)
103 (72%)
46 (82%)
65 (32%)
51 (35%)
14 (25%)
Performance of SCT, n
Any SCT
SCT in CR after 1st salvage
SCT in later CR
21 (10%)
7 (5%)
14 (25%)
SCT without CR
63 (31%)
45 (31%)
18 (32%)
51 (25%)
41 (28%)
10 (18%)
No SCT
Outcome according to SCT*
38% ⫾ 4%
36% ⫾ 5%
43% ⫾ 8%
SCT in CR after 1st salvage
56% ⫾ 7%
50% ⫾ 8%
77% ⫾ 12%
SCT in later CR
39% ⫾ 11%
51% ⫾ 20%
34% ⫾ 13%
SCT without CR
20% ⫾ 5%
18% ⫾ 6%
25% ⫾ 11%
0%†
0%†
0%†
Any SCT
No SCT
Patients with relapse during or after chemotherapy and without Ph⫹/BCR-ABL⫹ ALL or CNS involvement.
*Survival rates are shown as the probability of survival ⫾ SD at 3 years.
†Survival at 1 year.
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
OUTCOME OF RELAPSED ADULT LYMPHOBLASTIC LEUKEMIA
2039
Figure 4. OS in 200 patients with relapse during or after
chemotherapy, no Phⴙ ALL, and no CNS involvement and for
whom data on salvage therapy and SCT were available.
(A) OS according to performance of SCT: SCT, n ⫽ 149 (solid
line), 38% ⫾ 4% after 3 years, median 14.7 months; no SCT,
n ⫽ 51 (dashed line), 0% after 1 year, median 2.7 months
(P ⬍ .0001). (B) OS according to SCT timing: SCT in CR after first
salvage, n ⫽ 65 (solid line), 56% ⫾ 7% after 3 years, median not
reached; SCT in later CR, n ⫽ 21 (short dashed line), 39% ⫾ 11%
after 3 years, median 14.8 months; and SCT without CR, n ⫽ 63
(long dashed line), 20% ⫾ 5% after 3 years, median 9 months
(P ⬍ .0001).
after therapy completion, probably from a small number of
quiescent leukemia cells that did not acquire multiple drug
resistance.
The increasing drug resistance after multiple treatment approaches is also evident from the fact that the response rates
decreased to 33% in patients with failure after first salvage and to
25% in patients with relapse after SCT, which is the most intensive
prior treatment approach available. Consistent with this, the MD
Anderson Cancer Center reported CR rates of 31% in primary
refractory disease and early relapse18 and 18% for second salvage.10
In the present study (as in all other retrospective studies of adult
ALL), salvage therapies were chosen by local physicians, although
some general rules for regimen selection were considered, including the use of short, intensive regimens to treat early relapses and
the repetition of standard induction in late relapses. Overall, the
approaches used herein represent clinical practice in more than
100 participating hospitals. Most importantly, repeated induction
was the most favorable approach, with a 90% CR rate in late
relapses. FLAG-IDA was a frequently used regimen in early
relapse of B-precursor ALL, resulting in a CR rate of 42%. Before
nelarabine became available, CLAEG was frequently used in
relapsed T-ALL; however, remission rates with that treatment were
only approximately 20%. Data reported for nelarabine are superior,
with remission rates of 21%-36%9,19 in generally negatively
selected groups of adults with relapsed T-ALL.
The OS after relapse in the present study was influenced by
4 major factors: age, duration of first remission, response to salvage
therapy, and subsequent SCT. In patients younger than 25 years,
survival rates of 38% were surprisingly favorable, whereas in
patients older than 45 years, survival was very poor (12%). Oriol
et al reported 15% survival in patients younger than 30 years
compared with 10% in those above 30 years.6 Fielding et al
described 12% survival in those younger than 20 years and 3%-4%
in those older than 35 years.5 With increasing age, remission rates
in response to salvage therapy decrease. In the present study, the
CR rate was most favorable in patients younger than 25 years
(53%), which was still inferior compared with the results of
pediatric relapse trials showing remission rates as high as 84% with
intensive prolonged cyclical chemotherapy.20 Children, and probably also young adults, tolerate intensive retreatment at relapse,
which may increase the chance of achieving a second remission.
