Outcome in 146 patients with paediatric acute myeloid leukaemia treated according to the AML99 protocol in the period 2003–06 from the Japan Association of Childhood Leukaemia Study

The acute myeloid leukaemia (AML) 99 trial conducted previously in Japan for the treatment of de novo paediatric AML showed excellent results, with a 5‐year overall survival (OS) and event‐free survival (EFS) of 75·6% and 61·6%, respectively. To examine reproducibility of these results in another cohort, the outcome of 146 newly diagnosed AML paediatric patients prospectively registered in the Japan Association of Childhood Leukaemia Study (JACLS) from 2003 to 2006 was compared to that of 240 patients in the original AML 99 clinical trial. The 5‐year EFS and OS achieved in the new cohort was 66·7 ± 4·0% and 77·7 ± 8·0% respectively, which were comparable to those obtained in the original AML 99 clinical trial, although less frequent core‐binding factor (CBF) AML (29·5% vs. 37%) and an almost equal frequency of allogeneic haematopoietic stem cell transplantation (allo‐HSCT) during first complete remission (16·5% vs. 19%) were observed. The 5‐year EFS in patients with a normal karyotype (NK) (n = 35, 54·9 ± 15·1%) was inferior in the present cohort when compared to the original AML99 trial. This study confirmed the excellent outcome of the original AML99 protocol.     

Improved outcome for children with non‐high risk acute lymphoblastic leukaemia after using an ALL IC‐BFM 2002‐based protocol in Shanghai,China

We report the outcome of 92 non‐high risk children with acute lymphoblastic leukaemia (ALL) following a Berlin‐Frankfürt‐Münster (BFM) Intercontinental ALL ‐based protocol. Compared with a matched historical control group, we found a lower incidence of treatment‐related early death (1·2% vs. 10·9%, P = 0·015), a higher 6‐year event‐free survival (75·4 ± 4·9% vs. 58·2 ± 6·7%, P = 0·02), reduced total in‐hospital costs per person (US $) (10267·0 vs. 18331·0, P < 0·001) and fewer total in‐hospital days (164 vs. 296, P < 0·001). This ALL‐BFM based protocol was quite tolerable in our institution and will be extended to high‐risk patients.     

Treatment outcome of CRLF2 -rearranged childhood acute lymphoblastic leukaemia: a comparative analysis of the AIEOP-BFM and UK NCRI-CCLG study groups

The prognostic relevance of CRLF2 ‐rearrangements in childhood acute B‐cell precursor lymphoblastic leukaemia (ALL), was assessed by a comparative analysis of 114 non‐Down‐syndrome patients (99 P2RY8‐CRLF2+ , 15 IGH@‐CRLF2+ ), 76 from the AIEOP‐BFM ALL 2000 and 38 from the MRC ALL97 trials. The 6‐year cumulative relapse incidence of P2RY8‐CRLF2+ patients treated on the two trials was not statistically different: 0·37 ± 0·06 vs. 0·25 ± 0·08 (P = 0·194). In contrast, 0/9 IGH@‐CRLF2+ AIEOP‐BFM, but 5/6 ALL97 patients relapsed. Conclusively, P2RY8‐CRLF2+ patients had an intermediate protocol‐independent outcome while the different prognosis of IGH@‐CRLF2+ patients could be related to the different structures of the applied treatment protocols.     

RUNX3 promoter hypermethylation is frequent in leukaemia cell lines and associated with acute myeloid leukaemia inv(16) subtype

Correlative and functional studies support the involvement of the RUNX gene family in haematological malignancies. To elucidate the role of epigenetics in RUNX inactivation, we evaluated promoter DNA methylation of RUNX1, 2, and 3 in 23 leukaemia cell lines and samples from acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) and myelodysplatic syndromes (MDS) patients. RUNX1 and RUNX2 gene promoters were mostly unmethylated in cell lines and clinical samples. Hypermethylation of RUNX3 was frequent among cell lines (74%) and highly variable among patient samples, with clear association to cytogenetic status. High frequency of RUNX3 hypermethylation (85% of the 20 studied cases) was found in AML patients with inv(16)(p13.1q22) compared to other AML subtypes (31% of the other 49 cases). RUNX3 hypermethylation was also frequent in ALL (100% of the six cases) but low in MDS (21%). In support of a functional role, hypermethylation of RUNX3 was correlated with low levels of protein, and treatment of cell lines with the DNA demethylating agent, decitabine, resulted in mRNA re‐expression. Furthermore, relapse‐free survival of non‐inv(16)(p13.1q22) AML patients without RUNX3 methylation was significantly better (P = 0·016) than that of methylated cases. These results suggest that RUNX3 silencing is an important event in inv(16)(p13.1q22) leukaemias.     

