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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From Onco-Ematologia Pediatrica, Ospedale dei Bambini
G. Di Cristina, Palermo; Onco-Ematologia Pediatrica, IRCCS Policlinico
San Matteo, Pavia; Clinica Pediatrica and Medical Statistics Section,
University of Milano Bicocca; Clinica Pediatrica, University of
Bologna; Clinica Pediatrica, University of Torino; Oncoematologia
Pediatrica, Ospedale Pausilipon; Ematologia Pediatrica, IRCCS Ospedale
Bambin Gesù of Roma; and Onco-Ematologia Pediatrica, IRCCS G. Gaslini, Genova, Italy.
One hundred ninety-eight children and adolescents were entered in
the Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)-ALL95 study for high-risk acute lymphoblastic leukemia (ALL).
Inclusion criteria were poor response to initial
prednisone/intrathecal methotrexate (prednisone-poor response [PPR]),
resistance to induction therapy, translocation t(9;22), infants with
the t(4;11), or CD10 The definition and treatment of high-risk
childhood acute lymphoblastic leukemia (ALL) remain controversial.
Consensus criteria of the Rome/National Cancer Institute
Workshop1 have been useful in promoting greater uniformity
among international leukemia study groups, but they are limited by
failure to identify subgroups with poor prognosis defined by genetic
alterations or poor blast cell sensitivity to chemotherapy. In the last
decade, the Associazione Italiana di Ematologia ed Oncologia Pediatrica
(AIEOP)2 and the Berlin-Frankfurt-Muenster (BFM) study
groups have emphasized the role of corticosteroid sensitivity of
leukemic blasts at the time of diagnosis, a risk feature first
described and subsequently assessed by the BFM group.3,4
Patients with at least 1000 blast cells/µL peripheral blood
after 7 days of prednisone monotherapy and one injection of intrathecal
methotrexate (IT-MTX) were considered to have a poor response to
prednisone (PPR) and no more than a 35% chance of becoming long-term
disease-free survivors on standard therapeutic
protocols.3-5 Other high-risk features included failure to
achieve complete remission (CR) after the first 6 weeks of induction
therapy, presence of the clonal translocation t(9;22), or age
younger than 1 year with either t(4;11) or CD10 Initial attempts to improve outcome in this high-risk group using a
modified version of the intensive BFM-ALL REZ protocol for relapsed
ALL6 yielded unsatisfactory results in the
BFM-ALL-905 and the AIEOP-ALL91 studies.2 We
attributed this outcome to insufficient leukemia control, despite the
use of a series of 9 alternating blocks of non-cross-resistant drugs.
In these 2 studies, the second part of the traditional BFM induction
phase (protocol Ib) was omitted as was the traditional reinduction
phase. Designated protocol II, the latter treatment is generally
considered an integral part of BFM-type therapy4 and has
been used by the Children's Cancer Group (CCG) to improve leukemia
control in patients with delayed responses to induction
therapy.7,8 Therefore, in the subsequent AIEOP-ALL95 study
started in May 1995, we replaced most of the former consolidation phase
(ie, 6 of the 9 multidrug blocks) with a reinduction phase consisting of protocol II, repeating it twice in the context of an otherwise conventional BFM treatment for high-risk ALL. Reported here are the
results of our modified therapy administered to the series of patients
at high risk as diagnosed from May 1995 to December 1999.
