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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1843-1849 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.7265 Comparison of the Results of the Treatment of Adolescents and Young Adults With Standard-Risk Acute Lymphoblastic Leukemia With the Programa Español de Tratamiento en Hematología Pediatric-Based Protocol ALL-96
From the Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, Badalona; Hospital La Fe; Hospital Clínico Universitario, Valencia; Hospital General, Alicante; Hospital Clínico San Carlos; Hospital Doce de Octubre, Madrid; Hospital del Mar; Hospital Vall d'Hebron, Barcelona; Hospital Universitario Virgen del Rocío, Sevilla; Hospital Morales Meseguer, Murcia; and the Hospital Universitario Carlos Haya, Málaga, Spain Corresponding author: Josep-María Ribera, Servicio de Hematología Clínica, Institut Català d'Oncologia-Hospital Universitari Germans Trias i Pujol, C/ Canyet S/N, 08916 Badalona, Spain; e-mail: jribera{at}iconcologia.net
Purpose Retrospective studies have shown that adolescents and young adults with acute lymphoblastic leukemia (ALL) treated with pediatric protocols have better outcomes than similarly aged patients treated with adult protocols, but prospective studies comparing adolescents and young adults using pediatric schedules are scarce. The ALL-96 protocol was addressed to compare the toxicity and results of a pediatric-based protocol in adolescents (age 15-18 years) and young adults (age 19-30 years) with standard-risk (SR) ALL. Patients and Methods Adolescents (n = 35) and young adults (n = 46) received a standard five-drug/5-week induction course followed by two cycles of early consolidation, maintenance with monthly reinforcement cycles up to 1 year in continuous complete remission (CR) and 1 year with standard maintenance chemotherapy up to 2 years in CR. Results Adolescents and young adults were comparable in the main pretreatment ALL characteristics. The CR rate was 98% and. after a median follow-up of 4.2 years, 6-year event-free survival (EFS) and overall survival (OS) were 61% (95% CI, 51% to 72%) and 69% (95% CI, 59% to 79%), respectively, with no differences between adolescents and young adults. The hematologic toxicity in consolidation and reinforcement cycles was higher in young adults than in adolescents. Slow response to induction therapy was the only parameter associated with poor EFS (34% v 67%) and OS (40% v 76%). Conclusion The response to the pediatric ALL-96 protocol was identical in adolescents and young adults despite a slight increase in hematologic toxicity observed in adults. This justifies the age-unrestricted use of pediatric regimens to treat patients with SR ALL.
Development of effective therapy for children with acute lymphoblastic leukemia (ALL) is one of the great successes of clinical oncology, with long-term survival achieved in over 80% of patients.1 Within childhood ALL, older children have shown inferior outcomes, and within adult ALL, younger adults have shown superior outcomes. Retrospective studies focused on patients age 15 to 21 years showed that adolescents and young adults (AYA) treated with adult ALL protocols have poorer outcomes than similarly aged patients treated with pediatric protocols.2-9 Five-year event-free survival (EFS) for AYA treated with pediatric and adult regimens range from 64% to 69% and 34% to 49%, respectively.10-12 Prospective clinical trials using pediatric regimens to treat adolescents and adults up to 30 years or even older with standard-risk (SR) ALL are currently ongoing. Preliminary reports have shown an encouraging rate of complete remission (CR) of more than 90% and a promising EFS probability of 60% to 70%.13-15 The PETHEMA (Programa Español de Tratamiento en Hematología) Group has developed common protocols to treat children and adults with high-risk (HR) ALL.16,17 In 1996 we developed a common pediatric-based protocol (ALL-96) for children with intermediate-risk ALL, and for AYA with SR ALL. In the present article, we analyze the results and compare both sets of patients.
Study Eligibility SR ALL was defined in adolescents (age 15 to 18 years) and young adults (age 19 to 30 years) fulfilling all the following criteria: WBC count at or lower than 30 x 109/L, and absence of t(9;22), t(1;19), t(4;11) or any other 11q23 rearrangements. Patients were not eligible if they had previously received antileukemic treatment or had uncontrolled or severe cardiovascular, hepatic, or renal disease not resulting from ALL or severe psychiatric condition. Patients with ALL-L3 (Burkitt's-type ALL) or T-cell lymphoblastic lymphoma were not included. Patients were centrally registered after informed consent was obtained from adult patients or from parents or guardians for patients younger than 18 years. The study was approved by the institutional review boards of all participating centers, and the procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975. The study was initiated in June 1996 and closed for patient inclusion in June 2005.