Persistent MRD before and after allogeneic BMT predicts relapse in children with acute lymphoblastic leukaemia

Minimal residual disease (MRD) during early chemotherapy is a powerful predictor of relapse in acute lymphoblastic leukaemia (ALL) and is used in children to determine eligibility for allogeneic haematopoietic stem cell transplantation (HSCT) in first (CR1) or later complete remission (CR2/CR3). Variables affecting HSCT outcome were analysed in 81 children from the ANZCHOG ALL8 trial. The major cause of treatment failure was relapse, with a cumulative incidence of relapse at 5 years (CIR) of 32% and treatment‐related mortality of 8%. Leukaemia‐free survival (LFS) and overall survival (OS) were similar for HSCT in CR1 (LFS 62%, OS 83%, n = 41) or CR2/CR3 (LFS 60%, OS 72%, n = 40). Patients achieving bone marrow MRD negativity pre‐HSCT had better outcomes (LFS 83%, OS 92%) than those with persistent MRD pre‐HSCT (LFS 41%, OS 64%, P < 0·0001) or post‐HSCT (LFS 35%, OS 55%, P < 0·0001). Patients with B‐other ALL had more relapses (CIR 50%, LFS 41%) than T‐ALL and the main precursor‐B subtypes including BCR‐ABL1, KMT2A (MLL), ETV6‐RUNX1 (TEL‐AML1) and hyperdiploidy >50. A Cox multivariate regression model for LFS retained both B‐other ALL subtype (hazard ratio 4·1, P = 0·0062) and MRD persistence post‐HSCT (hazard ratio 3·9, P = 0·0070) as independent adverse prognostic variables. Persistent MRD could be used to direct post‐HSCT therapy.     

Prognostic relevance of dic(9;20)(p11;q13) in childhood B‐cell precursor acute lymphoblastic leukaemia treated with Berlin‐Frankfurt‐Münster (BFM) protocols containing an intensive induction and post‐induction consolidation therapy

The presence of a dicentric chromosome dic(9;20) has been reported to have an unfavourable prognosis in children with B‐cell precursor acute lymphoblastic leukaemia (BCP‐ALL). As outcome may be influenced by type and composition of treatment, we analyzed 19 BCP‐ALL patients with dic(9;20) who have been treated with ALL‐BFM (Berlin‐Frankfurt‐Münster) protocols that included a 4‐drug induction and subsequent consolidation therapy. All patients were good responders to prednisone and in complete remission after induction therapy. Eight patients had no molecular disease after induction and another eight patients had levels ≤10^?4 after consolidation therapy. After a median follow‐up of 3·4 years, probabilities of 5‐year event‐free and overall survival were 75 ± 11% and 94 ± 6%, respectively. Of note, there was a tendency for extramedullary disease in case of relapse (two of three relapses with central nervous system involvement). In conclusion, in the context of ALL‐BFM protocols dic(9;20)‐positivity appeared to have a favourable prognosis, which could be due to a dose‐ and time‐intensified induction and induction consolidation therapy. Given that in vitro studies have shown high cellular sensitivity of dic(9;20)‐positive leukemic blasts to l ‐asparaginase and cytarabine, it is reasonable to speculate that both drugs, as given early during BFM‐like induction and consolidation therapy, may have contributed to this good outcome.     

