Comorbidities and sex differences in causes of death among mantle cell lymphoma patients – A nationwide population‐based cohort study

Abstract

The prognosis for mantle cell lymphoma (MCL) remains poor. Our aim was to assess the impact of comorbidities on survival and causes of death. For 1,385 MCL patients (1,009 males, 376 females) diagnosed in 2000–2014 (median age 71 years, range 22–96) comorbidities ≤ 10 years of diagnosis were classified according to the Charlson comorbidity index (CCI; 0, 1, 2+). Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to compare lymphoma‐specific and all‐cause mortality rates. Model‐based predictions were used to obtain probabilities of death. Overall, 44% had any comorbidity (CCI 1+) and 28% severe comorbidity (CCI 2+). Over a median follow‐up of 3·7 years (range 0–16), 633 (46%) died, the majority (76%) from lymphoma. Severe comorbidity was independently associated with higher all‐cause [hazard ratio (HR) = 1·52; 95% CI: 1·24–1·85) and lymphoma‐specific mortality (HR = 1·31; 95% CI: 1·04–1·65). Particularly among patients with connective tissue, renal and psychiatric diseases, and dementia. Among females with any comorbidity, non‐lymphoma deaths represented a larger proportion of all deaths, compared to males with any comorbidity. In general, more efficient lymphoma treatments need to be considered also for patients with severe comorbidity. However, among females with any comorbidity, the likelihood of non‐lymphoma death was still considerable, perhaps favouring a more liberal use of a “wait and watch” approach.

Full text

Comorbidities and sex differences in causes of death among
mantle cell lymphoma patients –A nationwide population-
based cohort study
Ingrid Glimelius,
1,2
Karin E.
Smedby,
2,3
Sandra Eloranta,
2
Mats
Jerkeman
4
and Caroline E. Weibull
2
1
Department of Immunology, Genetics and
Pathology, Clinical and Experimental
Oncology, Uppsala University and Uppsala
Akademiska Hospital, Uppsala,
2
Department of Medicine, Division of
Clinical Epidemiology, Karolinska Institutet
and Karolinska University Hospital,
Stockholm,
3
Department of Medicine Solna,
Division of Hematology, Karolinska
University Hospital and Karolinska
Institutet, Stockholm and
4
Department of
Oncology, Skane University Hospital, Lund,
Sweden
Received 3 May 2019; revised 22 August 2019;
accepted for publication 24 August 2019
Correspondence: Ingrid Glimelius, MD, PHD,
Uppsala University Hospital, Oncology Clinic,
Entrance 78, 751 85 Uppsala, Sweden.
E-mail: Ingrid.Glimelius@igp.uu.se
This study was presented at ASH 2018 (Blood
2018 132:2891)
Summary
The prognosis for mantle cell lymphoma (MCL) remains poor. Our aim was
to assess the impact of comorbidities on survival and causes of death. For
1,385 MCL patients (1,009 males, 376 females) diagnosed in 2000–2014 (me-
dian age 71 years, range 22–96) comorbidities ≤10 years of diagnosis were
classified according to the Charlson comorbidity index (CCI; 0, 1, 2+).
Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to
compare lymphoma-specific and all-cause mortality rates. Model-based pre-
dictions were used to obtain probabilities of death. Overall, 44% had any
comorbidity (CCI 1+) and 28% severe comorbidity (CCI 2+). Over a med-
ian follow-up of 37 years (range 0–16), 633 (46%) died, the majority (76%)
from lymphoma. Severe comorbidity was independently associated with
higher all-cause [hazard ratio (HR) =152; 95% CI: 124–185) and lym-
phoma-specific mortality (HR =131; 95% CI: 104–165). Particularly
among patients with connective tissue, renal and psychiatric diseases, and
dementia. Among females with any comorbidity, non-lymphoma deaths rep-
resented a larger proportion of all deaths, compared to males with any
comorbidity. In general, more efficient lymphoma treatments need to be con-
sidered also for patients with severe comorbidity. However, among females
with any comorbidity, the likelihood of non-lymphoma death was still con-
siderable, perhaps favouring a more liberal use of a “wait and watch”
approach.
Keywords: mantle cell lymphoma, comorbidity, sex, lymphoma-specific
mortality, cause of death.
Introduction
Mantle cell lymphoma (MCL) represents approximately 5%
of all lymphomas in the Western world, and mainly affects
elderly patients. Due to the continuously increasing life
expectancy, the incidence of MCL is expected to increase and
the elderly patients will likely be more burdened by other
associated diseases (comorbidities). By defining specific
causes of death and estimating lymphoma-specific and all-
cause mortality in a population-based unselected cohort of
MCL patients, the impact of comorbidities on survival can
be addressed, aiding treatment decisions for frail comorbid
patient groups.
The overall incidence of MCL is consistently strikingly
higher in men than in women (84 vs. 34 per 10,000
individuals) and a heterogeneity in prognosis by sex has also
been observed (Zhou et al., 2008; Abrahamsson et al., 2014).
This prognostic heterogeneity is likely to be partly related to
disease biology (Kluin-Nelemans & Doorduijn, 2018; Pease &
Morrison, 2018), but could also be explained by e.g. the
presence of comorbidities. Comorbidities may differ in type
and severity among men and women, may affect adherence
to recommended treatment, and may occasionally lead to a
decision not to treat. Still, the magnitude and prognostic
impact of specific comorbid conditions in MCL has not been
described previously in a population-based setting.