Patients
Diagnostic studies
Immunophenotyping was performed at the AIEOP reference laboratory by flow cytometry with a large panel of commercial monoclonal antibodies directed against the following surface and intracellular antigens: CD1a, CD3, CD4, CD5, CD7, CD10, CD13, CD14, CD15, CD19, CD20, CD24, CD33, CD34, CDw65, HLA DR, IgM, and terminal desoxyribonucleotidyl transferase. Threshold positivities were set at 20% for surface antigens and 10% for intracellular markers, according to the BFM family criteria.10 CR was defined as no physical signs of leukemia, no detectable leukemic cells on the blood smears, bone marrow with active hemopoiesis, cerebrospinal fluid with fewer than 5 cells/µL, and no blasts on cytospin. Treatment in patients who did not achieve CR after the first 6 weeks of therapy (protocol Ia) was continued with phase Ib and consolidation (see below). Only patients who did not obtain CR by the end of consolidation phase were defined as resistant to this protocol. Treatment The treatment plan is summarized in Table 1. Briefly, patients underwent 7 days of prephase steroid therapy (at increasing doses up to 60 mg/m2) together with one dose of IT-MTX. Induction therapy consisted of protocol I (Ia: vincristine, prednisone, daunomycin, L-asparaginase; Ib: cyclophosphamide, 6-mercaptopurine, cytarabine),4 followed by consolidation therapy with 3 blocks of non-cross-resistant drugs, including either high-dose methotrexate (HD-MTX; 5 g/m2) or high-dose cytarabine (HD-ARAC; 2 + 2 g/m2).5,6 Reinduction therapy consisted of protocol II, followed by interim maintenance therapy during which cranial irradiation (dosing based on age and central nervous system [CNS] status) was delivered, and by a second protocol II without IT chemotherapy. Maintenance therapy consisted of 28-day cycles of oral 6-mercaptopurine (50 mg/m2, days 1-21), weekly intramuscular methotrexate (20 mg/m2, days 1, 8, 15), pulses of prednisone (40 mg/m2, days 22-26), and vincristine (1.5 mg/m2, day 22). An interval of 2 weeks between each part of therapy (induction, consolidation, reinduction, and maintenance) was scheduled to allow marrow reconstitution. Total duration of treatment was 24 months. Bone marrow transplantation (BMT) from a matched related donor was advised for patients in first CR with the following characteristics: failure to achieve CR after the first 6 weeks of induction therapy (protocol Ia); infants with the t(4;11) translocation or a CD10 B-lineage immunophenotype;
t(9;22) translocation; PPR; and either a T-cell immunophenotype or a
leukocyte count of 100 000/µL or the t(4;11) translocation. BMT from
an alternative donor, though not recommended, was performed in 12 patients considered at particularly high risk for treatment failure;
one patient underwent autologous BMT.
Treatment burden Treatment burden in the AIEOP-ALL95 high-risk study was evaluated on the basis of need for blood derivatives (packed red blood cells, platelets) and need for and duration of intravenous antibiotic therapy, central venous line, and hospitalization.Statistical analysis Event-free survival (EFS) and survival curves were constructed by the Kaplan-Meier method. The log-rank test was used for univariate comparisons, and the Cox regression model was used to adjust the main comparisons by other prognostic features (leukocyte count, cutoff 100 000/µL; immunophenotype, T vs non-T; age, cutoff 10 years; and sex).11 The starting point for the observation time was the date of diagnosis. Death in induction, resistance, relapse, death in continuous CR (CCR), and secondary malignancy were considered adverse events in the calculation of EFS rates (induction death and resistance were considered events at time zero), whereas death from any cause was the sole event in determining overall survival. In both analyses, the observation time was censored at the last follow-up date if no event was noted. Follow-up was updated as of December 31, 2000; 1 (0.5%) patient was lost to follow-up. The primary analyses describe the outcome of the therapeutic approach for high-risk (HR) ALL, including the option of BMT, but secondary analysis was also performed after censoring the observation times on the date of transplantation. To gauge the efficacy of our modified therapy, we compared the outcome of high-risk patients in study AIEOP-ALL95 with that of a subgroup of patients from AIEOP-ALL912 selected according to the eligibility criteria of the AIEOP-ALL95 study.
Laboratory and clinical characteristics of the 198 patients
treated in the HR protocol are shown in Table
2. Eligibility criteria are presented in
hierarchical order; thus, column (1) counts all patients who were
resistant to protocol Ia of the induction therapy, regardless of the
remaining features, and so on for the subsequent columns. Consequently,
column (4) identifies the patients who were defined as HR only because
of their poor response to prednisone (ie, they indeed achieved CR and
were negative for t(9;22) or t(4;11) translocations; PPR-only).
