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Improved survival in chronic lymphocytic leukemia in the past decade: A population-based study including 11,179 patients diagnosed between 1973-2003 in Sweden

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Abstract

Clinical management of chronic lymphocytic leukemia patients has changed considerably over the last years, reflected in an increased use of prognostic markers, new therapeutic agents and procedures, and supportive care measures. However, to date, clinical trials have not shown a survival benefit. Using population-based data from Sweden, we assessed variations in survival among all chronic lymphocytic leukemia patients (n=11,179) reported from 1973-2003. Relative survival ratios were computed as measures of patient survival. Overall we found significantly improved (p<0.0001) 5-, 10-, and 20-year relative survival ratio for the entire cohort during the study period. Improved 5- and 10-year relative survival ratio was found for all age-groups (p<0.0001) and both sexes. Compared to females, however, males had a significantly inferior survival in all age groups and calendar periods (p<0.0001). Younger chronic lymphocytic leukemia patients had a superior survival compared to older chronic lymphocytic leukemia patients, in all calendar periods (p<0.0001). Five-year relative survival ratio has not improved in the youngest chronic lymphocytic leukemia patients since the 1980s; however, older patients have had a continuous improvement in 5 year-relative survival ratio. The observed improvements are likely due to improved therapeutic developments and supportive care. Our findings suggest that elderly chronic lymphocytic leukemia patients might benefit more from the recently introduced drugs in chronic lymphocytic leukemia. Future clinical trials are needed to better define underlying mechanisms of observed heterogeneity in chronic lymphocytic leukemia survival by age and sex, and evaluate the role of newer chronic lymphocytic leukemia therapy in the elderly.
haematologica | 2009; 94(9) |1259 |
Original Article
Funding: this research was
supported by grants from the
Swedish Cancer Society,
Stockholm County Council, the
Karolinska Institutet founda-
tions, and the Intramural
Research Program of the
National Institutes of Health
(NIH), National Cancer Institute
(NCI).
Acknowledgments: the authors
thank Ms. Fereshte Ebrahim,
The National Board of Health
and Welfare, Stockholm,
Sweden, for important efforts in
setting up this database.
Manuscript received on
February 23, 2009. Revised
version arrived April 2, 2009.
Manuscript accepted on April 8,
2009.
Correspondence:
Sigurdur Yngvi Kristinsson,
Department of Medicine,
Division of Hematology,
Karolinska University Hospital,
SE-171 76 Stockholm,
Sweden. E-mail:
sigurdur.kristinsson@karolins-
ka.se
Background
Clinical management of chronic lymphocytic leukemia patients has changed considerably
over the last years, reflected in an increased use of prognostic markers, new therapeutic
agents and procedures, and supportive care measures. However, to date, clinical trials have
not shown a survival benefit.
Design and Methods
Using population-based data from Sweden, we assessed variations in survival among all
chronic lymphocytic leukemia patients (n=11,179) reported from 1973-2003. Relative sur-
vival ratios were computed as measures of patient survival.
Results
Overall we found significantly improved (p<0.0001) 5-, 10-, and 20-year relative survival
ratio for the entirecohortduring the study period. Improved 5- and 10-year relative sur-
vival ratio was found for all age-groups (p<0.0001) and both sexes. Compared to females,
however, males had a significantly inferior survival in all age groups and calendar periods
(p<0.0001). Younger chronic lymphocytic leukemia patients had a superior survival com-
pared to older chronic lymphocytic leukemia patients, in all calendar periods (p<0.0001).
Five-year relative survival ratio has not improved in the youngest chronic lymphocytic
leukemia patients since the 1980s; however, older patients have had a continuous
improvement in 5 year-relative survival ratio.
Conclusions
The observed improvements are likely due to improved therapeutic developments and
supportive care. Our findings suggest that elderly chronic lymphocytic leukemia patients
might benefit morefrom the recently introduced drugs in chronic lymphocytic leukemia.
Futureclinical trials areneeded to better define underlying mechanisms of observed het-
erogeneity in chronic lymphocytic leukemia survival by age and sex, and evaluate the role
of newer chronic lymphocytic leukemia therapy in the elderly.
Key words: chronic lymphocytic leukemia, prognosis, survival, sex, older age,
population-based.
Citation: Kristinsson SY, Dickman PW, Wilson WH, Caporaso N, Björkholm M, and Landgren O.
Improved survival in chronic lymphocytic leukemia in the past decade: a population-based study
including 11,179 patients diagnosed between 1973-2003 in Sweden. Haematologica 2009;94:1259-
1265. doi:10.3324/haematol.2009.007849
©2009 Ferrata Storti Foundation. This is an open-access paper.
Improved survival in chronic lymphocytic leukemia in the past decade:
apopulation-based study including 11,179 patients diagnosed
between 1973-2003 in Sweden
Sigurdur Y. Kristinsson,1Paul W. Dickman,2Wyndham H. Wilson,3Neil Caporaso,3Magnus Björkholm,1
and Ola Landgren1,3
1Department of Medicine, Division of Hematology, Karolinska University Hospital Solna and Karolinska Institutet, Stockholm,
Sweden; 2Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden, and 3National Cancer
Institute, National Institutes of Health, Bethesda, Maryland, USA
ABSTRACT
S.Y. Kristinsson et al.
