Mipi blood 2008

doi:10.1182/blood-2007-06-095331
Prepublished online Oct 25, 2007;
2008 111: 558-565
Network
German Low Grade Lymphoma Study Group (GLSG) and the European Mantle Cell Lymphoma
Eimermacher, Hannes Wandt, Joerg Hasford, Wolfgang Hiddemann, Michael Unterhalt and for the
Peter, Wolfram Jung, Bernhard Wörmann, Wolf-Dieter Ludwig, Ulrich Dührsen, Hartmut
Kluin-Nelemans, Michael Pfreundschuh, Marcel Reiser, Bernd Metzner, Hermann Einsele, Norma
Eva Hoster, Martin Dreyling, Wolfram Klapper, Christian Gisselbrecht, Achiel van Hoof, Hanneke C.
cell lymphoma
A new prognostic index (MIPI) for patients with advanced-stage mantle
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CLINICAL TRIALS AND OBSERVATIONS
Anew prognostic index (MIPI) for patients with advanced-stage mantle cell
lymphoma
Eva Hoster,1,2 Martin Dreyling,1 Wolfram Klapper,3 Christian Gisselbrecht,4 Achiel van Hoof,5 Hanneke C. Kluin-Nelemans,6
Michael Pfreundschuh,7 Marcel Reiser,8 Bernd Metzner,9 Hermann Einsele,10 Norma Peter,11 Wolfram Jung,12
Bernhard Wo¨rmann,13 Wolf-Dieter Ludwig,14 Ulrich Du¨hrsen,15 Hartmut Eimermacher,16 Hannes Wandt,17 Joerg Hasford,2
Wolfgang Hiddemann,1 and Michael Unterhalt,1 for the German Low Grade Lymphoma Study Group (GLSG) and the
European Mantle Cell Lymphoma Network
1Department of Internal Medicine III, and 2Department of Medical Informatics, Biometry, and Epidemiology, University of Munich, Munich, Germany; 3Institute of
Pathology, Lymph Node Registry, University of Kiel, Kiel, Germany; 4Department of Hematology, Hoˆpital Saint Louis, Paris, France; 5Department of Hematology,
Akademisch Ziekenhuis St-Jan, Bruges, Belgium; 6Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, the
Netherlands; 7Department of Internal Medicine I, Saarland University Medical School, Homburg, Germany; 8Department of Internal Medicine I, University of
Cologne, Cologne, Germany; 9Department of Oncology and Hematology, Klinikum Oldenburg, Oldenburg, Germany; 10Department of Internal Medicine II,
University Hospital of Wu¨rzburg, Wu¨rzburg, Germany; 11Department of Hematology/Oncology, Carl-Thiem Hospital, Cottbus, Germany; 12Department of
Hematology and Oncology, University of Go¨ttingen, Go¨ttingen, Germany; 13Sta¨dtisches Klinikum Braunschweig, Braunschweig, Germany; 14Department of
Hematology and Oncology, Helios Klinikum Berlin-Buch, Berlin, Germany; 15Department of Hematology, University Hospital Essen, Essen, Germany;
16Department of Hematology and Oncology, Katholisches Krankenhaus Hagen, Hagen, Germany; and 17Medical Department 5, Klinikum Nu¨rmberg Nord,
Nuremberg, Germany
There is no generally established prog-
nostic index for patients with mantle cell
lymphoma (MCL), because the Interna-
tional Prognostic Index (IPI) and Follicu-
lar Lymphoma International Prognostic
Index (FLIPI) have been developed for
diffuse large cell and follicular lymphoma
patients, respectively. Using data of
455 advanced stage MCL patients treated
within 3 clinical trials, we examined the
prognostic relevance of IPI and FLIPI and
derived a new prognostic index (MCL
international prognostic index, MIPI) of
overall survival (OS). Statistical methods
included Kaplan-Meier estimates and the
log-rank test for evaluating IPI and FLIPI
and multiple Cox regression for develop-
ing the MIPI. IPI and FLIPI showed poor
separation of survival curves. According
to the MIPI, patients were classified into
low risk (44% of patients, median OS not
reached), intermediate risk (35%,
51 months), and high risk groups (21%,
29 months), based on the 4 independent
prognostic factors: age, performance sta-
tus, lactate dehydrogenase (LDH), and
leukocyte count. Cell proliferation (Ki-67)
was exploratively analyzed as an impor-
tant biologic marker and showed strong
additional prognostic relevance. The MIPI
is the first prognostic index particularly
suited for MCL patients and may serve as
an important tool to facilitate risk-adapted
treatment decisions in patients with ad-
vanced stage MCL. (Blood. 2008;111:
558-565)
© 2008 by The American Society of Hematology
Introduction
Mantle cell lymphoma (MCL) is a relatively rare lymphoma entity
accounting for approximately 3% to 6% of all non-Hodgkin lymphoma
(NHL) cases.1-3 It has a poor prognosis with reported median overall
survival (OS) of only 30 to 43 months.1,2,4 In the late 1980s, it was
controversially debated whether centrocytic lymphoma, as defined by
the Kiel classification,5 represented a separate lymphoma entity and
whether it corresponded to the intermediate lymphocytic lymphoma or
lymphocytic lymphoma of intermediate differentiation of the Working
Formulation.6 After detection of the characteristic translocation t(11;14)
associated with those lymphoma subtypes and based on further
morphologic analyses, Banks et al7 proposed in 1992 the term “mantle
cell lymphoma” for this now widely accepted entity of malignant
lymphomas.