Diagnostic Procedure
Treatment and Criteria for Response
Hematopoietic growth factors (granulocyte colony-stimulating factor) were used according to institutional practice during the C1 and C2 phases to allow the administration of chemotherapy as scheduled. Hospitalization, management of infections, and transfusion policies were carried out according to the institutional discretion. CR was defined as the absence of clinical manifestations of ALL, neutrophil count higher than 1.5 x 109/L, platelet count higher than 150 x 109/L and hemoglobin levels higher than 100 g/L, with fewer than 5% of blast cells in BM. Patients with blast cells in BM greater than 5% at the end of the induction phase were considered induction failures. Two patterns of response were considered20: (1) slow, defined as the presence of more than 10% of blast cells in the BM aspirate performed on day 14 of treatment; and (2) good, defined as less than or equal to 10% of BM blast cells or hypoplastic BM on day 14. EFS was defined as the time from diagnosis to failure, relapse, death or last follow-up. Overall survival (OS) was defined as the time from study entry to death or last follow-up.
Statistical Analysis
Patients Three hundred thirty-one patients were enrolled from June 1996 to June 2005 in 25 Spanish hospitals. Of these patients, 244 were children (age 1 to 14 years) with intermediate-risk ALL and 87 (26%) were age 15 to 30 years. Two young adult patients did not fulfill intermediate risk criteria on review [one biphenotypic ALL, one with t(4;11)] and four had insufficient follow-up (< 2 years). Thus, 81 adolescents (n = 35) and young adults (n = 46) were considered for analysis. Table 2 shows the main clinical and biologic features of the whole series and compares these characteristics among adolescents and young adults. The median age was 20 years (range, 15 to 30 years) and 50 patients (62%) were males. Thirty-six patients presented a normal karyotype. Abnormal karyotypes included nine cases (15%) of high hyperdiploidy, four (7%) of low hyperdiploidy, one (1%) of hypodiploidy, and seven (12%) of pseudodyploidy including one case each of t(14;14), t(1;11), t(7;14), del(11p), 14q+, and add(5) and one case of undetermined chromosome marker. Three cases (5%) had a complex karyotype. Insufficient or no metaphases could be obtained in the 21 remaining cases.
Therapy Results Overall, 79 patients (98%) achieved CR. On day 14 of induction therapy, 69 patients (85%) and 10 patients (12%) achieved good and slow response, respectively. One patient died during induction, and the remaining one failed to respond and died as a result of toxicity from rescue treatment (Table 3). Four slow responders switched to an HR protocol, and the remaining six patients continued with the scheduled consolidation program. No initial variable was found to be significantly associated with induction failure or slow response (Table 3). Significant differences were not observed either in the rate of response to therapy or in the frequency of CR between AYA (Table 2).
Among the 69 good responders, 17 (25%) relapsed. Two relapses occurred during the first year of treatment, six during the second (maintenance), and nine after completion of treatment. Five (56%) of nine patients who relapsed after completing treatment were in second CR at the last follow-up versus only one relapsing during therapy. Among the 10 slow responders, six relapsed and died, one died in remission during consolidation therapy, and three patients remained in first CR at last follow-up (one patient after HR treatment and allogeneic stem-cell transplantation [SCT], and two after the consolidation and maintenance therapy of the ALL-96 protocol). Seven patients remained alive and in second CR at last contact, four of whom had relapsed 1 to 4 years after completing maintenance treatment, representing 58% of very late relapses, and two patients had relapsed during the first year out of maintenance treatment (50% of patients relapsed during that period). Only one patient (12%) of eight who relapsed during maintenance could be rescued durably, and none of the four early relapses (during consolidation/reinduction period) achieved a durable second CR. No differences in the sites of relapse were observed between AYA (Table 4).