Conversely, the performance of SCT is correlated with age. It
remains unclear to what extent both effects are the result of disease
biology, actual patient condition, and real toxicities or of physicians’ decision to select less-toxic chemotherapies and avoid
transplantation in older patients.
In a recently reported pediatric trial, the OS in patients younger
than 19 years was 36%, although the number of early relapses
within 18 months from diagnosis was only 26% compared with
71% in the present study. The rate of SCT was 34% in the pediatric
trial compared with 88% in young adults in our trial.14 Although the
limitations of a retrospective compared with a prospective trial
have to be taken into account, these data show that outcome of
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
2040
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
GÖKBUGET et al
relapsed ALL in adolescents and young adults may also depend
strongly on performance of SCT.
In relapsed ALL, the response to first salvage therapy is
probably the most important prognostic factor. In the present study,
survival rates were 47% in patients with CR after first salvage,
compared with 13% in failure cases. The only approach to
improving outcome in patients with chemotherapy resistance is the
use of targeted treatments with an alternative mechanism of action,
such as antibody therapies.
Overall, 75% of the evaluable relapse patients without prior
SCT in our analysis received SCT at some stage of disease after
relapse. Seventy percent of patients with CR after first salvage were
transferred to SCT in ongoing second CR. Allogeneic transplantation rates were higher compared with those in previously published
studies, which ranged from 17%-58% in relation to patients
achieving a second CR.3,4,6 Ph⫹ ALL (9%) and patients with CNS
involvement (5%) were excluded from the present analysis.
Furthermore, for proper comparison, it is important to consider the
number of patients having a prior SCT in the different study
populations: 13%-20% for prior allogeneic SCT and 26%-38% for
autologous or allogeneic SCT in other retrospective analyses4-6
compared with 31% prior allogeneic SCT in the present study. In
the largest retrospective analysis by Fielding et al, the overall
transplantation rate after relapse was 24% in patients without prior
SCT and 35% in those patients who also lived long enough after
relapse to have the chance of a transplantation. The high transplantation rates in the patients in the present study were due to the
availability of large donor banks representing the ethnic mix of the
population and a health care system covering the costs for SCT.
Rapidity of donor identification is extremely important because
other trials have shown that the second remission only lasts for
approximately 6 months.6
The results of the present study confirm that no long-term
survival can be achieved without transplantation in relapsed adult
ALL. The survival probability, including that of patients with
extramedullary or CNS relapse, was 0% at 3 years without
transplantation. The superior survival of transplantation patients
after relapse compared with chemotherapy alone was also confirmed by Fielding et al in a landmark analysis that excluded
chemotherapy patients with survival times shorter than 100 days.5
It is still debated whether attempts should be made to achieve
CR before transplantation or if it is acceptable to perform
transplantation in patients in partial remission without additional
salvage therapy. In the present study, outcome was significantly
poorer for patients receiving transplantation without CR compared
with those with CR after first or later salvage. Furthermore, registry
data from the European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry show
that the survival of allogeneic sibling SCT is superior if performed
during the second remission (29%-34%) rather than during advanced disease (15%-18%).21,22 Data for matched, unrelated SCTs
are similar,23 and Tavernier et al reported significantly better
survival after SCT performed during the second CR (33%)
compared with failure (12%) and immediate SCT at relapse (8%).4
These results support the strategy of offering relapse patients
several lines of salvage therapy, thus increasing the chance to
perform SCT during CR.
For future optimization, the detection of persistent or recurrent
minimal residual disease should be considered as a trigger for
initiation of salvage therapy because patients with molecular
relapse have a high risk of hematologic relapse.24 The molecular
response to salvage may be an essential prognostic factor because it
influences the outcome of subsequent SCT.25 In addition, it is
essential to improve SCT procedures. Specific conditioning regimens should be evaluated in relapsed ALL, and posttransplantation
strategies, such as donor-lymphocyte infusions, maintenance
therapy, or minimal residual disease–based targeted therapy to
reduce relapse rate, should be explored.
The data presented herein are relevant for future evaluations of
new experimental drugs. Patients with primary refractory disease,
early relapse, refractory relapse, or relapse after SCT are candidates
for experimental treatments because of their poor response to
conventional approaches. Outcome is strongly correlated with the
achievement of CR, which is therefore a suitable end point.