|1260 | haematologica | 2009; 94(9)
Introduction
Chronic lymphocytic leukemia (CLL) is the most com-
mon leukemia of adults in Western countries with an
annual incidence of 2-4.5 per 100,000 in the general pop-
ulation.1,2 It affects males twice as frequently as females
and is a disease of older individuals (median age 73.0
years for whites).2
After decades of therapeutic stability, clinical manage-
ment of CLL patients is now rapidly evolving.3Initially,
CLL was considered an indolent, relatively homoge-
neous but incurable disease. The introduction of purine
analogs in the early 1980s followed by monoclonal anti-
bodies and immunomodulatory drugs (IMiDs) have
revitalized clinical research in CLL.4Complementing
these new therapies have been the identification of bio-
markers such as CD38, immunoglobulin (Ig) mutational
status and ZAP-70, that augment prognostication, reflect
disease pathogenesis and heterogeneity of the disease,
offering the opportunity for risk adjusted treatments.3,4
Despite such advances, however, clinical trials have yet
to show improved overall survival in CLL.5-8
Clinical trials, compared to general practice, are asso-
ciated with a certain degree of patient selection, reflect-
ed in under-ascertainment of elderly patients. Typically,
the average age at diagnosis of CLL is around ten years
younger in clinical trials5-8 compared to that reported in
the general population.1,2 Indeed, there are only sparse
population-based data available on survival patterns in
CLL. Using the publicly available US National Cancer
Institute’s (NCI) Surveillance, Epidemiology and End
Results (SEER) database, Brenner et al. recently conduct-
ed a population-based study designed to evaluate sur-
vival patterns among CLL patients diagnosed in 2000-
2004 compared to those diagnosed in 1980-1984.9In
their study,5-year survival has improved for all age
groups over the past two decades; and increased 10-year
survival was observed for all except the oldest patients.9
Although these findings are intriguing, there are data
indicating both a significant delay and under-reporting
of CLL to the applied database, and an increase in earli-
er stage CLL due to changes in diagnostic practices over
time.10,11 As pointed out by Brenner et al., delayed regis-
tration and potential under-registration for CLL might
impact survival trend analyses for CLL based on the
NCI-SEER database while additional studies areneeded
to confirm and expand their findings.9
In order to overcome these deficiencies and assess sur-
vival in a whole population, we conducted a large popu-
lation-based study in Sweden which has provided uni-
versal medical health careavailable for its entirepopula-
tion (currently approximately 9 million people) since the
mid-1950s. We identified all CLL patients (n=11,179)
diagnosed in the period 1973-2003, with follow-up until
December 31, 2004. The aims of the study wereto
define CLL survival patterns in the Swedish population
and evaluate the effect of newly introduced therapeutic
agents on survival in the entire population. Since previ-
ous studies have suggested that older CLL patients have
moreaggressive clinical disease and an adverse biomark-
er profile,12,13 we hypothesized that it may be possible to
detect heterogeneity in survival benefits (i.e. more
aggressive disease may receive greater benefit from
more effective therapy), measured by longitudinal sur-
vival patterns by age.
Design and Methods
Central registers
Information on every patient diagnosed with a malig-
nant disorder in Sweden has been reported to the cen-
tralized, nationwide Swedish Cancer Register since 1958
with a nearly complete capture.14,15 The Swedish Cancer
Register contains diagnosis, sex, date of birth, date at
diagnosis, and hospital where the diagnosis was made.
All physicians are obliged by law to report every cancer
case to the registry. In contrast to many other countries,
patients with lymphoproliferative malignancies in
Sweden are typically diagnosed, treated and followed
clinically by physicians at a few hospital-based hematol-
ogy or oncology centers. Each individual in Sweden
receives a unique national registration number and every
death date is recorded in the Causes of Death Register.
Information on the number of stem cell transplantations
in CLL patients reported from Swedish centers during
the study period was obtained from the EBMT register.
Patient cohort
Information on all patients diagnosed with CLL from
January 1, 1973 to December 31, 2003 was identified in
the Swedish Cancer Register (ICD-7 code 204.1); incom-
plete data were excluded. By linking the registration
number to the Causes of Death Register, data on date of
death was collected from January1, 1973 to December
31, 2004. Information was gathered for sex, date of
birth, date of diagnosis, date of death, and hospital
wherethe patient was diagnosed. During the study peri-
od, hematology/oncology clinics were confined to a few
regional university hospitals, which offer inpatient hos-
pital care to a defined primary catchment area in addi-
tion to being the referral center for a whole health care
region. The remaining hospitals in the country serve
regions with fewer inhabitants and offer inpatient care.
We had no access to information on clinical stage,
prognostic markers, treatment, or other clinical or labo-
ratory data for the collected cohort. Approval was
obtained from the Karolinska and the NIH institutional
review boards for these studies. Informed consent was
waived because we had no contact with study subjects.
Survival analyses
Relative survival ratios (RSR) wereused as the meas-
ure of patient survival.16 RSR has key advantages in that
it does not rely on the accurate classification of cause of
death; instead it provides a measure of the total CLL
associated excess mortality irrespective of whether the
excess mortality is directly or indirectly related to CLL.
Estimated from life tables, RSR is defined as the
observed survival in the patient group (where all deaths
are considered events) divided by the expected survival
of a comparable group from the general population.
Expected survival was estimated using the Hakulinen
method from Swedish population life tables stratified
by age, sex, and calendar period.17 Five-, 10-, and 20-
year RSR with 95% confidence intervals (CI) were cal-
culated for CLL patients during four calendar periods:
1973-1979, 1980-1986, 1987-1993, and 1994-2003.
Thus, 5-, 10-, and 20-year RSR provide a measure of the
fraction of CLL patients who survived their malignancy
at five, ten and 20 years.
Using Poisson regression models adjusted for sex, age
group (<50, 50-70, and >70 years), calendar period, and
hospital category (university vs. non-university) at diag-
nosis, we estimated excess hazard ratios (EHR) of death
among CLL patients. All calculations were performed
using SAS 8.1 (SAS Institute, Cary, NC, USA).
Results
Between January 1, 1973 and December 31, 2003 a
total of 11,179 patients with CLL (mean age 70 years;
62% males) were reported to the Swedish Cancer
Registry in Sweden. During the study period, the annu-
al age-adjusted mean incidence for CLL was 6.5 per
100,000 for males and 3.1 per 100,000 for females,
respectively.Although rates in men briefly rose to 8.1
per 100,000 in the mid-1980s and declined to 4.7 per
100,000 in the mid-1990s, the overall incidence pattern
was stable; for females the age-adjusted incidence pat-
tern was stable. The fraction of CLL patients being diag-
nosed at University hospitals was 29% (Table 1).
Patients diagnosed in non-university hospitals had a
1.12-fold (95% CI 1.04-1.21) higher excess mortality
(Table 2). A total of 73 stem cell transplantations [43
allogeneic and 30 autologous (ASCT)] were reported to
the EBMT register during the study period, the majori-
ty (95%) in the last calendar period.
Overall survival pattern
For patients in all age groups and sexes, the overall 5-
year RSR improved with patients diagnosed in the last
(1994-2003) calendar period showing a significantly
lower excess mortality (EHR=0.30, 95% CI 0.27-0.34)
compared to patients diagnosed in the first (1973-1979)
calendar period (Table 2). We found that 5-, 10-, and 20-
year RSR improved significantly (p<0.0001, likelihood
ratio test) for the complete cohort during the study peri-
od (Figure 1). The 5-year RSR estimates for the four cal-
endar periods were 0.46, 0.57, 0.62, and 0.73, respec-
tively. The 10-year RSR estimates were 0.24, 0.35, 0.38,
and 0.53, respectively. Twenty-year RSR estimates
could only be computed for the first and second calen-
dar periods; the estimates for these calendar periods
were 0.12 and 0.19, respectively (Table 3).
