1. health and fitness
2. disease

CLINICAL TRIALS AND OBSERVATIONS
Improved outcome in multisystem Langerhans cell histiocytosis is associated with
therapy intensification
Helmut Gadner,1 Nicole Grois,1 Ulrike Po¨tschger,1 Milen Minkov,1 Maurizio Arico`,2 Jorge Braier,3 Valerie Broadbent,4
Jean Donadieu,5 Jan-Inge Henter,6 Robert McCarter,7 and Stephan Ladisch,7 for the Histiocyte Society
1Children’s
Cancer Research Institute, St Anna Children’s Hospital, Vienna, Austria; 2Pediatric Hematology/Oncology, University of Palermo, Palermo, Italy;
Nacional de Pediatria J. Garrahan, Buenos Aires, Argentina; 4Addenbrookes Hospital, Cambridge, United Kingdom; 5Assistance-Publique Hoˆpitaux de
Paris, Hopital Trousseau, Paris, France; 6Childhood Cancer Research Unit, Department of Women and Child, Karolinska University Hospital, Stockholm,
Sweden; and 7Children’s Research Institute, Children’s National Medical Center, Washington, DC
3Hospital
Multisystem Langerhans cell histiocytosis
(MS-LCH) is associated with high mortality
when patients have risk organ involvement
(ROⴙ) or are younger than 2 years. In an
international randomized trial, LCH-II, we
intensified their treatment: arm A consisted
of 6 weeks of daily prednisone and weekly
vinblastine followed by 18 weeks of daily
6-mercaptopurine with vinblastine/prednisone pulses; etoposide was added in arm
B. Considering all 193 randomized risk patients, there were similar outcomes: rapid
(6 weeks) response (arm A vs arm B: 63%/
71%), 5-year survival probability (74%/79%),
disease reactivation frequency (46%/46%),
and permanent consequences (43%/37%).
However, (1) patients younger than 2 years
without RO involvement (ROⴚ) had 100%
survival and uniformly high (> 80%) rapid
response, (2) ROⴙ patients not responding
within 6 weeks had highest mortality, and
(3) importantly, the more intensive arm B
reduced mortality in ROⴙ patients (relative
hazard rate, accounting for differences in
risk organ involvement, of 0.54; 95%
CI ⴝ 0.29-1.00). Finally, comparison of ROⴙ
patients in LCH-I and LCH-II confirmed that
increasing treatment intensity increased
rapid responses (from 43% in arm A LCH-I to
68% in arm B LCH-II; P ⴝ .027) and reduced
mortality (from 44% in arm A LCH-I to 27% in
arm B LCH-II; P ⴝ .042). We conclude that
intensified treatment significantly increases
rapid response and reduces mortality in
risk MS-LCH. This trial was registered at
http://www.controlled-trials.com as no. ISRCTN57679341. (Blood. 2008;111:2556-2562)
© 2008 by The American Society of Hematology
Introduction
Langerhans cell histiocytosis (LCH) is a reactive clonal proliferation of dendritic cells1-3 that comprises a wide range of clinical
presentations, from localized disease (single-system disease) with
excellent outcome to disseminated disease involving 2 and more organs
or systems (multisystem disease, MS-LCH).4-6 Treatment has varied
from conservative to intensive combination chemotherapy.7-10 When the
systems involved are “risk organs” and/or the patient is younger than
2 years at diagnosis, MS-LCH has been considered particularly devastating, and as carrying a potentially fatal prognosis.11,12
In 1991, the Histiocyte Society initiated LCH-I, a randomized
international clinical trial for MS-LCH, comparing the efficacy of
6-month single-agent therapy with either vinblastine or etoposide
(VP-16).13 The drugs did not differ in disease response, reactivation, permanent consequences, survival, or toxicity. However, the
results were inferior in some respects to previous reports based on
more aggressive therapy.8,13 That suggested that therapy for
MS-LCH patients should be intensified. We therefore designed the
next randomized controlled trial, LCH-II, to evaluate combining
vinblastine and VP-16, in an intensified 6-month regimen.