Disseminated lymphoblastic lymphoma in children and adolescents: results of the COG A5971 trial: a report from the Children's Oncology Group

The Children's Oncology Group's A5971 trial examined central nervous system (CNS) prophylaxis and early intensification in paediatric patients diagnosed with CNS‐negative Stage III and IV lymphoblastic lymphoma. Using a 2 × 2 factorial design, the study randomized patients to Children's Cancer Group (CCG) modified Berlin‐Frankfurt‐Muenster (BFM) acute lymphoblastic leukaemia (ALL) regimen with intensified intrathecal (IT) methotrexate (MTX) (Arm A1) or an adapted non‐Hodgkin lymphoma/BFM‐95 therapy with high dose MTX in interim maintenance but no IT‐MTX in maintenance (Arm B1) . Each cohort was randomized ± intensification (cyclophosphamide/anthracycline) (Arms A2/B2). For the 254 randomized patients, there was no difference in 5‐year event‐free survival (EFS) for the four arms: Arm A1 , 80% [95% confidence interval (CI) 67–89%] and Arm A2 , 81% (95% CI 69–89%); Arm B1 , 80% (95% CI 68–88%) and Arm B2 , 84% (95% CI 72–91%). The cumulative incidence of CNS relapse was 1·2%. Age <10 years and institutional imaging response at 2 weeks was associated with improved outcomes (P < 0·001 and P = 0·014 for overall survival). CNS positive patients (n = 12) did poorly [5‐year EFS of 63% (95% CI 29–85%)]. For CNS‐negative patients, there was no difference in outcome based on CNS prophylaxis (IT‐MTX versus HD‐MTX) or with intensification.     

research paper: Differential expression of HDAC3, HDAC7 and HDAC9 is associated with prognosis and survival in childhood acute lymphoblastic leukaemia

Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment, including haematological malignancies. We evaluated the mRNA gene expression profile of 12 HDAC genes by quantitative real‐time polymerase chain reaction in 94 consecutive childhood acute lymphoblastic leukaemia (ALL) samples and its association with clinical/biological features and survival. ALL samples showed higher expression levels of HDAC2, HDAC3, HDAC8, HDAC6 and HDAC7 when compared to normal bone marrow samples. HDAC1 and HDAC4 showed high expression in T‐ALL and HDAC5 was highly expressed in B‐lineage ALL. Higher than median expression levels of HDAC3 were associated with a significantly lower 5‐year event‐free survival (EFS) in the overall group of patients (P = 0·03) and in T‐ALL patients (P = 0·01). HDAC7 and HADC9 expression levels higher than median were associated with a lower 5‐year EFS in the overall group (P = 0·04 and P = 0·003, respectively) and in B‐lineage CD10‐positive patients (P = 0·009 and P = 0·005, respectively). Our data suggest that higher expression of HDAC7 and HDAC9 is associated with poor prognosis in childhood ALL and could be promising therapeutic targets for the treatment of refractory childhood ALL.     

Outcome of children with acute myeloid leukaemia (AML) experiencing primary induction failure in the AIEOP AML 2002/01 clinical trial

Paediatric patients with acute myeloid leukaemia (AML) who fail induction due to primary resistance to chemotherapy account for a significant proportion of cases and have a particularly dismal prognosis. We report the clinical and biological data, and final outcome of 48 paediatric patients with primary‐resistant AML enrolled in the Associazione Italiana di Ematologia e Oncologia Pediatrica AML 2002/01 clinical trial. These patients had a significantly higher white blood cell count at diagnosis compared to other AML patients. Cytogenetic and molecular features did not differ between patients with primary induction failure and patients allocated to the high‐risk group. For the whole patient population, the probability of overall survival, event‐free survival (EFS) and disease‐free survival (DFS) was 21·8% ± 6·2, 20·4% ± 5·9, and 49·5% ± 11·3, respectively. Twenty‐eight (58%) patients received haematopoietic stem cell transplantation (HSCT); 3 were autologous and 25 were allogeneic. Patients who underwent HSCT had improved EFS (31·2% vs. 5%, P < 0·0001). Only one of the 20 patients who did not receive HSCT is alive and disease free. The 19 patients in complete remission at time of HSCT showed significantly better DFS than the 9 with active disease (46% vs. 0%, P = 0·02). This study represents one of the largest series with long‐term follow up of paediatric AML patients with primary refractory disease. Children who underwent transplantation had an encouraging long‐term outcome. Disease recurrence remains the major cause of treatment failure; a better understanding of the disease biology is desirable to develop more effective treatment strategies.     

