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Blood, Vol. 94 No. 10 (November 15), 1999:
pp. 3294-3306
Improved Treatment Results in Childhood B-Cell Neoplasms With Tailored
Intensification of Therapy: A Report of the
Berlin-Frankfurt-Münster Group Trial NHL-BFM 90
By
Alfred Reiter,
Martin Schrappe,
Markus Tiemann,
Wolf-Dieter Ludwig,
Elif Yakisan,
Martin Zimmermann,
Georg Mann,
Andreas Chott,
Wolfram Ebell,
Thomas Klingebiel,
Norbert Graf,
Bernhard Kremens,
Stefan Müller-Weihrich,
Hans-Jürgen Plüss,
Felix Zintl,
Günter Henze, and
Hansjörg Riehm
From the Department of Pediatric Hematology and Oncology,
Medizinische Hochschule, Hannover, Germany; the Lymphnode Registry of
The Society of German Pathologists, Institute of Hematopathology,
Christian-Albrechts-Universität, Kiel, Germany; the Department of
Hematology, Oncology and Tumor Immunology, Charité, Humboldt
University Berlin, Berlin, Germany; the St. Anna Kinderspital, Vienna,
Austria; the Department of Pathology, University of Vienna, Vienna,
Austria; the Department of Pediatric Hematology and Oncology,
Charité, Humboldt University, Berlin, Germany; the Department of
Pediatrics, University of Tübingen, Tübingen, Germany; the
Department of Pediatrics, University of Saarland, Homburg, Germany; the
Department of Pediatric Hematology and Oncology, University of Essen,
Essen, Germany; the Department of Pediatrics, Technical University,
München, Germany; the Department of Pediatrics, University of
Zürich, Zürich, Switzerland; and the Department of
Pediatrics, Friedrich Schiller University, Jena, Germany.
 |
ABSTRACT |
In study NHL-BFM 90, we investigated whether the serum lactate
dehydrogenase (LDH) concentration and early response are useful markers
for stratification of therapy for childhood B-cell neoplasms in
addition to stage, if the outcome of patients with abdominal stage III
and LDH  500 U/L can be improved by high-dose (HD) methotrexate (MTX)
at 5 g/m2 instead of intermediate-dose (ID) MTX at 500 mg/m2 in the preceding study 86; whether 2 therapy courses
are enough for patients with complete resection; and whether combined
systemic and intraventricular chemotherapy is efficacious for central
nervous system-positive (CNS+) patients.
After a cytoreductive prephase, treatment was stratified into 3 risk
groups: patients in R1 (completely resected) received 2 5-day courses
(ID-MTX, dexamethasone, oxazaphorins, etoposide, cytarabine,
doxorubicin, and intrathecal therapy), patients in R2 (extra-abdominal
primary only or abdominal tumor and LDH <500 U/L) received 4 courses
containing HD-MTX, and patients in R3 (abdominal primary and LDH 500
U/L or bone marrow/CNS/multilocal bone disease) received 6 courses.
Incomplete responders after 2 courses received an intensification
containing HD-cytarabine/etoposide. Patients with no or necrotic tumor
thereafter received 3 more courses; 6 patients with viable tumor
received autologous bone marrow transplantation. From April 1990 through March 1995, 413 evaluable patients were enrolled (R1, 17%; R2,
40%; and R3, 43%). The 6-year event-free survival (pEFS) was 89% ± 2% for all and 100%, 96% ±2%, and 78% ± 3% in R1,
R2, and R3, respectively. The pEFS of patients with abdominal stage III
and LDH 500 U/L was 81% ± 4% as compared with 43% ± 10% in
study 86. Of 26 CNS+ patients, 5 died early, but only 3 relapsed.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
THE INTRODUCTION OF short, intensive
therapy courses primarily based on cyclophosphamide, methotrexate
(MTX), and intrathecal (i.th.) therapy resulted in improved survival
rates of children suffering from mature B-cell
neoplasms.1-8 Conclusions from 3 previous trials of the
Berlin-Frankfurt-Münster (BFM) group were that 3 courses of
chemotherapy are enough for patients with completely resected localized
tumors and that 6 courses are as good as 8 for patients with advanced
stage disease.3 High-dose (HD) MTX therapy (5 g/m2) instead of intermediate-dose (ID) MTX (0.5 g/m2) improved the outcome of patients with acute B-cell
leukemia (B-ALL).5 Central nervous
system-negative (CNS ) patients do not
need CNS irradiation for prevention of CNS relapses.5,6 An
intraventricularly applied chemotherapy is likely to be beneficial for
patients with CNS disease.5 Patients with incomplete tumor regression after 2 or 3 therapy courses had an increased risk of
failure, particularly if they had histologically active residual tumors. There was no evidence of a curative role of
surgery or radiotherapy.5,6,9
However, these intensive treatment strategies carry acute and late
risks. But, after failure of first-line therapy, the probability of
survival is poor.10 Therefore, further improvement of
therapy requires optimized tailoring of treatment intensity to the
patient's risk of failure. In our previous trials, treatment intensity
was stratified according to the St. Jude staging system.11
Descriptions of tumor burden as an important prognostic
factor12-14 are in line with the hypothesis of Goldie and
Coldman15 that the proportion of multiple resistant cells
correlates with tumor mass. Yet, the parameters of tumor mass, eg,
serum level of lactic dehydrogenase (LDH),12 were not used
for stratification of therapy because they correlate with
stage.16 However, stage III of the St. Jude's staging
system includes patients with largely varying tumor mass. In our
previous trial, NHL-BFM 86, patients with stage III and pretherapeutic
serum LDH concentrations 500 U/L had a significantly worse outcome
than those with lower LDH values (6-year event-free survival
[pEFS], 43% ± 10% [n = 23] v 85% ± 6% [n = 35]). Therefore, in study NHL-BFM 90, LDH was used as an
additional parameter for stratification of therapy intensity.