Seventy-six percent (151 of 198) had PPR; in 119 (60.1%) patients,
this was the sole high-risk feature. The next most frequent high-risk
factor was resistance to induction therapy on protocol Ia (42 of 198, 21.2%), followed by the t(9;22) translocation (26 of 198, 13.1%), and infant age with either t(4;11) or CD10
Three (1.5%) patients died on induction therapy (due to
mediastinal syndrome, brain hemorrhage, or septicemia) (Table 3), and
11 (5.6%) failed to achieve CR by the end of consolidation therapy;
thus, the CR rate in this high-risk group was 92.9% (184 of 198).
Relapse was the most common cause of treatment failure and occurred in
55 (27.8%) children at a median time of 12 months after remission
induction (range, 1-63 months). Most of the relapses were in the bone
marrow (46 isolated and 5 combined); 4 patients had an isolated relapse
in the CNS. Ten patients died during continuous CR With a median follow-up of 3.2 years, the estimated 4-year
probabilities of EFS and overall survival were 56.5% (SE, 3.9%) and
62.8% (SE, 3.9%), respectively. Figure
1 shows the EFS curves for the 4 subgroups defined in Table 2. Their outcomes were significantly heterogeneous according to the log-rank test (P = .0001),
and this result was maintained after adjusting the comparison (for leukocyte count, immunophenotype, age) in a Cox model.
The PPR-only subgroup had a 4-year EFS of 70.1% (SE, 4.7%).
Patients who were PPR-only but also had T immunophenotype (n = 34) or
leukocyte counts exceeding 100 000/µL (n = 30) had 4-year EFS of
66.6% (SE, 8.2%) and 60.1% (SE, 9.6%), respectively (Figure 2). Noticeably, PPR-only patients who had
both unfavorable features (n = 21) had a 4-year EFS of 61.2% (SE,
10.8%).
The subgroup of patients who were resistant to protocol Ia had the worst prognosis, with a 4-year EFS of 25.6% (SE, 7.1%); by definition, this group included all 11 resistant patients. The t(9;22) and infant t(4;11)/CD10 According to study design, a subset of 15 patients underwent BMT from a matched-related donor. Twelve other patients underwent BMT from alternative donors (9 matched unrelated donor, 2 mismatched donors, 1 fetal liver). One patient underwent autologous BMT. Of the patients who underwent transplantation, 18 remained in CCR for a median of 33 months (range, 1-54 months) after BMT; 6 patients died in remission and 4 had relapses. When EFS curves were calculated censoring the observation time at the date of BMT, results in the 4 subgroups did not change (Table 3). The overall 4-year EFS estimate was significantly better than that obtained in the group of 114 patients selected with the same high-risk criteria and treated in study AIEOP-ALL91: 56.5% (SE, 3.9%) versus 40.2% (SE, 4.6%) (P = .002). The distribution of patient characteristics in the 2 groups was similar, and the advantage in overall EFS was maintained when the test for comparison was stratified by the 4 subgroups in a Cox model (P = .0005) and when the observation time was censored at the date of BMT. (Four-year EFS rates in AIEOP-ALL95 versus AIEOP-ALL91 were 57.2% [SE, 4.2%] versus 39.8% [SE, 5.1%] [P = .0007]). Although the relatively small size precluded meaningful
comparison of the remaining subgroups, the PPR-only subgroup was also analyzed separately. In protocols 95 and 91, the estimated 4-year EFS
was 70.1% (SE, 4.7%) versus 48.9% (SE, 6.2%), respectively, and the
difference was significant (P = .01) independently of other prognostic factors (white blood cell [WBC] count,
immunophenotype, age, and sex, which were included in a Cox model).
Noticeably, in the PPR-only subgroups, by definition, the EFS curves do
not include resistance as an event (Table
3). However, an advantage was still
observed in the AIEOP-ALL95 study compared with the AIEOP-ALL91 study
when all patients with PPR were considered: 4-year EFS was 61.1% (SE,
4.4%) versus 42.8% (SE, 5.4%) (P = .008), respectively
(Figure 3).
