ORIGINAL ARTICLE. Haut-Levêque, Bordeaux, France and 22 Department of Hematology, Novartis Pharma, Rueil Malmaison, France. Patients and methods

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1 (2006) 20, & 2006 Nature Publishing Group All rights reserved /06 $ ORIGINAL ARTICLE Imatinib and methylprednisolone alternated with chemotherapy improve the outcome of elderly patients with Philadelphia-positive acute lymphoblastic leukemia: results of the GRAALL AFR09 study A Delannoy 1, E Delabesse 2, V Lhéritier 3, S Castaigne 4, F Rigal-Huguet 5, E Raffoux 6, F Garban 7, O Legrand 8, S Bologna 9, V Dubruille 10, P Turlure 11, O Reman 12, M Delain 13, F Isnard 14, D Coso 15, P Raby 16, A Buzyn 2, S Caillères 17, S Darre 18, C Fohrer 19, A Sonet 20, C Bilhou-Nabera 21, M-C Béné 9, H Dombret 6, P Berthaud 22 and X Thomas 3 for the Group for Research in Adult Acute Lymphoblastic (GRAALL) 1 Department of Hematology, Hôpital de Jolimont, Haine-Saint-Paul, Belgium; 2 Department of Hematology, CHU Paris-Necker, Paris, France; 3 Department of Hematology, Hôpital E Herriot, Lyon, France; 4 Department of Hematology, Hôpital A Mignot, Versailles, France; 5 Department of Hematology, Hôpital Purpan, Toulouse, France; 6 Department of Hematology, Hôpital Saint-Louis, Paris, France; 7 Department of Hematology, Hôpital Michallon, Grenoble, France; 8 Department of Hematology, Hôtel-Dieu, Paris, France; 9 Department of Hematology, CHU Nancy Brabois, Nancy, France; 10 Department of Hematology, Hôtel-Dieu, Nantes, France; 11 Department of Hematology, Hôpital Dupuytren, Limoges, France; 12 Department of Hematology, CHU de Caen, Caen, France; 13 Department of Hematology, Hôpital Bretonneau, Tours, France; 14 Department of Hematology, Hôpital Saint-Antoine, Paris, France; 15 Department of Hematology, Institut Paoli Calmettes, Marseille, France; 16 Department of Hematology, Hôpital L Pasteur, Colmar, France; 17 Department of Hematology, CH d Aix, Aix-en-Provence, France; 18 Department of Hematology, Hôpital C Huriez, Lille, France; 19 Department of Hematology, Hôpital de Hautepierre, Strasbourg, France; 20 Department of Hematology, Cliniques Universitaires de Godinne, Yvoir, Belgium; 21 Department of Hematology, CHU du Haut-Levêque, Bordeaux, France and 22 Department of Hematology, Novartis Pharma, Rueil Malmaison, France Acute lymphoblastic leukemia (ALL) in the elderly is characterized by its ominous prognosis. On the other hand, imatinib has demonstrated remarkable, although transient, activity in relapsed and refractory Philadelphia-positive acute lymphoblastic leukemia (Ph þ ALL), which prompted us to assess the use of imatinib in previously untreated elderly patients. ALL patients aged 55 years or older were given steroids during 1 week. Ph þ ve cases were then offered a chemotherapy-based induction followed by a consolidation phase with imatinib and steroids during 2 months. Patients in complete response (CR) after consolidation were given 10 maintenance blocks of alternating chemotherapy, including two additional 2-month blocks of imatinib. Thirty patients were included in this study and are compared with 21 historical controls. Out of 29 assessable patients, 21 (72%, confidence interval (CI): 53 87%) were in CR after induction chemotherapy vs 6/21 (29%, CI: 11 52%) in controls (P ¼ 0.003). Five additional CRs were obtained after salvage with imatinib and four after salvage with additional chemotherapy in the control group. Overall survival (OS) is 66% at 1 year vs 43% in the control group (P ¼ 0.005). The 1-year relapse-free survival is 58 vs 11% (P ¼ ). The use of imatinib in elderly patients with Ph þ ALL is very likely to improve outcome, including OS. (2006) 20, doi: /sj.leu ; published online 13 July 2006 Keywords: lymphocytic; acute; aged; imatinib; Philadelphia chromosome confers a dismal prognosis to the disease except in patients amenable to stem cell transplantation. 