In study NHL-BFM 90, the goals for the treatment group B-NHL/B-ALL were
to investigate whether a system for stratification of treatment
intensity based on resectability, LDH, and stage is appropriate;
whether the outcome of patients with abdominal stage III and LDH 500
U/L can be improved by intensified chemotherapy; whether survival of
patients with incomplete initial response can be improved by stepwise
intensification of therapy, including autologous blood stem cell
transplantation; whether for patients with completely resected
localized tumors therapy can further be reduced from 3 to 2 5-day
courses; whether for patients with low tumor mass (LDH <500
U/L) therapy can be reduced from 6 to 4 courses when HD-MTX is used
instead of ID-MTX; and whether combined intravenously and
intraventricularly applied chemotherapy without radiotherapy is
efficacious treatment for patients with CNS disease.
We report here on the treatment strategy and results of children and
adolescents suffering from mature B-cell neoplasms enrolled in the
study NHL BFM-90 from Austria, Germany, and part of Switzerland during
a period of 5 years. Results are compared with those of trial NHL-BFM
86 as a historical control.
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PATIENTS AND METHODS |
Patients.
Children and adolescents up to 18 years of age newly diagnosed with any
kind of non-Hodgkin's lymphoma (NHL) or B-ALL were eligible for trial NHL-BFM 90. Exclusion criteria were the following: acquired immunodeficiency syndrome (AIDS)-related NHL, severe immunodeficiency, posttransplantation lymphoma, and pre-existing disease prohibiting chemotherapy. From April 1990 through March 1995, 682 eligible patients were enrolled from 90 clinics in Austria, Germany, and Switzerland after informed consent of their guardians had
been obtained. The study population was subdivided according to NHL
subtype into 3 groups with different therapy strategies: therapy group
non-B (n = 162, patients with lymphoblastic lymphoma [precursor-B-cell
or T-cell] or peripheral T-cell lymphoma), therapy group B-NHL/B-ALL
(n = 431, patients with mature B-cell-NHL [B-NHL] or B-ALL), and
therapy group ALCL (n = 89, patients with anaplastic large-cell
lymphoma [ALCL]). We report here on the treatment and results of
therapy group B-NHL/B-ALL. Of the 431 patients of group B-NHL/B-ALL, 18 patients (4%) were excluded from the evaluation for the following
reasons: no therapy applied due to an individual decision (1 patient,
alive after complete resection), premature withdrawal (1 patient,
alive), treatment according to therapy strategy non-B (2 patients, 2 relapses), treatment according to therapy strategy ALCL (1 patient,
free of disease), treatment according to protocol of previous trial
NHL-BFM 86 (1 patient, free of disease), treatment according to a pilot
protocol (6 patients, 1 relapse), allogeneic bone marrow
transplantation (BMT; 1 patient, free of disease), and no
intraventricular chemotherapy despite CNS disease (5 patients [1
received cranial irradiation], 2 CNS relapses). Finally, 413 patients
with B-cell neoplasms were evaluable for response.
Diagnosis.
Cases were classified according to the updated Kiel-Classification for
Non-Hodgkin's Lymphomas.17 The corresponding terms of the
Revised European American Lymphoma (REAL) Classification18 are given in Table 3. Immunophenotyping of fresh cell suspensions was
performed as previously described.19 In 341 patients, the diagnosis of B-NHL was based on histopathology and
immunohistochemistry. From 233 (68%) of these 341 patients, the
histopathological material was reviewed centrally by a reference
laboratory of the study. Sixteen cases were classified as Burkitt's
lymphoma due to L3 morphology according to French-American-British
(FAB) criteria20 of cells from malignant effusions. The
presence of surface Igs (sIg) was proven in 11 of these 16 patients.
Immunophenotyping was incomplete in 2 cases due to inappropriate
material, whereas from 3 patients no material was available for central
immunopheotyping. Fifty-six patients were diagnosed with B-ALL due to
the presence of 25% or more FAB L3 blasts in the bone marrow (BM). The
expression of sIg was shown by immunophenotyping in 41 of these 56 patients. Immunophenotyping was incomplete in 9 cases due to
inappropriate material, whereas from 5 patients no material was
available for central immunopheotyping. In 1 case, the FAB-L3 blasts
did not express sIg.
Staging.
The St. Jude staging system11 was used. Staging studies
included physical examination, peripheral blood and BM aspiration smears, cerebrospinal fluid (CSF) analyses, ultrasonography, x-ray, computed tomography (CT) or magnetic resonance imaging (MRI), and
skeletal scintigraphy. In patients with an otherwise proven diagnosis
of NHL, bone involvement was diagnosed if imaging studies showed bone
lesions. Initial CNS disease was diagnosed if at least 1 of the
following was present: morphologically identifiable lymphoma cells in
the CSF on cytospin-preparations (regardless of the number), cerebral
infiltrates on cranial CT or MRI, or cranial nerve palsy that was not
caused by an extradural or extracranial mass. Testicular involvement
was diagnosed clinically as the presence of painless enlargement of 1 or both testicles, provided that the diagnosis of NHL was otherwise
established. The total serum LDH activity was measured as a routine
laboratory test using standard methods.21 The normal limits
of serum LDH values varied between the participating clinics. The
comparability of measured enzyme activities measured in different
laboratories is monitored by an external quality control system.
Stratification of treatment intensity.