Methods
Patient entry and randomization
Eligible patients (confirmed histopathology, multisystem [MS] disease, age
younger than 18 years, and no prior specific therapy) were entered, with
informed consent obtained in accordance with the Declaration of Helsinki,
from 98 pediatric institutions through 7 study subcenters and stratified into
2 groups, risk and low risk.14,15 The study and study protocol have been
approved by the Institutional Review Board of each institution participating
in the trial. The risk patients, the subject of this report, either had
involvement of risk organs (RO⫹; ie, liver, lung, and hematopoietic system
or spleen) or had disease onset at younger than 2 years of age.11,12 Low-risk
MS-LCH patients, those 2 years or older and without RO involvement
(RO⫺), will be reported elsewhere.
Patients randomized to arm A received an initial treatment of continuous
oral prednisone (40 mg/m2 daily in 3 doses for 4 weeks tapering over
2 weeks) and vinblastine (6 mg/m2 intravenous bolus weekly for 6 weeks);
those in arm B received etoposide in addition (150 mg/m2 per day, 1-hour
infusion weekly for 6 weeks). Continuation therapy was 6-mercaptopurine
(50 mg/m2 daily orally) and pulses of oral prednisone (40 mg/m2 daily in
3 doses, days 1-5) and vinblastine (6 mg/m2 per day once every 3 weeks) in
arm A, with 150 mg/m2 VP-16 every 3 weeks added in arm B. The total
duration of treatment was 24 weeks (Figure 1).
Study objectives
The primary end point was response after 6 weeks of therapy (rapid
response), defined as complete resolution (no evidence of active disease,
NAD) or continuous regression of all signs and symptoms. Patients who
were “worse” (disease progression or death) or “intermediate” (“stable” but
active disease or the appearance of new lesions in one site and regression in
another)4,5,13 were considered nonresponders. Re-evaluations were performed after 12, 18, and 24 weeks of therapy, then every 3 months for
Submitted August 10, 2007; accepted December 4, 2007. Prepublished online as
Blood First Edition paper, December 18, 2007; DOI 10.1182/blood-2007-08-106211.
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.
The online version of this article contains a data supplement.
© 2008 by The American Society of Hematology
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BLOOD, 1 MARCH 2008 䡠 VOLUME 111, NUMBER 5
THERAPY INTENSIFICATION AND OUTCOME IN LCH
2557
Figure 1. LCH-II treatment arms for risk patients.
2 years, every 6 months for 2 years, and then yearly. Secondary end points
were comparisons of therapeutic efficacy with respect to overall survival, time to
NAD, reactivations after NAD, incidence of permanent consequences (PCs), and
treatment-related toxicities. Nonresponse by week 6 was considered treatment
failure and the protocol recommended switching from arm A to arm B, or from
arm B to a salvage therapy of the LCH-S studies.16,17
Statistical methods
All data, compiled using standardized questionnaires, were reviewed for
safety and completeness by an independent review board (Mainz, Germany). Analyses were conducted based on the intention-to-treat principle,
at the study reference center (Vienna, Austria).
The primary end points (ie, rapid response rates) of the 2 treatment arms
were compared using the ␹2 test, and the confidence interval for the
difference in response rates was calculated according to Newcombe Method
10.18 Interim analyses were planned using an error-spending procedure with
rules for early termination according to O’Brien and Fleming.19 According
to our power calculation, the estimated response rate in the control group
(prednisone and vinblastine without etoposide) was predicted to be 60%
(derived from the LCH-I data13). With the addition of etoposide, we sought
to detect an improvement of the response rate by 20% (ie, a response rate of
80%). With a sample size of 75 patients in each group and a significance
level of 5% (2-sided), the power was considered to be 76%.
The secondary end points were survival, disease resolution, incidence
of reactivation, and permanent consequences. Survival probabilities from
randomization were estimated to each participant’s last follow-up evaluation based on the Kaplan-Meier method and differences in survival were
assessed by the log-rank test. The analysis of RO⫹ patients was stratified
according to subcenter. In an exploratory analysis, Cox regression was used
to evaluate the impact of each arm of LCH-II accounting for differences in
risk organ involvement, as well as increasing treatment intensity in the
4 arms of the 2 sequential randomized studies, LCH-I and LCH-II (LCH-I
arm A ⬍ LCH-I arm B ⬍ LCH-II arm A ⬍ LCH-II arm B) on survival. For
the evaluation of 6-week response, logistic regression was used.