The negative prognostic impact of comorbidities is well
established for non-Hodgkin lymphoma patients overall
(Wieringa et al., 2014; Saygin et al., 2017; Antic et al., 2018;
Wasterlid et al., 2018). For example, in a study of 962 diffuse
research paper
ª2019 British Society for Haematology and John Wiley & Sons Ltd doi: 10.1111/bjh.16317

large B-cell lymphoma (DLBCL) patients, a high comorbidity
score was independently associated with a threefold increased
risk of death (Antic et al., 2018), and among elderly patients
comorbidity had a better discriminative power than the
International Prognostic Index (IPI). Male sex was recently
shown as an independent predictor for worse survival in
elderly DLBCL patients (Eyre et al., 2019). Assessment of the
impact of comorbidity in MCL has so far almost exclusively
been restricted to the group eligible for transplantation
(Yamasaki et al., 2018; Kyriakou et al., 2019) and only one
study has investigated the impact on all-cause survival in
MCL of all ages (Cohen et al., 2016). In the era of targeted
therapy, novel adverse events are expected (Arora & Portell,
2018; Ye et al., 2018), and having comorbidities may further
increase the risk of side effects from the treatments, empha-
sizing the importance of benchmarking survival also in these
groups.
Results from clinical trials are not representative of all
MCL patients, as patients in trials are highly selected; they
are younger and have a better prognosis (Augustin et al.,
2018). Population-based studies can thus provide additional
information (Smedby & Eloranta, 2018), especially regarding
patients not eligible for transplantation.
Here, we aim to characterize the burden of comorbidities
and which specific comorbidities MCL patients have. In
addition, we aim to assess the impact of comorbidities on
lymphoma-specific and all-cause mortality, treatment choice,
and causes of death to provide knowledge to support treat-
ment decisions among comorbid MCL patients.
Methods
Study population
All MCL patients diagnosed between 2000 and 2014 in Swe-
den registered in the Swedish Lymphoma Register (Abra-
hamsson et al., 2011) (n=1,385) were included in this
population-based cohort study. No patients were excluded
on the basis of previous malignancies. The Swedish Lym-
phoma Register was introduced in the year 2000, and is
linked to the National Cancer Register to assure complete
coverage of lymphoma cases. Linkage between Swedish regis-
ters is possible thanks to a personal identification number
unique to all residents. Available data included patients’
characteristics, diagnostic date, and clinical information [i.e.,
disease presentation: stage according to Ann Arbor, MCL
international prognostic index (MIPI), Eastern Cooperative
Oncology Group (ECOG) performance status, and primary
treatment]. MIPI is the sum of age, performance status,
leukocyte count and lactate dehydrogenase (LDH)/upper
limit normal and their regression coefficients and is scored
according to low, intermediate and high risk (Geisler et al.,
2010). The MCL patients were linked to the Patient Register
(covering all inpatient care nationwide since 1987 and spe-
cialist outpatient care since 2001). From the Patient Register,
we then identified patients who had been treated with high-
dose chemotherapy and autologous and allogenic stem cell
transplantation (ASCT and allo-SCT) [using International
Classification of Diseases (ICD) codes as presented in
Table SI and as previously described (Glimelius et al., 2015)].
Furthermore, the Swedish Cause of Death Register (Brooke
et al., 2017), with virtually complete data since 1952, was
linked to the cohort to collect dates and causes of death
among the MCL patients. In addition, highest achieved edu-
cational level was ascertained from the Longitudinal Inte-
grated Database for Health Insurance and Labour Market
studies (LISA).
Exposure
Information on comorbidities within a 10-year time window
prior to diagnosis was obtained from the Swedish Patient
Register including records of main and secondary diagnoses
of hospital admissions and hospital outpatient care. The
Swedish Cancer Register was also used to ascertain all prior
malignancies (Barlow et al., 2009). In the event of several
prior malignancies, the most recent prior to MCL diagnosis
was considered. Comorbidities were classified according to
the Charlson comorbidity index (CCI), established in 1987
(Charlson et al., 1987), and further categorized according to
CCI 0, 1, or 2+. Additionally, all comorbidities included in
the CCI, with the addition of psychiatric disease and atrial
fibrillation, were analysed individually. Prior diagnoses of
unspecified non-Hodgkin lymphoma were not considered in
the calculation of CCI, to avoid the risk of including misclas-
sified MCL diagnoses.
Outcome and follow-up
Patients were followed from the date of MCL diagnosis until
date of death or end of follow-up (December 2015), which-
ever occurred first. Both all-cause and lymphoma-specific (to
ensure that all MCL deaths were captured) mortality was
assessed. Lymphoma-specific mortality was defined as a death
certificate indicating any lymphoma death (ICD-10 codes
C80-C88, C911, or C919). Specific causes of death other
than lymphoma were defined and reviewed using the under-
lying cause of death information (according to ICD-10).
Statistical methods
Counts and percentages were calculated overall, and sepa-
rately for patients dying from lymphoma or all causes of
death combined, by CCI, patient characteristics, and clinical
features (including Ann Arbor stage, MIPI, treatment and
ECOG performance status). The chi-square test was used to
test for a difference in the distribution of the CCI (0, 1 or
2+) between males and females. To illustrate the burden of
comorbidities in the patient population, frequencies and per-
centages of specific comorbid conditions were also calculated.