Since the international acceptance of MCL in the revised European-
American lymphoma (REAL) classification8 in 1994 many reports on
clinicopathologic features, treatment, clinical course, and prognostic
factors for patients with MCL have been published.1,2,4,9-17 Treatment
results have overall been unsatisfactory, although a substantial variation
in outcome was noted among individual cases with a small fraction of
patients even achieving long lasting remissions. Unlike the International
Prognostic Index18 (IPI) for diffuse large B-cell lymphomas or the
Follicular Lymphoma International Prognostic Index19 (FLIPI) for
follicular lymphomas, no broadly accepted prognostic index has been
defined for MCL so far. Previous reports revealed serious limitations
applying the IPI and FLIPI to MCL patients,1,2,4,9-14,16,17,20 and the
development of a prognostic index specific to MCL patients has been
postulated.12,20 In addition, controversial results have been published
concerning the prognostic value of several candidate prognostic factors,
but results were mostly based on limited samples of fewer than
130 patients.
Submitted June 16, 2007; accepted September 27, 2007. Prepublished online
as Blood First Edition paper, October 25, 2007; DOI 10.1182/blood-2007-06-
095331.
The online version of this article contains a data supplement.
Presented in part in oral form at the 48th annual meeting of the American
Society of Hematology, Orlando, FL, December 12, 2006.
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 USC section 1734.
© 2008 by The American Society of Hematology
558 BLOOD, 15 JANUARY 2008 ⅐ VOLUME 111, NUMBER 2

We analyzed the pooled data of the most recent randomized trials of
the German Low Grade Lymphoma Study Group (GLSG) and the
European MCLNetwork to validate the IPI, FLIPI, and other prognostic
factors, and to develop, if needed, a new prognostic index that is
particularly suited for patients with advanced stage MCL.
Methods
Patients
Data from 3 consecutive randomized trials, GLSG1996,21 GLSG2000,22
and European MCL Trial 1,23 which were performed between 1996 and
2004, were included in this analysis. Local ethics committees of the
participating centers approved the study protocol, and written informed
consent was obtained from all patients in accordance with the Declaration
of Helsinki. Patient entry criteria of all trials were identical with the
exception of age, which was limited up to 65 years in the European MCL
trial. Otherwise all 3 trials recruited treatment-naive patients with advanced
Ann Arbor stage III or IV MCL. Central pathology review was mandatory
to ensure a high quality of histologic diagnosis. Exclusion criteria
comprised serious concomitant diseases, bad performance status, or signifi-
cant impairment of organ function.21-23 The initial diagnostic work-up
comprised a bone marrow biopsy, ultrasound examination of the abdomen,
and computed tomography (CT) scans of chest and abdomen. Normal organ
function was assured by the respective laboratory tests, as well as by
echocardiograms and electrocardiograms.
Treatment protocols
The GLSG1996 trial21 compared the response rates of initial chemotherapy
with CHOP (cyclophosphamide, hydroxy-daunorubicin, vincristine and
prednisone) and MCP (mitoxantrone, chlorambucil, prednisone). In 2000,
the GLSG2000 trial22 was initiated to assess the additional efficacy of
incorporating the monoclonal CD20-antibody rituximab to primary CHOP
in terms of time-to-treatment failure. In both GLSG trials, patients older
than 65 years and responding to initial chemotherapy received interferon-␣
(IFN␣) maintenance therapy. Younger patients were randomized between
consolidating myeloablative radiochemotherapy followed by autologous
stem cell transplantation (ASCT) and IFN␣ maintenance within the
European MCL Trial 1.23 Detailed study design and results of the respective
trials have been published previously.21-23
Candidate prognostic factors and outcome parameters
All baseline variables were considered as candidate prognostic factors,
namely age, sex, Eastern Cooperative Oncology Group (ECOG) perfor-
mance status,24 Ann Arbor stage, presence of B-symptoms, bone marrow
involvement, spleen involvement, number of involved nodal areas, number
of extranodal sites, size of largest involved lymph node, and laboratory
parameters such as white blood cell (WBC), lymphocyte, granulocyte,
monocyte, and platelet counts, hemoglobin (Hb), lactate dehydrogenase
(LDH), albumin, and serum ␤2-microglobulin levels. Because upper limits
of normal (ULN) differed considerably between laboratories for LDH,
albumin, and ␤2-microglobulin, ratios to ULN were calculated. In addition,
the known prognostic indices established in other lymphomas, IPI,18 and
FLIPI19 were assessed. The outcome parameter was OS calculated from the
day of recruitment to death from any cause or to the latest follow-up date.
In line with IPI and FLIPI, our aim was to establish a clinical prognostic
index (mantle-cell lymphoma international prognostic index, MIPI) easily
available in clinical practice. Besides the clinical parameters, the prolifera-
tion markers Ki-67 and number of mitoses, possibly the most important
prognostic markers in MCL,1,2,4,11,14-17 have been assessed centrally and in a
standardized way. Thus, we analyzed the additional prognostic relevance of
cell proliferation and exploratively developed a combined biologic index
(MIPIb) incorporating the effect of cell proliferation.
Statistical methods
To validate IPI and FLIPI, Kaplan-Meier OS curves stratified for risk group
were calculated and compared by the log rank test. In addition, the
individual risk factors constituting IPI and FLIPI, respectively, were
checked for independent prognostic relevance by multiple Cox regression
analyses.
