ALBERT

Description: Abstract 18 Introduction: Long-term survival in pediatric relapsed AML is only 20-30%. Optimal reinduction therapy is unknown, and there is a concern about cardiotoxicity with repeated anthracycline use at relapse. Preclinical in vitro and animal studies, and limited clinical data suggest that liposomal daunorubicin (DaunoXome®, DNX) is less cardiotoxic. These considerations lead to a phase III study, in the setting of the International BFM Study Group. Materials and methods: FLAG was randomised against FLAG/DNX in the 1st reinduction course. The conventional 5-days FLAG only was recommended as the 2nd course. DNX was dosed at 60 mg/m2/day on days 1, 3 and 5. After induction, allogeneic stem cell transplantation was generally recommended, but time-to-transplant could be bridged by high- or low-intensive consolidation therapy. Primary endpoint of the study was early treatment response, based on bone marrow examination shortly before reinduction course 2, and defined as either good (≤20% leukemic blasts) or poor (〉20% leukemic blasts). This endpoint was chosen because of its prognostic value in earlier relapsed AML BFM-trials, and because compliance with an extended protocol guideline was likely to be suboptimal within the context of a highly multinational and multicenter AML Relapse protocol. However, secondary endpoints were defined, including the CR2 rate determined after 2 courses, long-term survival, and toxicity. Patients with AML M3 and those 〉18 years of age at initial diagnosis were ineligible. The study opened in most countries in 2002/2003. The study closed for accrual on April 1, 2009 when the required 360 fully eligible and evaluable patients had been randomized. Early and late relapsed AML was defined as a relapse within or after 1 year from initial diagnosis, but this only influenced treatment in that early relapsed AML patients were eligible for haploidentical SCT, while late relapsed AML patients were eligible for autologous SCT, if a matched or partly mismatched transplant was not possible. Thirteen groups from 20 countries and 〉100 centers have enrolled patients, with informed consent and after approval of the study by regulatory authorities. Data are presented according to intention-to-treat, with a median follow-up of 2.7 years for patients at risk. Results: Overall 4-year probability of survival (pOS) was 35% SE 2%, the overall CR2 rate 62%. The good early responders had a 4-year pOS of 45% SE 3% versus 10% SE 3% for poor responders (p

Description: Survival of pediatric relapsed AML is 20–30%. An important prognostic factor at relapse is duration of CR1, but the relevance of early treatment response at relapse has not been reported and is the subject of this report. In 2001 we initiated a prospective study for pediatric relapsed AML, excluding AML M3. FLAG is being used for 2 consecutive courses. Liposomal daunorubicin (DNX) as a potentially less cardiotoxic anthracycline was added or not in a 1:1 randomised fashion to the first course of FLAG. Efficacy data for both study arms are still blinded as the study is ongoing until early 2008. More than 500 patients from 13 groups worldwide were registered by April 2007. This analysis was confined to the 324 patients who are eligible, fully evaluable and relapsed before 1 January 2007, and of whom day 15 (from start of chemotherapy) and/or day “28” (obtained between days 28 and 42 from start of the 1st course) bone marrow (BM) examinations are evaluable. Day 15 BM findings did not affect therapy, while more than 20% blasts on day “28” means the patient is off-protocol and eligible for more experimental therapy or no further treatment. Fifty-three percent of evaluable patients relapsed early (within one year from diagnosis). Absolute blast counts between day 15 and day “28” correlated significantly, but not very strongly (Rho 0.57, P

Description: Introduction Acute lymphoblastic leukemia (ALL) in infants under 1 year of age is rare and has a poor outcome compared to ALL in older children. It is characterized by a high expression of MLL gene rearrangements, high tumor load and myeloid features. In 1999, a large collaborative international study, Interfant-99, was initiated with the aims to determine: (1) the outcome of a new treatment protocol including ALL and AML elements; (2) in a randomised way the value of a late intensification course with high dose araC and methotrexate; (3) which clinical and biological factors have independent prognostic value within infant ALL. Event-free survival (EFS) and overall survival (OS) were primary endpoints and analysed on an intention to treat basis. Results 17 study groups representing 〉20 countries enrolled 482 patients leading to by far the largest trial ever reported in infant ALL. 79% of cases had an MLL rearrangement. Of these, 53% was t(4;11), 20% t(11;19), 11% t(9;11) and 16% had other MLL partner fusion genes. Death in induction rate was 3.8% and 2.3% did not achieve CR at the end of induction, so CR rate was 94%. Death rate in CCR was 5.2%. Relapses occurred in 36% of cases and were mainly isolated bone marrow relapse. Median time from 1st CR to relapse was 8 months. The overall 4-year EFS is 47% and OS is 55%. This is at least comparable to the best historical controls and better than most of those of the participating study groups. Especially outcome of high-risk patients, defined by poor response to one week prednisone, had improved. The late intensification course with HD-araC and HD-MTX did not improve outcome. Cox model showed that MLL rearrangement and age 300x10e9/L and poor prednisone response were also of independent prognostic value. The outcome was not depending on the type of MLL rearrangement. Conclusions Results of this first international treatment protocol for infant ALL are very satisfactory. Early bone marrow relapse remains the major cause of treatment failure indicating that early treatment intensification is necessary. The large international collaboration has enabled the start of studies to improve outcome for infant ALL. The new Interfant-06 study will stratify the patients based upon MLL status, age and WBC and will study the value of the use of two early "AML" courses in a randomised way.