I. Glimelius et al.
2ª2019 British Society for Haematology and John Wiley & Sons Ltd

Patients with more than one comorbidity contributed with
counts to more than one specific condition. Hazard ratios
(HRs) with 95% confidence intervals (CIs), comparing rates
of all-cause and lymphoma-specific mortality between levels
of covariates, were estimated using flexible parametric sur-
vival models with the baseline rate modelled as a restricted
cubic spline with four interior knots. Unadjusted models
were fitted for all variables. For CCI and all specific comor-
bid conditions; three different models (A–C) sequentially
adjusted for calendar year of diagnosis, age at diagnosis, sex,
highest achieved education level (≤9 years/10–12 years and
>12 years of schooling) (Model A), +stage (Model B) and +
MIPI (Model C) were also evaluated. Year and age were
modelled as restricted cubic splines with three interior knots.
To estimate the association between specific comorbidities
and mortality, Model A was further re-parametrised using
the method proposed by McKnight et al. (1999). This
approach allows isolation of the impact of a single specific
comorbidity on lymphoma-specific and all-cause mortality
(compared to patients free from comorbidities). Kaplan–
Meier (unadjusted) and model-based (using Model A) esti-
mates of the all-cause and lymphoma-specific survival were
calculated for the first ten years after diagnosis. Model-based
estimates were used to calculate ten-year cumulative proba-
bilities of death due to lymphoma and other causes (in the
presence of competing risks) for specific covariate patterns,
by CCI and separately for men and women (Hinchliffe &
Lambert, 2013). To this end, the predictions of the absolute
risks were based on CCI, sex, age at diagnosis, and calendar
year in order to reduce the number of covariate patterns to
maximise statistical robustness of the results.
All analyses were complete-case-based, in the sense that
patients were excluded from a model if they had missing
information on any variable included in that model. Number
of patients contributing to each model is given. In a sensitiv-
ity analysis fitting crude models to the patients contributing
with information to adjusted models, i.e. excluding those
with missing on any of the adjustment variables, interpreta-
tion was not altered.
All statistical analyses were done using Stata (StataCorp,
2017. Stata Statistical Software: Release 15. College Station,
TX: StataCorp LLC).
Ethics
The study was approved by the Regional Board of the Ethical
Committee in Stockholm, Sweden (2007/1335-31/4, 2010/
1624-32).
Results
Demographics
We identified 1,385 MCL patients (1,009 males, and 376
females) (Table I), with a mean follow-up of 37 years (range
0–16). The median age was 71 years (range 22–96). In total,
606 patients (44%) had a comorbidity (CCI 1+) at the time
of diagnosis, among which 388 (28% of all) had severe
comorbidity (CCI 2+). Patients with high CCI were older;
patients without comorbidities CCI 0 had a median age of
68 (range 22–93), patients with CCI 1 had a median age of
74 (range 43–95) and among patients with CCI 2+, the med-
ian age was 76 (range 48–96). There was, however, no differ-
ence in the distribution of comorbidity scores between males
and females (P
v2
=026).
All-cause and lymphoma-specific mortality by
comorbidity
Patients with CCI 1 and CCI 2+had a higher all-cause mor-
tality and lymphoma-specific mortality than patients without
comorbidities at diagnosis (Table I, Fig 1). In analyses
adjusted for calendar year, educational level, MIPI and sex,
CCI 2+remained an independent predictor of all-cause as
well as lymphoma-specific mortality (adjusted HR =131, 95
% CI: 104–165, Table II).
Frequencies of specific comorbidities
Dividing the score by specific comorbidities revealed that 230
patients (17%) had a prior malignancy, among which 72
patients (31%) had prostate cancer. Additionally, 193
patients (14%) had prior coronary heart disease, and 127
(9%) had concomitant diabetes. Other comorbidities were
history of cerebrovascular disease (n=94, 68%), and pul-
monary diseases (n=97, 7%). Atrial fibrillation (AF) is not
included in the CCI, but was still investigated, as this is a
well-known side effect of Bruton’s Tyrosine Kinase (BTK)
inhibitors, increasingly used in treatment of MCL. Ninety
patients (65%) were diagnosed with AF prior to diagnosis of
MCL. Psychiatric disorders were present among 33 patients
(24%) and investigated for its potential interference with
accepting intensive treatment regimens.
Mortality by specific comorbidities
Patients with dementia (n=11), history of connective tissue
disease (n=38), renal disease (n=39) or psychiatric disease
all had significantly higher lymphoma-specific mortality (Fig
2), and all-cause mortality (Figure S1) compared to patients
without any comorbidity. For patients with history of acute
myocardial infarction (n=193) (including congestive heart
failure), its relation to lymphoma-specific mortality was of
borderline significance (Fig 2). However, patients with a his-
tory of acute myocardial infarction (n=193) (including con-
gestive heart failure) and metastatic cancer (n=10) had a
higher all-cause mortality (Figure S1). Among the 292
patients (21%) selected for an ASCT, no significant effects of
specific comorbidities on lymphoma-specific mortality were
observed, although increased point estimates regarding risk
Comorbidity in mantle cell lymphoma
ª2019 British Society for Haematology and John Wiley & Sons Ltd 3

were seen for patients with a history of cerebrovascular dis-
ease, metastatic cancer, and psychiatric disorders (Figure S2).