1 The proportion of Ph þ ALL cases increases with age, up to 30 50%. It has been suggested, however, that in very old persons, the proportion of Ph þ ALL decreases again. 2 In contrast with younger adults, the presence of Ph chromosome has no impact on the overall survival (OS) of older patients probably because of the poor prognosis of Ph ALL in the elderly. 3 Imatinib is an orally given selective competitive inhibitor of the BCR/ABL protein-tyrosine kinase (the fusion protein encoded by the chimeric BCR/ABL gene), the platelet-derived growth factor receptor a and b and the c-kit receptor kinase. 4 The activity of imatinib in Ph þ ALL was first demonstrated in relapsing or refractory cases with 29% of patients obtaining a complete hematological remission. 5 However, the median time to progression in responsive patients was only 2.2 months. More recently, imatinib used alone or combined with chemotherapy proved tolerable and effective in young adults with previously untreated Ph þ ALL. 6,7 Here, we report on the use of imatinib during the consolidation/salvage and maintenance treatment of elderly adults with previously untreated Ph þ ALL. The outcome of a cohort of Ph þ ALL elderly patients from our previous study, treated with chemotherapy but no imatinib, was used as a comparison. Patients and methods Introduction Philadelphia (Ph) chromosome is present in approximately 25% of young adults with acute lymphoblastic leukemia (ALL) and Correspondence: Professor A Delannoy, Department of Hematology, Hôpital de Jolimont-Lobbes, Rue Ferrer, 159, B-7100 Haine-Saint- Paul, Belgium. a.delannoy@skynet.be Received 15 April 2006; revised 11 June 2006; accepted 14 June 2006; published online 13 July 2006 Patients From January 2003 to November 2004, 30 patients, aged 55 years or older, with previously untreated Ph þ ALL, were included in the present study initiated by the Group for Research on Adult Acute Lymphocytic (GRAALL) after giving written informed consent. Eighteen French and two Belgian hospitals contributed to this study. Before inclusion, Ph chromosome and/or BCR/ABL presence were demonstrated by classical cytogenetic study or by molecular biology. Exclusion criteria were active concomitant neoplastic disorder, serum

2 creatinine superior to twice the upper limit of normal (ULN), serum bilirubin 41.5 ULN, unless resulting from liver involvement by blast cells, transaminases 42.5 ULN and heart disease score 42 according to the New York Heart Association grading. Pretreatment evaluation included history and physical examination, complete blood count with differential, and bone marrow aspiration for morphological, flow cytometry, molecular and cytogenetic studies. Performance status was determined according to the Eastern Cooperative Oncology Group (ECOG) rating system. Cardiac function was assessed by echocardiogram or radionuclide ventriculography before starting chemotherapy with anthracyclines Phase Days Treatment Prephase -7 to 0 Methylprednisolone : 40 mg/m 2 daily Intrathecal methotrexate :10 mg Induction 1-35 Vincristine : 1mg/m 2 d.1,8,15,22 Cyclophosphamide : 400 mg/m 2 d.1,8,15,22 Daunorubicin : 40 mg/m 2 d.1,8,15,22* Methylprednisolone : 60 mg/m 2 on alternate days d.1 to 22 Intrathecal methotrexate : 10mg, two times Consolidation/salvage Imatinib 600 mg daily Methylprednisolone:96 mg d. 49 to 52 and d. 79 to 82 Intrathecal methotrexate: 10 mg,two times Block mercaptopurine: 60 mg/m 2 d. 96 to 126 Cranial irradiation (18 Gray in 10 doses) from d. 96 Daunorubicin: 40mg/m 2 d. 127 ARA-C:60 mg/m 2 s.cut. d. 127 to 131 Asparaginase: 500U/Kg I.V. or s.cut d. 127 to 131 Block Imatinib 600 mg daily Methylprednisolone: 96 mg from day 169 to 172 and from day 197 to 200 Block ARA-C: 1 g/m 2 I.V.as 2-hour infusion BiD x 5 days from day 216 Mitoxantrone: 10 mg/m 2 I.V.on days 216 and 