research paper
A national study on conditional survival, excess mortality and
second cancer after high dose therapy with autologous stem
cell transplantation for non-Hodgkin lymphoma
Knut B. Smeland,1,2 Cecilie E. Kiserud,1
Grete F. Lauritzsen,3 Anne K. Blystad,3
Unn-Merete Fagerli,4,5 Ragnhild S.
Falk,6 Øystein Fluge,7 Alexander Foss
a,3
3
1,8
Arne Kolstad, Jon H. Loge, Martin
Maisenh€
older,9 Bjørn Østenstad,3
Stein Kvaløy2,10 and Harald Holte3
1
National Advisory Unit on Late Effects, Depart-
ment of Oncology, Oslo University Hospital,
2
Faculty of Medicine, University of Oslo,
3
Department of Oncology, Oslo University
Hospital, Oslo, 4Department of Oncology, St.
Olavs Hospital, 5Department of Cancer Research
and Molecular Medicine, Norwegian University
of Science and Technology, Trondheim, 6Oslo
Centre for Biostatistics and Epidemiology,
Research Support Services, Oslo University
Hospital, Oslo, 7Department of Oncology and
Medical Physics, Haukeland University Hospital,
Bergen, 8Department of Behavioural Sciences in
Medicine, Faculty of Medicine, University of
Oslo, Oslo, 9Department of Oncology, University
Hospital of North Norway, Tromsø, and 10Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital Oslo, Oslo,
Norway
Summary
This national population-based study aimed to investigate conditional survival and standardized mortality ratios (SMR) after high-dose therapy with
autologous stem-cell transplantation (HDT-ASCT) for non-Hodgkin lymphoma (NHL), and to analyse cause of death, relapses and second malignancies. All patients ≥18 years treated with HDT-ASCT for NHL in
Norway between 1987 and 2008 were included (n = 578). Information
from the Cause of Death Registry and Cancer Registry of Norway were
linked with clinical data. The 5-, 10- and 20-year overall survival was 61%
(95% confidence interval [CI] 56–64%), 52% (95%CI 48–56%) and 45%
(95%CI 40–50%), respectively. The 5-year survival conditional on having
survived 2, 5 and 10 years after HDT-ASCT was 81%, 86% and 93%. SMRs
were 123 (95%CI 110–139), 49 (95%CI 41–59), 24 (95%CI 18–32)
and 10 (95%CI 06–18) for the entire cohort and for patients having survived 2, 5 and 10 years after HDT-ASCT respectively. Of the 281 deaths
observed, 77% were relapse-related. Treatment-related mortality was 36%.
The 10-year cumulative incidence of second malignancies was 79% and
standardized incidence ratio was 20 (95%CI 15–26). NHL patients treated
with HDT-ASCT were at increased risk of second cancer and premature
death. The mortality was still elevated at 5 years, but after 10 years mortality equalled that of the general population.
Keywords: NHL, autologous stem cell transplantation, conditional survival,
SMR, lymphoma.
Received 26 August 2015; accepted for
publication 17 December 2015
Correspondence: Knut Bjøro Smeland,
National Advisory Unit on Late Effects,
Department of Oncology, Oslo University
Hospital, P O Box 4953 Nydalen, NO-0424
Oslo, Norway.
E-mail: [email protected]
Non-Hodgkin lymphoma (NHL) comprises a heterogeneous
group of more than 30 types of malignancies arising from Bor T-lymphocytes, together accounting for about 3% of new
cancers diagnosed in Norway (Cancer Registry of Norway
2015). The NHL types differ in their biology, natural course
and prognosis. With improved diagnosis and treatment, survival after most NHLs has improved in recent decades, and
First published online 23 February 2016
doi: 10.1111/bjh.13965
5-year relative survival in Norway has now reached 70% for
all types combined (Cancer Registry of Norway 2015).
Over the last two to three decades, high-dose therapy with
autologous stem cell transplantation (HDT-ASCT) has
become an established therapeutic option for many types of
NHL. For some types it is reserved for relapsed or progressive disease only, while it for others is given to consolidate a
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
Conditional survival and SMR after HDT-ASCT for NHL
first remission (Ljungman et al, 2010). Despite improvements
in first-line therapy, HDT-ASCT still is an important and
frequently used option in the treatment of NHL (Smeland
et al, 2013a). The indications have expanded and changed
with time, and the number of patients treated with HDTASCT each year in Europe has gradually increased (Passweg
et al, 2013; Smeland et al, 2013a,b).
Conditional survival is a statistical method to estimate
survival of a cohort under the condition that the group has
already survived a certain period of time, producing more
relevant information for cancer survivors than traditional
survival estimates from time of HDT-ASCT. Conditional survival has previously been reported after HDT-ASCT for
Hodgkin lymphoma (Smeland et al, 2015) and all haematological malignancies together (Vanderwalde et al, 2013). The
latter single-centre study reported 5-year relative survival for
all NHL together (n = 1028) of 62%, increasing to 82% and
87% conditional on having survived 5 and 10 years after
HDT-ASCT, respectively (Vanderwalde et al, 2013). Schans
et al (2014) also reported conditional survival in newly diagnosed NHL patients, reporting differences between subtypes,
with a strong improvement in the first year after diagnosis
for patients with diffuse large B-cell lymphoma (DLBCL),
and a slight improvement for each additional year for follicular lymphoma (FL). However, conditional survival has not
been studied after HDT-ASCT for specific NHL subtypes.