However, long-term survival depends almost exclusively on performance of SCT.
The results of the present study provide reference data for future
clinical trials in relapsed ALL subdivided according to disease
stage and immunologic subtype. Our results emphasize that
relapsed ALL could be cured in a considerable proportion of
patients with optimized salvage therapy, including targeted, experimental drugs followed by SCT during a continuous second CR.
Acknowledgments
The authors thank Ms Regina Reutzel for study coordination and
data management and the GMALL study group for referring
patients to the participating study centers and for follow-up
documentation.
This study was supported by grants from Deutsche Krebshilfe
(702657Ho2), the Federal Ministry of Education and Research
(BMBF 01GI9971/8), and the German Carreras Foundation
(DJCLS R10/11).
Authorship
Contribution: N.G. and D.H. designed the research; N.G. coordinated the study, performed the statistical analysis, and wrote the
manuscript; and all authors recruited the study patients, performed
the study procedures, collected and verified the data, and reviewed
and approved the manuscript.
Conflict-of-interest disclosure: The authors declare no competing financial interests.
Correspondence: Nicola Gökbuget, Goethe University Hospital, Department of Medicine II, Theodor-Stern-Kai 7, 60590
Frankfurt, Germany; e-mail: [email protected].
References
1. Bassan R, Hoelzer D. Modern therapy of acute
lymphoblastic leukemia. J Clin Oncol. 2011;29(5):
532-543.
2. Gökbuget N, Hoelzer D. Treatment of adult acute
lymphoblastic leukemia. Semin Hematol. 2009;
46(1):64-75.
3. Thomas DA, Kantarjian H, Smith TL, et al. Pri-
mary refractory and relapsed adult acute lymphoblastic leukemia: characteristics, treatment results, and prognosis with salvage therapy.
Cancer. 1999;86(7):1216-1230.
4. Tavernier E, Boiron JM, Huguet F, et al. Outcome of treatment after first relapse in adults
with acute lymphoblastic leukemia initially
treated by the LALA-94 trial. Leukemia. 2007;
21(9):1907-1914.
5. Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG
2993 study. Blood. 2007;109(3):944-950.
6. Oriol A, Vives S, Hernandez-Rivas JM, et al.
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
BLOOD, 6 SEPTEMBER 2012 䡠 VOLUME 120, NUMBER 10
7.
8.
9.
10.
11.
12.
13.
Outcome after relapse of acute lymphoblastic leukemia in adult patients included in four consecutive risk-adapted trials by the PETHEMA Study
Group. Haematologica. 2010;95(4):589-596.
Jeha S, Gaynon PS, Razzouk BI, et al. Phase II
study of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia. J Clin Oncol. 2006;24(12):1917-1923.
Berg SL, Blaney SM, Devidas M, et al. Phase II
study of nelarabine (compound 506U78) in children and young adults with refractory T-cell malignancies: a report from the Children’s Oncology
Group. J Clin Oncol. 2005;23(15):3376-3382.
DeAngelo DJ, Yu D, Johnson JL, et al. Nelarabine induces complete remissions in adults with
relapsed or refractory T-lineage acute lymphoblastic leukemia or lymphoblastic lymphoma:
Cancer and Leukemia Group B study 19801.
Blood. 2007;109(12):5136-5142.
O’Brien S, Thomas D, Ravandi F, et al. Outcome
of adults with acute lymphocytic leukemia after
second salvage therapy. Cancer. 2008;113(11):
3186-3191.
Brüggemann M, Raff T, Flohr T, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):11161123.
Freund M, Diedrich H, Ganser A, et al. Treatment
of Relapsed or Refractory Adult Acute Lymphocytic Leukemia. Cancer. 1992;69:709-716.
Giona F, Annino L, Rondelli R, et al. Treatment of
OUTCOME OF RELAPSED ADULT LYMPHOBLASTIC LEUKEMIA
adults with acute lymphoblastic leukaemia in first
bone marrow relapse. Br J Haematol. 1997;97:
896-903.
14. Koller CA, Kantarjian HM, Thomas D, et al. The
hyper-CVAD regimen improves outcome in relapsed acute lymphoblastic leukemia. Leukemia.
