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Blood, Vol. 92 No. 8 (October 15), 1998:
pp. 2730-2741
By
From the Department of Pediatric Hematology and Oncology,
Medizinische Hochschule Hannover, Hannover, Germany; the Clinica
Pediatrica, Università di Pavia, Pavia, Italy; the Oncogenetic
Laboratory, University Children's Hospital, Gie Among 4,760 acute lymphoblastic leukemia (ALL) patients
enrolled from 1986 to 1995 in two subsequent trials of the BFM and AIEOP study group, 61 patients were found to have Philadelphia chromosome-positive (Ph+) ALL. These patients were
analyzed for presenting features and treatment outcome to identify
specific prognostic factors. Treatment stratification was based on
initial cell mass and early response as determined by blast count in
peripheral blood after a 7-day induction prephase with prednisone and
one dose of intrathecal methotrexate on day 1. All patients were
treated by similar intensive Berlin-Frankfurt-Münster (BFM)
protocols. The median age of Ph+ patients was 7.5 years,
the median white blood cell count (WBC) was 75 × 109/L,
77% of patients had common ALL, and 29% coexpressed myeloid markers.
After a median observation time of 4.2 years, 29 of 61 patients are
alive (survival probability [pSUR] at 4 years, 0.49; standard error
[SE], 0.06), and 24 of 61 are in first complete remission (CR1;
probability of event-free survival [pEFS] at 4 years, 0.38; SE,
0.06). Twenty (35%) of 57 evaluable patients had © 1998 by The American Society of Hematology.
THE IDENTIFICATION OF specific risk
factors that prevent successful treatment of childhood acute
lymphoblastic leukemia (ALL) is being pursued by all major study groups
worldwide. The presence of the t(9;22)(q34;q11) translocation, commonly
known as Philadelphia chromosome (Ph1), in about 3% to 5%
of all children with ALL is considered as one of the molecular markers
associated with a particularly high risk for treatment
failure.1-6 This translocation causes a rearrangement
between the protooncogene c-ABL and a gene called the breakpoint
cluster region (BCR). Whereas the breaks in c-ABL occur mainly in the
same region (between the exons a1 and a2) on chromosome 9, two
different ones affect the breakpoint cluster region on chromosome 22:
the more frequent one (approximately in 2 of 3 of all cases) shows a
break in the minor breakpoint cluster region (m-BCR) between the exons
e1 and e2. This is predominant in ALL. In 1 of 3 of all Ph+
ALL cases, the major (M-) BCR found between exons b2 and b3 or exons b3
and b4 is affected. M-BCR is also found in nearly all patients with
chronic myelogenous leukemia (CML). Chimeric proteins of
210 kD (p210) and 190 kD (p190) result from the M-BCR/ABL and m-BCR/ABL
rearrangements, respectively.7 These fusion proteins cause
a deregulation of protein tyrosine kinase activity. Both forms of the
chimeric gene (BCR/ABL) can be detected by polymerase chain reaction
(PCR) and fluorescent in situ hybridization.8,9 This is
especially useful in large multicenter trials, because this technique
allows faster prospective identification of Ph+ ALL than
the use of cytogenetic analysis.10
Parallel to the recent research on molecular markers such as the ones
found in Ph+ ALL, investigation of cellular and clinical
response to therapy has contributed significantly to the identification
of subsets of patients with higher probability for therapy resistance
or relapse. In several large cohorts of ALL patients, the in vivo and
the in vitro sensitivity of the leukemic clone has been
evaluated.1,11-17 The detection of genetic markers such as
t(9;22)/BCR/ABL as well as the identification of resistance to therapy
has direct impact on clinical management, because such high-risk
features form the basis for treatment intensification, including
allogeneic bone marrow transplantation (allo-BMT). However, advances in
the cure of childhood ALL have not yet included patients with
Ph+ ALL. Only in a very few cases has successful
chemotherapy with or without additional allo-BMT been
described.1,4-6,18-20 To identify subsets of
Ph+ ALL that might need different therapeutic approaches,
we retrospectively evaluated the BFM and AIEOP database for the years
1986 through 1995. Presenting features and treatment response of all
available cases were analyzed to evaluate the impact of chemotherapy
with and without allogeneic BMT and to identify subsets with different prognoses.