Thus, this population-based multi-centre study aimed to
investigate overall and conditional survival, excess mortality,
cause of death and second cancer risk in a national cohort of
NHL patients treated with HDT-ASCT.
Patients and methods
Patients
All adult patients (aged 18 years or older) treated with HDTASCT for NHL in Norway between 1987 and 2008 were
included. In the period 1987–1995, HDT-ASCT was given at
the Norwegian Radium Hospital (Oslo) only, whereas from
1996 the treatment has been given at the five Norwegian university hospitals: Oslo University Hospital (formerly Norwegian Radium Hospital and Ullev
al University Hospital),
Haukeland University Hospital (Bergen), St. Olavs University
Hospital (Trondheim) and the University Hospital of North
Norway (Tromsø). The combined catchment area of these
hospitals covered the entire country. In the first period the
high dose regimen consisted of total body irradiation (TBI)
and high dose cyclophosphamide, and from 1996 of
chemotherapy only (BEAM: carmustine, etoposide, cytarabine and melphalan). From 1994, the stem cell source changed from bone marrow to peripheral blood progenitor cells.
This has been described in detail in an earlier publication
(Smeland et al, 2013b).
The patients were identified through treatment records
and registries at each hospital, and cross-checked against
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
reports from multidisciplinary meetings, the clinical quality
register for lymphomas at Oslo University Hospital and
radiotherapy registers. Details on diagnoses, treatment and
relapse after HDT-ASCT were collected retrospectively from
patients’ charts.
Using the 11-digit personal identification number given to
all Norwegian inhabitants, the cohort was linked with
national registries for information about date and cause of
death (Cause of Death Registry; http://www.fhi.no/artikler/?
id=86276) and data on second malignancies (the Cancer
Registry of Norway; http://www.kreftregisteret.no/en/). The
Cancer Registry of Norway contains information on all new
cancers occurring in Norway and, based on compulsory
reporting for all hospitals, laboratories and physicians, the
overall completeness has been reported to be 988% (Larsen
et al, 2009).
Statistics
The cohort was followed longitudinally from the date of
HDT-ASCT. For overall survival (OS), including conditional
OS, standardized mortality ratio (SMR) and cause of death,
the cohort was followed to the date of death or censored at
30 June 2014. When studying progression-free survival (PFS)
the cohort was followed to the date of death or disease
relapse/progression, whichever occurred first, or censored at
31 December 2011. Different cut-offs for analysis of PFS and
OS were used because information on relapse from the different hospitals only were available until end of 2011, while
information about time and cause of death were available
until 30 June 2014. OS and PFS were calculated by Kaplan–
Meier method with P-values obtained from log-rank tests.
Cox proportional hazard regression models (univariate and
multivariate) were fitted to evaluate the effect of factors
potentially influencing OS for DLBCL, FL and transformed
lymphoma combined and for each lymphoma type separately. Explanatory variables were added to the multivariate
model in a stepwise forward manner, and kept in the model
if statistically significant (P < 005) or affecting the hazard
ratio (HR) of the other variables in the model. Variables with
high correlation with variables already in the model were
excluded. Two-way interaction between all variables was
tested by entering cross-product terms one-by-one. The
assumption of proportional hazards, verified graphically and
checked using test of proportional hazard assumption, was
met in all the analyses presented, but not when analysing the
whole cohort together (latter data therefore not presented).
Most of the patients with peripheral T-cell lymphoma
(PTCL) and mantle cell lymphoma (MCL) in the cohort had
previously been included in prospective trials led by the Nordic Lymphoma Group (Andersen et al, 2003; Geisler et al,
2008; d’Amore et al, 2012), and the samples sizes for Burkitt
lymphoma (BL) and lymphoblastic lymphoma (LBL) were
small. Therefore, separate regression analyses were not preformed for these lymphoma types.
433
K. B. Smeland et al
Conditional survival was calculated using the life-table
method: the probability of surviving an additional number of
years given that the person has already survived a period of
time. One-, 5- and 10-year OS were computed conditional
upon having survived each additional year from HDT-ASCT
as long as 15 or more patients were alive at start of the follow-up year.
SMRs and standardized incidence ratios (SIRs) were calculated as the ratios of observed to expected mortality and incidence, respectively. Death statistics and cancer incidence for
the Norwegian population were extracted from Statistics
Norway (http://www.ssb.no/en) and the Cancer Registry of
Norway (http://www.kreftregisteret.no/en/), respectively. Reference rates were computed for 3-year calendar periods and
5-year age-groups for each sex. Expected mortality and incidence rates were computed by applying the period-, sex- and
age-specific mortality/incidence to the observed person-years
in the cohort.