The prognostic relevance of the candidate prognostic factors was
evaluated using univariate Cox regression for OS. Subsequently, multiple
Cox regression with backward variable selection was performed to identify
independent prognostic factors. Size of largest involved lymph node, spleen
involvement, lymphocyte, granulocyte, and monocyte counts, albumin, and
serum ␤2-microglobulin levels were not included in multiple regression
because of a high number of multivariately missing values. Bone marrow
involvement was excluded because of high congruence with stage IV.
Continuous parameters were not categorized a priori because this would
have negatively affected the power of the analysis.25 ECOG performance
status was classified into 3 groups: asymptomatic (ECOG 0), symptomatic
but ambulatory and able to carry out light work (ECOG 1), and unable to
work or bedridden (ECOG 2-4). WBC count, LDH, and ␤2-microglobulin
were analyzed on the log-scale because of highly skewed distributions. The
proportional hazards assumption and the linearity assumption for the final
model were checked using scaled Schoenfeld residuals26,27 and martingale
residuals,28 respectively.
Prognostic groups were defined by categorizing the prognostic score
(linear predictor) of the final Cox regression model. 2 optimal cutpoints
were found maximizing the log rank statistic according to the “minimal P
value approach,”29 and P values for the log rank statistic were adjusted for
multiple testing by the Bonferroni method. For practical reasons referring to
clinical application of the prognostic index, the goal was to define 3 risk
groups, none of which comprised more than 50% of the patients. An
explorative simplification of the new classification rule was developed
categorizing the prognostic factors according to standard cutpoints. The
simplification with the best concordance to the original index measured by
Cohen weighted kappa30 was chosen.
Internal validation was performed applying the refined bootstrap
described by Efron.31 Random data splitting in training and validation
sample was not performed because this internal validation procedure
reduces the power for both model development and validation and is known
to be inferior to bootstrap validation.31,32 Bootstrap validation used the
likelihood ratio or log rank test statistic, the calibration slope (regression
coefficient of the prognostic score), Harrell concordance index c33 for
censored outcome variables, and the measure of separation SEP34 for
survival curves.
Statistical analyses were performed using SAS version 9.1 (SAS
Institute, Cary, NC) and R version 2.2.1 (www.r-project.org). Significance
level was 5% for all analyses.
Results
Patient characteristics, treatment, and outcome
Between May 1996 and October 2004, 455 patients with advanced
stage MCL entered the trials. The median age was 60 years
(34-86 years) and 76% of the patients were male. Eighty-four
percent of the patients were in Ann Arbor stage IV, 79% had bone
marrow involvement. Forty-three percent presented with B-
symptoms and 9% were unable to work or bedridden (ECOC 2-4).
Further patient characteristics are depicted in Table 1.
Initial cytoreductive chemotherapy comprised CHOP in 56% of
the patients, 31% of the patients received R-CHOP, 11% MCP, and
2% other chemotherapy regimens. Of the 438 patients evaluable for
treatment response, 351 (80%) achieved a complete or partial
remission, and 80 (18%) a complete remission. Treatment in
remission was ASCT in 80 patients, IFN␣ maintenance in
199 patients, and 72 patients obtained no therapy in remission. Of
PROGNOSTIC INDEX FOR ADVANCED MANTLE CELL LYMPHOMA 559BLOOD, 15 JANUARY 2008 ⅐ VOLUME 111, NUMBER 2

the 455 patients, 159 had died and the median OS was 57 months
with a median follow-up of surviving patients of 32 months.
IPI and FLIPI
According to the IPI, 99 patients (23%) were classified as low risk
(LR), 173 patients (40%) as low intermediate risk (LIR),
119 patients (28%) as high intermediate risk (HIR), and 41 patients
(9%) as high risk (HR); in 23 patients the IPI could not be evaluated
due to missing data. The median OS was not yet reached in the LR
group with a 5-year OS rate of 59%, and 61 months in the LIR
group, 45 months in the HIR group and 20 months in the HR group
(P Ͻ .001, Figure 1). LIR and HIR groups comprised together
more than two-thirds of the patients and were not well separated. In
multiple Cox regression age, ECOG performance status and LDH
were prognostic for OS, whereas the number of extranodal sites
was not (Table 2) .
The FLIPI could be determined in 418 patients of whom 26
(6%) were classified as LR, 124 patients (30%) as intermediate risk
(IR), and 268 patients (64%) as HR. The median OS was not yet
reached for LR and IR patients with a 5-year OS rate of 61% and
57%, respectively, and 48 months in the HR group (P Ͻ .001,
Figure 2). LR and IR groups were not separated and the large high
risk group had relatively good outcome. In the multiple Cox
regression, age and LDH were prognostic for OS, whereas neither
hemoglobin nor the number of involved nodal areas were of
prognostic relevance (Table 3).
Prognostic factors
Neither sex, Ann Arbor stage (III vs IV), bone marrow involve-
ment, number of extranodal sites or number of nodal areas, nor
platelet count or albumin showed prognostic relevance for OS in
univariate analyses. In contrast, age, ECOG performance status,
B-symptoms, spleen involvement, maximal lymph node size,
WBC, lymphocyte, granulocyte, and monocyte counts, LDH, Hb,
and ␤2-microglobulin had a significant impact on OS (Table 4).