The median follow-up was 4.2 years (range, 2 to 10 years). The OS rate at 6 years for the whole series was 69% (95% CI, 59% to 81%), 76% (95% CI, 65% to 87%) for the 69 patients who achieved a good response, and 40% (95% CI, 9% to 71%) for the 10 slow responders (P = .012; Figs A1 and A2, online only). The 6-year EFS for the whole series was 61%, (95% CI, 51% to 72%), and, respectively, 67% (95% CI, 56% to 78%) and 34% (95% CI, 5% to 63%) for good and slow responders (P = .01; Figs A1 and A2). No other factors were associated with an adverse outcome. No differences were observed between AYA in either EFS (60% and 95% CI, 43% to 77% v 63% and 95% CI, 48% to 78%; P = .97; Fig 1) or OS (77% and 95% CI, 63% to 91% v 63% and 95% CI, 46% to 80%; P = .44; Fig 1). A Cox regression analysis showed that only slow response to induction therapy was associated with a poor EFS (odds ratio [OR] = 2.99; 95% CI, 1.25 to 7.17) and OS (OR = 3.26; 95% CI, 1.22 to 8.70).
Treatment-Related Toxicity and Morbidity A full assessment for toxicity was performed in 630 courses of chemotherapy (80 induction, 69 C1, 69 C2, and 412 reinductions; Table 5). Sixty-eight percent of patients developed grade 3 to 4 neutropenia (median duration, 16 days; range, 2 to 41 days) and 44% developed grade 3 to 4 thrombocytopenia (median duration, 9 days; range, 1 to 35 days) during induction. Febrile neutropenia was observed in 43 patients (54%), and one patient died as a result of infection. Seven patients (8%) presented hypersensitivity reactions to asparaginase requiring interruption of the drug. No patient had to abandon consolidation therapy. C1 course was delayed in 17 patients (25%) because of induction toxicity, mainly infections. Fifty-two percent of patients developed grade 3 to 4 neutropenia (median duration, 5 days; range, 1 to 17 days), 16% grade 3 to 4 thrombocytopenia (median duration, 2 days; range, 1 to 14) and there were 27 episodes (39% of patients) of grades 1 or 2 febrile neutropenia. In adolescents, grade 4 neutropenia occurred in 44% of C1 cycles, with a median duration of 5 days (range, 1 to 14 days) and grade 4 thrombocytopenia in 10% with a median duration of 5 days (range, 4 to 7 days). In turn, in young adults severe neutropenia was present in 59% of patients (median duration, 5 days; range, 1 to 17 days) and severe thrombocytopenia in 33% (median duration, 3 days; range, 1 to 14 days). The C2 course had to be delayed or modified in nine cases (16%; eight young adults and one adolescent; P = .031) as a result of toxicity in the previous cycle. The incidences of grade 3 to 4 neutropenia and thrombocytopenia were 32% and 4%, respectively, with a maximum duration of 1 week for all patients. Fifteen episodes of febrile neutropenia were recorded, one leading to fatal septic shock. There was a higher number of grade 1 infections in young adults (13 young adults v one adolescent; P = .007).
The adverse effects in the 412 reinduction cycles were usually mild, but dose modifications of asparaginase or vincristine were performed in 80 cycles (19%; 25 of 165 cycles in adolescents v 55 of 166 cycles in young adults; P = .03). Other grade 1 to 2 toxicities included an elevation in transaminases (3% of cycles) or infections (4%). Mild neurotoxicity was registered in seven patients. One patient developed irreversible myelopathy secondary to intrathecal methotrexate.24 Maintenance therapy was not associated with important toxicities, although dose adjustments of mercaptopurine or methotrexate were made in 42% and 11% of patients during the first and second year of therapy, respectively. Nine episodes of grade 1 infections were recorded (seven during the first year). The median interval of time between CR and the onset of maintenance-1 was 138 days (interquartile interval, 114 to 153 days) days, with no differences between adolescents (143 days) and young adults (136 days). Maintenance-1 therapy was delayed for more than 1 month in four adolescents and nine young adults. Delays during reinductions were significantly more frequent in young adults than in adolescents (median duration of maintenance-1, 7 and 6.4 months, respectively; P = .04).