Analysis of the requirements for supportive care throughout the
various phases of treatment is shown in Table
4 for patients with available data. Red
blood cell transfusions were necessary for approximately 90% of the
patients during protocols Ia and Ib, and consolidation with blocks were
necessary for approximately 65% of the patients during protocol II.
Platelet support was mainly restricted to the induction and
consolidation phases. Intravenous antibiotics were also required for a
substantial proportion of patients during intensive chemotherapy
phases; the peak frequency was 82% during consolidation block therapy
(mean duration of treatment, 14 days; range, 2-40 days). During the
same phase, 83% of patients required a central venous line, and the
mean hospital stay was 32 days (range, 6-65 days) compared with 22 days
(3-58 days) during protocol Ia. No cases of cardiac failure were
reported, and cardiac function in patients in complete remission, off
therapy, and without transplantation, measured as ejection or
shortening fraction (in 80% of the patients), was in the normal range.
Traditionally, age and leukocyte count, as well as DNA content and immunophenotype, have been considered the most useful prognostic factors in the clinical management of childhood ALL, though they often fail to accommodate patients who do not respond to induction/consolidation therapy or who have relapses on postremission regimens. The BFM experience has clearly demonstrated that in vivo response to 7 days of prephase steroid therapy is a powerful predictor of treatment outcome.3,4,12-14 In the AIEOP-ALL91 study, the high-risk group had a 5-year EFS rate of only 40% (SE, 4%),2 which was not remarkably different from the results achieved in ALL-BFM90, 34% (3%) at 6 years of follow-up.5 In this last study, PPR was recognized as the most powerful independent prognostic factor in a large unselected cohort of patients with childhood ALL who achieved remission on protocol Ia. In the AIEOP and the BFM studies, rotational administration of high-dose chemotherapy blocks did not provide significantly better leukemia control than standard BFM chemotherapy.4 The present data suggest an improvement in the prognosis of childhood ALL patients with PPR as their only high-risk feature. Despite the retrospective nature of the analysis, the 2 study populations (AIEOP-ALL95 and AIEOP-ALL91) were comparable with regard to eligibility requirements, age, leukocyte count, and immunophenotype so that the improvement in 4-year event-free-survival is most likely mainly related to differences in therapy. In the AIEOP-ALL95 study, treatment intensification was achieved with the use of a more traditional BFM-type backbone chemotherapy, consolidation with only 3 blocks, and repeated use of protocol II. This approach resulted in a significant improvement for the subgroup of high-risk patients defined as PPR-only. Interestingly, this advantage extended also to patients showing the association of adverse prognostic factors such as T phenotype, suggesting that this modified BFM-type therapy, developed also according to the experience of the CCG group,8 is particularly effective for such patients. This improvement, as shown in Figure 3, may account for the improvement obtained in the outcome of the whole group of PPR patients. It should be noted, however, that rotational intensive block chemotherapy, as already reported,2,5 provided results inferior to those of conventional BFM-type chemotherapy.4,15 Unfortunately, this improvement does not extend to all high-risk subgroups. Patients who did not achieve CR by the completion of protocol Ia, with or without detectable clonal translocations, remain the subgroup at highest risk for leukemic relapse with a 4-year EFS rate of 25.6% (SE, 7.1%). Patients with clonal translocations had a 4-year EFS of approximately 50%; nonetheless, the simultaneous presence of PPR with these features confers a poor prognosis. As with most programs of intensive chemotherapy, the modified treatment devised for AIEOP-ALL95 requires careful monitoring to prevent fatal or life-threatening complications. On average, these patients spent approximately 100 days in the hospital during the 5 intensive treatment phases covering the first 9 months from diagnosis. However, the death rate in first CR was only 2%, justifying wider application of this therapy in patients with high-risk ALL. Although this treatment regimen included a high cumulative dose of anthracycline (daunomycin and doxorubicin) of 410 mg/m2, cardiac function was not reported as a clinical problem after treatment completion in this study. These results underscore the treatment dependence of high-risk prognostic features in children with ALL. The ability to rescue high-risk patients from the toxic effects of intensified chemotherapy would appear to justify further attempts to identify occult high-risk features, such as polymerase chain reaction-detectable minimal residual disease, as a means to refine treatment and ultimately to increase the cure rate in childhood ALL.