Therapy was stratified into 3 risk groups
(Fig 1) according to the following
definitions. Risk group 1 was defined as patients with initial complete
resection of the lymphoma manifestation. Risk group 2 was defined as
patients with no or incomplete resection of lymphoma manifestations,
for which 1 of the following criteria is met: only extra-abdominal
sites or abdominal site and LDH less than 500 U/L, measured
before beginning chemotherapy. Risk group 3 was defined as patients
with no or incomplete resection of abdominal lymphoma and LDH
500 U/L, all patients with BM involvement or/and CNS disease, or/and
multifocal bone involvement.
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| Fig 1.
Treatment strategy. Patients were stratified into 3 risk
groups: R1, R2, and R3. The composition of therapy courses is given in
Table 1. V, cytoreductive prophase; CR, complete response; SL-OP,
second-look operation; ABMT, autologous BMT or blood stem cell
transplantation.
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Chemotherapy.
The therapy courses are given in Table 1.
All patients received a 5-day cytoreductive prephase. Hydration of
3,000 to 4,500 mL/m2/d, alkalization with
NaHCO3 intravenously (IV), and allopurinol were
administered to prevent acute cell lysis syndrome. By July 1, 1993, an
amendment of the cytoreductive prephase was introduced because of the
incidence of early toxic death. Cyclophosphamide doses were reduced to
2, and prednisone was replaced by dexamethasone at 5 mg/m2/d on days 1 and 2 and at 10 mg/m2/d on
days 3, 4, and 5. After the 5-day prephase, the first course of
chemotherapy should be initiated the next day depending on the
condition of the patient. The median delay of the initiation of the
first course of chemotherapy was 0 days (range, 0 to 52 days). Patients
in risk group R1 received 2 therapy courses A, B. Patients in risk
group R2 received 4 courses AA-BB-AA-BB. Patients in risk group R3
received 6 courses AA-BB-AA-BB-AA-BB. Conditions for starting the
second and third course of therapy were as follows: platelets greater
than 50,000/µL and neutrophils greater than 200/µL after the nadir
of postchemotherapeutic cytopenia was passed; for subsequent courses 4, 5, and 6, neutrophils should be greater than 500/µL. The minimal
interval between the first day of 2 successive courses should be at
least 2 weeks.
In the therapy courses AA and BB, which contain MTX at 5 g/m2, the MTX serum concentration were measured at 24, 36, 42, and 48 hours from the start of the MTX IV infusion. The serum
levels of MTX should be  150 µmol/L at 24 hours from start of MTX
infusion, less than 3 µmol/L at 36 hours, 1 µmol/L at 42 hours,
and 0.4 µmol/L at 48 hours. Leucovorin rescue (racemic folinic
acid) was administered IV at 30 mg/m2 at 42 hours and at 15 mg/m2 at 48 and 54 hours after the start of MTX infusion.
If the MTX serum concentrations was higher than expected at 42 or 48 hours, measurements of the MTX serum levels and administration of
leucovorin rescue were continued every 6 hours until the serum MTX
concentration decreased to less than 0.25 µmol/L. The dose of
leucovorin was adjusted as follows: MTX serum level of greater than 1 to 2 µmol/L, leucovorin at 30 mg/m2; MTX level of greater
than 2 to 3 µmol/L, leucovorin at 45 mg/m2; MTX level of
greater than 3 to 4 µmol/L, leucovorin at 60 mg/m2; and
MTX level of greater than 4 to 5 µmol/L, leucovorin at 75 mg/m2. If the MTX level exceeded 5 µmol/L, the leucovorin
dose was calculated according to the formula leucovorin (in milligrams) = MTX serum concentrations (in micromoles per liter) × body
weight (in kilograms) and was administered as an IV infusion to avoid hypercalcemia.
In patients with overt CNS disease, a device for intraventricular
application of chemotherapy was implanted before the second course of
therapy. MTX at 3 mg and 2.5 mg prednisolone were administered on days
1, 2, 3, and 4 and 30 mg cytarabine was administered on day 5 of
courses AA and BB. In courses CC, 3 mg MTX and 2.5 mg prednisolone were
administered on days 3, 4, 5, and 6; 30 mg cytarabine was administered
on day 7 (dose reduction for patients <3 years).
Patients in risk groups R2 and R3 who had a residual tumor and/or
persistent blasts in the BM and/or in the CSF after 2 therapy courses
received therapy course CC (Table 1). Patients were re-evaluated after
course CC. In case of a persistent mass, a second-look operation was
performed. If no viable lymphoma tissue was found, therapy was
continued with 3 more courses AA-BB-CC. If viable lymphoma tissue was
found, then megadose chemotherapy with autologous BM or blood stem cell
rescue was performed. The high-dose chemotherapy consisted of busulfan,
etoposide, and cyclophosphamide (Table 2).
In CNS+ patients, thiotepa was administered instead of
cyclophosphamide.
Local therapy modalities.
In case of localized disease, complete surgical resection was
recommended if it could be easily and safely accomplished without the
risk of functional impairments. In advanced stage disease, restricting
initial surgery to the minimum required for gaining appropriate
diagnostic tissue was recommended. Second-look surgery should follow
the same guidelines. Local radiotherapy was not performed. In male
subjects with testicular involvement, orchiectomy and radiotherapy was
not foreseen.
Response criteria.
The treatment success was determined by the rate of EFS of the
patients. Events were death due to any cause, tumor progression, and
second malignancy. Tumor response was evaluated after each course of
therapy. Follow-up studies were performed at 4- to 6-week intervals
during the first 1.5 years. In patients with BM or/and CNS involvement,
control punctures of BM or/and CSF were performed only until the BM or
the CNS, respectively, was cleared from blasts. Progression was defined
as a recurrence of lymphoma proven by biopsy or regrowth of an
incompletely resolved tumor. The diagnosis of isolated progression in
the BM was based on 25% or more blasts in the BM. The diagnosis of
isolated progression in the CNS was based on the appearance of blasts
in the CSF.