When estimating the probability of death from NHL,
death from other causes was considered as a competing
event. When studying the risk of second malignancies and
when studying the risk of relapse, death of any cause was
considered as competing event. Due to competing event, we
used the cumulative incidence to estimate these probabilities
to avoid bias in the analyses. Competing risk regression,
according to the method of Fine and Gray (1999), was performed to adjust for the competing risk of deaths. The
strength of the association between each variable and the
outcome was assessed using the sub-hazard ratio (SHR) with
accompanying 95% confidence intervals (CIs).
Definitions and measurements
Age at diagnosis and at HDT-ASCT was divided in three
groups: <40 years, 40–59 years and ≥60 years. Time periods
were divided in three based on time of HDT-ASCT
(1987–1995, 1996–2002 and 2003–2008), where the first
period corresponds to the period where the high dose regimen consisted of TBI and bone marrow was used as stem
cell source. To assess the effect of early relapse, time from
NHL diagnosis to HDT-ASCT was dichotomized to more
or less than 3 years. Disease status at HDT-ASCT was
defined according to standard treatment response criteria
after induction chemotherapy (Cheson et al, 2007): complete remission (CR), complete remission unconfirmed
(CRu), partial response (PR) and stable disease (SD).
Treatment-related mortality was defined as death within
100 d from a direct complication to HDT-ASCT and not
associated with tumour progression, determined from
patient charts. Otherwise, the cause of death registered in
the Norwegian Cause of Death Registry was used. Second
malignancy was defined as any new malignancy other than
NHL diagnosed after HDT-ASCT, until cut-off at 31
December 2012, and grouped as lymphoid/haematopoietic
(International Classification of Diseases (ICD)-10 codes
434
C81, C90-96, D45-47) or solid malignancies (all other cancer diagnoses).
A P-value ≤005 (two-sided) was considered statistically
significant. Analyses were performed using STATA 13 software
(StataCorp LP, College Station, TX).
Results
Patient characteristics
In total, 578 NHL patients aged 18 years or older were treated with HDT-ASCT in Norway between 1987 and 2008
(Table IA), including 348 patients with de novo DLBCL
(n = 187), FL (n = 74) and transformed B-cell lymphomas
(n = 87) (Table IB). The majority of these patients received
HDT-ASCT in second or subsequent remission. Most of the
remaining patients with PTCL (n = 93), MCL (n = 67), LBL
(n = 45) and BL (n = 17) were treated in first remission in
clinical trials. The median age was 47 (range 17–67) years at
diagnosis and 51 (range 18–69) years at HDT-ASCT; 65%
were males.
Overall and progression-free survival
The median observation time for OS and PFS were 67 years
(range 0–27) and 48 years (range 0–24), respectively. The 5, 10- and 20-year OS from HDT-ASCT for the entire cohort
was 61% (95% CI 56–64%), 52% (95% CI 48–56%) and
45% (95% CI 40–50%) respectively. The corresponding PFS
was 45% (95% CI 41–49%), 39% (95% CI 35–43%) and
34% (95% CI 29–40%). The OS and PFS for the different
NHL-types are shown in Fig 1.
Uni- and multivariate Cox analyses of potential influencing factors for OS after HDT-ASCT for de novo DLBCL, FL
and transformed lymphoma combined are shown in Table II.
In multivariate analysis, age over 60 years at diagnosis, time
from diagnosis to HDT-ASCT of less than three years and
more than three previous treatment lines were significantly
associated with poorer OS, while receiving rituximab as part
of the induction therapy before HDT-ASCT was significantly
associated with better OS. Separate Cox-regression analyses
for DLBCL, FL and transformed lymphoma showed similar
results (Tables SI–SIII), with some exceptions. While prior
rituximab treatment did not affect OS when DLBCL, FL and
transformed lymphoma were analysed together, it was associated with poorer OS in multivariate analysis when DLBCL
was analysed separately (Table SI). To further examine the
effect of rituximab as part of induction therapy before HDTASCT, we analysed the rituximab-na€ıve and rituximabexposed DLBCL patients separately. Receiving rituximab-containing induction therapy was still associated with improved
survival in uni- and multivariate analyses for both rituximab-na€ıve (univariate HR = 044, 95% CI 024–079,
P = 001 and multivariate HR = 048, 95% CI 025–092,
P = 003) and rituximab-exposed (univariate HR = 036,
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
Conditional survival and SMR after HDT-ASCT for NHL
Table IA. Patient
subtypes.