Among the 218 patients who received Nordic-MCL2/
MCL3 protocol-based treatment, including rituximab and
dose-intensified CHOP (cyclophosphamide, hydroxydauno-
mycin, oncovin, prednisone) alternating with cytarabine and
consolidation with high-dose chemotherapy and ASCT (Kol-
stad et al., 2014; Eskelund et al., 2016) very few were found
to have comorbidities [24 (11%) patients had CCI 1 and 14
(36%) CCI 2+, Table SII].
Causes of death
Of the 838 patients who died during follow up, the majority
(n=633, 76% of the deceased patients) died from lymphoma
(Table I). This was true also for patients with comorbidity
(CCI 1+). Overall, there was no difference between males and
females with respect to proportion of patients dying from lym-
phoma or other causes (Table SIII). However, when investigat-
ing the cumulative probability of dying due to lymphoma and
other causes by age, sex, and CCI score in the presence of com-
peting risks, the absolute risk of dying from other causes was
higher among women (Fig 3). For example, among patients
aged 70 years at diagnosis with CCI 1+, 16% of males and
55% of females died due to other causes (Fig 3 and supporting
information,). The causes of deaths besides lymphoma among
males (n=155) were other malignancies (n=43), cardiovas-
cular diseases (n=52), lung disorders (n=14), infections
(n=7), other somatic disorders (n=19), accidents/suicide
(n=14) and unknown (n=5). Among females, other causes
Table I. Frequencies, proportions and hazard ratios (HRs) with 95% confidence intervals (CIs) for all-cause and lymphoma-specific mortality
among 1,385 patients diagnosed with mantle cell lymphoma (MCL) in Sweden in 2000–2014, by demographic and clinical characteristics.
Variable N(col %)
All-cause deaths:
n(col % among
all patients)
All-cause Mortality:
HR†(95% CI)
Lymphoma deaths:
n(col % among
deceased patients)
Lymphoma-specific
Mortality: HR†(95% CI)
Overall 1,385 (100) 838 (100) –633 (100) –
Charlson comorbidity index
0 779 (563) 418 (499) 100 338 (534) 100
1 218 (157) 153 (183) 171 (142–206) 113 (179) 152 (123–188)
2+ 388 (280) 267 (319) 190 (162–221) 182 (288) 155 (129–186)
Year of diagnosis
2000–2004 366 (264) 302 (360) 100 239 (378) 100
2005–2009 433 (313) 304 (363) 085 (072–100) 223 (352) 077 (064–093)
2010–2014 586 (423) 232 (277) 068 (057–081) 171 (270) 059 (048–072)
Age at diagnosis
<60 227 (164) 77 (92) 100 60 (95) 100
60-69 393 (284) 189 (226) 201 (154–263) 140 (221) 181 (133–245)
70–79 464 (335) 318 (380) 371 (288–478) 245 (387) 342 (257–456)
≥80 301 (217) 254 (303) 703 (541–915) 188 (297) 608 (451–820)
Sex
Male 1,009 (729) 612 (730) 100 457 (722) 100
Female 376 (271) 226 (270) 102 (088–119) 176 (278) 107 (090–127)
Highest achieved education level
≤9 years of schooling 547 (395) 407 (486) 168 (144–196) 309 (488) 165 (138–197)
10–12 years of schooling 498 (360) 268 (320) 100 204 (322) 100
>12 years of schooling 300 (217) 138 (165) 081 (066–100) 101 (160) 078 (061–099)
Missing 40 (29) 25 (30) –19 (30) –
Stage
Ann Arbor I 89 (64) 33 (39) 050 (033–075) 17 (27) 035 (020–060)
Ann Arbor II 131 (95) 74 (88) 100 56 (89) 100
Ann Arbor III 176 (127) 96 (115) 086 (063–116) 60 (95) 072 (050–104)
Ann Arbor IV 936 (676) 588 (702) 127 (100–162) 470 (743) 134 (101–176)
Missing 53 (38) 47 (56) –30 (47) –
MIPI
Low risk (<57) 158 (114) 43 (51) 100 30 (47) 100
Intermediate risk (57–61) 303 (219) 125 (149) 200 (141–283) 91 (144) 200 (132–303)
High risk (>61) 574 (414) 426 (508) 612 (445–841) 332 (525) 638 (437–931)
Missing 350 (253) 244 (291) –180 (284) –
†Unadjusted hazard ratios from main effect flexible parametric survival models assuming proportional hazards. MIPI was calculated as a linear
function of age, performance status, leukocyte count, and lactate dehydrogenase (LDH)/upper limit normal using the formula proposed by (Hos-
ter et al., 2008).
