Blood, Vol. 95 No. 8 (April 15), 2000:
pp. 2729-2729
CORRESPONDENCE
 |
To the Editor: |
Treatment outcome in infant acute lymphoblastic leukemia
We read with interest the paper of Dördelmann et
al1 on prednisone (PDN) response as the strongest predictor
value of outcome in infant acute lymphoblastic leukemia (ALL).
Between June 1989 and November 1998, 60 (3.1%) infants, among 1963 children less than 18 years of age, were registered and treated according to the Children Leukemia Cooperative
Group-European Organization for Research and Treatment of Cancer
(CLCG-EORTC) protocol 58881. Patients were stratified according to the
same risk factor (RF) as defined in Dördelmann et als
paper:1 RF < 0.8 assigned them to the low risk (LR)
group, and RF 
0.8 to the standard risk (SR) group.
Patients with prednisolone poor response (PPR), with t(9;22) or
t(4;11) and/or not in remission (marrow blasts < 5%) on day 35 were assigned to the very high risk group (VHR).
Protocol CLCG-EORTC 58881 was very similar to the protocol ALL-BFM86
except for the following points: (1) prednisolone instead of prednisone
and additional It MTX were used during induction, (2) protocol II was
given to all LR and SR patients, (3) VHR patients, after induction,
received 9 blocks of multiagents chemotherapy, followed by
conventional maintenance for 1 year. In addition, a proportion of the
patients were randomized to receive the following: (1) either
Erwinia or E coli asparaginase (all ALL patients in induction and consolidation) (2) HD MTX versus Ara-C plus HD MTX during
interval therapy (standard risk patients) (3) pulses of 6 MP IV during
maintenance therapy (all patients). In contrast with
Berlin-Frankfurt-Münster (BFM) protocol, no patient received prophylactic or therapeutic cranial irradiation.
The overall event free survival (EFS) rate at 4 years in the 60 ALL
infants treated with the same protocol was 41%. Univariate analysis of
prognostic factors is given in the
Table. Age below 6 months had no
significant influence on EFS, but white blood cell (WBC) counts of at
least 100 × 103/µL, PPR, presence of very high risk
features, immunophenotype (CD10
or CD34+) had a significative
negative influence on EFS. The leucocyte count had the most important
impact. The EFS of infants with initial leucocyte count lower than 100 × 103/µL was 65%, which is comparable to that of older
children with initial leucocyte count between 10 and 100 × 103µL (Figure 1).
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| Fig 1.
Probability of EFS for infants with ALL, according to
white blood cell (WBC) counts at diagnosis.
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| Fig 2.
Probability of EFS for infants with ALL presenting poor
prednisolone response (PPR), according to their CD10
expression.
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In contrast with the ALL-BFM results, the EFS of the 17 PPR infants
with CD10 ALL was 29% (Figure 2),
whereas in the Germany study, none of these infants survived. The
difference between the 2 studies might be treatment-related.
Nevertheless, the overall results are similar with a global EFS of
41%. Of note is that the proportion of infants with CD10+ and steroid
good response (PGR) respectively was higher in the BFM study than in
the EORTC 58881 trial: 40% versus 22% for CD10+ and 74% versus 64%
for PGR. Probably, the percentage of VHR patients is higher in the
EORTC series, as the proportion of PPR was higher, due to the late
administration of the It MTX.2
The number of patients was small in both studies (although twice as
high in the BFM study), and conclusions with regard to the relation
weight of different prognostic features should not be accepted without
qualification. Results of the ongoing international protocol Interfant
99 will be essential to a refined ranking of the most important
prognostic factors and to further progress in the treatment of this
high-risk group.3-6
Alina Ferster
Yves Benoit
Nadine Francotte
Marie-Françoise Dresse
Anne Uyttebroeck
Emmanuel Plouvier
Antoine Thyss
Patrick Lutz
Geneviève Marguerite
Catherine Behar
Françoise Mazingue
Patrick Boutard
Frederic Millot
Xavier Rialland
Françoise Mechinaud
Lucilia Norton
Alain Robert
Jacques Otten
Etienne Vilmer
Noel Philippe
Christine Waterkeyn
Stefan Suciu
For the Children Leukemia Cooperative Group
EORTC
Pediatric
Hemato-oncology
Hôpital Universitaire des Enfants Reine
Fabiola
Brussels, Belgium
| |
References |
1.