217 At recovery: 6-mercaptopurine 60 mg/m 2 daily Block Imatinib 600 mg daily Methylprednisolone: 96 mg d. 289 to 292 and d. 317 to 320 Block recovery** Block 6 Recovery- 395 Block recovery Block 8 Recovery- 455 Block recovery Block 10 Recovery- 730 Vincristine: 0.4 mg daily as continuous I.V. infusion d. 336 to 339 Doxorubicin: 9 mg/m 2 as continuous I.V. infusion d. 336 to 339 Methylprednisolone: 96 mg d. 336 to mercaptopurine: 60 mg/m 2 daily Methotrexate: 20mg/m 2 weekly (oral) Etoposide:200mg/m 2 d. 396 Cyclophosphamide: 1 g/m 2 d mercaptopurine: 60 mg/m 2 daily Methotrexate: 20mg/m 2 weekly (oral) Cyclophosphamide: 650 mg/m 2 d.456 ARA-C: 75mg/m 2 s.cut. d. 456 to 459 Thioguanine: 60 mg/m 2 d.457 to mercaptopurine: 60 mg/m 2 daily Methotrexate: 20mg/m 2 weekly (oral) * the last two doses of daunorubicin were omitted if less than 21% blast cells were present in the day 15 bone marrow aspiration. **Recovery to neutrophil count 1x10 9 /L and to platelet count 75x10 9 /L Figure 1 Flowchart of the study protocol. Patients with ALL are given a prephase with steroids during which their Ph status is determined. If found Ph þ, they proceed with an induction phase, consisting of chemotherapy. Irrespective of the response to induction, patients then proceed with a consolidation/salvage phase consisting of imatinib and steroids. Only patients in CR at that point are given blocks of maintenance chemotherapy. The total duration of treatment is 2 years.

3 1528 Treatment The flowchart of the study protocol is presented in Figure 1. After a prephase with steroids, during which the Ph status of ALL patients was determined, Ph þ ve patients were offered to enter the AFR09 study. The induction phase consisted of chemotherapy without imatinib. Irrespective of the response to induction, patients were then given a consolidation/salvage therapy based on imatinib 600 mg daily and steroids. Only patients in complete response (CR) after the consolidation/ salvage phase were offered to proceed with the 10 maintenance blocks, including two additional 2-month blocks of imatinib. Dose adaptation. In patients with non-hematological grade II toxicity, imatinib was stopped until regression to grade I toxicity. If grade II toxicity recurred, the dose of imatinib was reduced from 600 to 400 mg daily or to 300 mg daily in case of recurrence on 400 mg. In patients with grade III or IV toxicity, imatinib was withheld until regression to grade I toxicity and was then resumed at the dose of 400 mg daily or 300 mg if recurrence occurred while on 400 mg daily dose. Special rules for dose adaptation were recommended in case of liver toxicity. Imatinib had to be interrupted in patients with bilirubin 41.5 and o3 times ULN or with AST/ALT 42.5 and o5 times ULN if a 50% increase of bilirubin and/or AST/ALT concentration was observed on imatinib. At bilirubin or AST/ ALT normalization, imatinib could be resumed at the dose of 400 mg daily. Imatinib was also interrupted in patients with white blood cell (WBC) count lower than /l and/or platelet count less than /l, and was resumed at the dose of 400 mg (if recovery occurred within 2 weeks) or 300 mg (if recovery occurred later). In case of recurring hematological toxicity, imatinib dosage could be reduced to 300 mg daily. During maintenance, the dose of 6-mercaptopurine was adapted to the neutrophil and platelet counts, with half the dose being given when the neutrophil count was between 1 and /l and/or the platelet count was between 50 and /l. Below these thresholds, 6-mercaptopurine was temporarily withheld. Supportive therapy. Granulocyte colony-stimulating factor was administered during induction at the dose of 5 mg/kg daily from day 9 until granulocyte recovery to more than /l and was permitted during subsequent phases of therapy in patients with a neutrophil count lower than /l. Transplantation. Allogeneic stem