Patients
Diagnostic Studies
Cytogenetic and molecular genetic analysis. Both techniques were performed on the majority of patients in the central reference laboratories of both study groups according to previously described methods.10,25 Prospective screening of all patients with ALL for the BCR/ABL rearrangement was initiated in November 1992 in the BFM trial. In the case of a positive result for BCR/ABL by reverse transcription-PCR (RT-PCR), a second independent laboratory was required to confirm the finding from a separately stored sample if cytogenetics did not detect the t(9;22) translocation. Immunophenotyping.
Peripheral blood and BM samples were tested for surface antigens by a
panel of commercially available monoclonal antibodies defining the
T-cell and B-precursor cell subtypes. Subgroups of B-precursor ALL were
defined as follows: pre-pre-B (or pro-B)-ALL: TdT+,
CD19+, CD10 Patient Stratification and Treatment The treatment schedule in the four protocols was based on a common BFM-backbone chemotherapy protocol as previously described.1,22 That schedule provided a risk group stratification based on cell mass at diagnosis (BFM risk factor [RF]), calculated from initial blast cell count, liver and spleen size,28 immunophenotype, and early blast cell reduction in peripheral blood (prednisone response). In trials ALL-BFM 90 and AIEOP-ALL 91, the risk group definition of high-risk ALL included the presence of Ph+ ALL as defined by cytogenetic or moleculargenetic techniques. In trial AIEOP-ALL 91, large cell mass (BFM RF 1.7) and central nervous system
(CNS) disease were additional criteria for high-risk group
assignment. The treatment of high-risk patients was modified in the
latter two trials to include three different high-dose consolidation
elements that were derived from the BFM ALL-REZ protocol29
and to perform allo-BMT if a matched, related donor could be
identified. Details of the treatment schedule have been provided
elsewhere.21,30 Briefly, the treatment schedule for high-risk patients in trials ALL-BFM 90 consisted of 30 days of induction (protocol I/A) with prednisone (60 mg/m2/d) for
30 days (7 days at prephase, 14 days at full dose, and then tapered
down over 9 days); L-asparaginase (10,000 U/m2, every 3 days, 6 times); intrathecal methotrexate (IT MTX) on days
1, 15, and 29; daunorubicin (30 mg/m2) and vincristine (1.5 mg/m2) on days 8, 15, 22, and 29, respectively. In AIEOP
9103, the induction phase was 1 week longer with a slightly different
time schedule after day 8, including 1 more week of prednisone and a
delayed start of L-asparaginase. In both protocols, induction therapy
was followed by intensive consolidation consisting of nine 6-day cycles
containing combinations of dexamethasone, vindesine/vincristine, 6-thioguanine/6-mercaptopurine, ifosfamide, etoposide, triple drug
intrathecal therapy, and high-dose therapy with either methotrexate or
cytarabine. Some patients received granulocyte colony-stimulating factor (G-CSF; 5 µg/kg/d subcutaneously [SC]) after each cycle of
high-dose therapy.30 After intensive consolidation,
prophylactic cranial irradiation was applied (18 Gy) and maintenance
therapy with a total therapy duration of 24 months was initiated. If a matched donor was available for allo-BMT, the conditioning regimen was
to be started not earlier than after the third cycle of intensive consolidation. With regard to BMT, the general policy in both study
groups was to consider matched related donor BMT to be an alternative
treatment option for Ph+ ALL patients. However, in this
series, there are no data concerning matched donor availability as a
result of systematic screening for donors. This prevents us from
knowing whether all patients with a matched donor underwent BMT. In the
statistical analysis several strategies were implied to avoid any
selection bias as far as possible in a BMT/chemotherapy comparison.