Dördelmann M, Reiter A, Borkhardt A, et al.
Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia.
Blood.
1999;94:1209-1217[Abstract/Free Full Text].
2.
Thyss A, Suciu S, Bertrand Y, et al.
Systemic effect of intrathecal Methotrexate during the initial phase of treatment of childhood acute lymphoblastic leukemia. The European Organization for Research and Treatment of Cancer Children's Leukemia Cooperative Group.
J Clin Oncol.
1997;15:1824-1830[Abstract/Free Full Text].
3.
Crist W, Pullen J, Boyett J, et al.
Clinical and biologic features predict a poor prognosis in acute lymphoid leukemias in infants: a pediatric oncology group study.
Blood.
1986;67:135-140[Abstract/Free Full Text].
4.
Chessells JM, Eden OB, Bailey CC, Lilleyman JS, Richards SM.
Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials. Report from the Medical Research Council Working Party on Childhood Leukaemia.
Leukemia.
1994;8:1275-1279[Medline]
[Order article via Infotrieve].
5.
Pui CH, Behm FG, Downing JR, et al.
11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia.
J Clin Oncol.
1994;12:909-915[Abstract/Free Full Text].
6.
Ferster A, Bertrand Y, Benoit Y, et al.
Improved survival for acute lymphoblastic leukaemia in infancy: the experience of EORTC-childhood Leukaemia Cooperative Group.
Br J Haematol.
1994;86:287-290.
| |
Response: |
Early response in infant ALL determines prognosis
We are pleased that our study on prognostic factors in infant
acute lymphoblastic leukemia (ALL) during BFM trials1
provoked some discussion as indicated by Ferster et al's letter. We
think their data may give some important additional information
regarding the prognostic value of certain clinical and biologic
features in infant ALL. But in our opinion, their results are neither
new nor inconsistent with our results. They also do not substantially question the findings and conclusions of our study.
In contrast to Ferster et al's statement, we think that the EORTC used
both different treatment stratification and different treatment for a
substantial proportion of infants. Because antileukemic treatment
itself is a well-known prognostic factor, this may significantly influence the prognostic value of clinical or biologic
features.2 On the one hand, patients treated under the
CLCG-EORTC protocol 58881 were stratified according to the same risk
features, namely, tumor cell burden (BFM risk factor) and prednisone
response. But in contrast to BFM, the translocation t(4;11) qualified
for treatment in the highest-risk group (VHR in EORTC), and this may
explain the much higher percentage of VHR patients in the EORTC series as compared to our study also (68% vs 26%). Among infants, the proportion of patients carrying this specific translocation is relatively high and ranged between 30 and 50% in several
reports,3-7 including the EORTC (53%) and the BFM (31%)
studies. Because of carrying t(4;11) alone, almost half of all infants
in the EORTC trial (26 of 49) received the very intensive high-risk
treatment regimen, as compared to 12% of infants in our series, who
presented with a prednisone poor response (PPR) and the t(4;11).
According to our data, more than half of the infants with t(4;11) had a prednisone good response (PGR) and were treated with standard BFM
therapy (medium-risk group). In addition, application of cytarabine during interval therapy for EORTC-SR patients (corresponding to BFM-MR)
may be an additional significant treatment difference because
cytarabine is considered to be potent drug for treatment for AML,
hybrid leukemias, and infant ALL. Whether the higher percentage of
PPR in this EORTC trial (35%), as compared to our study
(26%), was caused by the early administration of 1 intrathecal dose of
methotrexate (on day 1) under BFM protocols remains speculative. It
could also be explained by the small number of patients.