characteristics,
all
Non-Hodgkin
lymphoma
Table IA. (Continued)
Total (n = 578)
Total (n = 578)
n
Age at diagnosis (years)
Median (range)
<40
40–59
≥60
Age at HDT-ASCT (years)
Median (range)
<40
40–59
≥60
Sex
Female
Male
Diagnosis
Diffuse large B-cell lymphoma
Peripheral T-cell lymphoma
Transformed lymphoma
Follicular lymphoma
Mantle cell lymphoma
Lymphoblastic lymphoma
Burkitt lymphoma
Other/not specified
Ann Arbor stage at diagnosis
I
II
III
IV
Missing
High dose regimen
TBI + high dose Cyclophosphamide
BEAM
Radiotherapy
None
Mediastinal
Other
Prior Rituximab
No
Yes
Unknown
Rituximab as induction
No
Yes
Unknown
Treatment period
1987–1995
1996–2002
2003–2008
Time from diagnosis to HDT-ASCT (months)
Median (range)
≥ 3 years
< 3 years
Treatment lines before HDT
1
47 (17–67)
178
336
64
31%
58%
11%
51 (18–69)
144
315
119
25%
54%
21%
201
377
35%
65%
187
93
87
74
67
45
17
8
32%
16%
15%
13%
12%
8%
3%
1%
42
86
128
311
11
7%
15%
22%
54%
2%
87
491
15%
85%
207
156
215
36%
27%
37%
494
79
5
85%
14%
1%
376
197
5
65%
34%
1%
90
188
300
16%
32%
52%
15 (0–387)
155
423
27%
73%
180
31%
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
n
%
300
88
10
52%
15%
2%
231
302
45
40%
52%
8%
%
2
≥3
Missing
Disease status at HDT
CR/CRu
PR/SD
Missing
95% CI 015–087, P = 002 and multivariate HR = 025,
95% CI 009–098, P = 001) patients treated with HDTASCT for DLBCL.
No significant interactions were observed in any of the
analyses.
Conditional survival
The 1-, 5- and 10-year conditional OS for the entire cohort
of NHL patients are shown in Fig 2A. After surviving two
years from HDT-ASCT, the chance of surviving the next year
increased from 79% at HDT-ASCT to 96%. The 5-year OS
increased from 61% at HDT-ASCT to 81%, 86% and 93%
conditional on having survived 2, 5 and 10 years, respectively. The 10-year OS, conditional on having survived 2, 5
and 10 years was 72%, 81% and 86%, respectively. The conditional 5-year OS for each NHL-type is shown in Fig 2B,
showing a steady increase in survival for each additional year
survived for most NHL-types, with the exception of MCL.
Standardized mortality ratios
The entire cohort of NHL patients treated with HDT-ASCT
had 12-fold increased risk of death compared to the age-,
sex- and period-matched Norwegian population (Table III).
Conditional on having survived 2, 5 and 10 years after HDTASCT, the SMRs decreased for all lymphoma types. While
still significantly elevated after 5 years for some NHL-types
(transformed, FL and MCL), there was no increased mortality for any of the lymphoma types with sufficient observation
time to be calculated after 10 years [SMR for all NHL 10
(95% CI 06–18)].
Cause of death
By 30 June 2014, 281 deaths (49%) were observed. Treatment-related mortality occurred in 21 patients (36% of all,
7% of deceased patients) and 216 patients died of NHL
relapse (37% of all, 77% of deaths). The remaining causes of
death were second cancers (n = 20, 7% of deaths), cardiovascular disease (n = 8, 3%), infections (n = 6, 2%), pulmonary
435
K. B. Smeland et al
Table IB. Patient characteristics, selected B-cell lymphoma.
DLBCL (n = 187)
FL (n = 74)
n
%
N
%
n
%
n
%
26%
65%
9%
46 (23–64)
23
46
5
31%
62%
7%
49 (26–64)
15
66
6
17%
76%
7%
48 (18–66)
87
233
28
25%
67%
8%
22%
59%
19%
50 (29–65)
13
50
11
18%
67%
15%
55 (34–66)
3
58
26
3%
67%
29%
52 (19–67)
57
219
72
16%
63%
21%
43%
57%
26
48
35%
65%
32
55
37%
63%
139
209
40%
60%
9%
22%
23%
43%
3%
2
7
16
49
0
3%
9%
22%
66%
7
9
29
41
1
8%
10%
33%
47%
1%
26
57
89
170
6
7%
16%
26%
49%
2%
7%
23
31%
10
12%
46
13%
93%
51
69%
77
89%
302
87%
27%
21%
52%
21
30
23
28%
41%
31%
21
16
50
24%
18%
58%
92
85
171
26%
25%
49%
82%
18%
0%
51
22
1
70%
30%
1%
67
20
0
77%
23%
0%
272
75
1
78%
22%
0%
67%
33%
0%
42
31
1
58%
42%
1%
53
34
0
61%
39%
0%
220
127
1
63%
37%
0%
9%
44%
48%
24
12
38
32%
16%
51%
10
30
47
12%
35%
54%
50
124
174
14%
36%
50%
25%
75%
375 (3–137)
38
51%
36
49%
58 (9–387)
58
29
67%
33%
26 (2–387)
143
205
41%
59%
7%
87%
5%
1%
3
38
32
1
4%
52%
43%
1%
3
41
42
1
3%
47%
48%
1%
19
242
83
4
5%
70%
24%
1%
37%
21
28%
25
29%
115
33%
Age at diagnosis (years)
Median (range)
49 (18–66)
<40
49
40–59
121
≥60
17
Age at HDT-ASCT (years)
Median (range)
51 (19–67)
<40
41
40–59
111
≥60
35
Sex
Female
81
Male
106
Ann Arbor stage at diagnosis
I
17
II
41
III
44
IV
80
Missing
5
High dose regimen
TBI + high dose
13
cyclophosphamide
BEAM
174
Radiotherapy
None
50
Mediastinal
39
Other
98
Prior Rituximab
No
154
Yes
33
Unknown
0
Rituximab as induction
No
125
Yes
62
Unknown
0
Treatment period
1987–1995
16
1996–2002
82
2003–2008
89
Time from diagnosis to HDT-ASCT (months)