Response Evaluation Prednisone good response (PGR) in vivo was defined as the presence of less than 1,000 lymphoblasts/µL blood after the first 7 days of prednisone therapy (dose increasing to 60 mg/m2/d; on average, 320 mg/m2/7 d) and after one IT injection of an age-adapted dose of methotrexate on day 1.1,11,13,22 Conversely, prednisone poor response (PPR) was defined if the blast count at day 8 was1,000/µL. Two BFM patients were not evaluable
for analysis of early response due to false induction therapy, and 2 AIEOP patients were not evaluable due to missing report of prednisone
response.
Statistical Analysis Differences in the distribution of variables among patient subsets were analyzed using the Fisher exact test for categorized variables and the Wilcoxon rank-sum test for continuous variables. The Kaplan-Meier method was used to estimate event-free survival (pEFS) and survival (pSUR) probabilities, with differences compared by the two-sided log-rank test.31 EFS time was calculated as the interval from date of first diagnosis to the date of last follow-up or of first event. Events were resistance to induction/consolidation (including allogeneic BMT as postinduction regimen), relapse, and death from any cause. Failure to achieve remission (early death, progression/nonresponse [resistant leukemia]: no CR within 6 months from diagnosis) was assigned a time zero. Second malignancies were not observed. Survival analysis considered death of any cause as an event. For univariate comparison, survival probabilities after 4 years were calculated and compared by using the Kaplan-Meier test. This test is especially suitable to compare survival probabilities when the vast majority of events has already occurred, and the proportion of cured patients is of interest.32 In the multivariate analysis using the Cox model,33 several variables (age >/<10 years, age >/<6 years, white blood cell count [WBC] >/<100 or 200 or 25 × 109/L, blast count on day 8 >/<100, prednisone response [blasts day 8 >/<1,000], remission induction, and coexpression of myeloid markers) derived as risk factors from analysis of the general ALL population were investigated for possible influence on EFS or survival in the study population. The role of BMT as compared with chemotherapy alone was evaluated with methods that attempt to overcome the problems related to the time-to-transplant bias. In the Cox model, the variable treatment was expressed with a time-dependent indicator. The test adopted for comparing EFS of patients treated with BMT and chemotherapy or with chemotherapy alone was a modified Mantel-Byar test,34 which accounts for the waiting time to BMT, ie, all patients were considered to be under risk for chemotherapy up to the time of alternative treatment (date of BMT). For graphical comparison (Kaplan-Meier plots) of chemotherapy versus BMT, all patients with EFS or survival times less than the median time to BMT (0.5 years) were excluded from the chemotherapy group. In addition, for better comparison of both treatment subsets, nonresponse or partial response before BMT was not evaluated as an event if BMT was part of the intensive consolidation treatment. Computations were performed using SAS-PC (Version 6.12; SAS Institute Inc, Cary, NC).
Patient Characteristics Cytogenetics and molecular genetics. Sixty-one patients with Ph+ ALL were identified. In 50 patients, diagnosis was based on cytogenetics (n = 21) or on the results from cytogenetics and RT-PCR (n = 29). Ph+ ALL was diagnosed in 11 patients by RT-PCR alone, but no difference in patient characteristics as compared with those defined cytogenetically was found. The overall incidence of 1.3% for Ph+ ALL does not represent the real incidence and is lower than previously reported,35 because only a minority of the enrolled patients had been investigated by cytogenetics and/or molecular genetics. After screening for BCR/ABL was initiated in the BFM trial, the incidence was 3.2%.10 Ten of 40 patients (25%) identified by molecular genetics as carrying the BCR/ABL rearrangement (see Tables 1 and 3) were found to have the breakpoint M-BCR. In 30 patients, the breakpoint m-BCR was detected. No difference in patient characteristics was found between patients with m-BCR or M-BCR.10 At relapse, not all patients were checked for the presence of t(9;22) or BCR/ABL rearrangement, but the majority of the analyzed patients was found to be positive. Clinical features.