Sex, stage, B-symptoms, number of extranodal sites, number of
nodal areas, platelet count, and hemoglobin lost their prognostic
relevance in multiple Cox regression with backward variable
selection on the dataset of 409 complete cases. Age, ECOG
performance status, LDH, and WBC counts were identified as the
4 independent prognostic factors for OS. Relative risk (RR) of
increased age was 1.04 per year (95% CI 1.02-1.06, PϽ.001), RR
of patients with poor performance (ECOG Ͼ 1) was 2.01 (95% CI
1.19-3.39, P ϭ .009), and patients with a tenfold elevated LDH or
WBC count had a RR of 3.92 (95% CI 1.48-10.37, P ϭ .006) and
2.56 (95% CI 1.66-3.95, P Ͻ .001), respectively (Table 5). Accord-
ingly, the MIPI prognostic score was calculated as
MIPI score ϭ [0.03535 ϫ age (years)] ϫ age (years)]
ϩ 0.6978 (if ECOG Ͼ 1)
ϩ [1.367 ϫ log10(LDH/ULN)]
ϩ [0.9393 ϫ log10(WBC count)]
Mantle cell lymphoma international prognostic index (MIPI)
The median value of the prognostic score in 409 patients was 5.78
(4.31-9.18), 10% of the values were below 5.16 and 90% of the
Table 1. Baseline patient characteristics
Parameter Quantity n
Median age, y (range) 60 (34-86) 455
Sex, no. male (%) 344 (76) 455
ECOG 0, no. (%) 147 (33) 452
ECOG 1, no. (%) 263 (58) 452
ECOG 2-4, no. (%) 42 (9) 452
Stage IV, no. (%) 384 (84) 455
B-symptoms present, no. (%) 196 (43) 451
Bone marrow involvement present, no. (%) 360 (79) 453
Extranodal sites more than 1, no. (%) 143 (32) 445
Median no. involved nodal areas, (range) 8 (0-11) 432
Median max. lymph node size, cm (range) 4 (0.5-24) 387
Spleen involvement present, no. (%) 225 (54) 420
Median WBC count, 109/L (range) 7.9 (1.0-764) 451
Median lymphocyte count, 109/L (range) 2.1 (0.35-625) 422
Median granulocyte count, 109/L (range) 4.2 (0.19-26.4) 413
Median monocyte count, 109/L (range) 0.5 (0.014-10.9) 408
Median platelet count, 109/L (range) 188 (3-1346) 452
Median LDH/ULN (range) 0.86 (0.15-5.3) 443
Median hemoglobin (males),g /L, (range) 133 (55-175) 342
Median hemoglobin (females),g /L, (range) 124 (30-149) 109
Median albumin/ULN (range) 0.8 (0.36-1.26) 268
Median ␤2-microglobulin/ULN (range) 1.1 (0.06-8) 285
Data in column 3 (“n”) are number of data points for parameter.
Figure 1. Overall survival according to the International Prognostic Index risk
groups.18 LR indicates low risk; LIR, low intermediate risk; HIR, high intermediate
risk; and HR, high risk.
Table 2. Prognostic relevance of the IPI18 (n ‫؍‬ 432) risk factors for
overall survival determined in a multiple Cox regression
Prognostic factor Comparison RR 95% LCL 95% UCL P
Age, y Ն 60 vs Ͻ 60 1.7 1.2 2.3 .002
ECOG 2-4 vs 0-1 2.8 1.8 4.5 Ͻ.001
LDH elevated vs normal 1.6 1.2 2.3 .006
No. of extranodal sites Ͼ 1 vs Յ1 1.2 0.8 1.6 .33
Ann Arbor stage was III or IV in all patients.
RR indicates relative risk; LCL, lower confidence limit; UCL, upper confidence
limit; and ECOG, ECOG performance status.
Table 3. Prognostic relevance of the FLIPI19 (n ‫؍‬ 418) risk factors
for overall survival determined in a multiple Cox regression
Prognostic factor Comparison RR 95% LCL 95% UCL P
Age, y Ն 60 vs Ͻ 60 1.8 1.3 2.5 .001
LDH elevated vs normal 1.8 1.3 2.5 .001
Hemoglobin, g/L Ͻ120 vs Ն120 1.1 0.8 1.6 .50
No. involved nodal areas Ͼ 4 vs Յ 4 1.1 0.7 1.6 .80
Ann Arbor stage was III or IV in all patients.
RR indicates relative risk; LCL, lower confidence limit; and UCL, upper confi-
dence limit.
560 HOSTER et al BLOOD, 15 JANUARY 2008 ⅐ VOLUME 111, NUMBER 2

values below 6.63. Potential cutpoints between 5.15 and 6.65 in
steps of 0.05 were assessed. On this basis, the value 6.2 showed the
best discrimination (log rank statistic 53.06, 1 degree of freedom,
df) and defined a high-risk group of 84 patients (21%, score Ն 6.2).
For the definition of an intermediate-risk group, the value of 5.7
was identified as best discriminator (log rank statistic 61.11, 2 df).
In this way 145 patients were classified as intermediate risk (35%,
5.7 Յ score Ͻ 6.2). The remaining 180 patients belonged to the
low-risk group (44%, score Ͻ 5.7). After Bonferroni correction for
the P values calculated from the log rank statistics, the separation
of these risk groups remained statistically significant. Median OS
was not reached in the low risk group with a 5-year OS of 60%, and
it was 51 months and 29 months in the intermediate-risk group and
the high-risk group, respectively (Figure 3).
The internal validation procedure correcting for overoptimism
by bootstrap showed stability of statistical significance and prognos-
tic separation (Table 6). In addition, the bootstrap corrected
performance measures for the new prognostic classification system
appeared to be better than the results of the external validation of
the IPI and FLIPI.