The results of this prospective pediatric-based study show that response to therapy and prognosis is identical in AYA with SR-ALL despite slightly poorer tolerability of chemotherapy in adults. Slow response to therapy was observed with the same frequency in the two age groups and was the only parameter with prognostic significance for survival. Despite the long follow-up and the uniform inclusion criteria for AYA, the cutoff level of WBC used for the definition of SR ALL in this trial was probably too low for T-cell ALL. Several studies have defined as SR ALL patients with WBC counts less than 30 x 109/L in precursor B-cell ALL and less than 50 x 109/L or 100 x 109/L in T-cell ALL.25,26 However, it is of note that the prognostic significance of baseline WBC can be ameliorated with the use of more intensive chemotherapy regimens, especially in induction and early consolidation, as occurred in the ALL-96 study. In fact, the kinetics of response to ALL therapy supersedes pretreatment parameters in many studies, as occurred in the present trial, and the results did not vary when specific subsets of patients were excluded (ie, T-ALL). A second limitation in the present trial is the lack of study of minimal residual disease (MRD). This is currently one of the most relevant prognostic factors in childhood ALL and some prospective data suggest that the same applies to adults with SR ALL.25,27 The prognostic relevance of MRD was not sufficiently known at the time of the design of the present study, although day 14 bone marrow blasts is a fairly adequate surrogate variable. AYA with ALL are treated by either adult or pediatric specialists in most countries.11,12 However, in the ALL-96 study all young adults and most adolescents were treated by adult specialists in adult hematology units because in Spain the cutoff age to separate children and adults is 15 years. Recent studies have focused on patients age 15 to 21 years2-9,28 but few have evaluated the results in young adults up to 30 years or more.13-15 These studies have retrospectively compared the results of treatment in adult versus pediatric settings and found that patients treated with pediatric protocols in the United States and Europe had significantly better outcomes than patients treated with adult schedules.2-9 Some reasons could explain these differences.10-12 First, more children with ALL are enrolled onto clinical trials because ALL represents 20% to 25% of all malignancies in 1- to 15-year-olds, 5% in 15- to 19-year-olds, and less than 10% in patients older than 20 years.29 Second, treatments in pediatric studies are usually more intense. The cumulated doses of vincristine, steroids, anthracyclines, asparaginase, and cyclophosphamide in our ALL-96 protocol are very similar to those of other pediatric-based protocols.3 Third, differences in disease biology or drug resistance mechanisms cannot be ruled out. Finally, occult differences in practices among adult hematologists and pediatricians might not be identifiable but could influence the therapeutic results. Many of these considerations do not apply to the ALL-96 study and, consequently, the identical results observed in AYA are basically explained by the use of a pediatric-based protocol. Although the number of recruited patients is relatively small, results do not suggest that differences are likely to emerge in a larger sample. Some ongoing studies are using pediatric-based protocols in adults up to age 30 years or even up to 50 or 60 years.13-15 The French Group for Research in Adult ALL (GRAALL) has reported the results in 212 patients age 15 to 55 years.15 In this study there was 8.6-fold, 3.7-fold, and 16-fold increase in cumulative doses of prednisone, vincristine, and asparaginase, respectively, compared with the previous adult-based Leucémie Aigue Lymphoblastique de l'Adulte (LALA)-9 protocol. The CR rate was 93% and the 2-year disease-free survival (DFS) and OS probabilities were 56% and 62%, respectively. Recently, the Dana-Farber Combined Adult/Pediatric ALL Consortium has applied a pediatric protocol to adults age 18 to 50 years. The preliminary results in 71 patients show a CR rate of 82% with promising 2-year DFS and OS probabilities of 76% and 81%, respectively.13 In turn, the Princess Margaret Hospital14 used a pediatric protocol in 68 adult patients (17 to 71 years), with a CR rate of 85% and 3-year OS and DFS of 65% and 77%, respectively. In addition to these results, the tolerability of these protocols in adults is an important issue. The results of the present study show that this pediatric approach is feasible in young adults, with only two patients with chemotherapy-related deaths and no withdrawals because of excess toxicity. The consolidation cycles had to be delayed in 25% and 16% of patients, respectively. Dose modifications were required in 19% of reinduction cycles and dose adjustments of mercaptopurine or methotrexate had to be made in 42% and 11% of patients during the first and second years of therapy, respectively. It is important to note that, except for more hematologic toxicity during C1 and increased toxicity requiring dose reduction in the reinductions in young adults, there were no relevant differences between AYA with regard to treatment-related toxicity and morbidity. Furthermore, success of salvage therapy for relapsed patients appeared to be associated with time to relapse only and not to age, further reinforcing the similarity between the two age groups. Although the results of this study in SR ALL only defined by pretreatment characteristics are promising, they may be improved by a better selection of patients in CR. Patients with slow response to induction therapy must be treated with protocols for HR ALL patients. Sequential measurements of MRD would allow the establishment of a MRD-based risk stratification that would be useful to select patients in the MRD-HR group who may be switched to HR ALL approaches including SCT.25,27 Current clinical trials are focusing on "the ages of uncertainty" (ie, the 18- to 50-year-old population) and preliminary results of these and our trials, suggest that age-unrestricted, biology-based therapy should probably be the standard for all patients with ALL. Pediatricians and adult hematologists treating patients with ALL should cooperate because joint efforts could likely result in more cures and higher quality of life among patients with ALL.