Cumulative incidence rates were used to estimate the rate of complete
disease resolution, disease reactivation after NAD, and PCs, to account for
the competing risk of death.20 The rate of development of PCs was
calculated in those patients with no evidence of these at diagnosis, and
statistical comparisons were performed as described by Gray.21 Toxicity
frequencies were compared by the ␹2 test and by WHO grade 0-IV using the
Cochran-Armitage test for trend.22 Sensitivity analyses were performed to
assess the impact of missing data, local pathological diagnosis, or patient
recruitment through different subcenters, on the primary end point of the study,
the response at 6 weeks. This analysis showed that it is highly unlikely that
missing data regarding response at 6 weeks (the nonevaluable patients) could
significantly change the conclusions of the findings of the study.
Results
Patient accrual and treatment
From May 1996 through March 2001, 193 of 279 patients
enrolled in the risk group were randomized, 93 to arm A and 100
to arm B. Demographic characteristics between the 2 arms were
equivalent (Table 1), except for some unexpected mild differences in the risk profile between the 2 arms. One hundred
forty-six of 193 patients were RO⫹ and 47, who were RO⫺, were
included because of disease onset at younger than 2 years. Of
those not randomized, proportionately more were in the RO⫺
group, in which the randomization rate was only 55%, compared
with 75% of RO⫹ patients. Fifteen RO⫹ patients lacked
complete histopathologic confirmation.
Sixty-eight percent of randomized patients (50/80 in arm A,
68/93 in arm B) completed the 24 weeks of treatment per protocol
(Figure 2). Nine responders (4 in arm A, 5 in arm B, 5%) with early
complete disease resolution stopped therapy prematurely, while
8 patients (all RO⫹ at diagnosis; 5/85 in arm A, 3/93 in arm B) died
during the 6-month treatment period.
Table 1. Patient demographic characteristics
Treatment arm, no. (%)
A
Total n (%)
93 (48)
B
100 (52)
Sex
Male
46 (49)
53 (53)
Female
46 (51)
47 (47)
Age at diagnosis
Median, y
1
1
Minimum, mo
1
1
Maximum, y
17.5
16.5
Younger than 2 y
81 (87)
84 (84)
2 y or older
12 (13)
16 (16)
Risk organ involvement
Liver
68 (73)
78 (78)
38 (41)
45 (45)
Lungs
36 (39)
21 (21)
Hematopoietic system
31 (33)
40 (40)
Spleen
31 (33)
36 (36)
Data are number (%) unless otherwise indicated.
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GADNER et al
response rate (82% arm A, 85% arm B) than did RO⫹ patients
(P ⫽ .012; Table 2).
Survival
Figure 2. Patient flow through the stages of the randomized trial for risk
MS-LCH.
Response at week 6
The primary goal of the study was to achieve a higher rate of rapid
response. Response data were available on 91% (175/193) of the
randomized patients: 63% in arm A and 71% in arm B were rapid
responders (Table 2, P ⫽ .24; difference ⫽ 8%, 95% CI ⫽ ⫺6% to
21%). Among the RO⫹ patients, rapid responses were somewhat
less frequent: 56% in arm A and 68% in arm B (P ⫽ .18;
difference ⫽ 12%, 95% CI ⫽ ⫺4% to 31%). Importantly, the
42 young (⬍ 2 years old) RO⫺ patients had a much higher rapid
The 5-year survival probability (pSU) for all risk patients was
0.74 (⫾ 0.05; mean ⫾ SEM) in arm A and 0.79 (⫾ 0.04) in arm B
(Table 2, P ⫽ .26; difference ⫽ 5%, 95% CI ⫽ ⫺11% to 21%).