cell transplantation was permitted in patients included in this study, although the investigators were encouraged to include patients fit for highdose therapy in the GRALL s young adult protocol. Assessment of treatment results Prephase was intended to determine steroid sensitivity of individual patients as defined by a blast cell count in the peripheral blood lower than /l after 7 days on steroids. Patients with less than blast cells/l before starting steroids were classified as undetermined with regard to steroid sensitivity. A bone marrow examination was performed at day 15 of induction therapy, after induction therapy, after the consolidation/salvage phase and later only if indicated. CR was defined according to the Cancer and Group B s (CALGB) criteria, that is, bone marrow with less than 5% blast cells, neutrophil count /l and platelet count /l for at least 30 days. However, the latter two requirements were not taken into account in patients whose blood counts were not sustained for 30 days owing to overt toxicity of the subsequent phase of treatment. In addition, the CALGB s bone marrow cellularity requirement (normo- or hypercellular bone marrow) was not mandatory to define CR. Toxicity was evaluated according to the National Cancer Institute Expanded Common Toxicity Criteria. Control group As a control group, we used a cohort of 21 elderly patients with Ph þ ALL treated according to our previous protocol LALAG97. 8 Briefly, these patients were given an induction regimen similar to the one used in the present study, except for the absence of a steroid prephase and for a random allocation to vindesine vs vincristine. Consolidation/salvage consisted of mitoxantrone and cytarabine (similar to maintenance block 3 of the present study). Thereafter, interferon alpha was given during 3 months as a single agent. A late consolidation with vincristine, doxorubicin and dexamethasone (similar to maintenance block 5 of the present study, except that dexamethasone 40 mg daily was used instead of methylprednisolone) was then started and, finally, maintenance with 6-mercaptopurine and methotrexate was given for 18 months. Statistics This is a non-randomized Phase II study. The major end point of the study was OS. The study was intended to accrue 30 patients in 2 years. We considered that a 1-year OS superior to 70% would be a strong argument in favor of the use of imatinib in this population, as in our previous studies the 1-year OS of elderly Ph þ patients was approximately 50% with an upper 95% confidence interval (CI) of 70%. Secondary end points for this study were the rate of CRs after induction and after consolidation, relapse-free survival (RFS), impact of steroid sensitivity on response and on survival, toxicity of imatinib and assessment of residual disease. The data were analyzed in February 2006, 14 months after the last patient was included. Proportions were compared with the use of the Fisher s exact test. The Mann Whitney U-test was used to compare continuous data. OS was calculated according to the method of Kaplan and Meier from the day of study entry to death of any cause or date last known alive, whereas RFS was calculated from the date of CR until relapse. 9 CI denotes 95% confidence interval. The log-rank test was used in order to compare survival data. The influence of continuous covariates on survival time was calculated using the proportional hazard regression analysis. Results Patient characteristics The main patient and control characteristics at diagnosis are shown in Table 1. Patients from both groups were similar with respect to major characteristics at diagnosis. However, patients from this study were older, and more female subjects were accrued in the control study. Full flow cytometry analysis on diagnostic bone marrow examination was available in 23 patients and was typical of B-cell lineage ALL with, in addition,