1997;11:2039-2044.
15. Camera A, Annino L, Chiurazzi F, et al. GIMEMA
ALL - Rescue 97: a salvage strategy for primary
refractory or relapsed adult acute lymphoblastic
leukemia. Haematologica. 2004;89(2):145-153.
16. Giebel S, Krawczyk-Kulis M, Adamczyk-Cioch M,
et al. Fludarabine, cytarabine, and mitoxantrone
(FLAM) for the treatment of relapsed and refractory adult acute lymphoblastic leukemia. A phase
study by the Polish Adult Leukemia Group
(PALG). Ann Hematol. 2006;85(10):717-722.
17. Martino R, Bellido M, Brunet S, et al. Intensive
salvage chemotherapy for primary refractory or
first relapsed adult acute lymphoblastic leukemia:
results of a prospective trial. Haematologica.
1999;84(6):505-510.
18. Kantarjian HM, Thomas D, Ravandi F, et al. Defining the course and prognosis of adults with
acute lymphocytic leukemia in first salvage after
induction failure or short first remission duration.
Cancer. 2010;116(24):5568-5574.
19. Gökbuget N, Basara N, Baurmann H, et al. High
single drug activity of nelarabine in relapsed
T-lymphoblastic leukemia/lymphoma offers curative option with subsequent stem cell transplantation. Blood. 2011;118(13):3504-3511.
2041
20. Tallen G, Ratei R, Mann G, et al. Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse
stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM
90. J Clin Oncol. 2010;28(14):2339-2347.
21. Loberiza F. Summary Slides 2003: part III. IMBTR/
ABMTR Newsletter. 2006;10(2):6-9.
22. Chaidos A, Kanfer E, Apperley JF. Risk assessment in haemotopoietic stem cell transplantation:
disease and disease stage. Best Pract Res Clin
Haematol. 2007;20(2):125-154.
23. Cornelissen JJ, Carston M, Kollman C, et al. Unrelated marrow transplantation for adult patients
with poor-risk acute lymphoblastic leukemia:
strong graft-versus-leukemia effect and risk factors determining outcome. Blood. 2001;97(6):
1572-1577.
24. Raff T, Gökbuget N, Luschen S, et al. Molecular
relapse in adult standard risk ALL patients detected by prospective MRD-monitoring during
and after maintenance treatment - data from the
GMALL 06/99 and 07/03 trials. Blood. 2007;
109(3):910-915.
25. Bader P, Kreyenberg H, Henze GH, et al. Prognostic value of minimal residual disease quantification before allogeneic stem-cell transplantation
in relapsed childhood acute lymphoblastic leukemia: the ALL-REZ BFM Study Group. J Clin Oncol. 2009;27(3):377-384.
From www.bloodjournal.org by guest on July 12, 2017. For personal use only.
2012 120: 2032-2041
doi:10.1182/blood-2011-12-399287 originally published
online April 4, 2012
Outcome of relapsed adult lymphoblastic leukemia depends on
response to salvage chemotherapy, prognostic factors, and
performance of stem cell transplantation
Nicola Gökbuget, Daniel Stanze, Joachim Beck, Helmut Diedrich, Heinz-August Horst, Andreas
Hüttmann, Guido Kobbe, Karl-Anton Kreuzer, Lothar Leimer, Albrecht Reichle, Markus Schaich,
Stefan Schwartz, Hubert Serve, Michael Starck, Matthias Stelljes, Reingard Stuhlmann, Andreas
Viardot, Knut Wendelin, Mathias Freund and Dieter Hoelzer
Updated information and services can be found at:
http://www.bloodjournal.org/content/120/10/2032.full.html
Articles on similar topics can be found in the following Blood collections
Clinical Trials and Observations (4579 articles)
Free Research Articles (4578 articles)
Lymphoid Neoplasia (2575 articles)
Information about reproducing this article in parts or in its entirety may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests
Information about ordering reprints may be found online at:
http://www.bloodjournal.org/site/misc/rights.xhtml#reprints
Information about subscriptions and ASH membership may be found online at:
http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society
of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.
Copyright 2011 by The American Society of Hematology; all rights reserved.