Causes of death were disease progression (11 in arm A, 10 in arm
B), infectious complications (5 in arm A, 5 in arm B), organ failure
(4 in arm A, 2 in arm B), and acute nonlymphoblastic leukemia
(1 in arm B); 4 deaths were from unreported causes (3 in arm A,
1 in arm B). Mortality within 6 months (the anticipated treatment
duration) was lower in arm B (5% ⫾ 2%) than in arm
A (12% ⫾ 4%), and deaths after 2 years from diagnosis were rare
(n ⫽ 3). Significantly, all patients with disease onset at younger
than 2 years but who were RO⫺ survived (Table 2). The unadjusted
pSU of the 138 RO⫹ patients was 0.64 (⫾ 0.06) in arm A and
0.73 (⫾ 0.05) in arm B (P ⫽ .14; difference ⫽ 9%, 95%
CI ⫽ ⫺12% to 31%). In an exploratory analysis, RO⫹ patients
were stratified by clinical site, and accounting for differences in
risk organ involvement, Cox regression analysis uncovered significantly lower mortality in arm B versus arm A (relative hazard rate:
0.54, 95% CI ⫽ 0.29-1.00; P ⫽ .049). Finally, responders in each
arm had a superior survival rate to nonresponders in that arm (arm
A: P ⬍ .001, arm B: P ⫽ .003; Figure 3).
Nonresponse within 6 months triggered a therapy switch, according
to the protocol, in 26% (21/80) of patients in arm A and 18% (17/93) in
arm B. Of these 38 patients, 11 (52%) in arm A and 7 (41%) in arm B
died after switch to a salvage protocol, showing that nonresponse is
associated with high mortality that was not averted by a switch to
another treatment, and that the rate of mortality after nonresponse to
either of the 2 therapy arms was similar.
Disease resolution, reactivation, and permanent consequences
Seventy percent (124/178) of risk patients became disease free.
Achievement of NAD was greater in arm B, both within the first
year (62%; compared with 49% in arm A) as well as over the entire
5-year study period (P ⬍ .036; difference ⫽ 7%, 95% CI ⫽ ⫺6%
Table 2. Outcomes in LCH-II MS-LCH risk patients
Therapy arm, all risk patients
Risk organ involvement
Arm A
Arm B
P
ROⴙ
ROⴚ
P
53/84 (63)
65/91 (71)
.24
83/133 (62)
35/42 (83)
.01
Rapid (week 6) response
Responders/total (%)
Survival
Deaths/total
23/88
19/95
—
42/138
0/43
—
5-y pSU, % plus or minus SE
74 ⫾ 5
79 ⫾ 4
.26
69 ⫾ 4
100
⬍.001
55/85
69/93
—
84/135
40/43
Disease resolution
Patients NAD/total evaluated
Cumulative incidence, % plus or minus SE
—
⬍.001
.036
1y
49 ⫾ 6
62 ⫾ 5
—
49 ⫾ 4
78 ⫾ 7
—
3y
64 ⫾ 6
76 ⫾ 5
—
63 ⫾ 4
94 ⫾ 4
—
5y
72 ⫾ 5
79 ⫾ 4
—
68 ⫾ 4
100
—
Reactivations
Patients/total NAD
22/52
31/69
—
33/81
20/40
—
3-y cumulative incidence, % plus or minus SE
46 ⫾ 7
46 ⫾ 6
.62
44 ⫾ 6
52 ⫾10
.31
Reactivations in risk organs
3-y cumulative incidence, % plus or minus SE
4
9
—
13
0
—
8⫾4
13 ⫾ 4
.44
17 ⫾ 6
0
.44
Permanent consequences
Patients with PC/total
28/65
26/76
—
39/103
15/38
—
5-y cumulative incidence, % plus or minus SE
43 ⫾ 7
37 ⫾ 6
.25
39 ⫾ 5
40 ⫾ 9
.77
— indicates not applicable.
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THERAPY INTENSIFICATION AND OUTCOME IN LCH
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Figure 3. Rapid response and survival of MS-LCH ROⴙ patients in LCH-II. Kaplan-Meier analysis of survival of the responders (top line) and the nonresponders (ie,
intermediate [IR, middle line] and worse [bottom line]). The bar graphs compare survival in responders (Rs) versus nonresponders (NRs) in each therapy arm. Error bars
represent SEM.
to 20%). After 5 years, few patients in each arm still had active
disease. Forty-nine percent of RO⫹ patients and 78% of patients
younger than 2 years without RO involvement achieved NAD by
1 year (Table 2).