Median (range)
18 (2–213)
< 3 years
47
≥ 3 years
140
Treatment lines before HDT
1
13
2
163
≥3
9
Missing
2
Disease status at HDT
CR/CRu
69
436
DLBCL+FL+
transformed
(n = 348)
Transformed
(n = 87)
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
Conditional survival and SMR after HDT-ASCT for NHL
Table IB. (Continued)
PR/SD
Missing
DLBCL+FL+
transformed
(n = 348)
Transformed
(n = 87)
DLBCL (n = 187)
FL (n = 74)
n
%
N
%
n
%
n
%
99
19
53%
10%
50
3
68%
4%
59
3
68%
3%
208
25
60%
7%
15
20
1·00
0·75
0·50
0·25
25
0
0
0
Number at risk
MCL
BL
PTCL
LBL
1·00
0·75
0·50
0·25
0·00
Number at risk
DLBCL 187
FL 74
Transformed 87
5
10
15
20
25
Time from high dose therapy (years)
67
21
28
DLBCL
34
10
5
10
8
2
FL
1
2
0
54
13
48
34
MCL
(D)
0
67
17
93
45
Transformed
P = 0·76
0
0
0
Transformed
25
6
12
26
28
0
9
17
15
BL
0
8
2
12
PTCL
0
1
0
2
LBL
1·00
FL
5
8
2
20
0·75
DLBCL
29
13
3
15
0·50
56
23
24
10
Time from high dose therapy (years)
0·25
98
50
50
5
P < 0·01
0·00
10
Progression free survival (proportion)
5
Time from high dose therapy (years)
Number at risk
DLBCL 187
FL 74
Transformed 87
Progression free survival (proportion)
P < 0·01
0
0
(C)
Overall survival (proportion)
P = 0·61
0·00
1·00
0·25
0·50
0·75
(B)
0·00
(A)
Overall survival (proportion)
HDT-ASCT = high dose therapy with autologous stem cell transplantation; TBI = total body irradiation; BEAM = BCNU, etoposide, cytarabine
and melphalan; CR = complete remission; CRu = complete remission unconfirmed; PR = partial remission; SD = stable disease; DLBCL = diffuse
large B cell lymphoma; FL = follicular lymphoma.
Number at risk
MCL
BL
PTCL
LBL
0
5
10
15
20
25
Time from high dose therapy (years)
67
17
93
45
17
13
35
33
MCL
2
12
18
19
BL
0
8
6
14
0
4
2
8
PTCL
0
0
0
0
LBL
Fig 1. Overall survival (A and B) and progression-free survival (C and D) after high dose therapy with autologous stem cell transplantation
(HDT-ASCT) for non-Hodgkin lymphoma types: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), transformed lymphoma,
mantle cell lymphoma (MCL), Burkitt lymphoma (BL), peripheral T-cell lymphomas (PTCL) and lymphoblastic lymphoma (LBL).
disease (n = 5, 2%) and others/missing (n = 5). The 10-year
cumulative incidence of NHL deaths and deaths from other
causes were 41% and 12% respectively (Fig 3).
Relapse
By 31 December 2011, relapse was observed in 288
patients (50%). The 1-, 5- and 10-year cumulative
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
incidence of relapse was 26%, 47% and 51%, respectively. The median survival after relapse was 10 year
(95% CI 00–206), and the 5-year OS was 30% (95% CI
16–27%). Thirty-four patients were treated with
reduced intensity conditioned allogeneic transplantation
for relapse after HDT-ASCT. Twenty-four (71%) of
these were still alive at the end of follow-up, 30 June
2014.
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K. B. Smeland et al
Table II. Cox-regression analysis.
Univariate Cox
Age at diagnosis (years)
<40
40–59
≥60
Age at HDT-ASCT (years)
<40
40–59
≥60
Sex
Female
Male
Diagnosis
Follicular lymphoma
Diffuse large B-cell lymphoma
Transformed lymphoma
Stage at diagnosis
I
II
III
IV
High dose regimen
TBI
BEAM
Radiotherapy
None
Mediastinal
Other
Rituximab prior to HDT-ASCT
No
Yes
Rituximab as induction to HDT-ASCT
No
Yes
Treatment period
1987–1995
1996–2002
2003–2008
Time from diagnosis to HDT-ASCT
≥ 3 years
< 3 years
Treatment lines before HDT
1
2
≥3
Disease status at HDT
CR/CRu
PR/SD
Multivariate Cox
HR
95% CI
Ref
116
214
082–164
126–364
Ref
116
134
077–175
082–217
Ref
138
102–188
Ref
121
114
083–175
075–174
Ref
075
089
099
039–143
049–162
056–173
Ref
104
067–158
Ref
120
113
080–182
079–163
Ref
128
090–182
Ref
069
050–095
Ref
121
091
079–188
059–140
Ref
130
097–174
Ref
139
192
068–283
091–403
Ref
129
093–178
P
HR
95% CI
002*
Ref
127
272
090–180
157–472
Ref
134
099–183
Ref
064
046–088
159
110–229
Ref
152
283
074–312
128–627
P
0003*
023*
004
008
061**
043*
085
067**
017
002
001
032*
009
002*
001
0001
013
Uni- and multivariate Cox regression analyses of potential prognostic factors for overall survival after high dose therapy with autologous stem cell
transplantation (HDT-ASCT) for follicular lymphoma, de novo diffuse large B-cell lymphoma and transformed lymphoma (n = 348). Statistically
significant p-values are indicated in bold. *P for trend. **P for heterogeneity. HR = hazard ratio; CI = confidence intervals; TBI = total body irradiation; BEAM = BCNU, etoposide, cytarabine and melphalan; CR = complete remission; CRu = complete remission unconfirmed; PR = partial
remission; SD = stable disease.