Survival trends by age
Patients diagnosed at an older age (71+ years) had a
2.64-fold (95% CI 2.22-3.13) higher excess mortality
compared to patients diagnosed at a younger age (<50
years) (Table 2). Given the survival variations among
age groups, we conducted RSR analyses stratified by
age. The youngest (<50 years) patients (n=491) showed
improved survival over everytime period: 5-, 10-, and
20-year RSR (p<0.0001, likelihood ratio test) (Figure 2
and Table 3). For older (50-70 years) patients (n=4,461),
the 5-, 10-, and 20-year RSR all significantly improved
(p<0.0001, likelihood ratio test; Table 3). Improvements
in RSR for all time periods were also observed for the
oldest (>70 years) patients (n=6,227) (p<0.0001, likeli-
hood ratio test; Table 3).
Survival trends by sex
Wefound a significantly reduced (EHR=0.71, 95% CI
0.66-0.77, p<0.0001, likelihood ratio test) excess mortal-
CLL and survival
haematologica | 2009; 94(9) | 1261 |
Table 1. Patients’ characteristics at diagnosis.
Variable N(%)
Total number of CLL patients 11,179 (100)
Sex
Male 6,880 (62)
Female 4,299 (38)
Age group
50 years 491 (4)
51-70 years 4,461 (40)
71+ years 6,227 (56)
Hospital category
University hospital 3,220 (29)
Non-university hospital 7,959 (71)
Calendar period
1973-1979 2,067 (18)
1980-1986 2,594 (22)
1987-1993 2,288 (21)
1994-2003 4,230 (39)
Mean age (years, SD), per calendar period
1973-1979 70.2 (10.7)
1980-1986 70.7 (11.0)
1987-1993 71.7 (10.3)
1994-2003 70.6 (11.2)
CLL: chronic lymphocytic leukemia;SD: standard deviation.
Table 2. Excess hazard ratios and 95% confidence intervals (CI) of
dying during the first ten years after chronic lymphocytic leukemia
(CLL) diagnosis, stratified by sex, age group, hospital category, and
calendar period at CLL diagnosis.
Variable Relative hazard195% CI pvalue#
Sex
Male 1.00 (ref.) NA <0.0001
Female 0.71 (0.66-0.77)
Age group
<50 years 1.00 (ref.) NA <0.0001
51-70 years 1.51 (1.27-1.79)
71+ years 2.64 (2.22-3.13)
Hospital category
University hospital 1.00 (ref.) NA 0.004
Non-university hospital 1.12 (1.04-1.21)
Calendar period
1973-1979 1.00 (ref.) NA <0.0001
1980-1986 0.71 (0.65-0.78)
1987-1993 0.60 (0.55-0.66)
1994-2003 0.30 (0.27-0.34)
ref: reference; NA: not applicable; #:likelihood ratio test. 1All risk estimates
are simultaneously adjusted for all other variables in the table.
S.Y. Kristinsson et al.
|1262 | haematologica | 2009; 94(9)
ity for females compared to males (Table 2 and Figure 3).
Females had a significantly superior survival in all age
groups and calendar periods (p<0.001; Figure 3).
Discussion
In this large population-based cohort study of over
11,000 CLL patients diagnosed in Sweden between 1973
and 2003, we found significantly improved 5-year and,
most importantly 10-year CLL survival trends in all age
groups. Older CLL patients had a continuous improve-
ment in survival during the whole study period, while
younger CLL patients have had a stable survival since
the 1980s. Females had consistently better survival over
the study period in all age groups. Our survival analyses
showed that an increasing proportion of CLL patients
survive their malignancy for 20 years, particularly
younger patients. To improve our understanding of
these survival patterns, we investigated several hypothe-
ses including the influence of therapeutic-, diagnostic-,
disease-, and host-related factors.
Initiation of therapy in early stage patients has not
been shown to prolong survival,18 allowing asympto-
matic patients to be followed clinically without treat-
ment. Chlorambucil, the standard of care in Sweden
throughout the study period,19 can induce partial remis-
sions but few complete remissions, and survival with
this agent has been 3-5 years.7,20 The purine analog, flu-
darabine, as a single agent or in combination with
cyclophospamide, has been shown to improve response
compared to chlorambucil but not survival.7, 21
Fludarabine had been used as second-line agent in
Sweden since the 1990s and has only recently been
widely adopted as first-line treatment. Alemtuzumab, a
monoclonal antibody targeting CD52 was registered in
Sweden in 200122 for fludarabine-refractory patients.
While it can induce good responses, the effect on sur-
vival remains unclear.23 Rituximab, which targets CD20,
has single agent activity24 and is particularly useful in
combination therapy,25 but was not routinely used dur-
ing the study period. No prospective randomized clinical
trial has found ASCT to improve survival in CLL
patients, and it was not used frequently (n=30) during
the study period.26 Allogeneic transplantation is associat-
ed with a prolonged overall survival but considerable
treatment-related mortality.27 In our study, allogeneic
transplantation was only used in selected patients (n=43)
and could only marginally affect the survival estimates.
We were able to confirm and expand on the only prior
population-based study by Brenner et al.,9designed to
Figure 1. Overall relative survival ratios among chronic lymphocyt-
ic leukemia patients diagnosed in Sweden 1973-2003.
Figure 2. Relative survival ratios among chronic lymphocytic
leukemia patients diagnosed in Sweden 1973-2003, stratified by
age group at CLL diagnosis.
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0 1973-1979 1980-1986
1973-1979 1980-1986 1987-1993 1994-2003
1973-1979 1980-1986 1987-1993 1994-2003
1973-1979 1980-1986 1987-1993 1994-2003
Calendar period
Calendar period
Calendar period
Calendar period <50 years 51-70 years >71 years
<50 years 51-70 years >71 years
<50 years 51-70 years >71 years
20-year relative survival ratio 10-year relative survival ratio 5-year relative survival ratio
Relative survival ratio
5-year RSR
10-year RSR
20-year RSR
assess trends in CLL survival patterns over the past
decades. In their study, based on US NCI-SEER data,
between 1980-1984 and 2000-2004 they observed an
improved 5-year survival among CLL patients of all age
groups, and improved 10-year survival in all except the
oldest patient population.9In our study,we observed
improved 5- and 10-year survival in all age groups.
Differences between these two studies include the fact
that we used the total Swedish population as reference
group when calculating RSR estimates. In contrast, in
the study by Brenner et al., CLL survival from the
included states was related to the entire United States
population survival. Secondly,Sweden has a well estab-
lished government-funded public health care system
whereall residents by law areentitled to equal access to
health services. Furthermore, patients with CLL in
Sweden are almost exclusively diagnosed, treated, and
followed clinically by physicians at non-private hospi-
tal-based hematology units.