Simplified MIPI
The classification according to the new prognostic index involves
some elementary mathematical operations best performed using an
electronic calculator. To make the index most practicable, we
exploratively simplified it categorizing the individual prognostic
factors maintaining high concordance to the original index. Dichoto-
mizing the prognostic factors, as is commonly done, at standard
cutpoints (60 years for age, ULN for LDH, 10 ϫ 109/L for WBC
count) yielded low concordance to the MIPI (weighted kappa
0.56), and suboptimal separation of survival curves (Table 6, SEP).
Instead, weighting age, ECOG performance status, LDH, and
WBC with 0 to 3 points using 3 cutpoints each (Table 7) and
classifying patients with a total of at most 3 points as LR, patients
with 4 to 5 points as IR and patients with more than 5 points as HR,
yielded high concordance (weighted kappa 0.79) and good separa-
tion of OS curves (Table 6, SEP).
Prognostic relevance of cell proliferation
The percentage of Ki-67 positive cells was available in 236 lymph
node biopsies of the 455 MCL patients with a median of 14.5% and
range of 1.2% to 91.0%. The number of mitoses per square
millimeter was counted in 162 cases with a median of 4, range 0 to
72 and one extreme value of 1039, which was excluded from
further analysis. Both proliferation parameters showed strong
univariate prognostic relevance for OS with an RR of 1.29 (95% CI
1.16-1.44, P Ͻ .001) for Ki-67 elevated by 10% and 1.27 (95% CI
Table 4. Prognostic relevance for overall survival according to univariate Cox regression
Candidate prognostic factor Comparison n RR 95% LCL 95% UCL P
Age 10 years older 455 1.38 1.15 1.65 Ͻ.001
Sex Male vs female 455 1.12 0.77 1.63 .55
ECOG performance status 1 vs 0 452 1.61 1.10 2.35 .014
ECOG performance status 2-4 vs 0 452 4.80 2.84 8.12 Ͻ.001
ECOG performance status 2-4 vs 0-1 452 3.48 2.22 5.43 Ͻ.001
Ann Arbor stage IV vs III 455 1.09 0.70 1.70 .70
B-symptoms present vs absent 451 1.60 1.17 2.19 .003
Bone marrow involved vs not 453 1.04 0.70 1.54 .85
No. of extranodal sites 1 vs 0 445 1.25 0.72 2.16 .42
No. of extranodal sites Ͼ 1 vs 0 445 1.57 0.89 2.77 .12
No. of extranodal sites Ͼ 1 vs 0-1 445 1.30 0.94 1.80 .11
No. nodal areas 1 more 432 1.03 0.97 1.08 .34
Maximum tumor size 1 cm larger 387 1.06 1.01 1.10 .016
Spleen involved vs not 420 1.40 1.01 1.95 .044
WBC count 10-fold* 451 2.25 1.59 3.18 Ͻ.001
Lymphocyte count 10-fold* 422 1.97 1.40 2.77 Ͻ.001
Granulocyte count 10-fold* 412 4.69 2.06 10.71 Ͻ.001
Monocyte count 10-fold* 408 2.61 1.65 4.12 Ͻ.001
Platelet count 100 ϫ109/L more 452 1.01 0.88 1.16 .89
LDH 2-fold* 443 1.72 1.32 2.24 Ͻ.001
Hemoglobin 10 g/L more† 451 0.91 0.85 0.98 .009
Albumin ϩULN‡ 268 0.23 0.05 1.08 .063
␤2-microglobulin 2-fold* 285 1.53 1.22 1.92 Ͻ.001
LCL indicates lower confidence limit; UCL, upper confidence limit; and RR, relative risk.
*Log scale
†No significant interaction of hemoglobin and sex (P ϭ .43)
‡Quotient to ULN
Figure 2. Overall survival according to the Follicular Lymphoma International
Prognostic Index19 risk groups. LR, low risk; IR, intermediate risk; and HR, high
risk.

1.09-1.48, P ϭ .003) for the number of mitoses elevated by
10/mm2. In bivariable regression including Ki-67 and number of
mitoses, only Ki-67 remained independently significant, whereas
the number of mitoses lost its prognostic relevance (P ϭ .68,
n ϭ 126), and was thus excluded from further analyses. Patients
with Ki-67 assessed showed significantly less spleen and bone
marrow involvement, better performance status, more involved
nodal areas, and larger lymph nodes than patients without available
Ki-67. However, there was no significant difference in OS of
patients with or without data on Ki-67 (median OS 58 and
57 months, P ϭ .39).
Ki-67 remained independently significant from the MIPI clini-
cal score (regression coefficient 0.02142, P Ͻ .001) and inclusion
of Ki-67 did not substantially change the regression coefficient of
the MIPI score (0.9554, P Ͻ .001). Thus, we calculated the
combined biologic score by addition of 0.02142 times Ki-67 (%) to
the clinical score. Optimal cutpoints were 5.7 and 6.5 for the log
rank statistics with respect to OS, and Figure 4 shows OS according
to the so defined combined biologic index (MIPIb).
Discussion
Based on data of 455 patients with advanced stage MCL from
3 randomized trials of GLSG and European MCL Network, a new
prognostic index (MIPI, mantle cell lymphoma international prog-
nostic index) has been developed. The MIPI is the first prognostic
index specific to MCL patients and, more importantly, allows a
clear separation of 3 well-balanced groups of patients with
significantly different prognoses. The low-risk group comprised
44% of the patients with a median OS not yet reached after a
median follow-up of 32 months, and a 5-year OS rate of 60%. The
intermediate risk group consisted of 35% of the patients and
revealed a median OS of 51 months, while the high-risk group
(21%) had a poor outcome with a median survival of only
29 months. The MIPI is based on the 4 independent prognostic
factors age, ECOG performance status, LDH, and WBC counts,
which are clinical variables easily and routinely available in
clinical practice. A simplification of the MIPI was developed
allowing for bedside application reproducing the original index
remarkably well.