438
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
Conditional survival and SMR after HDT-ASCT for NHL
(B)
100
80
60
40
20
0
1 2 3 4 5 6 7 8 9 10 11 12
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
Time from high dose therapy (years)
Conditional 5–year overall survival (%)
OS and conditional OS (%)
(A)
100
80
60
40
20
0
0
1
2
3
4
5
6
7
8
9
10
11
12
Time survived from high dose therapy (years)
Overall survival (OS)
1-year OS conditional on surviving 1–21 years after HDT-ASCT
5-year OS conditional on surviving 1–17 years after HDT-ASCT
10-year OS conditional on surviving 1–12 years after HDT-ASCT
DLBCL
PTCL
FL
BL
Transformed
LBL
MCL
Fig 2. One-, 5- and 10- year conditional overall survival (OS) after high dose therapy with autologous stem cell transplantation (HDT-ASCT) for
non-Hodgkin lymphoma (A) and 5-year conditional overall survival for each NHL-type (B): diffuse large B-cell lymphoma (DLBCL), follicular
lymphoma (FL), transformed lymphoma, mantle cell lymphoma (MCL), Burkitt lymphoma (BL), peripheral T-cell lymphomas (PTCL) and lymphoblastic lymphoma (LBL). Calculated using the life-table method. Curves are given if 15 or more patients were alive at start of follow-up year.
Table III. Standardized mortality ratios.
SMR conditional on having survived
All NHL
Diffuse large B-cell lymphoma
Peripheral T-cell lymphoma
Transformed lymphoma
Follicular lymphoma
Mantle cell lymphoma
Lymphoblastic lymphoma
Burkitt lymphoma
SMR (95% CI)
2 years
5 years
10 years
123
142
179
103
122
58
125
111
49
43
39
54
75
45
39
22
24
17
21
25
47
24
20
22
10
02
19
08
19
(110–139)
(117–173)
(135–237)
(77–137)
(89–169)
(38–90)
(73–216)
(46–266)
(41–59)
(30–61)
(21–72)
(36–81)
(49–113)
(28–74)
(15–103)
(03–158)
(18–32)
(09–31)
(09–50)
(13–46)
(27–81)
(12–48)
(05–79)
(03–158)
(06–18)
(003–17)
(06–60)
(02–30)
(06–57)
24 (06–96)
25 (04–178)
Standardized mortality ratios (SMRs) and conditional SMRs for patients treated with high-dose therapy with autologous stem cell transplantation
(HDT-ASCT) for non-Hodgkin lymphoma (NHL) overall and for each NHL-type. Statistically significant increased SMRs are indicated in bold
(confidence interval (CI) not including 10).
Second malignancies
With median observation time 52 years (range 0–25) from
HDT-ASCT and 82 years (range 0–34) from diagnosis,
52 second malignancies occurred after HDT-ASCT in 50
patients (9%), including lymphoid/haematopoietic malignancies (n = 19) and solid malignancies (n = 33). The median time from HDT-ASCT to diagnosis of first second
malignancy was 51 years (range 01–177), 32 years (range
01- 153) and 57 years (range 04–177) for all malignancies, lymphoid/haematopoietic malignancies and solid malignancies, respectively. The 5- and 10-year cumulative
incidence of second malignancy was 42% and 79%,
respectively. The following were found to be statistically significantly associated with second malignancy in univariate
competing risk regression analyses: increasing age at diagnosis (SHR = 103, 95% CI 101–106, P = 0002), age at
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
HDT-ASCT (SHR = 105, 95% CI 102–108, P < 0001),
receiving rituximab at any time (SHR = 263, 95% CI 153–
451, P < 0001), time from diagnosis to HDT-ASCT
≥3 years (SHR = 322, 95% CI 186–558, P < 0001), >1
treatment line before HDT-ASCT (SHR = 204, 95% CI
100–417, P = 005) and not achieving CR before HDT
(SHR = 190, 95% CI 107–337, P = 003). When these
variables, excluding age at diagnosis (both age variables
could not be included in the same model), were used in a
multivariate analysis, only age at HDT-ASCT (SHR = 103,
95% CI 100–107, P = 003) and time from diagnosis to
HDT-ASCT ≥3 years (SHR = 230, 95% CI 120–440,
P = 001) remained significant.