Most, but not all studies, examining age as a predictor
of prognosis, have found older individuals to have poor-
er survival, and previous studies have reported more
lethal CLL disease among older patients.12,13 The
observed improved CLL survival among older patients
could be due to better effects of newer therapies on
more aggressive CLL or to the fact that improvements
in supportive care over time may permit the elderly to
benefit morefrom newer treatments.
We found a stable 5-year RSR of approximately 80-
85% among CLL patients diagnosed at the age of 50 or
lower over the time period of the study. In contrast to
older patients, we found no evidence of improved sur-
vival among younger patients since the early 1980s.
This age group poses a great clinical and public health
challenge due to the impact of shortened life expectan-
cy. Future clinical trials are needed to assess the optimal
therapy for younger CLL patients. Also, the number of
patients that can be evaluated for 20-year RSR is limit-
ed but it does document overall improved survival from
the 1973-1979 through the 1980-1986 period, particular-
ly in the younger subjects. Interestingly,females with
CLL have been found to have a more favorable prognos-
tic disease profile, for example, less advanced stage and
chromosomal abnormalities.28 We found females to
have a 29% lower excess mortality, compared to males,
and a consistently superior survival, in all calendar peri-
ods and across all age groups, as has been previously
reported29 and similar to the findings from the SEER
database.9The observed superior survival in females
may be due to underlying biological differences, social
factors, or differential effects of therapy. Future research
is needed to explore underlying mechanisms of these
observations.
We found CLL patients diagnosed at university hospi-
tals had a significant 12% lower excess mortality com-
pared to those diagnosed at non-university hospitals. In
Sweden, a similar difference has been observed among
multiple myeloma patients.30 The underlying mecha-
nism for the observed differences is probably multifac-
torial, and could be due to differences in diagnostics,
treatment, and supportive care. Alternatively, it could be
due to underlying referral mechanisms. For these rea-
sons, the present finding needs to be interpreted with
caution. Future work is needed to clarify the exact
underlying causes.
An important consideration when interpreting our
findings is the potential effect of lead time bias due to
early CLL detection. This issue is raised by the increased
CLL and survival
haematologica | 2009; 94(9) | 1263 |
Table 3. Relative survival ratios (RSR) and 95% confidence intervals (CI) among chronic lymphocytic leukemia (CLL) patients diagnosed in
Sweden 1973-2003, stratified by age group at CLL diagnosis.
Age group/calendar period 5-year 10-year 20-year
RSR (95% CI) RSR (95% CI) RSR (95% CI)
Combined
All ages (n=11,179)
1973-1979 0.46 (0.43-0.49) 0.24 (0.22-0.27) 0.12 (0.10-0.15)
1980-1986 0.57 (0.55-0.60) 0.35 (0.32-0.37) 0.19 (0.16-0.22)
1987-1993 0.62 (0.59-0.64) 0.38 (0.36-0.41) NA
1994-2003 0.73 (0.71-0.75) 0.53 (0.49-0.57) NA
<50 years (n=491)
1973-1979 0.66 (0.54-0.75) 0.38 (0.28-0.49) 0.20 (0.12-0.29)
1980-1986 0.87 (0.79-0.92) 0.63 (0.53-0.72) 0.55 (0.44-0.65)
1987-1993 0.86 (0.76-0.92) 0.62 (0.51-0.72) NA
1994-2003 0.82 (0.74-0.88) 0.73 (0.62-0.82) NA
51-70 years (n=4,461)
1973-1979 0.55 (0.51-0.58) 0.28 (0.25-0.32) 0.14 (0.11-0.17)
1980-1986 0.68 (0.64-0.71) 0.43 (0.39-0.47) 0.21 (0.17-0.25)
1987-1993 0.71 (0.68-0.75) 0.46 (0.41-0.50) NA
1994-2003 0.81 (0.78-0.83) 0.59 (0.53-0.64) NA
71+ years (n=6,227)
1973-1979 0.35 (0.32-0.39) 0.18 (0.14-0.23) 0.09 (0.03-0.21)
1980-1986 0.45 (0.41-0.49) 0.22 (0.19-0.27) 0.14 (0.07-0.23)
1987-1993 0.53 (0.49-0.57) 0.31 (0.26-0.35) NA
1994-2003 0.66 (0.63-0.70) 0.46 (0.39-0.53) NA
S.Y. Kristinsson et al.
|1264 | haematologica | 2009; 94(9)
use of automated cell counters and flow cytometry tech-
niques (employed in Sweden since the early 1990s) and
change in diagnostic criteria over time, such as a lower
lymphocyte count required to make the diagnosis.12,31 To
help address this question, we recently conducted a
nationwide validation study including 202 CLL cases
diagnosed in Sweden in the period 1964-2003.15 In that
study,therewas about 12% under-reporting of CLL
cases to the Swedish Cancer registry. Importantly, when
we examined this in greater detail, we observed under-
reporting was constant over time and present in all cal-
endar periods; it particularly occurred with elderly CLL
patients.15 In the present study, we evaluated the age-
adjusted incidence as well as the mean age at CLL diag-
nosis (Table 1), and we found both measures to be sta-
ble over time. When taken together, we believe these
data do not suggest that lead time bias is a major expla-
nation for the improved survival we have observed in
CLL.
In our study, we used a register-based cohort design,
which ensured a population-based setting and general-
ization of our findings. Thus, we were able to define the
impact of management and treatment strategies in CLL
introduced over a 30-year study period in the entire
Swedish population. Because the Swedish Cancer
Register has a veryhigh diagnostic validity for hemato-
logic malignancies,14 diagnostic misclassifications should
have caused only minimal bias in the present study.
Limitations include possible variations in diagnostic
practices over time and lack of detailed clinical data.
In conclusion, we found improved 5- and 10-year CLL
survival trends for all age groups. Our finding that
females had a superior survival confirms a better prog-
nosis compared to males. Younger CLL patients have not
improved their survival since the early 1980s. Future
clinical trials are needed to assess the role of newer CLL
therapies in older patients, with potential major public
health implications, given the relatively old average age
at diagnosis (about 70 years) for CLL patients in the gen-
eral population.
Authorship and Disclosures
SYK, MB, WHW, NEC, and OL, designed the study.