4 Table 1 Main characteristics of study and control patients 1529 Characteristic This study Control patients P-values n Male/female patients 16/14 4/ Median age and range 65.8 (58 78) 61.3 ( ) CNS involvement 1/30 0/21 1 Median WBC and range ( 10 9 /l) 15.5 ( ) 15 ( ) 0.3 WBC /l (%) ECOG performance status (0, 1, 2, 3) 8,17,4,1 3,10,6,2 0.1 a Hemoglobin o10 g/dl (%) Platelet count o /l (%) Albumin o3 g/dl (%) p190 bcr-abl /p210 bcr-abl 19/5 16/2 0.6 Abbreviations: CNS, central nervous system; WBC, white blood cell. a ECOG grade 0+1 vs 2+3. Table 2 Response to induction and salvage therapy This study Control patients P-values n F Induction therapy CR at completion of induction therapy 21 (70%) 6 (28.5%) Not evaluable for CR 1 a 0 F Death during induction therapy 2/30 0/ Alive with leukemia 6 15 F Salvage therapy Imatinib+steroids Additional chemotherapy CR at completion of salvage therapy 27 (90%) 10 b (48%) Death during salvage therapy Alive with leukemia 1 10 F Abbreviation: CR, complete response. a One patient was not assessable for CR because no bone marrow analysis was performed. b Twelve patients were offered salvage with chemotherapy. CD13, CD33 and CD117 expression in 10, four and two cases, respectively. Response to treatment Response to steroids. At diagnosis, 21 patients presented with more than blast cells/l in the peripheral blood and could, therefore, be assessed for corticosensitivity. Thirteen patients responded to corticotherapy (less than blast cells/l after treatment with steroids) and eight were resistant. Response to induction and consolidation therapy. Response to induction and consolidation/salvage therapy is shown in Table 2. One patient had no bone marrow study performed after induction and therefore could not be fully assessed for response. After completion of induction therapy, 21/29 (72%, CI: 53 87%) assessable patients were in CR and six were alive with leukemia. Two patients died during induction therapy, one from infection and one from sudden death. In the control group, 6/21 (29%, CI: 11 52%) patients were in CR (P ¼ 0.003) and 15 were alive with leukemia. After salvage therapy with imatinib, five additional patients obtained a CR. None died during that treatment phase. The patient who could not be assessed for response after induction therapy was in CR at completion of consolidation. In the control group, out of 12 patients offered salvage therapy after failing induction, four obtained a CR, whereas one died during salvage. Thus, salvage with imatinib and steroids proved successful in 5/6 patients, whereas salvage with chemotherapy in the control group was effective in 4/12 patients (P ¼ 0.1). Overall, 27/30 patients obtained a CR (90%, CI: 73 98%) vs 10/21 (48%, CI: 26 70%, P ¼ 0.001) in the control group. Survival. The survival analysis was performed after a 24-month median (range: 12 32) follow-up of surviving patients. At the time of analysis, 15 patients had died, one from sudden death, one from induction regimen-related toxicity, one with progressive disease after failing induction and salvage and 12 from progressive disease after relapse. OS of both study and control patients is presented in Figure 2. The 1-year OS was 66% (CI: 49 83%) vs 43% (CI: 24 62%) in the control group (P ¼ 0.004, log-rank test). The median survival of study patients was 23.2 vs 11.2 months in control patients. There was no impact of sex, age, performance status at diagnosis, WBC count, platelet count, hemoglobin concentration and of early response to chemotherapy (assessed by day 15 bone marrow study) on OS (data not shown). Relapse-free survival. After remaining in CR for a median of 10.6 months (range: 2 22), 16 patients relapsed, including one with a meningeal relapse. RFS is shown in Figure 3 and is significantly longer in the study group (median 20.1 vs 4.2 months, P ¼ , log-rank test).