Reactivations occurred in 45% of the patients who achieved NAD
(Table 2), with an equal probability of reactivation within 3 years of
NAD in each arm (0.46 ⫾ 0.07) and no substantial difference in the sites
of reactivations. Importantly, most reactivations were mild and did not
occur in risk organs, but rather in sites such as bone, skin, and pituitary
(diabetes insipidus, DI); the 3-year incidence of reactivations in risk
organs was only 0.08 (⫾ 0.04) in arm A and 0.13 (⫾ 0.04) in arm B and
never occurred in a patient without initial RO involvement.
PCs13,23 resulting from LCH were present at diagnosis in
19% of patients (Table 2) and developed subsequently in an
additional 38%. The probability of newly developing PCs within
1 and 5 years after diagnosis, respectively was almost equal in
the 2 treatment arms (0.19 ⫾ 0.05 and 0.43 ⫾ 0.07 in arm A,
and 0.17 ⫾ 0.04 and 0.37 ⫾ 0.06 in arm B). DI was the most
frequent PC, present in 14 patients at diagnosis and developing
in 28 patients during follow-up.24 An unexpected common
finding of concern was liver fibrosis,25 present at diagnosis in
9 patients and developing subsequently in an additional
9. Seventeen patients had lung fibrosis26,27 (4 patients at diagnosis and
13 subsequently). CNS radiographic abnormalities,28 detected in
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BLOOD, 1 MARCH 2008 䡠 VOLUME 111, NUMBER 5
Figure 4. Rapid response and mortality in the
4 treatment arms of LCH-I and LCH-II. The achievement of a rapid response (left panel) and the 5-year
mortality (right panel) of RO⫹ patients in the individual
treatment arms of LCH-I (A and B) and LCH-II (A and B)
displayed according to increasing treatment intensity
(left to right) are compared. Error bars represent SEM.
15 patients, were associated with clinical symptoms in 4 patients. Other
PCs (endocrinopathies, growth failure, orthopedic problems, hearing
impairment) were rare. The overall incidence of PCs in LCH-II was
similar to that in LCH-I.13
Toxicity
Toxicity was similar in the 2 arms and was comparable with that in
LCH-I.13 Seventeen patients, equally distributed between arms A
and B, had severe toxicity (WHO score III or IV) including severe
thrombocytopenia in 7, leucopenia in 5, and hepatotoxicity in 2. It
was not possible to distinguish between disease-induced and
therapy-related hematopoietic and hepatic toxicity. One patient
developed an atypical acute myeloid leukemia with monosomy 7 at
11 months after diagnosis and a relatively low cumulative dose of
1350 mg/m2 VP-16, raising the question as to whether the leukemia
was treatment related29,30 or a separate process.31
Impact of treatment intensity in MS-LCH
The higher RO⫹ patient survival in the more intensive arm B in LCH-II
led us to perform a combined analysis of rapid response and survival in
LCH-II and the less intensive previous LCH-I trial (for which all entry
and follow-up criteria were identical), to assess the impact of increasing
treatment intensity between the 2 studies. We found a markedly higher
rapid response rate (67%) taking all (ie, RO⫹ and RO⫺) patients in
LCH-II together, versus LCH-I (43%, P ⬍ .001). And, the increasing
treatment intensity over the 4 arms of these 2 controlled studies was
associated with an increase in the rapid response rate, both in all patients
(from 47% in arm A LCH-I to 72% in arm B LCH-II; P ⫽ .002) and in
RO⫹ patients (from 43% in arm A LCH-I to 68% in arm B LCH-II;
P ⫽ .027; Figure 4). Very importantly, mortality in RO⫹ MS-LCH
decreased from 44% in arm A LCH-I, to 27% in arm B LCH-II
(P ⫽ .042; Figure 4).