Statistical analysis.
Analyses of EFS were performed using the Kaplan and Meier
method22 with differences compared by the log-rank
test.23 EFS was calculated from the date of diagnosis to
the first event (death from any cause, tumor progress, or second
malignancy) or to the date of last follow-up. Patients lost to
follow-up (LFU) were censored at the time of their withdrawal. Rank
order comparisons of the prognostic relevance of different parameters
were examined by stepwise Cox regression analysis.24
Differences in the distribution of individual parameters among patients
subsets were analyzed using the  2 test or Fisher's
Exact Test. The statistical analysis was performed using the SAS
statistical program (SAS-PC, Version 6.12; SAS Institute Inc, Cary,
NC). Follow-up data were actualized as of October 1, 1998.
| |
RESULTS |
Patient characteristics.
Of the 413 evaluable patients, 92 were girls and 321 were boys. The
median age was 9.0 years (range, 1.2 to 17.9 years). The diagnoses of
the patients are given in Table 3. The
distribution of stages were stage I, II, III, IV, B-ALL in 12%, 28%,
41%, 6%, and 13% of patients, respectively. The median pretreatment
LDH level was 365 U/L (range, 80 to 17,000 U/L).
Figure 2 shows the distribution of serum
LDH values according to stage. Table 4 lists the distribution of patients according to risk groups and stages:
17% of patients were assigned to risk group R1, 40% to risk group R2,
and 43% to risk group R3. Patients with stages I and II were
subdivided between risk groups R1 and R2 according to complete versus
incomplete tumor resection. Patients with stage III were subdivided
1:73:95 between risk groups R1:R2:R3 according to LDH and localization
of the primary tumor. Six stage III patients with pretreatment LDH
500 U/L were assigned to risk group R2 due to exclusively
extra-abdominal disease. Of the 24 patients with stage IV disease, 12 had BM involvement, 9 had CNS disease, and 3 had both BM and CNS
disease. Fourteen of the 56 B-ALL patients had CNS involvement at
diagnosis. Of the 26 patients with CNS disease, 18 had CSF blasts (1 had also an intraparenchymal mass). The median number of CSF cells of
these patients was 9/µL (range, 1 to 1,000/µL). Three patients were
considered CNS+ due to an intraparenchymal mass and cranial
nerve palsy, and 5 patients had a cranial nerve palsy only. Four of the
26 CNS+ patients had an epidural mass. Another 5 patients
had epidural tumors without CSF blasts or intraparenchymal lesions, and
they were considered CNS. Three boys had unilateral
wheras 1 had bilateral testicular disease. The diagnosis of testicular
involvement was established by biopsy in 2 cases and clinically plus by
ultrasound in 2 cases. Twenty patients with impaired renal functions
due to kidney infiltration or/and acute cell lysis syndrome needed
hemodialysis.
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| Fig 2.
Distribution of pretreatment serum LDH concentrations
(logarithmic scale) according to stage of disease. ( ) Patients
surviving event-free; ( ) toxic death; ( ) patients suffering from
progress; (*) patients who developed second malignancy. From 16 patyients (2, 7, 2, 1, and 4 of stage I, II, III, IV, and B-ALL,
respectively) the LDH values are lacking. One of these patients (stage
IV) relapsed, and 2 B-ALL patients died of acute cell lysis syndrome.
One patient (stage III) with LDH less than 100 U/L and 3 patients
(B-ALL) with LDH greater than 10,000 are not depicted; 1 of them
(B-ALL) died of acute cell lysis syndrome.
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EFS.
At a median follow-up of 4.2 years (range, 1.0 to 7.1 years), the
estimate for pEFS is 88% ± 2% for the 431 eligible patients and
89% ± 2% for the 413 patients evaluable for response
(Fig 3A). Twenty-one patients were lost to
follow-up after a median event-free follow-up duration of 1.73 years
(range, 0.2 to 5.46 years).
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| Fig 3.
Kaplan-Meier estimate of EFS (A) for the whole group of
evaluable patients and (B) according to risk groups R1, R2, and R3. SE,
standard error.
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The following analysis of treatment results includes only the 413 evaluable patients. The pEFS at 6 years was 100%, 96% ± 2%, and
78% ± 3% for patients in risk groups R1, R2, and R3, respectively (Fig 3B). Eight patients in risk group R1 were treated according to
branch R2, and 12 patients of risk group R2 were treated according to
branch R3 due to individual decisions of the physicians in charge. The
pEFS at 6 years according to the treatment applied was 100%, 96% ± 2%, and 79% ± 3% for patients treated according to
branches R1, R2, and R3, respectively.
Events.
Forty-three patients suffered an adverse event
(Table 5). Three children in risk group R3
died early of acute cell lysis syndrome. Eleven children (3 in risk
group R2 and 8 in risk group R3) died of toxic death. Twenty-seven
children suffered from progression (2 in risk group R2 and 25 in risk
group R3). In 10 of these patients, progression occurred during
therapy; in 15 patients, progression occurred within 3 months after
completion of therapy. Local manifestations were the most
frequent site of tumor failure (19 of 27 cases), followed by BM and new
sites (Table 3). Two patients developed a secondary malignancy. The
histology of both second malignancies was again NHL. A girl who was 6.6 years of age at the first diagnosis Burkitt`s lymphoma developed a
second Burkitt`s lymphoma 3.5 years later. The light-chain restriction
of the first tumor was  , whereas the light-chain was  in the
second tumor. The second case was an 8.5-year-old boy with a first
diagnosis of B-ALL. Three years later, he developed a T-cell
lymphoblastic lymphoma. Two boys (1 with B-NHL, not further
classifiable, and 1 with Burkitt`s lymphoma) suffered from unusual
late recurrences 3.5 and 4 years after completion of therapy. One of
them was very recently diagnosed as suffering from X-linked
lymphoproliferative syndrome. In both cases, the clonal identity or
difference of the first and the second tumor could not be investigated
due to the lack of appropriate material.