5 1530 patients responsive to steroids (Figure 4, P ¼ 0.007, log-rank test), whereas RFS was not quite significantly affected by steroid sensitivity (P ¼ 0.06, data not shown). Figure 2 OS of control and study (AFR09) groups. Survival was significantly longer in the study group (P ¼ 0.004, log-rank test). Figure 3 RFS of control and study (AFR09) patients. RFS was significantly longer in the study group (P ¼ , log-rank test). Late relapses, however, are observed. Reasons for discontinuing treatment protocol. At the time of analysis, 21 patients had discontinued treatment according to the AFR09 protocol: three were not in CR after salvage (two early deaths and one failure), two were withdrawn from the study by their physician because of a raising level of residual disease and 16 had relapsed. There was no death in CR. A single patient was offered a stem cell transplant while in first complete remission. He relapsed 5 months later. Another patient relapsed after being left untreated during 2 months because of excessive toxicity (aspergillosis and long-lasting aplasia during consolidation with imatinib and methylprednisolone). Toxicity and adhesion to the treatment schedule. During induction therapy, a median duration of grade IV neutropenia (absolute neutrophil count o /l) of 17.5 days was observed (range: 1 32) vs 20.5 days (range: 7 64) in the control group (P ¼ 0.9). Grade III thrombocytopenia (platelet count o /l) lasted for 20 days (range: 0 41) vs 21.5 days (range: 2 46) in the control group (P ¼ 0.5). Twenty-five episodes of documented infection, including nine septicemias were reported. Grade III IV non-hematological toxicity was noted in nine patients during induction treatment, including venous thrombosis (two patients), pulmonary aspergillosis (two patients), cytomegalovirus pneumonia, hypofibrinogenemia, hemorrhage, severe mood disorder and acute renal failure, in one patient each. During consolidation, a pulmonary thromboembolism, a septicemia and a long-lasting neutropenia complicated by pulmonary aspergillosis were reported in one patient each. Data on compliance to imatinib dose are available for 26/28 patients. All but four received at least 90% of the full dose of imatinib. During maintenance, four additional episodes of septicemia were recorded, whereas severe polyneuropathy, cutaneous cancer, severe gastric hemorrhage, amyotrophy, unilateral blindness and cerebral ischemia were reported in one patient each. Figure 4 OS according to sensitivity to steroids. The survival of sensitive patients is longer (P ¼ 0.007, log-rank test). Note that patients with less than blast cells/l at diagnosis were not considered for assessing sensitivity to steroids. Predictive value of corticosensitivity. Out of 21 patients presenting at diagnosis with a blast cell count /l in peripheral blood, 13 were steroid-sensitive. In three patients, the response to induction therapy could not be determined (two early deaths and one with no bone marrow examination after induction). Out of 12 assessable corticosensitive patients, 10 obtained a CR after induction therapy, vs two out of six corticoresistant patients (P ¼ 0.1). OS was significantly longer in Discussion In this study, elderly patients with de novo Ph þ ALL were given induction treatment with chemotherapy followed by imatinib combined with steroids during three 2-month blocks. The imatinib blocks were administered 2 months apart, with the hope of minimizing the risk of inducing resistance to imatinib. Rotating courses of chemotherapy were given between and after the imatinib cycles. Comparison with our previous study of elderly Ph þ ALL patients strongly suggests that the prognosis of the disease was improved by the use of the present approach, in terms of both OS and RFS. Several factors may have contributed to an improved outcome. The CR rate in the present study was unexpectedly improved, compared to the previous study, while imatinib was introduced only after induction therapy. The induction regimen was identical in both protocols, except that in this study, all the patients were given a 7-day prephase with steroids, which may have contributed, to some extent, to an improved response rate, as suggested by a prompt clearance of blast cells in most patients after completion of the prephase. However, even if it

6 can be accepted that the addition of a prephase with steroids had an impact on the response rate, its magnitude remains unexpected. A better management of patients, including the systematic use of growth factors, may have reduced treatmentrelated toxicity but cannot account for an improved response rate. Imbalances between the patients characteristics in both studies are unlikely to have impacted on the response rates, as the two cohorts were well balanced with regard to major prognostic factors, such as WBC count, central nervous system invasion and performance status. The sex ratio was unbalanced with an excess of female patients in the control group (80.9 vs 46.6%). This is unlikely to have contributed to a better response to induction treatment in the study group, as female sex was never shown to be an adverse prognostic factor in the elderly with ALL. The present cohort was characterized by an older age compared with controls (median age, 65.8 vs 61.3 years), which, intuitively, could have worsened