Hematopoietic stem cell transplantation rates and long-term survival in acute myeloid and lymphoblastic leukemia: real-world population-based data from the Swedish Acute Leukemia Registry 1997-2006.

Abstract

Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in acute leukemia, but outcome is hampered by toxicity. Population-based data avoid patient selection and may therefore substitute for lack of randomized trials.
We evaluated alloSCT rates within the Swedish Acute Leukemia Registry, including 3899 adult patients diagnosed from 1997 through 2006 with a coverage of 98% and a median follow-up of 6.2 years.
AlloSCT rates and survival decreased rapidly with age >55 years. The 8-year overall survival (OS) was 65% in patients <30 years and 38% in patients <60 years and was similar for acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Among 1073 patients <60 years, alloSCT was performed in 42% and 49% of patients with AML and ALL, respectively. Two-thirds of the alloSCTs were performed in first complete remission, and half used unrelated donors, the same in AML and ALL. Regional differences in management and outcome were found: 60% of AML patients <40 years received alloSCT in all parts of Sweden, but two-thirds of AML patients 40-59 years had alloSCT in one region compared with one-third in other regions (P<.001), with improved 8-year OS among all AML patients in this age cohort (51% vs 30%; P = .005).
More Swedish AML patients received alloSCT, and long-term survival was better than in recently published large international studies, despite our lack of selection bias. There was no correlation between alloSCT rate and survival in ALL. In adult AML patients <60 years of age, a high alloSCT rate was associated with better long-term survival, but there was no such correlation in ALL.

Full text

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Hematopoietic stem cell transplantation rates
and long-term survival in acute myeloid and
lymphoblastic leukemia.

Real w orld population-based data from
the Sw edish Acute Leukemia Registry 1997-2006

Gunnar Juliusson1, Karin Karlsson1, Vladimir Lj Lazarevic1, Anders Wahlin2,
Mats Brune3, Petar Antunovic4, Åsa Derolf5, Hans Hägglund6, Holger
Karbach4, Sören Lehmann6, Lars Möllgård6, Dick Stockelberg3, Helene
Hallböök7, and Martin Höglund7, for the Swedish Acute Leukemia Registry
Group, the Swedish Acute Myeloid Leukemia Group, and the Swedish
Adult Acute Lymphoblastic Leukemia Group.

From the Departments of Hematology/Medicine at University Hospitals and Regional
Tumor Registries at Lund1, Umeå2, Göteborg3, Linköping4, Solna5, Huddinge6, and
Uppsala7, Sweden.

Correspondence to: Prof Gunnar Juliusson, Stem Cell Center BMC B10, Lund University,
SE 22185 Lund, Sweden. Gunnar.Juliusson@med.lu.se. Telephone + 46-46-171315, Fax
+ 46-46-2110908.

Running head: AlloSCT Rates and Survival in Acute Leukemia
Data presented at Oral Session at European Blood and Marrow Transplantation Group
Meeting, Vienna, March 2010.

Word counts: Abstract 243, Manuscript 3450
2 Tables, 5 Figures, 35 References.

Key words: acute myeloid leukemia, acute lymphoblastic leukemia, allogeneic stem cell
transplantation, population based, performance status, non-relapse mortality, survival
 
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ABSTRACT

Allogeneic stem cell transplantation (alloSCT) reduces relapse rates in
acute leukemia, but outcome is hampered by toxicity. Population-based
data avoid patient selection and may therefore substitute for lack of
randomized trials. We evaluated alloSCT rates within the Swedish Acute
Leukemia Registry, including 3899 adult patients diagnosed 1997-2006
with a coverage of 98% and a median follow-up of 6.2 years. AlloSCT
rates and survival decreased rapidly with age over 55. The 8-year overall
survival (OS) was 65% in patients < 30 years, and 38% < 60 years,
similar for AML and ALL.
Among 1073 patients < 60 years was alloSCT performed in 42% and 49%
of patients with AML and ALL, respectively. Two thirds of the alloSCTs
were done in CR1, and half used unrelated donors, same in AML and ALL.
Regional differences in management and outcome were found: in AML< 40
years 60% received alloSCT in all parts of Sweden, but in AML 40-59
years two thirds had alloSCT in one region as compared to one third in
other regions (p< 0.001), with improved 8-year OS among all AML patients
in this age cohort (51% vs 30% ; p= 0.005). More Swedish AML patients
received alloSCT and long-term survival was better than in recently
published large international studies, despite our lack of selection bias.
There was no correlation between alloSCT rate and survival in ALL.
In adult AML patients < 60 years a high alloSCT rate is associated with
better long-term survival, but there was no such a correlation in ALL.