SYK, MB, and OL obtained data. SYK, PWD, and OL
analyzed data. OL initiated this work and SYK and OL
wrote the report. All authors wereinvolved in the inter-
pretation of the results, and read, gave comments, and
approved the final version of the manuscript. SYK,
PWD, and OL had full access to all of the data in the
study and take responsibility for the integrity of the data
and the accuracy of the data analysis.
The authors reported no potential conflicts of interest.
AB
Figure 3. (A) Relative survival ratios (RSR) among chronic lympho-
cytic leukemia patients diagnosed at the age of 51-70 yearsin
Sweden 1973-2003, stratified by sex. (B) Relative survival ratios
(RSR) among chronic lymphocytic leukemia patients diagnosed at
the age of 70+ years in Sweden 1973-2003, stratified by sex.
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
1.0
0.8
0.6
0.4
0.2
0.0
10-year relative survival ratio
10-year relative survival ratio
5-year relative survival ratio
5-year relative survival ratio
Calendar period
1973-1979 1980-1986 1987-1993 1994-2003
1973-1979 1980-1986 1987-1993 1994-2003
1973-1979 1980-1986 1987-1993 1994-2003
1973-1979 1980-1986 1987-1993 1994-2003
Calendar period
Males
Female
Males
Female
Males
Female
Males
Female
Calendar period
Calendar period
CLL and survival
haematologica | 2009; 94(9) | 1265 |
References
1. Socialstyrelsen. Cancer Incidence in
Sweden 2006. Stockholm, Sweden;
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... Chronic lymphocytic leukemia is the most common type of leukemia in Western countries, with an agestandardized incidence rate ranging from 3.8 to 5.0 person-years in a contemporary era [1][2][3][4][5]. Annually, 800-1000 additional cases are diagnosed in the Netherlands [1]. ...
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Management of patients with chronic lymphocytic leukemia (CLL) is changing due to considerable advances in the therapeutic armamentarium, and new therapies will possibly continue to emerge in the near future. Therefore, the CLL working group of the Dutch-Belgium Haemato-Oncology Cooperative Group for Adults in the Netherlands (HOVON) necessitated revising the Dutch CLL guidelines. The current guideline is based on the expert opinion of the HOVON CLL working group members and focusses on well-designed clinical trials taking into account efficacy with special emphasis on toxicity, treatment duration and treatment intensity. This article provides recommendations on diagnosis, treatment strategies in front-line and relapsed setting and provides supportive care measurements during novel-based therapies as well as for infectious CLL-related complications. The recommendations presented here are intended to provide guidance for the management of CLL patients in the Netherlands, and take into account the availability of treatment strategies at the time of this publication.
... The past decades have witnessed significant therapeutic advances in CLL. Population-based studies corroborated these advances, showing a steady improvement in relative and overall survival over time across all age segments [1][2][3][4][5]. Nevertheless, these population-based studies also highlighted that excess mortality in CLL is still an ongoing threat in modern times. ...
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Studies on conditional relative survival (CRS) in chronic lymphocytic leukaemia (CLL) have hitherto been lacking in the literature. We predicted up-to-date estimates of 5-year RS at diagnosis and for each additional year survived (i.e., CRS) up to 15 years post-diagnosis among CLL patients diagnosed during 2007–2020. We showed that 5-year CRS continues to decline gradually with each additional year survived in a contemporary era with access to novel-based agents, irrespective of age. This finding indicates that CLL patients continue to experience substantial excess mortality compared to an age- and sex-matched group from the general population.
... Chronic lymphocytic leukemia (CLL) is the most prevalent form of leukemia in the Western world with an age-standardized incidence rate of 4-5 cases per 100,000 persons per year (1)(2)(3)(4)(5). The clinical course of CLL is characterized by marked heterogeneity, with some patients surviving for more than 10 years without treatment, whereas others suffer rapid disease progression and poor outcome, in spite of the availability of effective treatment regimens. ...
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The clinical course of chronic lymphocytic leukemia (CLL) is highly variable. Over the past decades, several cytogenetic, immunogenetic and molecular features have emerged that identify patients suffering from CLL with high-risk molecular features. These biomarkers can clearly aid prognostication, but may also be capable of predicting the efficacy of various treatment strategies in subgroups of patients. In this narrative review, we discuss treatment approaches to CLL with high-risk molecular features. Specifically, we review and provide a comprehensive overview of clinical trials evaluating the efficacy of chemotherapy, chemoimmunotherapy and novel agent-based treatments in CLL patients with TP53 aberrations, deletion of the long arm of chromosome 11, complex karyotype, unmutated IGHV, B cell receptor stereotypy, and mutations in NOTCH1 or BIRC3 . Furthermore, we discuss future pharmaceutical and immunotherapeutic perspectives for CLL with high-risk molecular features, focusing on agents currently under investigation in clinical trials.
... Hence, the lack of an increase in 2005-2009 over 2000-2004 was a sign that the better survival outcomes for women remained at their relatively higher level over men in 2005-2009, while the men improved. This finding is consistent with prior studies, which have shown that women with CLL respond better to treatment and survive longer than men [34][35][36]. Importantly, this trend persisted through the period 2005-2009. Subsequently, the 5-year relative survival for both men and women was approximately the same at 86.9% (95%CI; 84.9-88.6) ...
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In this population-based study, we used the SEER database (1985–2015) to examine survival outcomes in chronic lymphocytic leukemia (CLL) patients followed up to the era of advanced treatments including targeted therapies. Data were extracted for patients 15 years or older with a primary diagnosis of CLL. A period analysis was performed to estimate 5- and 10-year relative survival rates for patients diagnosed during different calendar periods from 1985 to 2015. A mixture cure model was used to examine long-term survivors’ proportions among patients diagnosed in 1985–2015 and for two cohorts diagnosed in 2000–2003, followed up to 2012 and 2004–2007, and followed up to 2015. Cox proportional hazard modeling was used for the two cohorts to estimate hazard ratios (HRs) of death adjusted for gender and age. The 5-year and 10-year age-adjusted relative survival rate ranged between 73.7 and 89.4% and from 51.6% to “not reached,” respectively, for calendar periods of 1985–1989 to 2010–2014. The long-term survivor proportions varied by age and gender from 0 to 59%. The HRs (95%CI) for the 2004–2007 cohort in comparison to the 2000–2003 cohort were 0.58 (0.43–0.78), 0.58 (0.48–0.70), 0.57 (0.49–0.0.67), 0.68 (0.54–0.85), and 0.83 (0.68–1.02) for the age categories of 45–54, 55–64, 65–74, 75–84, and ≥ 85 years, respectively. Overall, relative survival improved significantly for CLL patients diagnosed between 1985 and 2015. These improvements were markedly better following the introduction of targeted therapies.