The author(s) indicated no potential conflicts of interest.
Conception and design: Josep-María Ribera, Albert Oriol, Juan-José Ortega Provision of study materials or patients: Josep-María Ribera, Albert Oriol, Miguel-Angel Sanz, Mar Tormo, Pascual Fernández-Abellán, Eloy del Potro, Eugenia Abella, Javier Bueno, Ricardo Parody, Pilar Bastida, Carlos Grande, Inmaculada Heras, Concepción Bethencourt, Evarist Feliu, Juan-José Ortega Collection and assembly of data: Josep-María Ribera, Albert Oriol, Miguel-Angel Sanz, Mar Tormo, Pascual Fernández-Abellán, Eloy del Potro, Eugenia Abella, Javier Bueno, Ricardo Parody, Pilar Bastida, Carlos Grande, Inmaculada Heras, Concepción Bethencourt, Evarist Feliu, Juan-José Ortega Data analysis and interpretation: Josep-María Ribera, Albert Oriol, Miguel-Angel Sanz, Mar Tormo, Pascual Fernández-Abellán, Eloy del Potro, Eugenia Abella, Javier Bueno, Ricardo Parody, Pilar Bastida, Carlos Grande, Inmaculada Heras, Concepción Bethencourt, Evarist Feliu, Juan-José Ortega Manuscript writing: Josep-María Ribera, Albert Oriol, Miguel-Angel Sanz, Juan-José Ortega Final approval of manuscript: Josep-María Ribera, Albert Oriol, Miguel-Angel Sanz, Mar Tormo, Pascual Fernández-Abellán, Eloy del Potro, Eugenia Abella, Javier Bueno, Ricardo Parody, Pilar Bastida, Carlos Grande, Inmaculada Heras, Concepción Bethencourt, Evarist Feliu, Juan-José Ortega
The following centers and physicians have participated in the ALL-96 protocol: ICO-Germans Trias Pujol, Badalona (J.M. Ribera, A. Oriol); La Fe, Valencia (P. Montesinos, M.A. Sanz); General, Alicante (P. Fernández-Abellan, C. Rivas); Clínico San Carlos, Madrid (E. del Potro); Clínico Universitario, Valencia (M. Tormo), del Mar, Barcelona (E. Abella); Vall d'Hebron, Barcelona (P. Bastida, J. Bueno, J.J. Ortega); Virgen del Rocio, Sevilla (R. Parody); Morales Meseguer, Murcia (I. Heras); Doce de Octubre, Madrid (C. Grande); Carlos Haya, Málaga (C. Bethencourt); Clínico Universitario, Salamanca (J.M. Hernández-Rivas, J.F. San Miguel); Sonsoles, Avila (A. Barez); Clínico, Valladolid (J. Fernández-Calvo, D. Borrego); Son Dureta, Palma Mallorca (A. Novo, J. Besalduch); Mutua Terrassa (J.M. Martí); General, Valencia (M. Sánchez-Delgado); Miguel Servet, Zaragoza (A. Carboné, C. Calvo); Dr Peset, Valencia (M.J. Sayas); Clinico Virgen de la Victoria, Málaga (M.J. Moreno); Juan Canalejo, A Coruña (G. Deben); Puerta del Mar, Cadiz (V. Martín-Reina); ICO-Duran y Reynals (J. Sarrá); General, Segovia (J.A. Queizan).
Supported in part by Grants No. 97/1049 from the Fondo de Investigaciones Sanitarias, RD/060020/1056 from Retics, and FIJC P-EF/04 from the José Carreras International Leukemia Foundation. Presented at the 12th Congress of the European Hematology Association, June 7-10, 2007, Neue Messe Vienna, Austria. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 or Fisher's exact test were used to assess differences in proportions. All of the comparisons were two-tailed. Actuarial curves for EFS and OS were plotted according to the Kaplan-Meier method