 
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I NTRODUCTI ON
Acute leukemia is a group of heterogeneous diseases that affects all
ages1,2. Some entities, such as childhood ALL and acute promyelocytic
leukemia (APL) have become highly curable through intensive and
complex treatments developed during recent decades, but most acute
leukemia patients still eventually die from their disease. Genetic
characterization has increased our understanding of leukemia, defines
prognostic subgroups, and may be used to tailor therapy. However,
current therapy needs to be intensive and has limited selectivity; we still
await truly targeted therapy.
Allogeneic transplantation of hematopoietic stem cells (alloSCT) was
introduced to allow intensified treatment3. Twenty years ago4 registry data
confirmed that immune effects from alloSCT protect from leukemia
relapse, as suggested in the 1950’s5, which since then is well established
as the graft-versus-leukemia effect6,7. AlloSCT increases treatment-related
mortality, and is only applicable to a minority of patients8. Availability of
donors, comorbidities9, leukemia control and patient recovery from
toxicities are matters of concern. However, donor registries, improved
supportive care, and transplant procedures with less early toxicity10 have
increased the potential patient numbers for alloSCT.
Clinical studies11-18 always imply selection of patients, and alloSCT registry
studies7,19 report transplanted patients only. The comparison of patients
with and without donors is hampered by incomplete transplantation rate in
patients with donors, and is not useful in the era of unrelated donor
transplants. Randomization is the established technique to reduce the
influence of selection on the outcome of clinical studies, but has so far not
been performed to assess the impact of alloSCT. However, another way to
eliminate selection is to analyze large population-based clinical materials
provided that inclusion and outcome analysis both are complete.
The proportion of patients receiving transplant depends in part on the
indications used and definitions of disease risk. However, timing for donor
search is also crucial, since few have a suitable family donor, and donor
search from registries usually require several months. In the Swedish
Acute Leukemia Registry20,21 40% of AML patients below 60 years who
enter first complete remission (CR1) relapse, 25% within 6 months and
10% within three months from CR1. Fewer transplants would probably
result in higher relapse rates. Early donor search may therefore prevent
some relapses through SCT. Initial management of the patient, including
the induction and maintenance of remission, as well as support of physical
 
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and mental status are also important in order to get the patient to
transplant.
SCT is only one part of the overall treatment of acute leukemia, and to
evaluate its role it is essential to study its impact on the overall leukemia
population, and not focus on transplanted patients only. Population-based
studies provide the unique opportunity to evaluate all patients, including
consideration of pretransplant selection and initial management. The
Swedish Acute Leukemia Registry20 is a unique source for studies of acute
leukemia in a well-defined population. For the purpose of this analysis
specific validations of transplants were performed. Regional differences in
management20,21 highlight the importance of SCT for the achievement of
long-term survival.

PATI ENTS AND METHODS
The Swedish Cancer Registry is a nation-wide compulsory dual report
system developed in 1958, and the Swedish personal ID code system,
established in 1947, provides a unique possibility to track all individuals
eternally. The Swedish Adult Acute Leukemia Registry20 was founded in
1997 by the Swedish Society of Hematology, is supported by the Swedish
National Board of Health and Welfare, and run in collaboration with the
Regional Tumor Registries in each of the six Swedish health care regions,
each covering populations ranging from 0.9 to 1.9 million people, in total
9 million. Each region contains one university hospital with EBMT
accreditation for alloSCT, including access to unrelated donors. This
analysis includes patients diagnosed 1997 through 2006, but excludes
APL, since APL is rarely an indication for SCT.
Almost all patients below 60 years of age received intensive remission
induction (Table 1), in contrast to older AML patients, as previously
published20,21. Before 2006 there were no nationwide AML guidelines, but
standard anthracyclin (daunorubicin 60 mg/sqm or idarubicin 12 mg/sqm
days 1-3) and cytosine arabinoside based induction protocols followed by
repeated intensive consolidations22 were used. The ara-C dose during
induction was mostly 200 mg/sqm for 7 days, but 1 g/sqm b.i.d. was used
in some parts of Sweden for certain periods. ALL patients also received
short intensive combination chemotherapy as induction followed by
intensive consolidations and subsequent maintenance23,24. Patients with
high-risk AML and ALL according to established criteria22,24 were
recommended alloSCT in CR1, but intermediate risk AML patients could
 