... Moreover, OS benefit may be "diluted" by the ongoing emergence of therapeutic options that gradually improve OS in this disease. [42][43][44][45] Indeed, the US Food and Drug Administration (FDA) accelerated approvals of drugs to treat hematologic cancers were based mostly on surrogate endpoints, such as response rate and PFS. 46,47 Therefore, PFS is the current leading endpoint for drug approval, including in studies of early intervention in other hematologic malignancies, as discussed earlier. ...
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Of the estimated 21,000 patients who will receive a new diagnosis of chronic lymphocytic leukemia (CLL) this year in the United States, approximately 80% will have early-stage disease. Patients with early-stage disease do not meet the criteria in the 2018 International Workshop on CLL guidelines for the initiation of therapy, and therefore they are not routinely offered treatment. The current management of these patients follows a "watch-and-wait" paradigm, which entails a regular follow-up every 3 to 6 months that includes a physical examination and relevant laboratory testing to evaluate for disease progression. These recommendations are based on decades of careful observations showing that treatment in early-stage CLL does not improve overall survival. With the advent of better prognostic tools to identify patients at high risk, in addition to the recent approval of several novel oral agents with impressive efficacy, the time is ripe to re-examine this question. This review (1) summarizes the results of studies of early intervention in CLL that led to the current consensus for "watch and wait" in early-stage CLL, (2) discusses the role of contemporary risk stratification in early-stage CLL, (3) describes the adverse clinical complications of untreated CLL, and (4) presents the results of ongoing clinical trials of novel agents used in patients with early-stage CLL.
Article
Objective To evaluate temporal trends in survival and causes of death in patients with chronic lymphocytic leukemia (CLL) in a nationwide study. Methods The cohort consisted of 13,009 Swedish CLL patients diagnosed 1982-2013. Relative survival (RS) and excess mortality rate ratios (EMRR) with 95% confidence intervals (95% CIs) were estimated using flexible parametric survival models. Cause-specific hazard ratios (HRs) were estimated for the linear effect of 10-year increase in year of diagnosis. Results The excess mortality decreased comparing 2003-2013 to 1982-1992 (EMRR=0.53, 95% CI 0.48-0.58,). The 5-year RS increased between 1982 and 2012 for patients > 51 years at diagnosis and improved for patients ≤ 51 years after 2002. The rate of CLL-specific deaths decreased over time (HR=0.78, 95% CI 0.75-0.81). Compared to patients with no comorbidity, patients with 1 and 2+ Charlson Comorbidity Index points had HR=1.35 (95% CI 1.25-1.45) and HR=1.47 (95% CI 1.37-1.57) for CLL-related mortality, respectively. Conclusion Survival in CLL patients improved in the era of chemoimmunotherapy and this was largely explained by reduced CLL-related mortality. The increased rate of CLL-related mortality in patients with comorbidities emphasizes the importance of the newer and better tolerated targeted therapy.
Article
Despite the practice-changing advances achieved in the prognostic stratification and treatment of chronic lymphocytic leukemia (CLL), a large fraction of the world population resides in countries where access to many of these advances remains unavailable or subject to severe constraints. Although some of these countries display incidence rates of CLL that are lower than those of developed Western countries, a large number of patients are expected to be diagnosed with CLL in these regions every year. In this article, we review issues regarding management of CLL in some less-resourced countries, with a focus on the evidence basis for epidemiological and clinical information on this disease, the availability of diagnostic and therapeutic resources, and participation in clinical trials. Going forward, challenges that still need to be addressed include the development of unified countrywide registries, guidelines for management applicable to each country, wider availability of prognostic tools, access to new drugs, and policies that ensure these drugs are affordable to all patients worldwide.
Article
Older age has been shown to adversely impact overall survival (OS) in chronic lymphocytic leukemia (CLL) however, prior population-based studies did not analyze the impact of cytogenetic abnormalities or were prior to the availability of ibrutinib. Objectives i) We sought to compare outcomes of patients based on their age at treatment to examine if older age has an impact on OS in patients who were treated during the period when fludarabine-rituximab was the standard upfront therapy and when ibrutinib was first introduced and ii) compare outcomes based on whether the patient received primary treatment at an academic or community-based centre. Methods The BC Provincial CLL Database, a population-based database was used to include patients who have received treatment in British Columbia (BC), Canada between 2004 and 2016. Results A total of 1122 patients were included (<70 years at treatment, n = 589) with median age at diagnosis 66 years. Younger patients had higher Rai stage (55% vs. 44% stage I-II, p < 0.001), higher lymphocyte count at diagnosis (13 × 10⁹/L vs. 10 × 10⁹/L, p = 0.004), greater proportion with B-symptoms at diagnosis (15% vs 10%, p = 0.004), shorter time from diagnosis to treatment (13.9 months vs. 21.4 months, p = 0.001), higher proportion treated at an academic centre (79% vs. 69%, p < 0.001) and more were treated with fludarabine-rituximab or FCR (69% vs. 42%, p < 0.001) compared to older patients. Older patients had both a significantly (p < 0.001) shorter OS from treatment start (4.7 years) and disease specific survival (8.1 years) than younger patients (median OS and DSS not reached). Of interest, there was no difference in OS between patients treated at an academic centre or community centre (p = 0.087). First-line treatment with chemoimmunotherapy improved OS (HR 0.465, 95% CI: 0.381-.567). Conclusions Older age but not treatment-institution type adversely impacts overall survival and CLL survival in treated patients in BC.
Article
Objective Opportunistic infections in chronic lymphocytic leukemia (CLL) have been described in clinical trials, single‐center studies, and case reports. We performed a nationwide study to estimate the incidence and impact of inpatient opportunistic infections. Methods The incidence rate (IR) and incidence rate ratio (IRR) for Swedish CLL patients diagnosed 1994‐2013, and matched controls were calculated, as well as the case‐fatality ratio (CFR). Results Among 8989 CLL patients, a total of 829 opportunistic infections were registered (IR 16.6 per 1000 person‐years) compared with 252 opportunistic infections in 34 283 matched controls (IR 0.99). The highest incidence in the CLL cohort was for Pneumocystis pneumonia (200 infections, IR 4.03); Herpes zoster (146 infections, IR 2.94), and Pseudomonas (83 infections, IR 1.66) infections. The highest risk relative to matched controls was observed for Pneumocystis pneumonia (IRR 114, 95% confidence interval 58.7‐252). The 60‐day CFR for CLL patients with opportunistic infections was 23% (188/821), highest for progressive multifocal encephalopathy (5/7, 71%) and aspergillosis (25/60, 42%). Conclusion We have uniquely depicted the incidence of rare and serious infections in CLL patients and found a relatively high incidence of Pneumocystis pneumonia. Of the most common opportunistic infections, CLL patients with aspergillosis had the poorest prognosis.