The main initial features of each individual patient are provided in
Table 1 and summarized in
Table 2. Initial patient characteristics
did not differ between both study groups AIEOP and BFM. The median age
of all Ph+ patients was 7.49 years (range, 1.2 to 16.6 years). Forty-three patients were 1 to 9 years old and 18 patients were
Steroid response. When Ph+ patients were analyzed with regard to early response to prednisone, a threefold higher incidence (35%) of inadequate response to prednisone could be noted (Table 2) as compared with the incidence (10%) in the general ALL study population.1 As shown in Table 3, the median WBC, the median age, and the median blast cell count at day 8 were significantly different between PGR and PPR patients. The age of patients with PPR was higher, as was the median WBC at diagnosis compared with PGR. Interestingly, 10 of 37 patients with WBC greater than 100,000 at diagnosis had an adequate response to prednisone (PGR), 6 of whom remain alive. With regard to sex, type of breakpoint, and immunophenotype, no difference could be detected between patients with PGR and those with PPR (Table 3).
Treatment Results After the 5-week induction, BM examination showed resistant disease in 15 (25%) patients. No patient with PGR was resistant to induction, but 14 were found among patients with PPR (P < .0001, Fisher test) and 1 nonresponder was not evaluable for steroid response. Eventually, 55 of all 61 Ph+ patients achieved CR. Twenty-four relapses were observed: 23 occurred with BM involvement (1 combined with CNS involvement, 1 combined with bone lesions, and 1 with skin involvement) and only 1 isolated extramedullary recurrence (testis) was diagnosed (Tables 1 and 3).
Early Treatment Response and Outcome
Treatment Modality
Prognostic Factors for Survival
This retrospective analysis of 61 patients treated with intensive BFM
chemotherapy is one of the largest series of Ph+ childhood
patients reported so far. The results confirm the inferior prognosis of
this patient group when compared with the general ALL population.
However, adequate early steroid response can identify a large subset of
Ph+ ALL patients that appears to have a fair chance of
cure, even if allogeneic BMT cannot be performed.
Submitted February 2, 1998;
accepted June 10, 1998.
The authors thank W.D. Ludwig (Berlin, Germany) for the
immunophenotyping, E. Odenwald (Hannover, Germany) for excellent
technical assistance in cytology, D. Silvestri (Monza, Italy) and N. Götz (Hannover, Germany) for competent data management, and
Jennifer Meyers for proofreading the text. We thank all doctors and
nurses in the participating centers of the BFM and AIEOP study groups. Centers that enrolled patients for this study are listed in the Appendix.
BFM centers in Austria and Germany that enrolled Ph+
ALL patients: Augsburg, I. Kinderklinik, KZVA (Dr A. Gnekow);
Bayreuth, Kinderklinik, Klinikum Bayreuth (Prof G.F. Wündisch);
Berlin-Buch, II. Kinderklinik, Klinikum Berlin-Buch (Dr W. Dörffel); Cottbus, Kinderklinik, Carl-Thiem-Klinikum (Dr D. Möbius); Dresden, Kinderklinik, Bezirkskrankenhaus
Dresden-Neustadt (Dr V. Scharfe); Erfurt, Kinderklinik, Medizinische
Akademie (Dr G. Weinmann); Erlangen, Universitäts-Kinderklinik (Prof J.D. Beck); Essen, Kinder-und Poliklinik,
Universitätsklinikum Essen (Prof W. Havers, PD Fr.B. Kremens);
Frankfurt, Universitäts-Kinder klinik (Prof B. Kornhuber, Dr D. Schwabe); Freiburg, Universitäts-Kinderklinik (PD Dr C. Niemeyer); Gie AIEOP institutions in Italy that enrolled Ph+ ALL
patients: Ancona, Clinica Pediatrica (Prof G.V. Coppa, Dr L. Felici); Ancona, Divisione di Pediatria (Prof G. Caramia); Bari,
Clinica Pediatrica I (Prof F. Schettini, Dr N. Santoro); Bari, Clinica
Pediatrica II (Prof N. Rigillo, Dr S. Bagnulo); Bergamo, Div.