I. Glimelius et al.
4ª2019 British Society for Haematology and John Wiley & Sons Ltd

0·00
0·25
0·50
0·75
1·00
All-cause survival
0 2 4 6 8 10
Time since diagnosis (years)
Kaplan–Meier survival estimates
0·00
0·25
0·50
0·75
1·00
All-cause survival
0 2 4 6 8 10
Time since diagnosis (years)
Adjusted survival estimates
0·00
0·25
0·50
0·75
1·00
Lymphoma-specific survival
0 2 4 6 8 10
Time since diagnosis (years)
Kaplan–Meier survival estimates
0·00
0·25
0·50
0·75
1·00
Lymphoma-specific survival
0 2 4 6 8 10
Time since diagnosis (years)
Adjusted survival estimates
No comorbidity (CCI = 0) Mild comorbidity (CCI = 1) Severe comorbidity (CCI = 2+)
Time since diagnosis (years)Number of patients at risk
0246810
CCI = 0 779 543 344 202 115 76
CCI = 1 218 129 64 32 11 3
CCI = 2+ 388 186 93 46 20 9
Fig 1. All-cause (top panel) and lymphoma-specific (bottom panel) survival among patients diagnosed with mantle cell lymphoma (MCL) in
2000–2014, by level of comorbid disease at diagnosis according to the Charlson comorbidity index (CCI). Survival proportions are presented
unadjusted (Kaplan–Meier method) and adjusted for year, age, highest achieved educational level, and sex. [Colour figure can be viewed at
wileyonlinelibrary.com]
Table II. Adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing lymphoma-specific and all-cause mortality between
patients diagnosed with mantle cell lymphoma (MCL) in Sweden in 2000–2014 in different Charlson comorbidity index groups (0; no comorbidi-
ties, 1; mild comorbidity, 2+; severe comorbidity). All estimates are from main effects flexible parametric survival models assuming proportional
hazards.
Lymphoma-specific mortality
Model A Model B Model C
Charlson comorbidity index HR (95% CI) HR (95% CI) HR (95% CI)
0100 100 100
1115 (092–143) 112 (089–141) 108 (082–142)
2+ 114 (094–139) 121 (099–147) 131 (104–165)
All-cause mortality
Charlson comorbidity index HR (95% CI) HR (95% CI) HR (95% CI)
0100 100 100
1129 (106–156) 125 (102–153) 117 (092–148)
2+ 139 (118–165) 141 (119–168) 152 (124–185)
Model A is adjusted for calendar period of diagnosis, age at diagnosis, sex, and highest achieved education level. Year and age are modelled using
restricted cubic splines (N=1,345, 97% of patients). Model B is adjusted as in A with the addition of stage (N=1,293, 93% of patients). Model
C is adjusted as in B with the addition of MIPI but without adjustment for age at diagnosis (as MIPI score includes age) (N=965, 70% of
patients).
Comorbidity in mantle cell lymphoma
ª2019 British Society for Haematology and John Wiley & Sons Ltd 5

of death (n=50) included other malignancies (n=19), car-
diovascular diseases (n=17), other somatic disorders (n=9),
accident (n=1) and unknown (n=4).
Clinical presentation, sex and treatment differences by
comorbidities
Since the major cause of death was MCL in this population,
we investigated potential differences in selection of treat-
ments given to patients with comorbidities (Table SII). Over-
all in this cohort and in line with earlier investigations
(Abrahamsson et al., 2014), the prognosis was superior for
patients selected for “wait and watch” or for those fit to
receive NLG (Nordic Lymphoma Group)-MCL 2/3 protocol
treatment (Figure S3). For patients younger than 70 years
with CCI 2+, only 12% were considered eligible for NLG-
MCL2/3 (Table SII). Patients with CCI 2+were primarily
treated with CHOP or CHOP/cytarabine without ASCT, or
bendamustine with the addition of rituximab. A higher pro-
portion of females than males with CCI 2+were selected for
“wait and watch” (16% vs. 75%, Table SIII).
Discussion
Comorbidity was present at diagnosis in 44% of the patients
in this unselected population-based cohort of MCL patients.
Furthermore, a high CCI was an independent prognostic fac-
tor for not only all-cause but also for lymphoma-specific
mortality. Particularly patients with a history of connective
tissue disease, renal disease, dementia or psychiatric disorders
had higher lymphoma-specific mortality. The higher risk of
dying with lymphoma in these groups indicates that they
could not receive optimal MCL treatment and should be
given specific attention. Presence of cardiovascular disease,
with 14% presenting with prior coronary heart disease, may
also be associated with suboptimal antilymphoma treatment,
although its relation to lymphoma-specific mortality was
only of borderline significance. Lymphoma was the major
cause of death among males, irrespective of CCI score, and
among females with CCI 0, favouring active MCL treatment.
Among female patients with CCI 1+, the likelihood of dying
from disorders other than MCL was considerable, favouring
a more liberal use of the “wait and watch” approach.
Evidence before this study
Very few population-based studies have previously addressed
the impact of comorbidities on overall survival in MCL
(Cohen et al., 2016; Yamasaki et al., 2018; Kyriakou et al.,
2019), and none the impact on lymphoma-specific survival,
despite that nearly half of the patients have comorbidities at
diagnosis. A large study of 8,029 MCL patients showed that
among the 492 patients selected for deferred therapy, predic-
tive factors of improved overall survival were, not surpris-
ingly, younger age and lack of comorbidities, but also male
sex (Cohen et al., 2016). Another study of 162 relapsed/refrac-
tory MCL patients treated with ASCT (n=111) or allogeneic
SCT (n=51) showed a higher SCT-specific comorbidity
index to be a significant risk factor for worse overall survival
(Yamasaki et al., 2018). A recent investigation showed that
allogeneic SCT in non-Hodgkin lymphoma patients aged
>65 years provided similar lymphoma control as in younger
patients but was associated with higher non-relapse mortality
not fully explained by comorbidity (Kyriakou et al., 2019).
Our study is the first investigation of the impact of specific
comorbidities on lymphoma-specific survival in MCL of all
ages, aiding treatment decisions for frail patient groups.