The overall risk of second malignancy was doubled compared to the general Norwegian population (SIR 197, 95% CI
149–260). SIR for lymphoid/haematopoietic malignancies
439
0·3
0·2
0·1
0
Cumulative incidence
0·4
K. B. Smeland et al
0
5
10
15
20
25
Time from high dose therapy (years)
Fig 3. Cumulative incidence of deaths caused by non-Hodgkin lymphoma (blue line) after high dose therapy with autologous stem cell
support (HDT-ASCT) for non-Hodgkin lymphoma, with deaths
from other causes (red line) as the competing event.
and solid malignancies were 157 (95% CI 100–246) and 13
(95% CI 09–18) respectively.
Discussion
In this population-based study including the complete unselected cohort of adult Norwegian NHL patients treated with
HDT-ASCT from 1987 to 2008 we found that about half of
the patients were alive at 10 years after HDT-ASCT, and the
cohort had 12-fold increased mortality compared to the general population. However, the conditional survival improved
for each additional year survived, and the mortality rate
equalled that of the general population after 10 years
(SMR = 10 for the entire cohort).
These findings are in accordance with an American retrospective study that examined conditional relative survival
after HDT-ASCT from a single institution (Vanderwalde
et al, 2013), which reported 5-year relative survival of 62%
and SMR of 131 in 1028 cases of NHL. Conditional on having survived 10 years, the 5-year relative survival was 87%
and the SMR 14 (95% CI 08–22) (Vanderwalde et al,
2013). Examining 2-year survivors after HDT-ASCT, Bhatia
et al (2005) also found no excess mortality compared to the
general population 10 years after HDT-ASCT for NHL, while
Majhail et al (2009) reported a continued increased mortality
that did not approach the mortality of the general population beyond 10 years.
The conditional survival differed between the NHL subtypes. For the aggressive lymphomas DLBCL, PTCL, LBL
and BL, there was a marked improvement in conditional
survival after the first few years survived, followed by a
plateau as the survival approached 100%, and by only
5 years after HDT-ASCT, there was no statistically significant excess mortality for these groups of patients. For FL
there was an overall slight and continuing improvement in
conditional survival with increasing number of years, and
440
although still elevated beyond 5 years, the SMR was not
statistically different from the general population after
10 years. These patterns correspond to the understanding
of these lymphoma subtypes’ natural history and biological
behaviour, and are similar to the observations of Schans
et al (2014) who presented conditional survival from NHL
diagnosis.
MCL patients were treated with aggressive induction
chemotherapy and HDT-ASCT consolidation in three successive Nordic Lymphoma Group studies. While patients in the
first study (inclusion 1996–2000) were given CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone)
induction chemotherapy with disappointing treatment results
(Andersen et al, 2003), the two latter studies (alternating
CHOP and high dose cytarabine chemotherapy induction
with rituximab) resulted in improved treatment results with
70% 5-year OS (Geisler et al, 2008; Kolstad et al, 2014). Nevertheless MCL was the only subtype in which the conditional
survival did not improve with additional years survived in
our study. This may reflect a different pattern of relapse in
MCL after HDT-ASCT, and that the patients with MCL were
older than the rest of the cohort (median age at HDT-ASCT
56 years). Compared to the general population, the mortality
of MCL patients still decreased with additional years survived, and the SMR was more than halved after 5 years
(58–24), even though it did not normalize completely.
There were not enough MCL patients with sufficient observation time to calculate SMR after 10 years.
Older age at diagnosis, shorter time from diagnosis to
HDT-ASCT, more than three previous treatment lines and
not receiving rituximab as part of the induction therapy
before HDT-ASCT were associated with poorer OS after
HDT-ASCT for DLBCL, FL or transformed lymphoma.
These factors have all been found to be associated with survival in previous studies on HDT-ASCT for lymphoma (Bhatia et al, 2005; Majhail et al, 2009; Gisselbrecht et al, 2010;
Tarella et al, 2011; Vanderwalde et al, 2013; El-Najjar et al,
2014; Reddy et al, 2014; Redondo et al, 2014; Chen et al,
2015). The addition of the anti-CD20 monoclonal antibody
rituximab to standard chemotherapy has dramatically
improved response rates and survival in CD20-postive B-cell
lymphomas, both in first line (Feugier et al, 2005; Pfreundschuh et al, 2006) and as salvage before HDT-ASCT in rituximab-na€ıve patients (Vellenga et al, 2008). Conversely, the
randomized CORAL (Collaborative Trial in Relapsed Aggressive Lymphoma) study, designed to compare two rituximabcontaining salvage regimens before HDT-ASCT for DLBCL,
found that patients previously treated with rituximab had
poorer response and resulting poorer survival than rituximab-na€ıve patients (Gisselbrecht et al, 2010). In our cohort,
including only patients receiving HDT-ASCT, and hence not
those failing to respond to salvage therapy, prior rituximab
had no influence on survival for DLBCL, FL and transformed
lymphoma when analysed together. However, when de novo
DLBCL was analysed separately, prior rituximab treatment
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
Conditional survival and SMR after HDT-ASCT for NHL
was associated with poorer survival. On the other hand,
patients treated with rituximab-containing salvage therapy
before HDT-ASCT had better OS, both when examining
DLBCL, transformed and FL together, all DLBCL patients
together, and the rituximab-na€ıve and -exposed DLBCL
patients separately.