The application of the IPI18 for diffuse large B-cell lymphoma to
our MCL patient cohort revealed a lack of separation of the
2 intermediate-risk groups, which comprised more than two-thirds
of the patients. The application of the FLIPI19 for follicular
lymphoma to our MCL patients showed even worse results, with no
separation of low- and intermediate-risk groups and a large
high-risk group with relatively good outcome. In addition, of the
individual IPI and FLIPI risk factors, the number of extranodal
sites and the number of involved nodal areas showed no prognostic
relevance and hemoglobin no independent prognostic relevance in
our MCL patient cohort. ECOG performance status, which showed
high prognostic relevance in our analyses and many previous
reports, was not included in the development of the FLIPI.
Previous attempts to apply the IPI in particular to patients with
MCL proved rather unsatisfactory1,12-14,16,20 (Table 8). The IPI
showed either no prognostic relevance for OS,4,10,17 or the original
4 risk groups were combined to 312,14 or 2 risk groups1,11,16 or
different risk groups had very similar outcome.2,9,13,20 In addition,
of the 5 IPI risk factors, the number of extranodal sites showed
mostly no, and Ann Arbor stage inconsistent, prognostic relevance
in previous univariate analyses (Table 8).
In contrast to our results, a recent report by Møller et al20 stated
superiority of the FLIPI over the IPI in terms of size and number of
risk groups, separation of survival curves, and prognostic value of
individual risk factors. However, the number of patients analyzed,
93, was rather small, low- and intermediate-risk groups were not
well separated, and the high-risk group included more than half of
the patients. Interpretation of multiple Cox regression results was
hampered by inclusion of the interdependent factors IPI, FLIPI and
the individual prognostic factors.
Of the independent prognostic factors of the MIPI, consistent
prognostic relevance on OS had been shown for age, performance
status, and LDH in previous univariate analyses (Table 8). Hemato-
logic parameters were mostly not considered as candidate prognos-
tic factors. Three studies,1,11,12 however, included the WBC count
and described a prognostic relevance in univariate analysis. In
several studies peripheral blood involvement was included4,10-13
Figure 3. Overall survival according to the new prognostic index (MIPI). LR
indicates low risk, prognostic score less than 5.7; IR, intermediate risk, score 5.7 or
more but less than 6.2; and HR, high risk, score 6.2 or more. The prognostic score is
calculated as [0.03535 ϫ age (years)] ϩ 0.6978 (if ECOG Ͼ 1) ϩ [1.367 ϫ
log10(LDH/ULN)] ϩ [0.9393 ϫ log10(WBC count].
Table 5. Independent prognostic factors for overall survival identified by backward variable selection with multiple Cox regression on
significance level 5% for the Wald statistic
Prognostic factor Comparison ␤ SE RR 95% LCL 95% UCL P
Age 1 year older 0.03535 0.009604 1.04 1.02 1.06 Ͻ.001
ECOG 2-4 vs 0-1 0.6978 0.2663 2.01 1.19 3.39 .009
LDH 10-fold 1.367 0.4962 3.92 1.48 10.37 .006
WBC count 10-fold 0.9393 0.2220 2.56 1.66 3.95 Ͻ.001
The candidate prognostic factors included were age, sex, ECOG performance status, Ann Arbor stage, B-symptoms, number of extranodal sites, number of nodal areas,
WBC count, platelet count, LDH, and hemoglobin. The model was developed using 409 complete cases for the candidate prognostic factors. The same model was identified
using forward variable selection or a significance level of 10%.
␤ indicates the regression coefficient; SE, standard error; RR, relative risk; LCL, lower confidence limit; and UCL, upper confidence limit.

and showed significance in 34,12,13 of 5 univariate analyses and in
212,13 multiple regression analyses. The methods for the detection
of peripheral blood involvement, however, were mostly not ad-
equately described and sensitivity of different methods may vary
substantially. Although peripheral blood involvement may occur
without leukocytosis, a high WBC count probably reflects periph-
eral blood involvement, and our results thus may confirm previous
observations.12,13
Despite these encouraging results, it must be emphasized that
the current analyses did not include patients with limited stage I
or II MCL because for these patients no comparable clinical trial
is available. However, the prognostic relevance of stage is not
consistently seen in the literature, the proportion of patients with
stages I or II is rather low in MCL (Table 8) and they also require
a different therapeutic approach. Thus, as recommended by
Altman,35 to avoid any treatment bias, we limited our investiga-
tion to the advanced-stage MCL patients with standardized
treatments in randomized trials. The present data are also
limited to patients who can tolerate moderately intensive
chemotherapy. This limitation, however, also applies to the IPI18
and FLIPI19 and does not hamper the relevance of the MIPI
within these borders.