Article
This study aims to describe chronic lymphocytic leukemia (CLL) epidemiology, treatment patterns and outcomes in a 2.3-million-member healthcare provider database (Maccabi Healthcare Services, Israel). Newly-diagnosed CLL patients (1999–2017) were followed through 31/3/2018. A total of 1857 newly-diagnosed CLL patients were included. Annual incidence was 5.82 per 100,000 population. Median overall survival (OS) was 12.7 (95%CI: 11.8–13.5) years since diagnosis. Approximately 1/3 initiated treatment within 5 y. A statistical trend (p = 0.066) for improved OS over time was observed among younger patients (age <70 y) treated in 2009–2017 vs. 1999–2008). Among patients treated since 2009 (n = 411; median age = 68y), fludarabine–cyclophosphamide–rituximab (FCR), bendamustine–rituximab and obinutuzumab ± chlorambucil accounted for 19.5%, 12.2% and 11.4% of first line, respectively. Median (95%CI) time to next treatment and OS were 3.1(2.6–3.6) and 7.0(6.3–7.7) years, respectively. CLL incidence in Israel is comparable to developed countries. Real-world data suggest a trend of improved survival over the last decade among patients treated before age 70.
Article
The Research Group for Population-Based Cancer Registration in Japan has been conducting a cooperative study to estimate cancer incidence in Japan. Annual incidence has been estimated for the 14 years from 1975 to 1988. This report presents the age-specific, crude, and age-standardized incidence rates, as well as the number of incident cases by sex and site for each of the years 1975-1984 and for 1988. Long-term trends are also noted utilizing the data from four registries: Miyagi, Osaka, Hiroshima City, and Nagasaki City. These registries showed largely consistent trends in cancer occurrence, though with some minor variations between their respective areas.
Article
BACKGROUND The natural history of chronic lymphocytic leukemia (CLL) is changing, although the reasons (potential changes in the disease's biology or in patterns in patient characteristics, treatment, or referral) are unclear.METHODS This report uses National Cancer Data Base (NCDB) data, which reflect a hospital-based patient population from a broad spectrum of hospitals in the United States. Age, gender, race/ethnicity, income, treatment, overall survival, and relative survival were evaluated according to time period (1985–1990 and 1991–1995). Comparisons were made with U.S. population figures for 1990 and with series published over the last 70 years.RESULTSCLL comprised 22.6% of the 108,396 cases of leukemia in the data base. The risk of developing CLL increased progressively with age and did not plateau; the average age was 69.6 years. At the time of initial diagnosis, 60.5% of patients received no treatment (this proportion increased from 58.1% to 62.7% between the 2 time periods). Overall survival was 48.2% at 5 years and 22.5% at 10 years. The 5-year relative survival was 69.5%, 72.2%, 63.1%, and 41.7% for age groups <40, 40–59, 60–79, and 80+ years, respectively; these rates indicated that CLL, and not comorbid disease, caused the greatest percentage of deaths.CONCLUSIONS The risk of developing CLL increases progressively with age without plateauing and is 2.8 times higher for older men than for older women. There is an increasing trend toward no treatment at the time of initial diagnosis. Long term overall survival of CLL patients is poor. CLL is a more fatal disease among older individuals because of the disease itself, not because of comorbid conditions. Cancer 1999;86:2684–92. © 1999 American Cancer Society.
Article
BACKGROUND Although chronic lymphocytic leukemia (CLL) often is described as the most common leukemia in the U.S. and Western Europe, to the authors' knowledge the true incidence of CLL in the U.S. is unknown. CLL incidence is estimated from tumor registry reports based on tissue pathology and cancer treatment data. Tumor registry data may underestimate the incidence of CLL substantially because CLL can be diagnosed by flow cytometric analysis of peripheral blood cells, and the majority of patients do not require treatment at the time of diagnosis.METHODS To test the hypothesis that CLL has a higher incidence than estimated from tumor registry data, the authors compared the actual and reported incidence of CLL for a 10-year interval at the Central Arkansas Veterans Healthcare System (CAVHS). The accuracy of surveillance methods for new diagnoses of CLL was confirmed by reviewing the lymphocyte counts in 45,009 CAVHS patients over a 4-year period.RESULTSThe tumor registry correctly reported 58 of 93 patients with CLL (62.4%) who were diagnosed between January 1, 1990 and December 31, 1999. The tumor registry correctly reported 100% of patients with CLL diagnosed between 1990–1991 but reported only 34.5% of patients with CLL diagnosed between 1998–1999.CONCLUSIONS The incidence of CLL in the CAVHS was 37.6% higher than estimated from tumor registry data due to an increase in the use of peripheral blood immunophenotype as the only diagnostic test for CLL over the time period of the study. These data suggest that the true incidence of CLL may be substantially higher than estimated from tumor registry data. Cancer 2001;92:1325–30. © 2001 American Cancer Society.
Article
The Eastern Cooperative Oncology Group (ECOG) conducted a study in which patients with advanced chronic lymphocytic leukemia (CLL) were randomized between a regimen consisting of chlorambucil (30 mg/m2 orally day 1) and prednisone (80 mg orally days 1 to 5) (C + P) administered every 2 weeks and a more intensive regimen of cyclosphosphamide (300 mg/m2 orally days 1 to 5), vincristine (1.4 mg/m2 intravenously [IV] day 1), and prednisone (100 mg/m2 orally days 1 to 5) (CVP) given every 3 weeks. Treatment was continued for up to 18 months to maximal response. Of the 122 eligible patients, 60 received C + P, while 62 received CVP. With a median follow-up of 7 years, there were no significant differences in survival (4.8 v 3.9 years, P = .12), complete remission (CR) rate (25% v 23%; P = .83), or duration of response (2.0 v 1.9 years; P = .78) between C + P and CVP. Toxicity was modest despite the prolonged treatment. The long median survival of 4.1 years for stage III and IV patients is superior to that usually reported. This could stem from continuing treatment to maximal response rather than an increase in intensity of therapy. These results are comparable to those reported with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy by other investigators. The data suggest that intermittent C + P administered to maximal response continues to be the standard treatment approach for advanced CLL.