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also be considered if a suitable donor was available, and if the balance
between disease-related and transplant-related risk was judged to favour
alloSCT. Thus, early donor search was recommended for patients without
contraindication for alloSCT. Most young patients in relapse were treated
with an attempt to induce a second remission to be followed by alloSCT.
Selected patients with incomplete remission, such as partial induction
failure or early untreated relapse could also be considered for alloSCT.
Patients with favourable genetic risk were not selected for alloSCT in CR1.
Genetic risk factor evaluation is currently not available in the complete
registry. Given the unselected patient population the overall distribution of
risk factors would be similar as reported from previous and recent
Swedish22 and international studies. Cytogenetic risk factor25 analyses,
without molecular markers, have been performed in population-based
leukemia subsets in Sweden, not completely matching the current
registry: among 279 previously reported AML patients below 60 years,
excluding APL, 8% had CBF-leukemia, 71% intermediate-risk
cytogenetics, 18% high risk disease, and 4% had an unevaluable
karyotype22. In our most recent AML cohort on 243 patients below 60
years diagnosed since 2007 and including FLT3-ITD and NPM1-mutation
for risk classification, the corresponding figures were 14% , 54% , 28% ,
and 4% , respectively. In the Swedish ALL Registry on recently diagnosed
patients below 60 years 38% had high-risk disease, including 20%
Philadelphia-positive ALL26. Among adult ALL patients below 30 years 26%
had high-risk disease, as compared to 47% in patients aged 30-59 years.
Information on transplantation was specifically validated for all patients
below 60 years through the local registries at each of the six transplant
centres, but transplant-related factors, such as type of conditioning will
not be discussed here.
Survival was always checked using the Swedish Population Registry, with
a complete update in December 2008.
The leukemia registry asks if deceased patients have died in remission,
and the response ‘Yes’ was used to define ‘Non-relapse mortality’ (NRM)
at any time, whereas ‘No’ indicates ‘Leukemia death’. Patients who have
died with no such response reported were classified as ‘Death unspecified’,
which thus indicates range of uncertainty.
In previous analyses we found differences in management between the
different geographical regions, and we therefore evaluated possible
differences in transplant rates and outcomes according to region20,21.
 
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There is no difference in patient access to health care between the
regions, although the geographic distance to the transplant center may
vary. The overall health and survival of the total population is similar
between the regions.
The ethics of the study was approved by the ethics committee chairman in
Linköping at initiation of study. Statistical analyses were performed using
the Statistica software (Tulsa, OK, USA).

RESULTS
The Swedish Acute Leukemia Registry contains 3899 adult patients over
16 years with acute leukemia according to WHO criteria, diagnosed during
the full ten years from 1997 through 2006. Age and sex-adjusted
incidences are previously reported20,26. There were 3318 cases with AML,
including 113 with APL, 472 with ALL, and 109 with acute undifferentiated
or unclassified leukemia. This corresponds to 98% of all patients with
acute leukemia in the Swedish Cancer Registry. The median age of AML
(non-APL) patients was 71 years (quartile range [Q1-Q3], 60-79 years;
mean 68 years), and of ALL patients 54 years (Q1-Q3, 36-69 years; mean
52.2 years). The median observation of survivors was 6.2 years.
The proportion and number of patients receiving alloSCT at various
disease phases according to age are shown in Figure 1. In addition 8
patients 65-69 years received alloSCT, 7 of them in CR1. The SCT rates
decreased rapidly from age 55 in AML and at somewhat older age in ALL.
There were no sex differences in transplant rates.
Allogeneic stem cell transplants in patients below 60 years
Subsequent analyses thus focus on patients below 60 years of age at
diagnosis, i.e., 797 with non-APL AML, and 276 with ALL (Table 1).
AlloSCT was performed in 42% of patients with AML (non-APL) and in
49% with ALL. In AML-patients, alloSCT was performed in CR1, second
complete remission (CR2), and other disease phases in 29% , 8% , and 5%
of the overall patients, respectively, and the corresponding figures for ALL
were 33% , 12% , and 3% , respectively. Retransplants were not considered
in the analysis. Of patients with secondary AML 32% received alloSCT
(18% in CR1, 3% in CR2, 11% in other disease phases). In addition, 7%
of AML-patients and 3% of ALL-patients had autologous SCT; this
procedure was excluded from routine management in the latter part of the
study period, and will not be further discussed here.
 