We thank Dr Daniela Silvestri for her excellent contribution to this study.
Submitted September 5, 2001; accepted March 11, 2002.
Supported by MURST (grant 2001068982-007), Fondazione Tettamanti, Città della Speranza, and other charities and parent associations.
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 U.S.C. section 1734.
Reprints: Maurizio Aricò, Onco-Ematologia Pediatrica, Ospedale dei Bambini G. Di Cristina, Via Benedettini 1, Palermo, Italy; e-mail: arico{at}ospedalecivicopa.org.
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The following institutions enrolled patients in the AIEOP-ALL 95 study: Ancona, Clinica Pediatrica (Dr L. Felici, Dr P. Pierani); Bari, Clinica Pediatrica I (Prof F. Schettini, Dr N. Santoro); Bari, Clinica Pediatrica II (Prof N. Rigillo, Dr ssa S. Bagnulo); Bergamo, Div. Pediatria (Prof F. Bergonzi, Dr P. E. Cornelli), Ematologia (Prof T. Barbui); Bologna, Clinica Pediatrica (Prof G. Paolucci, Dr A. Pession, Dr R. Rondelli); Brescia, Clinica Pediatrica (Prof A. G. Ugazio, Dr A. Arrighini); Cagliari, Servizio di Oncoematologia Pediatrica (Prof P. F. Biddau, Dr ssa R. Mura); Catania, Divisione di Onco-Ematologia Pediatrica (Prof G. Schilirò, Dr L. Lo Nigro); Catanzaro, Div. di Ematologia (Prof S. Magro, Dr ssa C. Consarino); Firenze, Ospedale Meyer, Dipartimento di Pediatria, U. O. Oncoematologia Pediatrica (Profssa G. Bernini, Dr ssa A. Lippi); Genova, Ist. "G. Gaslini" (Prof G. Dini, Dr ssa C. Micalizzi); Milano Osp. Niguarda (Dr Fedeli); Milano Clinica Pediatrica (Dr Portaleone); Modena, Clinica Pediatrica (Profssa F. Massolo, Dr ssa M. Cellini); Monza, Clinica Pediatrica (Prof G. Masera, Dr V. Conter, Dr C. Rizzari, Dr M. Jankovic); Napoli, Ospedale Pausilipon (Prof V. Poggi, Dr ssa M. F. Pintà Boccalatte, Dr ssa C. De Fusco); Napoli, II Università, Dipartimento di Pediatrica, Servizio Autonomo di Oncologia Pediatrica, (Profssa M. T. Di Tullio, Dr ssa F. Casale, Dr ssa A. Murano); Napoli, Clinica Pediatrica II (Prof S. Auricchio, Dr A. Fiorillo, Dr ssa R. Migliorati); Napoli, Ospedale SS. Annunziata (Prof F. Tancredi, Dr A. Correra); Padova, Clinica Pediatrica II (Prof L. Zanesco, Prof G. Basso, Dr ssa C. Messina); Palermo, Clinica Pediatrica I (Profssa M. Lo Curto, Dr ssa G. Fugardi); Parma, Clinica Pediatrica (Dr G. Izzi, Dr ssa P. Bertolini); Pavia, Clinica Pediatrica (Profssa F. Severi, Dr M. Aricò, Dr F. Locatelli); Perugia, Divisione di Oncoematologia Pediatrica, Ospedale Silvestrini (Dr A. Amici, Dr P. Zucchetti); Pescara, Divisione di Ematologia (Dr A. Di Marzio, Dr R. Di Lorenzo, Prof G. Torlontano); Pisa, Clinica Pediatrica III (Prof P. Macchia, Dr C. Favre); Reggio Calabria, Divisione di Ematologia, Ospedali Riuniti (Prof F. Nobile, Dr ssa M. Comis); Roma, Divisione di Ematologia Pediatrica, Ospedale "Bambino Gesù"-(Prof G. De Rossi, Dr C. Miano); Roma, Cattedra di Ematologia (Prof F. Mandelli, Dr ssa AM Testi); Roma, Clinica Pediatrica (Prof G. Multari, Dr ssa B. Werner); Roma, Clinica