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Lack of negative impact of P hiladelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols

2012; Wiley; Volume: 159; Issue: 4 Linguagem: Inglês

10.1111/bjh.12043

1365-2141

Josep‐María Ribera, Olga García, Pascual Fernández, Esperanza Lavilla, Teresa Bernal, José González‐Campos, Salut Brunet, María‐Carmen Monteserín, Pau Montesinos, Josep Sarrà, María Calbacho, Alberto Álvarez‐Larrán, Mar Tormo, Albert Oriol,

Lung Cancer Treatments and Mutations

We have read with interest the article by Sive et al (2012) who reported a series of 100 older patients (aged 55–65 years) with acute lymphoblastic leukaemia (ALL) treated in the UKALLXII/ECOG2993 trial and compared with 1814 younger patients (aged 14–54 years). As expected, the older patients had poorer outcomes attributed to the combination of a poorer cytogenetic risk (especially by the presence of Philadelphia chromosome, Ph) and a significant morbidity and mortality during induction chemotherapy, with frequent delays and drug reductions. In this study, patients with Ph+ ALL were excluded from the analysis if they were treated with imatinib (Sive et al, 2012), which meant that it was not known whether this targeted therapy could improve the prognosis in this subset of patients. We report the results of two prospective parallel trials in older patients with ALL from the Spanish PETHEMA (Programa Español de Tratamiento en Hematología) Group showing equivalent survival in Ph- and Ph+ patients, the latter group being treated with minimal chemotherapy and imatinib, with less myelotoxicity and fewer infections in the imatinib-treated group. Between July 2007 and December 2011 patients aged more than 55 years were included in the ALLOLD07 (Clinical trialials.gov identification NCT 01366898) and ALLOPH07 (NCT 01376427) trials if they had Ph- or Ph+ ALL, respectively. The ALLOLD07 trial (Table 1) was derived from the Elderly ALL trial of the European Working Group for ALL (EWALL) (Goekbuget et al, 2008) and included induction therapy with vincristine (VCR) dexamethasone (DXM) and idarubicin (IDA) (phase 1), and cyclophosphamide (CPM) and cytarabine (ARA-C) (phase 2) for a total duration of 4 weeks. Consolidation treatment included six alternating cycles with intermediate-dose methotrexate (MTX) and asparaginase (ASP) (odd cycles) and ARA-C (even cycles). Maintenance therapy included mercaptopurine (MP) and MTX for up to 2 years, with monthly reinduction cycles with VCR and DXM until two years from the date of complete remission (CR). The ALLOPH07 trial (Table 1) included induction with imatinib (400 mg/d), VCR and DXM and maintenance with imatinib, MP and MTX for up to 2 years, with monthly reinduction cycles with VCR and DXM during the first year. Imatinib alone was given during the third year. Dasatinib (70 mg/12 h, PO) was allowed in cases of intolerance to imatinib. In the ALLOPH trial there was a 100% reduction in the cumulative doses of IDA, CPM, ARA-C and ASP, as well as omission of intermediate-dose MTX compared with the ALLOLD trial. Outcome measures included early death (ED) (defined as death before remission documentation), CR attainment, CR duration (defined as the time interval between CR and relapse or last control, in February 2012), overall survival (OS, defined as the time interval between the ALL diagnosis and death or last control,) and event-free survival (EFS, defined as the time from diagnosis to relapse, death or last control). Kaplan–Meier curves were used for survival analyses, and univariate comparisons were made with the log-rank test. P values < 0·05 were considered statistically significant. Odds ratios (OR) were calculated and reported with their 95% confidence intervals (CI). Twenty-eight valid patients were included in the ALLOLD07 and 32 in the ALLOPH07 trial. Both groups of patients were comparable for the main clinical and biological characteristics of ALL (Table 2). Early death was observed in 3 (11%) of patients in the ALLOLD07 vs. 4 (13%) in the ALL OPH07 trial; failure occurred in four patients (14%) vs. 1 (3%), and CR was attained in 21 (75%) vs. 26 (84%), respectively. With a median follow-up of 14 and 20 months respectively, the median (95% CI) of CR duration was 27 (13–41) months in the ALLOLD07 trial vs. 37(13–43) months in the ALLOPH07 trial; the median OS was 16 (8–23) months vs. 22 (9–35), and the medians EFS was 11 (6–16) months vs. 