Spleen involvement, maximal tumor size, serum ␤2-
microglobulin levels, and lymphocyte, granulocyte, and mono-
cyte counts were excluded from multiple Cox regression due to
missing data, but had shown univariate prognostic relevance on
OS. Nevertheless, further exploratory analyses revealed no
additional prognostic relevance of these variables to the 4 MIPI
prognostic factors. For ␤2-microglobulin this stands in contrast
to the results of Khouri et al.36 Two MIPI adverse prognostic
factors, higher age and worse ECOG performance status, are
also contraindications against more aggressive experimental
therapies, for which the MIPI could be applied to select
candidate patients. However, excluding age and ECOG perfor-
mance status as candidate prognostic factors, only LDH and
WBC count remained independent prognostic factors still
allowing for patient stratification. In addition, in the cohort of
patients younger than 65 years, the same 4 independent prognos-
tic factors were identified, thus, there was no “age-adjusted”
prognostic index as developed for the IPI. Finally, our findings
are independent of the choice of initial cytoreductive therapy,
because inclusion of treatment variables did not change the
relevance of the 4 independent prognostic factors. In particular,
the inclusion of primary rituximab treatment as covariate did not
change the final prognostic model. In addition, a significant
improvement in OS has not been shown for ASCT so far for
MCL patients.
Table 6. Bootstrap validation according to Efron et al31
Model Method Log rank-␹2 df c SEP
Cox model optimistic 55.84* 4 0.6867 1.00†
Cox model bootstrap 46.62* 4 0.6791 0.91†
MIPI optimistic 61.11 2 0.6668 1.59
MIPI bootstrap 47.64 2 0.6536 1.49
MIPIb optimistic 39.78 2 0.7096 1.74
MIPIb bootstrap 31.78 2 0.6962 1.58
Risk groups using standard cutpoints optimistic 34.77 2 0.6393 1.51
Simplified MIPI optimistic 63.15 2 0.6716 1.60
IPI external 38.83 3 0.6359 1.41
IPI LR/LIR vs HI vs HR external 35.36 2 0.6149 1.40
IPI LR vs LI/HI vs HR external 35.10 2 0.6170 1.31
IPI LR vs LI vs HI/HR external 24.22 2 0.6178 1.41
FLIPI external 14.14 2 0.5773 1.36
df indicates degrees of freedom; c, Harrell measure of concordance34 between expected and observed survival times; SEP, measure of separation35 of survival curves;
standard cutpoints: 60 years of age, upper limit of normal for LDH, 10 ϫ 109 leukocytes/L; optimistic, estimation using the data set of model development; bootstrap, estimation
corrected for overoptimism; and external, estimation using an independent data set.
*Likelihood ratio statistic.
†Calibration slope: regression coefficient of the prognostic score.
Table 7. Simplified prognostic index
Points Age, y ECOG LDHULN WBC, 109/L
0 Ͻ50 0-1 Ͻ0.67 Ͻ 6.700
1 50-59 — 0.67-0.99 6.700-9.999
2 60-69 2-4 1.000 -1.49 1.000-14.999
3 Ն70 — Ն1.5000 Ն15000
For each prognostic factor, 0 to 3 points were given to each patient and points
were summed up to a maximum of 11. Patients with 0 to 3 points in summary were
classified as low risk, patients with 4 to 5 points as intermediate risk, and patients with
6 to 11 points as high risk. ECOG performance status was weighted with 2 points if
patients were unable to work or bedridden (ECOG 2-4). LDH was weighted according
to the ratio to the ULN. Thus, for an ULN of 240 U/L, the cutpoints were 180 U/L,
240 U/L, and 360 U/L, for example.
— indicates not applicable.
Figure 4. Overall survival according to the combined biologic index (MIPIb) in
220 patients with Ki-67 available. LR indicates low risk, combined biologic score
(CBS) less than 5.7; IR, intermediate risk, CBS 5.7 or more but less than 6.5; and HR,
high risk, CBS 6.5 or more. The combined biologic score is calculated as 0.03535
times age (years) plus 0.6978 (if ECOG Ͼ 1) plus 1.367 times log10(LDH/ULN) plus
0.9393 times log10(WBC count) plus 0.02142 times Ki-67 (%).

In an attempt to develop a combined biologic index as
postulated by Ra¨ty et al15 and Tiemann et al,17 we included the
proliferation marker Ki-67 in our analyses and showed high
prognostic relevance independent from the MIPI prognostic
score. Including Ki-67 we exploratively defined a combined
biologic index (MIPIb) which revealed a low-risk group with
relatively good outcome. However, proliferation data were
available in only approximately half of the patients, and the
selection of patients with Ki-67 appeared to be nonrandom with
less spleen and bone marrow involvement and more and larger
lymph node involvement. As it is assessed on lymph node
biopsies, proliferation is not available in all MCL patients. In
addition, standardization and reproducibility of proliferation
assessment still requires improvement as essential prerequisite
to be used as molecular prognostic marker.37 Hence, a combined
biologic prognostic index including Ki-67 is currently not
applicable except for research studies.
We performed internal validation by bootstrap, the method
that achieves the highest possible power from the available
data,31,32 and could confirm a high stability of the developed
prognostic model. Nevertheless, an external validation on an
independent data set is still warranted to allow a broad
application of this prognostic tool.
In conclusion, our new prognostic classification tool, MIPI,
might be helpful to allow individualized, risk-adapted treatment
decisions in patients with advanced stage MCL, to hopefully
optimize treatment and to improve outcomes of this aggressive
disease. In addition, our results will allow stratification in clinical
trials, interstudy-comparisons of clinical trial results according to
patient risk profiles, and provide a basis for establishing future
novel biologic prognostic markers.
Acknowledgments
We thank the German Low Grade Lymphoma Study Group
and the European MCL Network for participation in this
study. Many thanks to Olaf Determann from the Lymph Node
Registry Kiel, who also worked intensively in providing the
proliferation data.