Ematologia Pediatrica (Prof F. Bergonzi, Dr P.E. Cornelli); Bologna,
Clinica Pediatrica III (Prof G. Paolucci, Dr A. Pession); Brescia,
Clinica Pediatrica (Prof A.G. Ugazio, Dr A. Arrighini); Cagliari,
Clinica Pediatrica (Prof P.F. Biddau, Dr R. Mura); Catania, Clinica
Pediatrica (Prof G. Schilirò, Dr S.P. Dibenedetto); Catanzaro,
Div. di Ematologia (Prof S. Magro, Dr C. Consarino); Firenze, Clinica
Pediatrica (Prof G. Bernini, Dr A. Lippi); Genova, Ist. "G.
Gaslini" (Prof P.G. Mori, Dr C. Micalizzi); Modena, Clinica
Pediatrica II (Prof F. Massolo, Dr M. Cellini); Monza, Clinica
Pediatrica Milano (Prof G. Masera, Dr V. Conter, Dr C. Rizzari);
Napoli, Clinica Pediatrica II (Prof S. Auricchio, Dr A. Fiorillo);
Napoli, Ospedale Pausilipon (Prof V. Poggi, Dr M.F. Pintà
Boccalatte); Napoli, Clinica Pediatrica I (Prof M.T. Di Tullio, Dr F. Casale); Napoli, Ospedale SS. Annunziata (Prof F. Tancredi, Dr A. Correra); Padova, Clinica Pediatrica II (Prof L. Zanesco, Dr C. Messina); Palermo, Clinica Pediatrica I (Prof M. Lo Curto, Dr P. D'Angelo); Parma, Clinica Pediatrica (Dr G. Izzi, Dr Bertolini);
Pavia, Clinica Pediatrica (Prof F. Severi, Dr M. Aricò); Pescara,
Divisione di Ematologia (Prof G. Torlontano, Dr A. Di Marzio); Perugia,
Ospedale Silvestrini (Dr A. Amici, Dr P. Zucchetti); Pisa, Clinica
Pediatrica III (Prof P. Macchia, Dr C. Favre); Reggio Calabria,
Ospedali Riuniti (Prof F. Nobile, Drssa M. Comis); Roma, Ospedale
"Bambin Gesù"-Ematologia (Prof G. De Rossi, Dr C. Miano);
Roma, Cattedra di Ematologia (Prof F. Mandelli, Dr A.M. Testi); Roma,
Clinica Pediatrica (Prof G. Multari, Dr B. Werner); S. Giovanni
Rotondo, Casa Sollievo della Sofferenza, Ematologia (Prof M. Carotenuto, Dr S. Ladogana); S. Giovanni Rotondo, Casa Sollievo della
Sofferenza, Pediatria (Prof P. Paolucci); Sassari, Clinica Pediatrica
(Prof T. Meloni, Prof D. Gallisai); Siena, Clinica Pediatrica (Prof A. Fois, Dr A. Acquaviva); Torino, Clinica Pediatrica (Prof E. Madon, Dr
R. Miniero, Dr E. Barisone); Trieste, Clinica Pediatrica (Prof P. Tamaro, Dr G. Zanazzo); Varese, Clinica Pediatrica (Prof L. Nespoli, Dr
S. Binda); Verona, Clinica Pediatrica (Prof L. Gaburro, Dr Marradi).
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en, Germany; the
Clinica Pediatrica, Ospedale S. Gerardo and the Institute of Biometry
and Statistics, Università di Milano, Italy; St Anna
Kinderspital, Wien, Austria; the Clinica Pediatrica, Università
di Torino, Torino, Italy; and the Institute of Human Genetics,
University of Heidelberg, Heidelberg, Germany.
Abstract
Introduction
Abstract
, cyIgM
the importance of early marrow response: Report from the Childrens Cancer Group.
J Clin Oncol
14:389,
1996