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Allogeneic donors were unrelated in 50 percent of the transplants, similar
for AML (51% ) and ALL (49% ), but unrelated donors were used in 46% of
SCTs performed in CR1 as compared to 61% of transplants in CR2.
AlloSCT in CR1 was performed at a median of 4.5 and 5.2 months from
diagnosis of ALL and AML, respectively, and there was a median of 3 and
3.5 months from CR1 to such transplants, respectively (Table 1).
Transplants with unrelated donors were performed about 6 weeks later
than sibling donor transplants.
Death rates due to different causes are shown in Figure 2, separately for
AML and ALL according to disease status at alloSCT, age group for
transplanted patients, and type of donor, with patients who did not
receive alloSCT shown for comparison. In AML there was low NRM, with
limited influence of disease status at SCT, age, and donor type, whereas
ALL patients over 40 years had somewhat higher NRM.
Overall survival
Overall survival for patients below 60 years of age is very similar for AML
and ALL (42% 5-year and 38% 8-year OS), despite that ALL patients are
younger due to their flat age-adjusted incidence up to 60 years26,27. More
ALL patients enter CR, but survival from CR1 is greater in AML than in ALL
(5- and 8-year OS from CR1 of adult patients < 55 years: 60% and 54% in
AML, vs 46% and 43% in ALL).
Overall survival according to age20,26 is shown in Figure 3. Young adult
patients less than 30 years had the best survival, i.e., 65% 8-year
survival in both ALL and AML. There was a continuous decrease of survival
with age20.
Disease status at transplant influenced survival from transplant in both
AML and ALL, mainly due to continuing relapses after alloSCT in later
phases. Age however had limited influence on survival for those AML
patients who actually received alloSCT. In ALL however, older age had
negative impact on survival also following alloSCT (Figure 3c-d).
Our study does not permit a donor vs no donor comparison, and patients
who receive transplant are obviously selected and different from those
who do not receive transplant. Among AML patients below 60 years those
who received alloSCT were younger than those who did not, whereas age
did not influence selection to alloSCT in ALL (Table 1). AML patients below
60 years who received alloSCT had better 5-year survival from CR1 than
 
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those who did not (61% vs 48% , log rank p= 0.0005), whereas this
difference was not seen in ALL (40% vs 50% , p= 0.8) (Figure 4).
Regional differences
We found that transplant rates for AML were higher in one of the health
care regions (SE), where 57/92 (62% ) of the patients below 60 years
received alloSCT, as compared to 274/705 (39% ) in other regions (Chi-
square 17.9, p< 0.001). This higher alloSCT rate in Region SE was due to
a higher rate in patients 40-59 years, i.e.,41/63 (65% ) as compared to
175/542 (32% ) in other regions (Chi-square 26.6, p< 0.001) (Figure 5a),
whereas all regions performed alloSCT in about 60% of AML patients < 40
years. AlloSCT for AML was in 69% performed in CR1, without differences
between age groups or regions. Thus, of AML-patients < 60 years, 45%
had SCT in CR1 in Region SE, vs 27% in other regions; corresponding
figures for AML-patients 40-59 years was 46% vs 22% .
There was a strong regional survival difference, with significantly more
patients with AML surviving in region SE as compared to other regions (log
rank analysis p= 0.04 in all patients < 60 years; p= 0.005 in patients 40-59
years [Figure 5b]). This survival difference was not due to differences in
outcome of transplanted patients (Figure 5c). Within the age group 40-59
years the distribution of risk factors between region SE and other regions
was similar, i.e., age (mean 51.8 vs 51.6 years, p= 0.63), performance
status (mean 1.0 vs 1.1, p= 0.19), and secondary AML (22% vs 17% ,
p= 0.50), respectively, and the median time from diagnosis to alloSCT in
CR1 was 160 days in region SE vs 161 days in other regions.
In ALL, regional differences were also identified, since regions UO and N
performed SCT in 60% of the patients as compared to 43% in other
regions (Chi-square, p< 0.01), but this difference was similar in all age
groups (63% vs 49% in ages < 40 years, and 58% vs 37% in ages 40-59
years [Figure 4]). The proportion of transplants performed in CR1 was
again two thirds and similar between regions and age groups. The high
alloSCT rate for ALL in regions UO and N did not transform into a survival
advantage.
Comparison w ith international data in AML
A number of large prospective clinical trials in younger patients with AML
from American and European cooperative groups have recently been
published11,12,15,18,28. We therefore performed a direct comparison of our
population-based study to published data as regards characteristics of the
study population, alloSCT rates, and outcome (patients up to and
 