Description: Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20%. Aiming at improved outcome, we initiated a prospective, randomised study for relapsed AML, excluding AML M3 and those 〉18 years of age at initial diagnosis. FLAG is being used for 2 consecutive courses: fludarabine 30 mg/m2/day x 5, cytarabine 2 g/m2/day x 5, G-CSF 200 μg/m2/dose for 6 days, starting day -1. Liposomal daunorubicin (DaunoXome, DNX) is a new anthracycline with potentially less cardiotoxicity. Therefore, DNX at 60 mg/m2/day on days 1, 3 and 5 was randomly added or not to the first course of FLAG. Main objectives are to determine the efficacy and toxicity of DNX when added to FLAG, and the long-term outcome in a large group of relapsed AML patients. Thirteen groups worldwide are enrolling patients. More than 400 patients were registered by March 2006. This planned 2nd interim analysis with blinded efficacy data concerns 322 eligible and evaluable patients with first relapsed AML, of whom 250 (78%) were actually randomised. Fifty-two percent of patients relapsed early (20% of blasts in the BM shortly before the 2nd course), was seen in 23% of patients, more often in early relapses (31%) than in late relapses (15%). Early death occurred in 6% of patients. Complete remission (CR) was achieved in 63% of patients after 2 courses, and they have a probability of survival at 3 years (3-yr pSurv.) of 47% compared to 33% for the total group and 8% for patients not achieving CR. Compared to early relapses, patients with late relapse had higher CR rates (76 vs 51%), and higher 3-yr pSurv.: 42% vs 23%. Similarly, patients with either t(8;21) or inv(16) had a significantly better outcome. Death in continuous CR occurred in 8.6% of 322 patients, without excess of deaths in one treatment arm. Nearly all patients in CR have been transplanted, the majority with a matched unrelated donor. There was significant grade III/IV toxicity, but no unexpected toxicity, and no clinically relevant differences between the arms with and without DNX, especially not in cardiotoxicity. In conclusion, it is feasible to perform a large randomised pediatric study in a very international setting. DNX added to FLAG does not result in major additional toxicity, but follow-up of cardiotoxicity should be extended as planned in this protocol. Late relapses do better in terms of CR and overall survival, as well as patients with t(8;21) or inv(16), but early relapses achieving CR have a realistic chance of survival as well with currently 23% of them in continuous CR. The study is ongoing until 360 eligible and fully evaluable patients have been randomised, to answer the question whether liposomal daunorubicin improves outcome in pediatric relapsed AML.

Description: The aim of this study was to find out whether the time required for disappearance of peripheral blast cells, or blast clearance, could be used to identify patients with a slow response to treatment associated with a poor prognosis of acute lymphoblastic leukemia (ALL). Our series consisted of 158 children with newly diagnosed ALL. The mean follow-up time was 69 months (range 22 to 140 months). Blast clearance was significantly associated with length of event-free survival. Only two of nine children with blast clearance greater than or equal to 2 weeks and 4 of 11 children with blast clearance of 11 to 13 days were in remission at the time of analysis as compared with 86 of 138 of the children with more rapid blast clearance. The respective 5-year event- free survivals were 17%, 36%, and 60% (P = .003). Multivariate analysis showed that the relative risk of death or relapse in patients with blast clearance of greater than 10 days was 5.2-fold (95% confidence limits 2.1 to 13.1) as compared with the others (P less than .001). Our results indicate that patients with a slow response to treatment can be identified by simple differential peripheral cell counts during the early induction phase well before or even instead of performance of a more invasive bone marrow aspiration.

Description: The aim of this study was to find out whether the time required for disappearance of peripheral blast cells, or blast clearance, could be used to identify patients with a slow response to treatment associated with a poor prognosis of acute lymphoblastic leukemia (ALL). Our series consisted of 158 children with newly diagnosed ALL. The mean follow-up time was 69 months (range 22 to 140 months). Blast clearance was significantly associated with length of event-free survival. Only two of nine children with blast clearance greater than or equal to 2 weeks and 4 of 11 children with blast clearance of 11 to 13 days were in remission at the time of analysis as compared with 86 of 138 of the children with more rapid blast clearance. The respective 5-year event- free survivals were 17%, 36%, and 60% (P = .003). Multivariate analysis showed that the relative risk of death or relapse in patients with blast clearance of greater than 10 days was 5.2-fold (95% confidence limits 2.1 to 13.1) as compared with the others (P less than .001). Our results indicate that patients with a slow response to treatment can be identified by simple differential peripheral cell counts during the early induction phase well before or even instead of performance of a more invasive bone marrow aspiration.