Comorbidities and current first- line treatment
recommendations
For young patients, the Nordic MCL2 regimen (rituximab
with dose-intensified CHOP and high-dose cytarabine fol-
lowed by high-dose chemotherapy and ASCT) has been asso-
ciated with favourable long-term outcome (Geisler et al.,
2012; Eskelund et al., 2016). In these studies (Geisler et al.,
Table III. Percentages of patients with specific comorbid conditions,
in total and stratified by Charlson comorbidity index (CCI). As
patients with CCI 2+ can have more than one comorbid condition,
the column percentage total exceeds 100%.
All patients
Patients with
comorbidities
CCI = 1 CCI = 2+
Comorbid condition n(col %) n(col %) n(col %)
Acute MI (incl. acute CHF) 193 (139) 61 (280) 132 (340)
Peripheral vascular disease 51 (37) 15 (69) 36 (93)
Cerebrovascular accident 94 (68) 34 (156) 60 (155)
Dementia 11 (08) 5 (23) 6 (16)
Pulmonary disease 97 (70) 29 (133) 68 (175)
Connective tissue disease 38 (27) 13 (60) 25 (64)
Peptic ulcer 55 (40) 20 (92) 35 (90)
Liver disease 15 (11) 6 (28) 9 (23)
Diabetes 127 (92) 35 (161) 92 (237)
Paraplegia 2 (01) 0 (00) 2 (05)
Renal disease 39 (28) 0 (00) 39 (101)
Cancer†230 (166) 0 (00) 230 (593)
Metastatic cancer 10 (07) 0 (00) 10 (26)
Psychiatric disorder‡33 (24) . .
Atrial fibrillation‡90 (65) . .
Total 1,385 (100) 218 (100) 388 (100)
Abbreviations: CCI, Charlson comorbidity index; MI, myocardial
infarction; CHF, coronary heart failure; HIV/AIDS is also included
in the CCI but no patients had this.
†Excluding mantle cell lymphoma (MCL), unspecified non-Hodgkin
lymphoma, and non-melanoma skin cancer.
‡This is not included in the definition of CCI but was added for this
specific study, psychiatric disorders also including alcohol and drug
abuse.
I. Glimelius et al.
6ª2019 British Society for Haematology and John Wiley & Sons Ltd

2012; Eskelund et al., 2016), the frequencies of comorbidities
were not reported but patients had to be fit for an autograft
and exclusion criteria were major organ dysfunction, HIV,
and uncontrolled infections. For patients selected for an
ASCT in our series (n=292) no specific comorbidity pre-
dicted poorer lymphoma-specific survival, in line with earlier
studies (Hermet et al., 2015). However, the specific sub-
groups of comorbidities in ASCT-treated patients give small
subgroups, thus the lack of significance of the findings might
be explained by lack of power. Groups with a high degree of
comorbidities were to a large extent also excluded from
high-dose treatment and ASCT, also among patients
<70 years of age. ASCT is usually given to younger patients
(<70 years). A French study of elderly non-Hodgkin lym-
phoma patients [≥70 years (range: 70–80), n=81, including
15 with MCL] showed that a transplantation was indeed
acceptable in the absence of comorbidity (73% of included
patients had no comorbidities) (Hermet et al., 2015), and
other groups have indicated similar findings (Dahi et al.,
2014). Improvements in supportive care and medical opti-
mization of the specific comorbidities (particularly
connective-tissue disease, renal disease, dementia or psychi-
atric disorders) could lead to an increase in the number of
patient eligible for a transplantation. Strategies to pursue this
will vary between the different comorbidities, but a multidis-
ciplinary approach involving both medical and social support
is needed.
Comorbidities and novel targeted treatments and other
treatment concepts
Non-transplant-eligible patients could also be targeted for
novel treatment concepts and drugs in order to improve sur-
vival (Cheah et al., 2019). Promising results have e.g. been seen
with the BTK inhibitor ibrutinib and with Bcl-2 inhibitors
(Wang et al., 2016; Arora & Portell, 2018; Kluin-Nelemans &
Doorduijn, 2018; Wang et al., 2018). Ibrutinib has shown high
efficacy in relapsed MCL patients (Wang et al., 2016), and is
now tested in first-line treatment and challenges the use of
rituximab chemotherapy alone in elderly patients, although
results from randomized trials (such as the ENRICH-trial) are
awaited. Patients with connective tissue disease, renal disease,
Acute MI (incl. CHF)
Peripheral vascular
Cerebrovascular accident
Dementia
Pulmonary
Connective tissue
Peptic ulcer
Liver
Diabetes
Paraplegia
Renal
Cancer*
Metastatic cancer
Psychiatric disorder**
Atrial fibrillation
Comorbidity
1·31 (0·99, 1·74)
0·88 (0·52, 1·47)
0·86 (0·60, 1·25)
2·62 (1·21, 5·70)
1·17 (0·81, 1·69)
1·90 (1·09, 3·31)
0·92 (0·58, 1·47)
1·46 (0·62, 3·41)
1·30 (0·93, 1·82)
0·47 (0·06, 3·62)
1·91 (1·15, 3·19)
1·05 (0·81, 1·36)
1·89 (0·73, 4·92)
1·81 (1·04, 3·16)
1·14 (0·75, 1·74)
HR (95% CI)
0·05 0·5 1 2 14
Lymphoma-specific mortality
Fig 2. Forest plot showing adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) comparing lymphoma-specific mortality between
mantle cell lymphoma (MCL) patients with a single specific comorbid condition, and MCL patients with no comorbidities.