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including 60 years; Table 2). Our study included virtually all patients,
including those who were not fit for intensive induction therapy, those
with poor performance status, and those with secondary AML, all factors
with negative impact on feasibility of alloSCT and outcome. Still the
Swedish alloSCT rate was clearly greater than that of published clinical
trials always including selected patient groups, and more importantly the
long-term overall survival seems superior (Table 2).

DI SCUSSI ON
We here present the largest truly population-based analysis on alloSCT
rates in adult acute leukemia. We report on all Swedish patients
diagnosed during a ten-year period, including those with poor
performance status and not eligible for intensive treatment that never
enter clinical studies. Long-term survival follow-up is complete.
Transplantation data were specifically validated through transplant centre
files. Our presented data is thus undisputable, however, the interpretation
should be discussed.
Our data show higher alloSCT rates in AML than what is recently published
from large clinical study groups, and in patients up to 60 years we see a
better long-term survival, despite worse prognostic features in the
unselected population (Table 2). Within Sweden, region SE had the best
survival of AML patients below 60 years, but the survival difference was
restricted to the age group 40-59 years. No difference in patient
characteristics was identified between region SE and other regions, as
could be expected due to the lack of selection. However, the alloSCT rate
in ages 40-59 was much higher in region SE, since AML-patients aged 40-
59 years here received alloSCT as frequently as younger patients, in
contrast to other parts of Sweden where older patients received alloSCT
less often than younger. A high alloSCT rate in patients close to 60 years
was possible through systematic use of intensive but less toxic
conditioning programs for alloSCT29,30, introduced in 1996 in region SE.
However, the choice of donor, the disease phase at transplant, as well as
the survival of those who were actually transplanted, were similar.
Together these data indicate a positive correlation between the alloSCT
rate and the long-term survival in AML.
AlloSCT was used as consolidation in CR1 for high-risk AML, but also for
intermediate risk disease when the benefit risk analysis was judged to
favour alloSCT. However, such benefit risk evaluation is always an
 
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individual interpretation of available data, but also based on tradition,
personal experience, and attitude towards SCT.
An important prerequisite of a positive impact of high alloSCT rates is low
transplant-related mortality, and the Swedish results are encouraging but
not exceptional, also in advanced disease, with unrelated donors and in
higher ages. This supports the utilization of alloSCT in such cases.
Overall survival from diagnosis of AML is highly age dependent20 (Figure
3). However, survival from alloSCT according to age did not show a similar
drop, but remained acceptable for those selected patients who receive
transplant for AML at somewhat older ages (Figure 3). This has also been
found in two other recent studies19,31. More older patients have
comorbidities and contraindications to alloSCT, and the positive outcome
for those who received alloSCT is likely due to a positive selection of
patients. However, the data from region SE rather suggests that there is a
possibility to improve survival if more of the many AML-patients over 50
years would receive alloSCT.
The alloSCT rate is dependent on several factors, such as inclusion criteria
according to protocol, where the genetic risk is more easily assessed than
the less objective interpretation of physical status, life style issues, and
comorbidity that constitute biological age. This has to be evaluated shortly
after diagnosis to ensure early initiation of donor search, in order to be
able to perform the transplant in due time. In most studies there are
proportions of patients with donors that still do not get to transplant, in
addition to those for whom donor search started too late. We noted the
best survival of AML patients in the region with the highest alloSCT rate,
reflecting an active donor search policy and a positive attitude towards
alloSCT. However, we cannot be sure that this rate per se is the main
reason for the positive outcome, and therefore should be implemented
elsewhere. A well organized health-care gets more patients to transplant
but should also provide efficient non- and pre-transplant treatment,
leading to the observed result. It might well be that a part of the observed
outcome difference is not depending on matters that are well defined in
clinical protocols, but instead due to logistics within the collaborating
institutions taking care of the patient. More efforts should be made to
analyse such procedure-related issues32.
Non-transplanted AML-patients did not as well as those who received
transplants (Figure 4), and there was no regional difference in the
outcome of non-transplanted patients. However, selection mechanisms
 