Description: The duration of the first complete remission is an accepted prognostic factor in pediatric relapsed AML, but a detailed analysis of the time to relapse: very early (24 mo from diagnosis) is lacking. This was therefore studied in patients who were enrolled in study Relapsed AML 2001/01. This prospective, randomised study for pediatric relapsed AML, excluding AML M3 and those 〉18 years of age at initial diagnosis, opened in most countries in 2002/2003. FLAG is given for 2 consecutive courses: fludarabine 30 mg/m2/day × 5 days, cytarabine 2 g/m2/day × 5 days, G-CSF 200 μg/m2/dose × 6 days, starting day −1. Liposomal daunorubicin (DaunoXome®, DNX; a new anthracycline with potentially less cardiotoxicity), at 60 mg/m2/day on days 1, 3 and 5 is added or not in a 1:1 randomised fashion to the first course of FLAG. After two courses, patients are eligible for allogeneic stem cell transplantation (allo-SCT), sometimes bridged by high-or low- intensity consolidation chemotherapy. Efficacy data for both arms are still blinded as the study remains open until late 2008. Early treatment response is defined as good in patients with ≤20% blasts in bone marrow (BM) at “day 28” (taken shortly before the start of the 2nd reinduction course), and as poor in patients with 〉20% BM blasts at day 28. Complete remission is determined after 2 reinduction courses using conventional criteria. Thirteen groups worldwide are enrolling patients. More than 500 patients were registered by April 2008, but this analysis relates to 427 eligible and fully evaluable patients diagnosed before 1 July 2007, also excluding patients who had not achieved documented first CR with initial firstline treatment. The majority of patients in study Relapsed AML 2001/01 progressed to an allo-SCT, with the exception of the subgroup of very early relapsed patients, many of whom had an early death and progressive disease which precluded allo-SCT. A total of 34 patients relapsed very early, 173 early, 162 late and 58 very late. So-called favourable cytogenetics, i.e. t(8;21) or inv(16), are found in all subgroups, but more frequently in the late/very late relapses. The table shows the outcome by time to relapse and treatment response. There is a significant trend (p

Description: Relapse occurs in 30–40% of newly diagnosed AML patients, with long-term survival in 20% of them. We initiated a study for relapsed AML excluding AML M3 and those 〉18 years of age. As backbone, FLAG is being used for 2 consecutive courses: fludarabine 30 mg/m2/day x 5, cytarabine 2 g/m2/day x 5, G-CSF 200 μg/m2/dose for 6 days, starting day −1. Liposomal daunorubicin (DaunoXome®, DNX) is a “new” anthracycline with potentially less cardiotoxicity, applicable in the total group of patients, and with the perspective to be useful at initial treatment as well. Therefore, DNX at 60 mg/m2/day on days 1, 3 and 5 was added or not in a 1:1 randomised fashion to the first course of FLAG. The ongoing prospective study must determine the efficacy and toxicity of DNX when added to FLAG, and the long-term outcome in a large group of relapsed AML patients. 13 groups worldwide are enrolling patients. 303 patients were registered as per April 2005. This planned interim analysis with blinded efficacy data concerns 226 eligible and evaluable patients with first relapsed AML, 140 (62%) being male. Median age at relapse was 9.7 (range, 0.7–18) years. 50% of patients relapsed within 1 year from initial diagnosis. The majority concerned isolated bone marrow relapse (85%), with 1% isolated and 5% combined central nervous system involvement. Median WBC at relapse was 4.0 (range, 0.4–293) x 109/l. Dominating FAB types are M2 with auer rods, M4 without eosinophils and M5. The randomisation was actually performed in 81% of patients. A total of 63% of patients was transplanted, the majority with a matched unrelated donor. Poor response to the 1st course of therapy (〉20% of blasts in the BM shortly before the 2nd course), was seen in 23% of patients. Early death occurred in 6% of patients. Complete remission (CR) was achieved in 62% of patients, and they have a probability of survival at 2 years (2-yr pSurv.) of 47±6% (compared to 33±5% for the total group), 38±9% for early relapses and 54±7% for late relapses. Patients not achieving CR had a 2-yr pSurv. of 5±4%. Compared to early relapses, patients with late relapse had higher CR rates (74 vs 51%), and higher 2-yr pSurv.: 42±6% vs 21±5%. There was significant grade III/IV toxicity, but no unexpected toxicity, and no clinically relevant differences between the arms with and without DNX, especially not in cardiotoxicity. In conclusion, it is feasible to perform a large randomised study in a very international setting. DNX added to FLAG does not result in major additional toxicity, but follow-up of cardiotoxicity should be extended as planned in this protocol. Late relapses do better in terms of CR and overall survival, but early relapses achieving CR have a realistic chance of survival as well. The study is ongoing until 360 patients have been randomised, to answer the question whether liposomal daunorubicin improves outcome in pediatric relapsed AML. Meanwhile, overall outcome is encouraging, with CR achieved in 62% of patients of whom 47% are survivors at 2 years.