This work was supported in part by grants from the Deutsche
Krebshilfe (T14/96/Hi 1, project No. 70-2208-Hi 2), the Bundesmin-
isterium fu¨r Bildung und Forschung, Kompetenznetz Maligne
Lymphome (no. 01 GI 9994), the European Commission (no.
LSHC-CT-2004-503351), and the Lymphoma Research Founda-
tion (no. MCLI-04-016).
Authorship
E.H. analyzed and interpreted data, performed statistical analysis,
and drafted the manuscript; MD, W.H., and M.U. designed the
Table 8. Previous reports on clinical characteristics, outcome, and prognostic factors of patients with MCL
First author Tiemann Ra¨ty Samaha Andersen Schrader Oinonen Møller Argatoff Weisenburger Zucca Bosch Decaudin Velders
Reference 17 15 13 1 16 12 20 4 14 9 11 10 2
Number 304 127 121 105* 95 94 93* 80* 68 65 59 45 41*
Median age, y 64 65 63 66 62% (Ͼ 60) 66 68 65 64 64 63 59 68
Male, % 76 64 67 75 77 59 71 70 75 67 74 78 61
Stage I/II, % 8 17 13 16 8 24 17 14 25 22 5 13 20
Median OS, mo ϳ36 34 37 30 ϳ30 41 37 43 38 42 49 ϳ56 31.5
Older than 60 y ϩ na ϩ† ϩ‡ ϩ ϩ na Ϫ na ϩ‡ Ϫ na na
Sex Ϫ na na Ϫ Ϫ Ϫ na na na Ϫ Ϫ na na
ECOG 2-4 vs 0-1 ϩ na ϩ ϩ Ϫ ϩ§ ϩ ϩ ϩ Ϫ ϩ na ϩ
Stage III/IV vs I/II ϩ na ϩ ϩ Ϫ ϩ na Ϫ Ϫʈ Ϫ Ϫ¶ Ϫ ϩ
B-symptoms ϩ na – Ϫ Ϫ ϩ na na ϩ Ϫ ϩ na na
Spleen inv. na na ϩ ϩ na Ϫ na na na Ϫ ϩ – na
Bone marrow inv. ϩ na na Ϫ Ϫ ϩ na na ϩ Ϫ na ϩ ϩ
Peripheral blood inv. na na ϩ na na ϩ na ϩ na na Ϫ Ϫʈ na
Extranodal sites, more than 1 ϩͯ na ϩ Ϫ Ϫͯ Ϫ Ϫ Ϫ na na Ϫ Ϫ ϩ
Bulk, larger than 10 cm na na Ϫ na na Ϫ na na na na na na na
Elevated LDH ϩ na ϩ ϩ ϩ ϩ na Ϫ na ϩ ϩ Ϫ Ϫ
WBC count na na na ϩ na ϩ na na na na ϩ na na
Hemoglobin na na ϩ ϩ na ϩ ϩ na na na na Ϫ na
Growth pattern ϩ ϩ Ϫ na na na na Ϫ ϩ na na na na
Cytology Ϫ ϩ Ϫ na na na na ϩ ϩ na ϩ Ϫʈ na
Mitotic index ϩ ϩ na na na na na ϩ Ϫ na ϩ na na
Ki-67 ϩ ϩ na Ϫ ϩ na na na na na na na ϩ
IPI Ϫ na ϩ** ϩ ϩ ϩ†† ϩ‡‡ Ϫ ϩ ϩ†† ϩ Ϫ ϩ‡‡
IPI risk group, no. 2 na 4 2 2 3 4 4 3 4 2 2 4
Prognostic relevance reported from univariate analyses on significance level .05 for overall survival.
ϩ indicates prognostic; Ϫ, not prognostic; inv, involvement; and na, not analyzed.
*Population based data.
†Age cutpoint 70 years.
‡Age cutpoint 65 years.
§ECOG performance status 0 vs Ͼ 0.
¶Stage I-III vs IV.
ʈP Ͻ .1.
**LR, LIR, HIR not separated.
††LIR, HIR not separated.
‡‡LIR, HIR, HR not separated.
͉Extra nodal involvement, yes vs no.

trials and revised the manuscript; W.K. provided proliferation data;
J.H. provided statistical expertise and revised the manuscript; C.G.,
A.v.H., H.C.K.-N., M.P., M.R., B.M., H. Einsele, N.P., W.J., B.W.,
W.-D.L., U.D., H. Eimermacher, and H.W. recruited, treated, and
documented patients.
E.H. is a candidate at the Faculty of Medicine of the Ludwig-
Maximilians-University Munich for her doctoral degree and part of
this work has been developed in partial fulfillment of the require-
ments for her degree.
A complete list of the members of the German Low Grade
Lymphoma Study Group and the European MCL Network who
contributed to this analysis appears in Document S1, available on
the Blood website; see the Supplemental Materials link at the top of
the online article.
Conflict-of-interest disclosure: M.P. is a member of the Advi-
sory Board of Roche, Genentech, and Lilly. M.D. received support
for clinical studies and speaker honoraria from Roche. W.H. is
member of the Advisory Board of Roche and received support for
clinical studies and speaker honoraria from Roche. The remaining
authors declare no competing financial interests.
Correspondence: Dr. Michael Unterhalt, Medizinische
Klinik III, Klinikum Gro␤hadern, Marchioninistr. 15, D-81377
Mu¨nchen, Germany; e-mail: Michael.Unterhalt@med.
uni-muenchen.de.
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