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influence outcome when patients are non-randomly divided according to
management, as in most transplant studies.
We did not find a corresponding correlation between alloSCT rate and
survival in ALL. Our AML and ALL patients come from the same total
population and are treated at the same institutions, and thus a direct
comparison of alloSCT utilization and outcome is possible. Two thirds of
young adults survive, similar for ALL and AML. However, the survival from
CR was better, and the negative impact of age was less in AML than in
ALL. Two thirds of the alloSCTs were performed in CR1 in both leukemia
types. When comparing survival for patients with or without alloSCT,
transplanted AML-patients did better, but this was not true in ALL (Figure
4). Furthermore, regional high rates of alloSCT were associated with
better survival in AML, but not in ALL. Philadelphia-chromosome positive
ALL constitutes an indication for alloSCT in CR1, but the precise role of
alloSCT in other ALL subsets has to be more clearly established, especially
in patients over 30 years of age where outcome is disappointing with or
without alloSCT.
There was no positive correlation between number of transplants
performed within the institution and outcome, the so called
transplantation ‘centre size’ effect33,34, since the best AML results were
seen in a region with a smaller transplant volume. Our data support the
assumption35 that one transplant team per million people might provide
optimal access to SCT.
We have here reported allogeneic transplantation rates in acute leukemia
from a total and unselected population diagnosed during a ten-year
period, with long-term follow up. We have identified similarities and
differences in management and outcomes of AML and ALL. Overall we
found that despite inclusion of all patients in the analysis there were high
alloSCT rates and a good overall survival. Even more, high alloSCT rates
in AML patients close to 60 years of age resulted in a survival comparable
to that of younger patients. Our data thus support early donor search and
an active management to ensure that eligible patients receive transplants
timely.


 
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Acknow ledgements. We thank data managers at the Regional Tumor
Registry Lund, and all Swedish hematologists who have carefully reported
all their patients to the registry. The registry receives funding from the
Swedish Association of Local Authorities and Regions (SKL).
Current members of the Swedish Acute Myeloid Leukemia group are
Martin Höglund (chairman), Petar Antunovic, Åsa Derolf, Gunnar
Juliusson, Vladimir Lazarevic, Sören Lehmann, Lars Möllgård, Dick
Stockelberg, Ulf Tidefelt, Anders Wahlin, and Lovisa Wennström.
Current members of the Swedish Adult Acute Lymphoblastic Leukemia
group are Helene Hallböök (chairperson), Tomas Ahlgren, Per Bernell,
Erik Hulegårdh, Hans Hägglund, Holger Karbach, Karin Karlsson, Piotr
Kozlowski, Olle Linder, Claes Malm, Alicja Markuszewska Kuczynska,
Bengt Smedmyr, Beata Tomaszewska-Toporska, Anders Wahlin, and Maria
Åström.

Authorship and conflict of interest. GJ is professor of Hematology at
the Lund Strategic Research Center for Stem Cell Biology and Cell Therapy
at Lund University, chairman of the Swedish Adult Acute Leukemia
Registry and the Acute Myeloid Leukemia Registry, and main responsible
for the analyses and the manuscript. MH is chairman of the Swedish
National AML group and chairman of the Swedish Society of Hematology.
KK is chairperson of the Acute Lymphoblastic Leukemia Registry and HeH
is chairperson of the Swedish Adult Acute Lymphoblastic Leukemia Group.
GJ, KK, VL, AW, PA, ÅD, HaH, HK, SL, LM, DS, HeH and MH are board
members of the Swedish National AML and ALL groups. MB is chairman of
the Swedish Blood and Marrow Transplant Group. All authors have
participated in data reporting, have evaluated data and approved
manuscript. There are no conflicts of interest regarding this manuscript.
 