Discussion
LCH-II, an international cooperative prospective randomized clinical
trial for the treatment of Langerhans cell histiocytosis, was built upon a
strategy developed from findings of our previous study, LCH-I,13 and
several earlier single and multicenter nonrandomized trials.6-8,32,33 These
studies showed that systematic approaches are critical to effective
treatment and that lack of response after an initial 6-week treatment is a
negative prognostic indicator in patients with risk MS-LCH.5,6,8,33,34
Building upon LCH-I, LCH-II intensified treatment during the first 6
weeks of therapy by combining the 2 agents tested individually in
LCH-I, vinblastine and etoposide, and adding continuous prednisone,
with the ultimate goal of reducing mortality in MS-LCH. Treatment was
well tolerated and reported toxicity was mostly mild. The effect of this
more intensive therapy in LCH-II was an increased rapid response that
was clearly superior to that of LCH-I, showing that the proportion of
responders at week 6 is influenced by the intensity of initial treatment.
Despite improvements in the treatment of LCH over the past
decades, mortality has remained high.7,8,13 Thus, it was a central
goal of LCH-II to improve patient survival by intensifying the
initial and continuation phases of the 6-month treatment. At first
glance, it appeared that overall survival (ie, of all patients
randomized in LCH-II) was only slightly improved over that in
LCH-I. However, when we examined survival of RO⫹ patients,
stratified by clinical site and accounting for differences in risk
organ involvement, a significantly higher survival rate was associated with the more intensive arm B. We discovered that RO
involvement is a discriminating risk factor for mortality. Surprisingly, when RO involvement was used to define mortality risk,
young age itself, initially identified by Lahey as a risk factor12 in
LCH, no longer appears to be a risk factor for mortality; there was
no death of any RO⫺ patient, even those younger than 2 years.
Hopefully, this outcome will dispel the widely held opinion that
young age, per se, portends a risk of mortality in LCH.4,11-13,23
Using this more refined definition of the risk category (ie, RO⫹),
we then analyzed the impact of a rapid response on survival, and
confirmed that persistence of active disease after an initial 6 weeks
of treatment is a second negative prognostic factor. In this high-risk
group (RO⫹ MS-LCH with persistence at week 6), we saw the
first signs of an increase in survival using the more intensive arm
B (Figure 3).
In an exploratory approach, we performed a comprehensive analysis
of the 2 sequential studies, LCH-I and LCH-II, and we observed that
rapid response to treatment occurred more likely with the incremental
increases in treatment intensity. Rapid response, together with the more
BLOOD, 1 MARCH 2008 䡠 VOLUME 111, NUMBER 5
intensive continuation therapy of LCH-II, was also reflected in improved survival. Possibly, extending the 6-month total treatment of
LCH-II to a full year might further reduce the overall mortality since the
Kaplan-Meier analysis showed that almost all mortality occurs within
slightly more than a year of the diagnosis of LCH (Figure 3). This is
currently being tested in LCH-III. As a corollary, RO⫹ patients who are
nonresponsive should be candidates for early use of experimental
therapies, as continuing them on further treatment was shown to be
ineffective in inducing disease resolution. This also underscores the
importance of early identification of these patients with high risk of
mortality (ie, those not responding within 6 weeks). Possible approaches
include different drug combinations, such as 2-CdA combined with
cytosine-arabinoside. This combination has shown some effectiveness,35 in contrast to 2-CDA used as a single agent in patients who were
nonresponders to their initial treatment in LCH-II. We did not observe
striking responses to 2-CDA alone in these patients (mortality rate of
46%, compared with the overall mortality rate of 52% among all
patients who switched from their initial therapy). Another possible
approach that shows promise is allogeneic stem-cell transplantation
(SCT) with intensity-reduced conditioning.36
Our findings suggest that vinblastine and etoposide remain mainstays in the treatment of LCH. In fact, until now, these are the only drugs
that have been studied and shown to be effective in prospective
randomized trials (as single agents in LCH-I and in combination in
LCH-II), and it has been shown that these drugs are also efficient in
treating recurrent disease. Whether the positive results of our trials can
be extended to the use of these drugs in treating adults affected by LCH
remains to be determined; a prospective study of this question is
currently under way. Similarly, in related variant disorders such as
Erdheim-Chester disease, in which anecdotally a few patients have been
successfully treated with continuous vinblastine or etoposide, a prospective study may be warranted as well.