EFS according to stage of disease and pretreatment LDH values.
pEFS according to stage is depicted in Fig
4. Table 6 summarizes adverse events
according to stage. Of the 56 B-ALL patients, 17 had 25% to 69%
L3-blasts in the BM, 1 of them died early, 3 died of toxicity, and 2 failed to respond to therapy. Thirty-nine B-ALL patients had greater
than 70% L3 blasts in the BM, 2 of them died early, 1 died of
toxicity, and 4 failed to respond to therapy. Figure 2 shows the
incidence of events according to stage and pretreatment LDH values.
pEFS of patients with stage III (pEFS, 88% + 3%; n = 169) was
significantly higher than pEFS of patients with stage IV+B-ALL (pEFS,
74% ± 5%; n = 80; P = .0059). However, in patients with
stage III and IV B-ALL, the LDH values varied over a wide range. pEFS
was significantly lower for patients with stage III/IV/B-ALL, with LDH
values greater than 1,000 U/L (pEFS, 70% ± 5%; n = 84) as
compared with those with LDH values less than 1,000 U/L (pEFS, 90% ± 3%; n = 158; P = .0001). In a Cox regression
analysis with the covariables stage (stage III v stage IV+B-ALL) and LDH (<1,000 v 1,000 U/L), LDH
greater than 1,000 U/L was the superimposed predictor for treatment
outcome (risk ratio, 6.450; P = .0017), whereas the prognostic
impact of stage IV+B-ALL was not significant (risk ratio, 2.726;
P = .3802).
CNS disease.
The pEFS at 6 years for the 26 patients with initial CNS disease (17 BM
positive and 9 BM negative) was 65% ± 9%. Two patients died early
of acute cell lysis syndrome, and 3 patients died of sepsis after the
first course of therapy before an Ommaya-reservoir was implanted (Table
6). Of the remaining 21 patients, 3 suffered from progression, but only
1 of them within the CNS.
Testicular involvement.
In 2 of the 4 boys with testicular involvement, no local therapy was
performed and both remained event-free. In 2 cases, orchiectomy was
performed after 3 courses of therapy due to suspected residual disease.
In both cases, histology did not show evidence for residual lymphoma.
One of these 2 patients died later in the course of sepsis, and the
second one remained event-free.
Outcome according to the kinetics of response to therapy.
The courses of patients in risk groups R2 and R3 are depicted in
Fig 5A and B, respectively. One patient in
risk group R2 and 9 patients in risk group R3 died of initial
complications or of infection before the response could be evaluated,
after the second course of therapy. One hundred sixty-six patients each were evaluable for response after the first 2 therapy courses in risk
groups R2 and R3. Using imaging methods, 46 patients (28%) in risk
group R2 and 73 patients (44%) in risk group R3 had tumor remnants
after 2 courses of therapy (P = .002). No patient with initial
BM or/and CNS involvement had persistent blasts in the BM or the CSF
after 2 courses. Of the 46 patients in risk group R2 with tumor
remnants, 2 suffered from subsequent progression as compared with 13 of
73 patients in risk group R3 with tumor remnants (P = .031). In
risk group R3, 8 patients had viable residual tumor after course CC: 6 received autologous BMT (ABMT); 1 suffered from
progression, 1 patient received local radiotherapy and suffered from
progression, and 1 patient had viable residual tumor in an ovary that
was completely resected. This patient received 3 more courses AA-BB-CC
and remained free of progression.
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| Fig 5.
Direction of treatment intensity and second-look surgery
according to response. (A) Course of patients in risk group R2; (B)
course of patients in risk group R3. ED, early death by acute cell
lysis syndrome; TD, toxic death; NED, no evidence of disease; SL-OP,
second-look operation; ABMT, autologous BMT; LRT, local radiotherapy;
FOP, free of progress; LFU, lost to follow-up.
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EFS according to histological subtypes.
pEFS at 6 years was 89% ± 2% for the 322 patients with
Burkitt-type lymphomas or B-ALL, 95% ± 3% for the 56 patients
with diffuse large B-cell lymphomas (including 8 patients with
mediastinal [thymic] B-cell lymphoma), and 84% ± 7% for the 35 patients with B-NHL not further classified (P > .14 for all comparisons).
Toxicity.
Apart from myelosuppression, mucositis was the leading toxic side
effect in this therapy and was related to the dose of MTX. Mucositis
World Health Organization (WHO) grade 2 occurred after 12%, 19%,
47%, 48%, and 13% of courses A, B, AA, BB, and CC, respectively. Febrile episodes were observed after 7%, 12%, 7%, 37%, 31%, and 24% of courses A, B, AA, BB, and CC, respectively. Nine patients died
of septicemia and enterocolitis (3 Pseudomonas aeruginosa, 1 Citrobacter, and 4 blood culture negative). Of these, 6, 2, and 1 patients died after the first, second, and third course of
chemotherapy, respectively. On July 1, 1993, the number of cyclophosphamide doses of the cytoreductive prephase was reduced from 5 to 2. Five of the 6 toxic deaths during the neutropenic phase after the
first course of therapy occurred before this amendment, with only 1 occurring thereafter. One patient died of acute cardiac insufficiency
after the fifth course of therapy. One patient died of acquired
respiratory distress syndrome after autologous BMT.
Comparison of results: NHL-BFM 90 and NHL-BFM 86.