Pediatrica (Prof Castello); S. Giovanni Rotondo, Ospedale "Casa Sollievo della Sofferenza," Divisione di Pediatria, Sezione di Ematologia ed Oncologia Pediatrica (Prof P. Paolucci, Dr S. Ladogana); Sassari, Clinica Pediatrica (Prof D. Gallisai, Dr C. Cosmi); Siena, Clinica Pediatrica (Prof G. Morgese, Dr A. Acquaviva, Dr A. D'Ambrosio); Torino, Clinica Pediatrica (Prof E. Madon, Prof R. Miniero, Dr ssa E. Barisone); Trieste, Clinica Pediatrica (Prof P. Tamaro, Dr G. A. Zanazzo); Varese, Clinica Pediatrica (Prof L. Nespoli, Dr ssa S. Binda); Verona, Clinica Pediatrica (Prof L. Tatò, Dr Marradi).
© 2002 by The American Society of Hematology.
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  A. Moricke, A. Reiter, M. Zimmermann, H. Gadner, M. Stanulla, M. Dordelmann, L. Loning, R. Beier, W.-D. Ludwig, R. Ratei, et al. Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95 Blood, May 1, 2008; 111(9): 4477 - 4489. [Abstract] [Full Text] [PDF]
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 C. Oudot, M.-F. Auclerc, V. Levy, R. Porcher, C. Piguet, Y. Perel, V. Gandemer, M. Debre, C. Vermylen, B. Pautard, et al. Prognostic Factors for Leukemic Induction Failure in Children With Acute Lymphoblastic Leukemia and Outcome After Salvage Therapy: The FRALLE 93 Study J. Clin. Oncol., March 20, 2008; 26(9): 1496 - 1503. [Abstract] [Full Text] [PDF]
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M. Arico, M. G. Valsecchi, C. Rizzari, E. Barisone, A. Biondi, F. Casale, F. Locatelli, L. Lo Nigro, M. Luciani, C. Messina, et al. Long-Term Results of the AIEOP-ALL-95 Trial for Childhood Acute Lymphoblastic Leukemia: Insight on the Prognostic Value of DNA Index in the Framework of Berlin-Frankfurt-Muenster Based Chemotherapy J. Clin. Oncol., January 10, 2008; 26(2): 283 - 289. [Abstract] [Full Text] [PDF]
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 E. V. Barry, S. E. Lipshultz, and S. E. Sallan Anthracycline-induced Cardiotoxicity: Natural History, Risk Factors, and Prevention ASCO Educational Book, January 1, 2008; 2008(1): 448 - 453. [Abstract] [Full Text] [PDF]
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A. Balduzzi, V. Conter, C. Uderzo, and M. G. Valsecchi Transplantation in Childhood Very High Risk Acute Lymphoblastic Leukemia in First Complete Remission: Where Are We Now? J. Clin. Oncol., June 20, 2007; 25(18): 2625 - 2626. [Full Text] [PDF]
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J.-M. Ribera, J.-J. Ortega, A. Oriol, P. Bastida, C. Calvo, J.-M. Perez-Hurtado, M.-E. Gonzalez-Valentin, V. Martin-Reina, A. Molines, F. Ortega-Rivas, et al. Comparison of Intensive Chemotherapy, Allogeneic, or Autologous Stem-Cell Transplantation As Postremission Treatment for Children With Very High Risk Acute Lymphoblastic Leukemia: PETHEMA ALL-93 Trial J. Clin. Oncol., January 1, 2007; 25(1): 16 - 24. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
that is, they
achieved CR and were negative for t(9;22) and t(4;11)
translocations