Article
Of the death certificates issued in Sweden in 1978 and stating cancer as the underlying or contributory cause of death, 1634 cases were unrecorded in the national cancer register. In 62 per cent of the cases the criteria for cancer registration were fulfilled. The non-reported cases represented a total deficit of 4.5 per cent calculated on cancer deaths in 1978. The factors responsible for the deficit were investigated. When the diagnosis had been histologically/cytologically confirmed the deficit was less than 2 per cent but was about 30 per cent when the diagnostic basis was only clinical. More than half of the non-notified cancer patients were older than 75 years. Exclusion of this age group and of myeloma and leukaemia cases gave a cancer-register deficit of 2.3 per cent. Non-notification to the Swedish cancer registry can be diminished by supplementation with data from death certificates, as practised in other Nordic countries. On regional basis these death certificates will now be collected and used as a supplement to the cancer notification in Sweden.
Article
Prednimustine, a new antitumour drug, is a chlorambucil ester of prednisolone. The present prospective randomized study compares the effect of continuous low-dose (B) and intermittent high-dose (C) prednimustine in previously untreated patients with progressive CLL and WDLL. The control group received continuous chlorambucil/prednisolone therapy (A). One hundred and eighteen patients, 88 CLL and 30 WDLL, were evaluable. Response to therapy (greater than 50% improvement) was noted in 61, 55 and 57% in groups A, B and C respectively. The difference was not statistically significant. Time to response, response duration and survival did not show any differences between the groups. Responding patients survived longer than patients with stationary and progressive disease. Median survival time was 72 months from diagnosis and 52 months from start of therapy, with no differences between the treatment groups. Toxicity of prednimustine was usually mild and similar to that of the two constituents. Treatment schedule C showed a slight advantage with regard to frequency of side effects. In conclusion, in this study the therapeutic effect of prednimustine was equal to that of its constituents administrated separately.
Article
Survival from cancer over a certain time period is often measured by the 'relative survival rate'. This is the ratio of the observed survival rate in the group of patients to the survival rate expected in a group of people in the general population, who are similar to the patients with respect to all of the possible factors affecting survival at the beginning of the period, except for the disease under study. When patterns of patient withdrawal differ for a number of subgroups of patients with equal relative survival rates, the current method of derivation of the relative survival rate is biased. A method based on the concept of an 'expected life table' is proposed for removal of the bias. Examples based on material from the Finnish Cancer Registry suggest that the practical performance of the proposed method is better than that of other alternatives, even when the relative survival rates in the subgroups are not equal.
Article
To characterize in detail the outcomes of HLA-identical sibling bone marrow transplantation for chronic lymphocytic leukemia (CLL) in patients younger than 60 years of age. Retrospective cohort study. 30 centers for bone marrow transplantation worldwide, which reported data on outcome of HLA-identical sibling bone marrow transplantation for CLL to the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry between 1984 and 1992. 54 patients diagnosed with CLL (median age, 41 years; range, 21 to 58 years). The median interval from diagnosis to transplantation was 37 months (range, 5 to 130 months). At the time of transplantation, 3 patients were at Rai stage 0; 10 were at stage 1; 10 were at stage 2; 7 were at stage 3; and 22 were at stage 4. Transplant regimens varied. Most patients received high-dose cyclophosphamide and total body irradiation, followed by infusion of bone marrow from an HLA-identical sibling. After transplantation, immune suppression with cyclosporine or methotrexate or both was generally used to prevent graft-versus-host disease. The primary outcome was survival. We also studied hematologic remission, defined as normalization of the leukocyte count, hemoglobin level, and platelet count, and absence of lymphadenopathy and splenomegaly. 38 patients (70%) achieved hematologic remission. Twenty-four (44%) remain alive a median of 27 months (range, 5 to 80 months) after transplantation. Three-year survival probability was 46% (95% CI, 32% to 60%). Three patients who received transplants at Rai stage 0 remain alive 21, 32, and 45 months after transplantation. Three-year survival probabilities were as follows: 68% (CI, 38% to 98%) in 10 patients who received transplants at Rai stage 1, 30% (CI, 2% to 58%) in 10 patients who received transplants at Rai stage 2, 57% (CI, 21% to 93%) in 7 patients who received transplants at Rai stage 3, and 34% (CI, 12% to 56%) in 22 patients who received transplants at Rai stage 4 CLL. Five patients (9%) died of progressive leukemia and 25 (46%) of treatment-related complications. Bone marrow transplants from HLA-identical siblings can result in hematologic remission and survival in persons with CLL, but it is uncertain how these results compare with those of conventional therapies.
Article
Fludarabine seems to be a promising treatment for patients with advanced chronic lymphocytic leukaemia (CLL). We compared fludarabine therapy with the combination of cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of CLL in a randomised, multicentre prospective trial. Patients older than 18 years of age were entered into the study if they presented with previously untreated B-cell lineage CLL (B-CLL) of Binet stages B or C or relapsed B-CLL pretreated with chorambucil or similar non-anthracycline-containing regimens. Patients were randomly assigned to either fludarabine (25 mg/m2 per day on days 1-5) or CAP (cyclophosphamide 750 mg/m2 per day and doxorubicin 50 mg/m2 per day on day 1, and prednisone 40 mg/m2 per day on days 1-5), both given for six courses. Of 196 evaluable patients, 100 were previously untreated whereas 96 patients had received prior therapy. Remission rates were significantly higher after fludarabine than CAP, with overall response rates of 60% and 44%, respectively (p = 0.023). A higher response rate to fludarabine was observed in both untreated (71% vs 60%, p = 0.26) and pretreated (48% vs 27%, p = 0.036) cases, although the difference was statistically significant only in pretreated cases. In the latter group, remission duration and survival did not differ between treatment groups with a median remission duration of 324 days after fludarabine and 179 days after CAP (p = 0.22) and median survival times of 728 days and 731 days, respectively. In untreated cases, on the other hand, fludarabine induced significantly longer remissions than CAP with the median not yet reached after fludarabine and a median of 208 days after CAP (p < 0.001). This effect also translated into a tendency towards longer overall survival after fludarabine (p = 0.087). Treatment-associated side-effects consisted in both regimens of predominantly myelosuppression and in particular granulocytopenia. CAP-treated patients had a higher frequency and severity of nausea and vomiting (25% vs 5%, p < 0.001) and alopecia (65% vs 2%, p < 0.001). Fludarabine provided an effective and well-tolerated therapy for patients with advanced CLL, which compared favourably with CAP as one of the most effective standard regimens. In second-line therapy, fludarabine induced a significantly higher rate of complete and partial remissions, while in first-line therapy a significant prolongation of remission was obtained, which may translate into an improvement of overall survival.