The pEFS at 6 years for B-NHL/-B-ALL patients was 89% ± 2% in
study NHL-BFM 90 as compared with 82% ± 3% in study NHL-BFM 86 (P = .0087; Table 7). pEFS was not
significantly different between both studies for patients with stage I,
stage II, stage IV, and B-ALL, respectively. However, for patients with
stage III disease, pEFS at 6 years was significantly higher in study NHL-BFM 90. The improvement in stage III patients was an increase of
pEFS from 43% ± 10% in study NHL-BFM 86 to 81% ± 4% in
study NHL-BFM 90 for those patients with abdominal disease and LDH
500 U/L (Fig 6).
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| Fig 6.
Kaplan-Meier estimate of EFS for patients with abdominal
stage III B-NHL and LDH 500 U/L in trial NHL-BFM 90 and in the
preceding trial NHL-BFM 86. SE, standard error.
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| |
DISCUSSION |
In trial NHL-BFM 90, a total of 431 children and adolescents with
mature B-cell neoplasms were enrolled, of whom 413 were evaluable for
response. The 6-year pEFS was 88% ± 2% for all 431 eligible
patients and was 89% ± 2% for the 413 evaluable patients. The
therapy strategy applied proved to be a highly efficacious treatment
not only for patients with Burkitt-type lymphomas and B-ALL, but also
for patients suffering from diffuse large B-cell lymphomas.
The results of trial NHL-BFM 90 demonstrate that the outcome of B-NHL
patients who were at high risk of progression could be significantly
improved by intensification of therapy. The improvement of treatment
results in study NHL-BFM 90 as compared with study NHL-BFM
866 was exclusively due to a significant increase of pEFS
for patients with abdominal stage III and LDH 500 U/L, who were the
target group for treatment intensification in study NHL-BFM 90. Compared with our preceding studies, these patients received HD-MTX
therapy at 5 g/m2 instead of ID-MTX at 0.5 g/m2. Furthermore, 44% of them received high-dose
cytarabine/etoposide therapy because of an incomplete tumor resolution
after 2 courses of therapy, and 6.6% of them received ABMT due to a
persistent viable tumor after 3 courses of therapy. pEFS for these
patient subgroup increased from 43% ± 10% in study NHL-BFM 86 to
81% ± 4% in study NHL-BFM 90.
Our data confirm that, in addition to stage, LDH as a parameter of
tumor burden is appropriate for stratification of treatment intensity
for patients with B-cell neoplasms. Approximately 40% of patients
present with stage III in the St. Jude system,11 which
includes patients with varying tumor burden and, therefore, who may
need different treatment intensities.25 In our previous studies, a cut-off of 500 U/L of the pretherapeutic LDH serum concentration distinguished 2 subgroups of stage III patients with
significantly different outcomes when they received uniform treatment,
including ID-MTX at 0.5 g/m2. The pEFS of patients with LDH
less than 500 U/L was comparable to that of patients with stage II
disease, whereas the pEFS of patients with abdominal stage III and LDH
500 U/L was less than 50%. Therefore, in study NHL-BFM 90, the
pretherapeutic LDH was used for stratification of treatment intensity
together with resectability and stage (BM and CNS involvement). As a
consequence, patients with stage III were subdivided into risk groups
R2 and R3. This stratification system enables the pretherapeutic
identification of 60% of patients (risk groups R1 + R2) with a
probability of EFS of 95% with limited therapy intensity. Almost all
patients at risk for failure are assembled in risk group R3.
As in many malignancies, the speed of the initial response to therapy
has prognostic impact for B-NHL-patients. In our previous studies, as
in other studies, patients with incomplete tumor regression after 2 or
3 therapy courses had an increased risk of failure, especially those
with viable residual tumors.1,5,6,9,26 Therefore, in study
NHL-BFM 90, we examined a strategy of stepwise intensification of
therapy for patients with incomplete response after 2 courses of
therapy. The first step of intensification was HD-cytarabine/etoposide,
which was described as being effective in relapsed
patients.27 Patients who still had residual tumor thereafter underwent second-look surgery. Those patients with viable
tumor received megadose chemotherapy with hematological stem cell
rescue as a second step of intensification.28 Although the
contribution of each step to patient outcome is difficult to judge,
some conclusions are possible. In patients with incomplete early tumor
regression, the risk of subsequent progression depends on the
patient's initial tumor mass. In risk group R2, only 2 of 46 patients
with residual tumor after 2 courses of therapy suffered from subsequent
progression, compared with 13 of 73 such patients in risk group R3.
Moreover, in risk group R3, the probability of progression-free
survival of patients with a residual tumor after 2 courses was
significantly higher for patients with pretreatment LDH values less
than 1,000 U/L as compared with those with LDH values 1,000 U/L (data
not shown).
Megadose chemotherapy with autologous stem cell rescue may be
beneficial for patients with histologically active tumor after 3 therapy courses. Of 6 patients who received ABMT, 1 suffered from
progression, whereas 4 of 5 such patients in study NHL-BFM 86 who did
not receive ABMT died of progressive disease.6 However, this ambitious approach including invasive monitoring of tumor regression was not sufficiently predictive of the course of the disease. We observed local recurrences among patients with complete resolution of tumors as determined by imaging and second-look surgery.
Contrarily, the majority of patients with tumor remnants who did not
receive second-look surgery remained subsequently free of progression.
Even the finding of viable residual tumor on second-look operation may
be not of unequivocal value, considering the total group of patients.
To identify 8 patients with viable residual tumor, 45 second-look
operations had to be performed. Our conclusion from this prospective
trial is that the strategy of guiding treatment according to the
clinical response to therapy is of limited value and carries
substantial risks. The interpretation of imaging and histological
material may also be biased by the investigators' knowledge that their
judgement has consequences on patient treatment.