The most common cause of death in the cohort was
relapse of NHL (almost 80% of deceased patients), followed by treatment-related mortality, second cancers and
cardiovascular disease, which is in accordance with previously published findings (Bhatia et al, 2005; Majhail et al,
2009; Seshadri et al, 2009; Vanderwalde et al, 2013; El-Najjar et al, 2014). While the cumulative incidence of NHL
deaths seemed to plateau at about 40% after 10 years,
deaths from other causes continued to increase beyond
15–20 years.
The risk of second cancer after NHL treatment in general
(Pirani et al, 2011) and after HDT-ASCT (Forrest et al,
2003; Seshadri et al, 2009; Tarella et al, 2011; Bilmon et al,
2014; El-Najjar et al, 2014) is well described, with reported
10-year cumulative incidence of second malignancy after
HDT-ASCT ranging from 5–21%. With 5- and 10-year
cumulative incidence of second cancer of 4% and 8%, our
cohort’s risk of second malignancy was twice that of the general Norwegian population (SIR = 20). The SIR was highest
for lymphoid/haematological malignancies (SIR = 16),
compared to solid malignancies, which did not have a statistically significant increased SIR (SIR = 13, 95%CI 090–
182). While this is in line with a large Australian population-based study (Bilmon et al, 2014), other studies with
longer observation times report risks of solid malignancies
2–3 times that of the general population (Forrest et al, 2003;
Seshadri et al, 2009; Tarella et al, 2011). Our median observation time for analysis of second cancer of 52 years from
HDT-ASCT (88 years for patients alive at 31 December
2012), is most likely too short to assess the true risk of solid
cancers that are known to occur later than haematological
malignancies, and most often beyond 10–15 years (Ng &
Mauch, 2009).
The median observation time for survival analysis of
67 years from HDT-ASCT (104 years for patients alive at
cut-off) is probably also too short to estimate the true risk of
other late effects and possible causes of non-relapse related
mortality, such as cardiovascular disease (Ng & Mauch,
2009). The cohort will therefore be followed further to detect
any such causes of increased mortality in the future.
To our knowledge, this is the first study reporting conditional survival and SMRs after HDT-ASCT for specific NHL
subtypes. The conditional survival rates can easily be utilized
in the provision of information to the NHL patients and are
therefore of high relevance in the clinical setting. Another
major strength of this study is the national population-based
design. Although the sample size is relatively small, all NHL
ª 2016 John Wiley & Sons Ltd
British Journal of Haematology, 2016, 173, 432–443
patients treated with HDT-ASCT over a 22-year period are
included, with well-characterized data from high-quality
national registries combined with detailed treatment data
from each hospital. Furthermore, the use of matched control
data from the same homogenous Norwegian population
allows reliable estimation of excess mortality and incidence
of second malignancies.
In conclusion, NHL patients treated with HDT-ASCT are
at increased risk of premature death, mainly due to relapse,
and of being diagnosed with a second cancer. However, conditional survival improved with different rates for most NHL
subtypes for each additional year survived, and while still elevated for some beyond five years, there was no excess mortality for any of the subtypes with sufficient numbers of
patients to estimate conditional SMR after 10 years. It is possible, however, that this good news can be offset by a longer
observation time than this study allowed for.
Author contribution
KBS: Study design, data acquisition, data analyses, data interpretation, manuscript preparation and editing. CEK: Study
design, data acquisition, data interpretation, manuscript editing and review. GFL: study concepts, data interpretation,
manuscript editing and review. AKB: Data acquisition, data
interpretation, manuscript editing and review. UMF: Data
acquisition, data interpretation, manuscript editing and
review. RSF: Study design, data analyses, manuscript editing
and review. ØF: Data acquisition, data interpretation, manuscript editing and review. AF: Study concepts, data interpretation, manuscript editing and review. AK: Study design,
data interpretation, manuscript editing and review. JHL:
Study design, data interpretation, manuscript editing and
review. MM: Data acquisition, data interpretation, manuscript editing and review. BØ: Data acquisition, data interpretation, manuscript editing and review. SK: Study design,
data interpretation, manuscript editing and review. HH:
Study design, data interpretation, manuscript editing and
review.
Conflict of interest
The authors report no potential conflicts of interest.
Supporting Information
Additional Supporting Information may be found in the
online version of this article:
Table SI: Cox-regression analyses for diffuse large B-cell
lymphoma.
Table SII: Cox-regression analyses for follicular lymphoma.
Table SIII: Cox-regression analyses for transformed
lymphoma.
441
K. B. Smeland et al
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British Journal of Haematology, 2016, 173, 432–443
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