21 (0–46) months (Fig S1), without significant differences between the two protocols. The duration of neutropenia in induction was significantly longer in the ALLOLD07 trial, as was extramedullary grade III-IV toxicity, especially infections (Table 1). Comparison of the two protocols identified no differences in toxicity during consolidation and maintenance. The results of these two parallel prospective protocols show that in the tyrosine kinase inhibitor (TKI) era, older patients with Ph+ ALL do not have poorer prognosis than those without Philadelphia chromosome. The ALLOLD07 protocol included moderate dose-intensity induction chemotherapy without ASP aimed to achieve CR with low toxicity, followed by an intermediate-intensity consolidation regimen based on MTX, ASP and ARA-C followed by a standard maintenance regimen. The results of the ALLOLD07 study were similar to those from the international UKALLXII/ECOG 2993 trial reported by Sive et al (2012) in terms of CR rate, OS and EFS although the follow-up in the present study was shorter. Regarding patients with Ph+ ALL, there are differences between the results of the UKALLXII/ECOG 2993 trial and the ALLOPH07 study, with a worse outcome (5-year EFS 0% vs. 4-year EFS 38%) for the former trial. It is of note that the ALLOPH07 study included a frank reduction in the dose intensity of chemotherapy compared to the UKALLXII/ECOG 2993 trial. Thus, the addition of imatinib contributed to the improvement in outcome (Ottmann et al, 2007; Vignetti et al, 2007; Rousselot et al, 2010; Foà et al, 2011), eliminating the negative impact of the Philadelphia chromosome on the prognosis of ALL in older patients in our study. The reduction in the frequency and intensity of the myelosuppression and in the frequency of severe infections in induction represented an additional advantage of the ALLOPH07 study. However, although the negative prognosis of Ph+ ALL has been eliminated in the TKI era, the results of the treatment of ALL in older patients are clearly unsatisfactory. The use of minimal residual disease monitoring for therapeutic decisions, the early use of reduced-intensity conditioning allografts in fit patients and the inclusion of targeted therapies are currently being explored in clinical trials and could constitute a hope for improving treatment results in these patients. Supported by grants RD06/0020/1056 from RTICC, PI10/01417 from FIS, Instituto Carlos III, and P-EF-11 from Jose Carreras Leukaemia Foundation. JMR and AO designed the study, analysed the data and wrote the paper. OG performed the research and analysed the data. PFA, EL, MTB, JGC, SB, CM, PM, JS, MC, AAL and MT provided the patients and reported the data. The following institutions and physicians participated in the study: ICO-Hospital Germans Trias i Pujol, Badalona (JM Ribera, O Garcia, A Oriol), Hospital General Universitario de Alicante, Alicante (P Fernández-Abellán), Hospital Xeral de Lugo, Lugo (E Lavilla), H Central de Asturias, Oviedo (MT Bernal), Hospital Virgen del Rocío, Sevilla (J González-Campos), Hospital de Sant Pau, Barcelona (S Brunet, J Sierra), Hospital de Getafe, Madrid (MC Monteserín), ICO Duran i Reynals (J Sarrá), Hospital Ramón y Cajal, Madrid (M Calbacho), Hospital del Mar, Barcelona (A Álvarez-Larrán, E Abella), Hospital Clínic de Valencia, Valencia (M Tormo, G Pérez), Hospital La Fe, Valencia (P Montesinos, MA Sanz), Hospital Universitario de Canarias, La Laguna (M Fernández, C Stoica), Hospital Marqués de Valdecilla, Santander (M Colorado, AM Méndez), Hospital Clínico de Málaga, Málaga (MJ Moreno), Hospital Clínic de Barcelona, Barcelona (J Esteve), Hospital Parc Taulí, Sabadell (S Piernas), Hospital de Fuenlabrada, Madrid (P Bravo), Hospital Virgen de la Concha, Zamora (M Sierra), Hospital Vall d'Hebron, Barcelona (P Barba), Hospital Torrecárdenas, Almería (MJ García), Hospital Clínico Universitario, Salamanca (JM Hernández-Rivas, JF San Miguel), Hospital Juan Canalejo, A Coruña (G Debén), Hospital Joan XXIII, Tarragona (A Llorente, L Escoda), Hospital de Jaén, Jaén (JA López), Hospital Infanta Leonor, Madrid (JA Hernández-Rivas), Hospital Doctor Peset, Valencia (M Pedreño, MJ Sayas), Hospital Arnau de Vilanova, Lleida (A García), Fundación Jiménez Díaz, Madrid (JL López), Complejo Hospitalario de Pontevedra, Pontevedra (ML Amador), Complejo Hospitalario de Ourense, Ourense (J del Río). 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