We agree with others that patients with localized stages I and II
should have limited therapy.29 However, in view of the poor
prognosis of relapsed patients, recurrences should be avoided completely.30 In trial NHL-BFM 90, it was shown that 2 5-day courses containing ID-MTX are enough therapy to avoid relapse in
patients with completely resected localized B-NHL. The cumulative dose
of doxorubicin (50 mg/m2) and that of oxazaphorins is below
the threshold of late gonadotoxicity31 for these patients.
However, it should be emphasized that resectability is determined by
the extent of the disease. However, because the extent of the disease
is the overriding predictor of outcome,9,32 disabling
surgical procedures to achieve complete resection are not justified.
For patients with no or incomplete resection but rather low tumor mass
(stage I and II and stage III with LDH <500 U/L), who constitute risk
group R2, treatment duration was reduced from 6 courses in the previous
trials to 4 courses in study NHL-BFM 90. Hereby, the cumulative doses
of cyclophosphamide, ifosfamide, and doxorubicin were reduced to 3 g/m2, 8 g/m2, and 100 mg/m2,
respectively. As compensation, ID-MTX was replaced by HD-MTX. Only 2 of
167 patients in risk group R2 failed to respond to therapy. Thirty of
the 167 patients (18%) in risk group R2 (2, 10, and 18 patients of
stage I, II, and III, LDH <500 U/L, respectively) received
HD-cytarabine/etoposide and a total of 6 therapy courses because of
incomplete tumor regression after 2 courses. However, the fact that, in
risk group R2, only 2 of 46 patients with residual tumor after 2 courses suffered from subsequent progression suggests that this
strategy was most probably an overtreatment of these patients. Hence,
further reduction of therapy for these patients has been integrated
into our ongoing trial NHL-BFM 95.
Initial CNS disease remains a challenge in patients with B-cell
neoplasms. Intriguing results were reported from the French study LMB
89 using HD-cytarabine, HD-MTX at 8 g/m2, and cranial
irradiation.33 However, the benefit of CNS irradiation for
CNS+ patients may be uncertain. Intraventricularly applied
chemotherapy provides a better distribution within the
CSF,34 and a higher concentration over time by
fractionation of dose35 can be achieved. In trial NHL-BFM
90, we investigated whether fractionated, intraventricularly applied
chemotherapy in combination with systemic HD-MTX therapy can provide
efficacious CNS-protection for CNS+ patients without using
radiotherapy. This strategy proved to be highly effective. Of the 26 CNS+ patients, 2 patients died of acute cell lysis syndrome
and 3 patients died of sepsis after the first course of therapy before an Ommaya-reservoir was implanted. Of the remaining 21 patients, 3 suffered from progression, and only 1 of them within the CNS.
Whereas potential late risks of the therapy were reduced at least for
part of the patients through reduction of the cumulative doses of
critical drugs and omission of cranial radiotherapy, the acute toxicity
of this treatment program is still a challenge. The contribution of
hematopoetic growth factors to ameliorate morbidity and mortality is
uncertain.8,36,37 Most deaths from infection occurred after
the first course of therapy. The incidence of toxic death at this point
was diminished after reduction of the intensity of the cytoreductive
prephase. Metabolic complications of acute cell lysis and impaired
renal function may also contribute to the risk of the early treatment
phase. Urate oxidase is able to reduce these complications and may be
most efficacious in reducing early deaths.38,39
Unfortunately, urate oxidase is not available in all countries and
could not be used in our trial. Severe orointestinal mucositis is the
most likely pathway for life-threatening or fatal infections. In our
therapy, severe mucositis is clearly related to HD-MTX. MTX is a
keystone component of all successful treatment programs for B-cell
neoplasms of childhood.7,8,33,40-42 However, doses and
schedules of the MTX therapies differ from 1 g/m2 to 8 g/m2 as IV infusions over 3 to 24 hours. Both antitumor
efficacy and toxicity may correlate with dose and time of exposure to
the drug. We consider it an important goal to find out the most
efficacious and least toxic schedule of MTX therapy for these children.
Therefore, in our ongoing trial, we are investigating in a randomized
fashion whether a reduced infusion time of the same dose of MTX will
result in less toxicity without jeopardizing treatment outcome.
| |
APPENDIX |
Study Committee of Trial NHL-BFM 90.
W. Dörffel, Berlin; W. Ebell, Berlin; N. Graf, Homburg; H. Gadner, Vienna; G. Henze, Berlin; G. Janka-Schaub, Hamburg; T. Klingebiel, Tübingen; St. Müller-Weihrich, Munich; I. Mutz, Leoben; H.J. Plüss, Zürich; R. Parwaresch, Kiel; A. Reiter, Hannover; H. Riehm, Hannover; G. Schellong, Münster; M. Schrappe, Hannover; F. Zintl, Jena.
Principal Investigators.