Description: Relapse remains the commonest adverse event in newly diagnosed AML patients, and the reported long-term survival after relapse in pediatric AML is 20–30%. Allogeneic stem cell transplantation (allo-SCT) in CR1 is employed by several groups with the aim of reducing the relapse rate. There is a widely held view that patients with AML who relapse after an allo-SCT in CR1 have no or minimal chances of long-term survival. However, such a cohort has never been described in the literature. Therefore, the outcome of children with AML who received an allo-SCT in CR1 and who subsequently relapsed and were enrolled in study Relapsed AML 2001/01 is described. This is a prospective, randomised study for relapsed AML, excluding AML M3 and those 〉18 years of age at initial diagnosis comparing FLAG with Daunoxome-FLAG. FLAG is given for 2 consecutive courses: fludarabine 30 mg/m2/day × 5 days, cytarabine 2 g/m2/day × 5 days, G-CSF 200 μg/m2/dose × 6 days, starting day −1. Liposomal daunorubicin (DaunoXome®, DNX; a new anthracycline with potentially less cardiotoxicity) at 60 mg/m2/day on days 1, 3 and 5 is added or not in a 1:1 randomised fashion to the first course of FLAG. After two courses, patients are eligible for allo-SCT, sometimes bridged by high-or low-intensity consolidation chemotherapy. Efficacy data for both arms are still blinded as the study remains open until the end of 2008. Thirteen groups worldwide are enrolling patients. More than 500 patients were registered by April 2008, but this analysis relates to 329 fully evaluable patients diagnosed before July 2007, who are known to have or have not received an allo-SCT in CR1. Reasons for allo-SCT in CR1 differ between groups, but in general it is reserved for higher-risk patients and predominantly those with a matched-sibling donor. As part of relapsed treatment, 214 patients underwent allo-SCT to consolidate second line therapy, and for 11 patients this was their second allo-transplant. Twenty-two (7%) of these 329 patients had undergone allo-SCT in CR1, 12 boys and 10 girls, the majority being between 1 and 10 years of age. Three out of these 22 patients had a favorable karyotype, i.e. inv(16) or t(8;21). The majority of these patients (17/22, 77%) had a late relapse (occurring at least one year from initial diagnosis) compared to 47% of relapsed AML patients who had not received an allo-SCT in CR1 (p=0.01). There was no significant difference in chemotherapy related morbidity or mortality between those children who had received an allo-SCT in CR1 and those who had not, including cardiotoxicity. The percentage of so-called poor early responders (more than 20% bone marrow blasts on day “28” sampled shortly before the 2nd reinduction course) was 24% versus 23% (n.s.) and the CR2 rate 45% versus 65% (p=0.09) in the yes and no allo-SCT in CR1 patients, respectively. Within late relapsed AML only, the rate of poor early responders was 23% versus 15% (n.s.) and the CR2 rate 50% versus 77% (p=0.03) in the yes and no allo-SCT in CR1 patients, respectively. Finally, 4-year probability of survival from relapsed AML was 27% (95%-C.I. 8–47%) in the “yes allo-SCT in CR1” subgroup compared to 33% (27–39%) in the remaining patients (n.s.). Limiting this analysis to late relapsed AML patients, it was 29% (6–53%) versus 45% (36–54), respectively (n.s.). Five of the 6 patients who survived after allo-SCT in CR1 (median follow up 2 years) received a second allo-SCT. In conclusion, the small number of trial patients who relapsed early and who had received an allo-SCT in CR1 suggests that clinicians may have been reluctant to enter these patients into trial. In general, patients with an early relapse of AML treated in this study have a reasonable chance of cure (Kaspers et al., ASH 2007 and 2008), but the very small number of such patients who had an allo-SCT in CR1 preclude any firm conclusions for that subgroup. Patients with a late relapse who have received an allo-SCT in CR1 appear to have a somewhat (but statistically not significant) inferior outcome compared to patients who were not transplanted in CR1. The probability of survival at 4 years from relapse of nearly 30% warrants the use of second line therapy in patients with a late relapse despite allo-SCT in CR1.