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TABLES AND FI GURES
Table 1. Summary of clinical findings in patients younger than 60 years

AML (non-APL)
All

797
401/396 (50%)
50 (40-55)
649 / 148 (19%)
762 (96%)
640 (99%)
122 (82%)
199 (100%)
486 (96%)
59 (81%)

580 (73%)
520 (80%)
60 (41%)
172 (86%)
361 (71%)
30 (41%)


ALL
All

alloSCT alloSCT
N
Sex: M/F (%F)
Age: m edian (Q1-Q3), years
De novo / secondary* (% sec)
Intensive treatm ent: all
De novo
Secondary*
WHO/ECOG PS 0
PS I/II
PS III/IV
331 (42%)
162/169 (51%)
45 (35-52)
284/47 (14%)

276
162/114 (41%)
39 (27-50)
276/14 (5%)
274 (99%)
260 (99%)
14 (100%)
71 (100%)
178 (99%)
19 (100%)
134 (49%)
83/51 (38%)
38 (27-47)
132/2 (1%)

CR rate: all
De novo
Secondary*
PS 0
PS I/II
PS III/IV
Days from Diagnosis to alloSCT:
m edian (Q1-Q3), all
AlloSCT in CR1
AlloSCT in CR2
AlloSCT, other phases
AlloSCT in CR1, sibling donor
AlloSCT in CR1, unrelated donor
Days from CR1 to AlloSCT in
CR1

244 (88%)
239 (91%)
5 (36%)
62 (87%)
162 (90%)
15 (79%)



173 (129-307)
156 (127-193)
609 (449-829)
132 (104-163)
136 (114-163)
176 (151-210)
106 (75-150)

168 (120-312)
139 (111-174)
833 (516-1147)
170 (103-155)
115 (103-155)
165 (137-181)
93 (75-132)
Legend. *) Secondary leukemia is defined by previous hematologic disease,
and/or previous cytotoxic treatment for malignant disorder. PS, performance
status according to WHO/ECOG. Q1-Q3, quartile range.

 
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Table 2. Patient characteristics, alloSCT rates, and outcomes of AML
patients up to and including 60 years in this study, as compared to five
recently published large AML studies.

Study
AML<61 yrs
Study
year
N Age
m edian
% 2nd
AML
% PS
0/I-II/III-IV
% Allo
SCT in CR1
OS %
5 yrs
OS %
8 yrs
OS m onths
m edian
Sweden 1997-
2006
851 51 23 25 / 66 / 9 27 41 35 26
Sweden
Region SE
Sam e 96 49 22 24 / 67 / 8 44 52 50 86
ECOG 2002-
2008
657 48 Few 5 18 / 37 16 / 24
EORTC
GIMEMA
1993-
1999
2157 44 4 43 / 55 / 2 15 33 17
GAMLCG 1993-
2005
520 45 0 12 32 20 / 28
MRC
AML12
1994-
2002
1658
1193
35 / 36
47
7
10
57 / 36 / 7
67 / 28 / 5
9
10
39 / 42
32

CALGB 2001-
2003
302 46 0 7
(46% autoSCT)
37 20 / 22

Legend: PS, performance status according to WHO/ECOG. OS, overall survival.
ECOG study15 randomized between two daunorubicin doses, EORTC/GIMEMA
study18 between different anthracyclin drugs, and GAMLCG study11 between TAD
HAM vs HAM HAM. Two subsets of the MRC AML12 study12 are shown, with
randomization between MAE and ADE (upper row), and between S-DAT and H-
DAT (lower row). CALGB study28 included patients< 60 years and randomized
between ADE with or without PSC-833. Survival data from both treatment arms
in a study are given if different. To facilitate comparison this table shows data on
Swedish adult patients up to and including 60 years of age.

 
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FI GURE LEGENDS
Figure 1. Proportion of patients receiving alloSCT in different disease
phases according to diagnosis and age. Number of patients is given below
graph.

Figure 2. Causes of death in patients below 60 years according to (a)
diagnosis and alloSCT at different disease phases, and for (b)
allotransplanted patients according to age and type of donor.
NRM indicates non-relapse mortality, i.e., death in remission. Death
unspecified indicates deceased patients without report stating death in
remission or death from leukemia. URD indicates unrelated donor. Number
of patients is shown below graph.

Figure 3. Overall survival from diagnosis according to (a) age in AML
patients, and (b) age in ALL patients, and survival from alloSCT in first
complete remission according to age for (c) AML, and (d) ALL.

Figure 4. Overall survival for patients< 60 years from CR1 date according
to alloSCT vs no transplant for (a) AML and (b) ALL).

Figure 5. Regional variation. (a) Proportion of patients 40-59 years
receiving SCT in different disease phases according to diagnosis and
region, (b) overall survival from diagnosis for AML patients 40-59 years,
and (c) overall survival from alloSCT in CR1 for AML patients < 60 years
according to region.

 
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