Somewhat surprisingly, incidences of reactivation and of
PCs were not reduced by the more intensive regimens of
LCH-II, compared with LCH-I.13 Intensive therapy appears to
have a profound effect on patients with very-high-risk disease
but has shown little to no advantage over milder therapy with
respect to disease resolution, reactivation, or PCs.13,37,38 These
become the problematic aspects of LCH once the risk of
mortality has been alleviated.37-39 Whether a milder but longer
continuation treatment could be more effective in preventing
reactivations, as suggested by the DAL-HX studies,8,34 remains
to be tested and is a central question being asked in the
Histiocyte Society LCH-III study.
Two salient points derived from the overall findings are
worth reemphasizing. First, in patients with risk organ involvement, the observed increase in the proportion of patients
achieving a rapid response to 60% to 70%, the reduction of
mortality to 20% to 25%, and the disappearance of risk organ
dysfunction in completely responding patients all support the
use of relatively intense therapy such as in LCH-II. Second, the
results of LCH-II underscore that it is not age itself but the
therapeutic response in risk organs that predicts outcome in young
(⬍ 2 years old) children with RO⫹ LCH. In the past, it was quite
possibly the relatively high incidence of LCH with risk organ involvement in very young (versus older) children combined with less
successful treatment then, than now, that caused the widely held belief
that young age is responsible for higher mortality of LCH. With our
current knowledge, therapy now can be tailored to the extent of disease
rather than the age of the patient.
In conclusion, the results of LCH-II clearly underscore that
RO involvement and rapid response to initial therapy are
THERAPY INTENSIFICATION AND OUTCOME IN LCH
2561
especially important in predicting outcome. When we compare
outcomes in the consecutive randomized LCH-I and LCH-II
studies, there is a strong indication that increasing treatment
intensity was associated with higher rapid response and survival
rates. This suggests that therapy intensification, often shunned
because of feelings either of hopelessness or of lack of
necessity, may be essential for successful treatment of high-risk
disease. Based on our experience, we can feel more confident
about a positive outcome in the majority of patients and less
fearful of “overtreating” certain patient subgroups. We should
continue to explore new intensive therapies for the high-risk
patients, while low-risk MS-LCH patients, identified by our
trials, can be excluded from intensive initial treatment. Of
particular significance, patients with high-risk disease who
respond rapidly to therapy, and very young patients without RO
involvement, can be given a much more optimistic prognosis for
survival than has been the case in the past.
Acknowledgments
The authors thank the additional members of the LCH-II Study
Committee: D. Komp, MD, S. Nicholson, MD, and J. Pritchard,
MD, for contributions in planning the study, and the many
physicians who participated in the LCH-II Study. We also thank
Elfriede Thiem for the excellent data management at the study
reference center in Vienna (Austria) and D. J. Michaelis, PhD, head
of the independent review board at the Institute of Medical
Statistics, Mainz, Germany, for the regular assessment of study
progress and stopping rules.
This work was supported by the Histiocytosis Association of
America, the Histiocytosis Association of Canada, the Children’s
Cancer Research Institute (CCRI; Vienna, Austria), Programme
Hospitalier de Recherche Clinique 96 (PHRC96) grants, Ministe`re
de la Sante´ et des Affaires Sociales (France), the Italian Ministry of
Health, Ricerca Finalizzata 2004, Associazioni Italiana per la
Ricerca sul Cancro e Istiocitosi (AIRI and AIRC; Italy), and the
Children’s Research Institute (Washington).
Authorship
Contribution: H.G. and S.L. wrote the paper; U.P. and R.M.
performed the statistical analyses; N.G. and M.M. contributed to
study coordination, data collection, and analysis; M.A., J.B., V.B.,
J.D., and J.-I. H. made clinical contributions and provided critical
paper review; all authors were involved in study design and final
approval of the paper.
A list of the Histiocyte Society LCH II study committee and
national study coordinators 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: The authors declare no competing financial interests.
Correspondence: Helmut Gadner, Children’s Cancer Research
Institute, St Anna Kinderspital, Vienna, Austria; e-mail:
[email protected]; or Stephan Ladisch, Children’s Research
Institute, Children’s National Medical Center, Washington, DC
20010; e-mail: [email protected].
2562
BLOOD, 1 MARCH 2008 䡠 VOLUME 111, NUMBER 5
GADNER et al
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