Comorbidity in mantle cell lymphoma
ª2019 British Society for Haematology and John Wiley & Sons Ltd 7

psychiatric disorders and, to some degree, a history of acute
cardiovascular disease, experienced a higher lymphoma-speci-
fic mortality than patients without any comorbidity, indicating
that they were not offered, or did not tolerate,and/or benefit
from the recommended chemotherapy treatment. The inclu-
sion of novel agents such as BTK inhibitors and Bcl-2 inhibi-
tors in first-line treatment may fill an unmet need for these
populations. Patients with cardiac failure may require concepts
free from or with lower doses of doxorubicin. For example,
the HEART 01 phase II trial reported that a non-PEGylated
liposomal doxorubicin combination regimen in patients with
DLBCL and cardiac comorbidity was feasible and resulted in a
72% overall response rate, and was similar to the results seen
in healthy patients receiving non-PEGylated doxorubicin
(Luminari et al., 2018). For patients with dementia, and severe
psychiatric comorbidities, treatments may not always be
0
0·2
0·4
0·6
0·8
1
Age 50
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 60
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 70
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 80
Cumulative probability
0 5 10
Time since diagnosis (years)
CCI = 0
0
0·2
0·4
0·6
0·8
1
Age 50
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 60
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 70
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 80
Cumulative probability
0 5 10
Time since diagnosis (years)
CCI = 1+
Males
0
0·2
0·4
0·6
0·8
1
Age 50
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 60
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 70
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 80
Cumulative probability
0 5 10
Time since diagnosis (years)
CCI = 0
0
0·2
0·4
0·6
0·8
1
Age 50
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 60
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 70
Cumulative probability
0 5 10
0
0·2
0·4
0·6
0·8
1
Age 80
Cumulative probability
0 5 10
Time since diagnosis (years)
CCI = 1+
Females
Death due to lymphoma Death due to other cause
Males Females
CCI=0
Probability (95% CI)
CCI=1+
Probability (95% CI)
CCI=0
Probability (95% CI)
CCI=1+
Probability (95% CI)
Age 50 Due to lymphoma 0.45 (0.33-0.58) 0.52 (0.36-0.68) 0.21 (0.05-0.36) 0.22 (0.02-0.42)
Due to other 0.06 (0.01-0.11) 0.13 (0.02-0.24) 0.19 (0.00-0.40) 0.41 (0.00-0.88)
Age 60 Due to lymphoma 0.63 (0.51-0.75) 0.67 (0.53-0.81) 0.31 (0.13-0.48) 0.30 (0.07-0.52)
Due to other 0.09 (0.03-0.15) 0.17 (0.05-0.29) 0.25 (0.03-0.47) 0.50 (0.09-0.91)
Age 70 Due to lymphoma 0.81 (0.71-0.91) 0.81 (0.69-0.92) 0.55 (0.34-0.76) 0.42 (0.15-0.70)
Due to other 0.09 (0.03-0.16) 0.16 (0.05-0.27) 0.31 (0.10-0.52) 0.55 (0.24-0.86)
Age 80 Due to lymphoma 0.87 (0.79-0.95) 0.82 (0.71-0.93) 0.70 (0.51-0.90) 0.50 (0.22-0.78)
Due to other 0.11 (0.03-0.19) 0.18 (0.07-0.29) 0.26 (0.07-0.44) 0.49 (0.02-0.72)
Fig 3. Stacked cumulative probabilities of lymphoma-specific and other-cause death stratified by sex, Charlson comorbidity index (CCI), and age,
among patients diagnosed with mantle cell lymphoma in 2000. The supporting table shows pointwise probabilities of lymphoma-specific and
other-cause deaths at 10 years after diagnosis with 95% confidence intervals (CIs). Predicted from a flexible parametric survival model, adjusted
for year, age, and sex (N= 1,385, 100% of patients). [Colour figure can be viewed at wileyonlinelibrary.com]
I. Glimelius et al.
8ª2019 British Society for Haematology and John Wiley & Sons Ltd

possible to deliver due to poor compliance, and treating the
malignant disease may be of lower priority. For patients with
some psychiatric comorbidities, it might be possible to deliver
more efficient treatments if both more medical, and social
support were available or if the MCL treatment was less
demanding. For example, more social support might be
needed if patients with severe psychiatric comorbidities should
tolerate the isolation phase during an ASCT.
The high frequency of patients presenting with cardiovas-
cular disorders (14% had prior heart disease in our investiga-
tion) is of potential concern for the use of BTK inhibitors.
BTK inhibitor use is a relative contraindication for warfarin
treatment (for example for patients with paroxysmal or per-
manent atrial fibrillation), due to the increased bleeding risk
and the long-term increased risk of hypertension. In a recent
review (Boriani et al., 2018), a proper pretreatment assess-
ment, careful choice of concomitant drugs, regular monitor-
ing, and a multidisciplinary approach were key principles in
the clinical management of patients before initiation of the
BTK inhibitor ibrutinib. More recently, next-generation BTK
inhibitors have emerged, such as acalabrutinib, presenting
promising results and tolerability, but also a different panor-
ama of side effects, stressing the importance of knowing the
occurrence of comorbidities prior to initiation of treatment
(Wang et al., 2018).