We agree, that most, if not all, differences between both studies are
caused by both the smaller number of patients evaluated (EORTC,
n = 60; BFM, n = 106) and, possibly, the type of treatment. We
certainly agree that "conclusions with regard to relation weight of
different prognostic features should not be accepted without qualification." But definition of independent parameters predicting outcome in infant ALL has been difficult so far. Besides our study, only 2 investigations have reported independent prognostic features in
infant ALL: MLL gene rearrangement8 and/or cytogenetic
11q23 rearrangement.9
Regarding analysis of prognostic factors in infant ALL, Ferster et al
basically demonstrated similar results to those of most other investigations, including our group's, with 2 exceptions: (1)
that age less than 6 months was no significant prognostic factor and
(2) that WBC was the most important prognostic feature in their study.
The pEFS for infants older or younger than 6 months was almost exactly
the same as in the respective subsets of our study, but for unknown
reasons their outcome difference was not significantly different.
Nevertheless, in accordance with other reports,3,7 age was
the second most important prognostic feature in our series, even by
multivariate analysis. By univariate analysis, we also noted both WBCs
of at least 100 000/µL and the lack of CD10 expression as poor
prognostic features. The pEFSs for these subgroups were almost
comparable in both trials (EORTC vs BFM: 26% vs 37% respectively, and
29% vs 35%, respectively). But both features lost their
significance in multivariate anlysis. Because the EORTC analysis was
performed by univariate analysis only, the independent value of the
reported prognostic features remains unclear. Finally, the analyses of
EORTC protocol 58881 could be hampered by the relatively short
observation time. The last patient evaluated entered the trial in
November 1998 and was probably just off treatment by the time of data analysis.
Based on the BFM infant data, an ongoing international trial for
treatment of infant ALL (INTERFANT 99) uses the prednisone response as
the only stratification factor. Among many others, the EORTC-CLCG also
takes part in this trial and has agreed to its treatment
stratification. The value of prognostic features should be proved by
prospective studies and multivariate analysis. Therefore, we may need
to wait for studies by other investigators and/or the results of the
INTERFANT 99 trial.
Michael Dördelmann
Martin Schrappe
Medizinische Hochschule Hannover
Department of Pediatric
Hematology and Oncology
Hannover, Germany
| |
References |
1.
Dördelmann M, Reiter A, Borkhardt A, et al.
Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia.
Blood.
1999;94:1209.
2.
Pinkel D.
Selecting treatment for children with acute lymphoblastic leukemia.
J Clin Oncol.
1996;14:4[Medline]
[Order article via Infotrieve].
3.
Chessells JM, Eden OB, Bailey CC, Lilleyman JS, Richards SM.
Acute lymphoblastic leukaemia in infancy: experience in MRC UKALL trials. Report from the Medical Research Council Working Party on Childhood Leukaemia.
Leukemia.
1994;8:1275.
4.
Lauer SJ, Camitta BM, Leventhal BG, et al.
Intensive alternating drug pairs after remission induction fot treatment of infants with acute lymphoblastic leukemia: a Pediatric Oncology Group study.
J Pediatr Hematol Oncol.
1998;20:229[Medline]
[Order article via Infotrieve].
5.
Heerema NA, Arthur DC, Sather H, et al.
Cytogenetic features of infants less than 12 months of age at diagnosis of acute lymphoblastic leukemia: impact of the 11q23 breakpoint on outcome: a report of the Childrens Cancer Group.
Blood.
1994;83:2274[Abstract/Free Full Text].
6.
Rubnitz JE, Link MP, Shuster JJ, et al.
Frequency and prognostic significance of HRX rearrangements in infant acute lymphoblastic leukemia: a Pediatric Oncology Group study.
Blood.
1994;84:570[Abstract/Free Full Text].
7.
Crist W, Pullen J, Boyett J, et al.
Clinical and biologic features predict a poor prognosis in acute lymphoid leukemias in infants: a Pediatric Oncology Group Study.
Blood.
1986;67:135.
8.
Cimino G, Rapanotti MC, Rivolta A, et al.
Prognostic relevance of ALL-1 gene rearrangement in infant acute leukemias.
Leukemia.
1995;9:391[Medline]
[Order article via Infotrieve].
9.
Pui CH, Behm FG, Downing JR, et al.
11q23/MLL rearrangement confers a poor prognosis in infants with acute lymphoblastic leukemia.
J Clin Oncol.
1994;12:909.