prognosis. However, within the population of elderly patients, an impact of age on survival has not been unequivocally demonstrated. Obviously, in such small cohorts, the possibility that chance accounted for some of the differences in favor of the present cohort cannot be overlooked. Yet, it should be mentioned that the CR rate (48%, CI: 26 70%) and median OS (11.2 months) observed in the control group are not unduly poor compared to those reported elsewhere in the elderly with Ph þ ALL. In the largest published cohort, a 71% CR rate (CI: 48 88%) in patients not given imatinib upfront and a 10.1 months median OS were observed in 21 old persons with Ph þ ALL. 3 In addition to an improved CR rate, an improved RFS was observed in this study, which points to a beneficial effect of post-induction therapy. Compared with our historical control and with previously reported studies in similar patients, the major alteration of post-induction therapy was the introduction of imatinib. The contribution of imatinib to an improved OS and RFS is in keeping with recent encouraging data from young adults with Ph þ ALL treated upfront with imatinib combined with various chemotherapy regimens and with preliminary data from older adults treated de novo with imatinib. 7,8,10,11 In Vignetti s study, two cohorts of patients are presented. In the first study, 22 patients in CR after induction chemotherapy were given maintenance with imatinib 800 mg daily. After a median follow-up of 20 months, 18 patients were still in CR with a 2-year disease-free probability of 79%. In the second study, 12 patients were treated upfront with imatinib and steroids. Eleven obtained a CR, with eight still in remission after a median follow-up of 7 months. 10 In Ottmann s study, 52 patients were randomly allocated to induction chemotherapy or to imatinib 600 mg daily. Consolidation treatment was identical in both arms of the study and consisted of chemotherapy associated with imatinib given continuously. Twenty-four of 25 patients given induction with imatinib achieved a CR vs 14/23 assigned to chemotherapy. After a median follow-up of 8 months, 17 patients were still in CR. 11 The prognostic impact of sensitivity to steroids has been assessed in younger adults by the Gruppo Italiano Malattie Ematologiche dell Adulto (GIMEMA) group and was shown to be correlated with OS. 12 In the present study, a similar prognostic value of steroid sensitivity on OS could be observed, although with the use of lower doses of steroids. Other classical predictors of survival in younger adults, such as the WBC count at diagnosis or age, failed to correlate with survival, although it cannot be excluded that the impact of many prognostic factors could have been obscured by the comparatively small size of this cohort. Minimal residual disease after induction or consolidation therapy was also repeatedly correlated with outcome in younger adults. 13,14 Although residual disease was measured using a quantitative real-time polymerase chain reaction procedure in the 10 laboratories involved in this study, the methodology was not standardized, which makes inter-patients comparisons questionable. Accordingly, this aspect of the study is not discussed here. Early deaths observed in this cohort were relatively few. However, morbidity was not negligible, mainly owing to infections during the first weeks of treatment. Although steroids could have improved the response rate to induction therapy, their contribution to early infections, including mycotic infections, cannot be ruled out. No unexpected toxicity was recorded during exposure to imatinib while 90% of patients received at least 90% of the scheduled dose of imatinib. Although this study is encouraging, the long-term fate of patients treated according to this protocol is unknown. Clearly, there is room for substantial improvement in the field of Ph þ ALL in the elderly. The optimal dose of imatinib, the proper duration of treatment, the value of chemotherapy given in addition to imatinib, the contribution of new tyrosine kinase inhibitors and the place, if any, of stem cell transplantation still remain to be determined. From the experience accumulating in younger patients, it seems reasonable to consider treating elderly patients upfront with imatinib combined or not with a relatively non-toxic chemotherapy. Post-induction therapy with intermittent imatimib alternated with chemotherapy or with continuous imatinib and chemotherapy or with continuous imatinib with no additional chemotherapy does not prevent relapses to occur, even if all these approaches clearly improved the outcome of elderly patients with Ph þ ALL. Finally, the use of new tyrosine kinase inhibitors during induction and postinduction therapy should be considered with the hope that the favorable pharmacological profile of these new agents will translate into improved clinical outcome. Acknowledgements Novartis France and Belgium generously provided imatinib for this study. The Hospices Civils de Lyon endorsed the administrative burden of the legal promotion of this study. References 1 Dombret H, Gabert J, Boiron JM, Rigal-Huguet F, Blaise D, Thomas X et al. Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukaemia: results of the prospective multicenter LALA-94 trial. 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