R. Mertens (Aachen); R. Angst (Aarau); A. Gnekow (Augsburg); R. Dickerhoff (St. Augustin); P. Imbach (Basel); G.F. Wündisch (Bayreuth); W. Dörffel (Berlin-Buch); G. Henze (Berlin,
Charité); E. Hilgenfeld (Berlin, Charité); U. Bode (Bonn);
W. Eberl (Braunschweig); H.J. Spaar (Bremen); H. Jacobi (Celle); I. Krause (Chemnitz); J.-D. Thaben (Coburg); D. Möbius (Cottbus); W. Andler (Datteln); H. Breu (Dortmund); G. Wei bach (Dresden,
University); W. Kotte (Dresden); U. Göbel (Düsseldorf);
J.D. Beck (Erlangen); W. Havers (Essen); G. Müller (Feldkirch);
B. Kornhuber (Frankfurt); C. Niemeyer (Freiburg); F. Lampert
(Gieen); M. Lakomek (Göttingen); C. Urban (Graz); H. Reddemann
(Greifswald); P. Exadaktylos (Halle); K. Winkler (Hamburg); H. Riehm
(Hannover); K-M. Debatin (Heidelberg); N. Graf (Homburg); C. Tautz
(Herdecke); F.M. Fink (Innsbruck); F. Zintl (Jena); I. Krüger
(Kaiserslautern); G. Nessler (Karlsruhe); H. Wehinger (Kassel); R. Schneppenheim (Kiel); H. Mener (Klagenfurt); M. Rister (Koblenz); F. Berthold (Köln); W. Sternschulte (Köln); C. Schulte-Wissermann (Krefeld); M. Domula (Leipzig); I. Mutz (Leoben); G. Schmitt (Linz); O. Stöllinger (Linz); L. Nobile (Locarno); P. Bucsky (Lübeck); H. Rütschle (Ludwigshafen); U. Caflisch
(Luzern); U. Mittler (Magdeburg); P. Gutjahr (Mainz); O. Sauer
(Mannheim); C. Eschenbach (Marburg); W. Tillmann (Minden); S. Müller-Weihrich (München, Technical University); C. Bender-Götze (München); R.J. Haas (München); P. Klose
(München-Harlaching); H. Jürgens (Münster); A. Feldmann (Neunkirchen); A. Jobke (Nürnberg); U. Schwarzer
(Nürnberg); G. Eggers (Rostock); R. Geib-König (Saarbrücken); H. Grienberger (Salzburg); H. Haas
(Schwarzach); F.J. Göbel (Siegen); R. Poier (Steyr); J. Treuner
(Stuttgart); R. Schumacher (Schwerin); A. Feldges (St. Gallen); H. Rau
(Trier); D. Niethammer (Tübingen); G. Hartmann (Ulm); D. Franke
(Vechta); H. Gadner (Wien, St. Anna Kinderspital); F. Haschke (Wien);
J. Weber (Wiesbaden); H.P. Krohn (Wilhelmshaven); J. Otte (Wolfsburg); A. Dohrn (Wuppertal); J. Kühl (Würzburg); H.J. Plüss
(Zürich).
Pathologists.
H. Mittermeyer (Aachen); B. Stamm (Aarau); R. Backmann (Augsburg); H. Ohnacker (Basel); M. Stolte (Bayreuth); H. Stein (Berlin); M. Dietel
(Berlin); W. Schneider (Berlin); H.J. Födisch, (Bonn); R. Donhuisen (Braunschweig); F.K. Köling (Bremen); J.O. Habeck (Chemnitz); P. Stosiek (Cottbus); E.W. Schwarze (Dortmund); M. Müller (Dresden); W. Hort (Düsseldorf); V. Becker
(Erlangen); L.D. Leder (Essen); S. Falk (Frankfurt); H.E. Schäfer
(Freiburg); W. Schultz (Gieen); E. Kunze (Göttingen); C. Schmid (Graz); G. Lorenz (Greifswald); F.W. Rath (Halle); U. Helmchen
(Hamburg); A. Georgii (Hannover); F. Otto (Heidelberg); K. Remberger
(Homburg); G. Mikuz (Innsbruck); D. Katenkamp (Jena); R. Wagner
(Kaiserslautern); W. Gusek (Karlsruhe); O. Klinge (Kassel); R. Parwaresch (Kiel); W. Wagner (Klagenfurt); F. deLeon (Koblenz); R. Fischer (Köln); O.M. Gokel (Krefeld); C. Wittekind (Leipzig); G. Leitner (Leoben); M. Weber (Linz); E. Pedrinis (Locarno); K. Wegener
(Ludwigshafen); A. Feller (Lübeck); J.O. Grebbers (Luzern); A. Roesser (Magdeburg); W. Thoenes (Mainz); U. Bleyl (Mannheim); C. Thomas
(Marburg); E. Jehn (Minden); K. Wurster (München, Technical
University); U. Löhrs (München); P. Meister
(München-Harlaching); M. Grundmann (Münster); P.H.
Wünsch (Nürnberg); H. Nizze (Rostock); H. Mitschke (Saarbrücken); O. Dietze (Salzburg); A. Hittmair (Schwarzach); G. Wittstock (Schwerin); D. Kunde (Siegen); A. Diener (St. Gallen); J. Feichtinger (Steyr); B. Kraus-Hounder (Stuttgart); H. Mäusle (Trier); P. Kaiserling (Tübingen); O. Haferkamp (Ulm); M. Respondek (Vechta); Th. Radasckiewicz (Wien); W. Remmle (Wiesbaden); G. Fischer (Wilhelmshaven); H.K. Müller-Hermelink (Würzburg);
T. Stallmach (Zürich).
Reference Laboratories.
Pathology: Lymphnode Registry of the Society of German
Pathologists, Institut of Hematopathology, University of Kiel (R. Parwaresch/M. Tiemann); Institut of Pathology, University of Vienna (T. Radasckiewicz/A. Chott). Immunophenotyping: W.-D. Ludwig,
Berlin; W. Knapp, Vienna.
| |
ACKNOWLEDGMENT |
The authors acknowledge the expert work of Edelgard Odenwald
(cytomorphology), Ulrike Meyer, U. Regelsberger (data management), and
Eckehard Schirg (central diagnostic radiology). We thank Jennifer Meyers for proofreading the English text.
| |
FOOTNOTES |
Submitted January 25, 1999; accepted July 7, 1999.
Supported by the Deutsche Krebshilfe, Bonn, Grant-No.M109/91/Re1.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Alfred Reiter, MD,
Justice-Liebig-University, Department of Pediatric Hematology and
Oncology, Feulgenstrasse 12, D-353, Giessen, Germany; e-mail:
alfred.reiter{at}paediat.med.uni-giessen.de.
| |
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ABSTRACT
INTRODUCTION