Comorbidities and the likelihood of dying from
lymphoma
The current investigation cannot provide a full answer as to
whether more patients could safely have been selected for
more intensive treatments. However, since the majority of
the patients died from their lymphoma this underscores that
MCL is difficult to treat, and that the lymphoma itself more
often leads to death than the comorbidities, in particular
among males. The likely scenario is that the majority of
MCL patients will eventually require treatment, irrespective
of the presence of comorbidity. With the right social and
medical support, we believe survival and quality of life could
be improved in MCL patients with comorbidities. Examples
of this include dose adjustments [which have been shown to
increase tolerability among comorbid patients with other
lymphoma subtypes (Eyre et al., 2016)], potential prephase
treatments in elderly patients and alternative treatment com-
binations (such as radio-immunotherapy) (Kumar et al.,
2018). Our results indicate that the groups targetable for
such modified interventions are those with connective tissue
disease, renal disorders, cardiovascular disease and psychiatric
comorbidities.
The large proportion of deaths from causes other than
lymphoma among females with any comorbidity may reflect
a more indolent lymphoma course; more females than males
were also selected for a “wait and watch” strategy. This indi-
cates that more female patients, in the event of no or minor
lymphoma-associated symptoms and especially those with
comorbidities, should be selected for an initial “wait and
watch” approach.
Strengths and limitations
The nationwide cohort with complete coverage of all diag-
nosed patients irrespective of age, sex, and socioeconomic sta-
tus are strengths in this population-based investigation,
enabling presentation of comorbidities in an unselected collec-
tion of patients. A limitation is that the sample size was still
somewhat small in subgroup analyses, resulting in higher
uncertainty. In addition, comorbidities and causes of death
(Brooke et al., 2017) were retrieved from register data. How-
ever, for prior malignancies, the National Cancer Registry was
used, with a 98% coverage, ensuring almost complete registra-
tion (Barlow et al., 2009), and for other specific comorbidities,
the nationwide Patient Register and the Cause of Death Regis-
ter have also been validated and show high coverage (Brooke
et al., 2017). Nearly all inpatient, and specialist outpatient care
in Sweden is governmentally provided and registered, giving a
comprehensive picture of the comorbidities prior to diagnosis.
The prognostic impact on lymphoma-specific survival using
the CCI after adjustment for the currently used prognostic fac-
tors included in the MIPI score, was rather limited in magni-
tude, but the specific comorbidities presented provided better
discriminative strength of prognosis.
Conclusions
In selecting the optimal treatment for patients with MCL,
the presence of concomitant diseases should be taken into
account. Particularly in women with comorbidities and few
MCL-related symptoms, a “wait and watch” approach should
be considered. The majority of patients will nevertheless die
from their lymphoma and in the development and introduc-
tion of new treatment regimens, consideration of tolerability
for patients with both somatic (specifically connective tissue
disease, renal disorders and cardiovascular disease) and psy-
chiatric comorbidities is important.
Author contributions
Design of the study: IG, SE, KES, CW. Statistical analysis and
figures: CW. Drafting of the manuscript IG. Data collection
KES, MJ. Critical review of the manuscript: all authors.
Ethics Approval
The study was approved by the Regional Board of the Ethical
Committee in Stockholm, Sweden (2007/1335-31/4, 2010/
1624-32).
Consent for publication
All authors consent to publication.
Comorbidity in mantle cell lymphoma
ª2019 British Society for Haematology and John Wiley & Sons Ltd 9

Availability for data and material
The data are a result of linkags of several nationwide registers
as described in the Methods section. The data are available
upon request from the corresponding author.
Conflict of interest
MJ: honoraria from Janssen, Gilead, Celgene, Roche and
Acerta and research support from Janssen, Celgene, AbbVie
and Gilead. KES: honoraria from Celgene and research sup-
port from Janssen. IG: honoraria from Janssen. SE has an
ongoing role as project manager in a public–private real-
world evidence collaboration between Karolinska Institutet
and Janssen Pharmaceuticals NV (contract: 5-63/2015).
Funding
This study was supported by the Swedish Cancer Society
CAN (2012/774). I. Glimelius was supported by the Swedish
Cancer Society (CAN 2016/440) and the Swedish Society of
Medicine. The funding agencies did not have a role in any
aspects of the study except funding.
Supporting Information
Additional supporting information may be found online in
the Supporting Information section at the end of the article.
Table SI. Diagnostic codes for identification of mantle cell
lymphoma (MCL) patients treated with autologous or allo-
genic stem cell transplantation, according to the International
Classification of Diseases (ICD-9 and ICD-10).
Table SII. Frequency and percentage of treatment groups
by Charlson comorbidity index, and by age at diagnosis
(<70/≥70 years).
Table SIII. Counts and percentages of deaths due to lym-
phoma and other causes, by Charlson comorbidity index and
treatment (<70/≥70 years), stratified by sex.
Figure S1. Forrest plot showing adjusted hazard ratios
(HRs) with 95% confidence intervals (CIs) comparing all-
cause mortality between mantle cell lymphoma (MCL)
patients with a single specific comorbid condition, to MCL
patients with no comorbidities.
Figure S2. Forrest plot showing adjusted hazard ratios (HRs)
with 95% confidence intervals (CIs) comparing lymphoma-
specific mortality between mantle cell lymphoma (MCL) patients
with a single specific comorbid condition and MCL patients with
no comorbidities, in a subset of patients who have undergone an
autologous stem cell transplantation (ASCT).
Figure S3. Unadjusted lymphoma-specific survival among
patients diagnosed with mantle cell lymphoma (MCL) in
2000–2014, by treatment (N=989, 71% of patients).
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