The inferior prognosis of adolescents with acute lymphoblastic leukaemia (ALL) is caused by a higher rate of treatment‐related mortality and not an increased relapse rate – a population‐based analysis of 25 years of the Austrian ALL‐BFM (Berlin‐Frankfurt‐Münster) Study Group

Adolescents aged 15–18 years with acute lymphoblastic leukaemia (ALL) have been historically reported to have a poorer prognosis than younger children. We retrospectively analysed the characteristics and outcome of 67 adolescents included in a population‐based series of 1125 non‐infant cases that were enrolled into four Austrian ALL‐BFM (Berlin‐Frankfurt‐Münster) multicentre trials at paediatric institutions within a 25‐year period. Five‐year event‐free survival (EFS) and overall survival (OS) were 66 ± 6% and 76 ± 5% respectively, and thus lower than in younger children (83 ± 1%, 91 ± 1%; P < 0·001). This was not due to an increased cumulative incidence of relapse (CIR) (5‐year CIR: 19 ± 5% vs. 13 ± 1%; P = 0·284), but due to an increased incidence of treatment‐related death [5‐year cumulative incidence of death (CID): 15 ± 4% vs. 3 ± 0%; P < 0·001] as a first event. Furthermore, while 44/67 (66%) non‐high‐risk adolescents had favourable 5‐year EFS and OS rates (76 ± 7%, 89 ± 5%), 18/67 (27%) high‐risk adolescents had an inferior outcome (5‐year EFS: 56 ± 12%, OS 61 ± 11%, P < 0·05). Among the latter patients the CID was significantly higher than in younger high‐risk children (22 ± 10% vs. 6 ± 2%; P = 0·020). Given that adolescent age is an independent risk factor for death as a first event, this specific age group may need particular vigilance when receiving intense BFM‐type chemotherapy, as relapse‐free survival is similar to younger children.     

Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO‐AML 2004 study

Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato‐Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event‐free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0·1% RD cut‐off level. RD‐negative and ‐positive patients after first induction showed a 5‐year EFS of 65 ± 7% and 22 ± 7%, respectively (P < 0·001) and an OS of 77 ± 6% (P = 0·025) and 51 ± 8%. RD‐negative and ‐positive patients at start of consolidation therapy had a 5‐year EFS of 57 ± 7% and 11 ± 7%, respectively (P < 0·001) and an OS of 78 ± 6% and 28 ± 11%) (P < 0·001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR):5·0; 95% confidence interval (CI):1·9–13·3] and OS (HR:7·0; 95%CI:2·0–24·5). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.     

Favourable outcome of patients with childhood acute promyelocytic leukaemia after treatment with reduced cumulative anthracycline doses

Acute promyelocytic leukaemia (APL) treatment often includes high cumulative doses of anthracyclines, which can cause long‐term cardiotoxicity. Here, we report the favourable outcome in 81 paediatric APL patients treated according to the consecutive acute myeloid leukaemia‐Berlin/Frankfurt/Muenster (AML‐BFM) trials ‐93/‐98/‐2004 with an anthracycline‐cytarabine regimen in combination with all‐trans‐retinoid acid (ATRA). Outcomes achieved by treatment with a reduced cumulative anthracycline dose (350 mg/m²) were comparable to those reported for studies with higher doses. Five‐year overall survival of the total cohort was 89 ± 4% and event‐free survival (pEFS) was 73 ± 6%. Overall survival was similar when comparing AML‐BFM trial periods (trial 93: 88 ± 8%, 98: 85 ± 7% and 2004: 94 ± 8%, P_(logrank) = 0·63). Seventy‐five (93%) patients achieved complete remission. Most fatal events occurred during the first 6 weeks of treatment. Long‐term cardiotoxicity was observed in one patient. Two patients suffered from secondary haematological malignancies. Salvage treatment was effective in 7/9 patients (78%) with relapsed APL, who now are long‐term survivors after second line combination treatment with arsenic trioxide (4/7 patients) and stem cell transplantation (5/7 patients). Our results demonstrate that – combined with ATRA – a lower cumulative anthracycline dose can be used safely to maintain high cure rates and promote the reduction of long‐term sequelae, such as cardiotoxicity in APL patients.     

Childhood near‐tetraploid acute lymphoblastic leukemia: an EGIL study on 36 cases

Objectives: Patients with near‐tetraploid (karyotype: 81 – 103 chromosomes) acute lymphoblastic leukemia (NT‐ALL) constitute about 1% of childhood ALL and data reported on them are limited and controversial. The aim of the study was to enlarge the knowledge on these rarely occurring ALL. Methods: The members of the European Group for Immunophenotyping of Leukemias (EGIL) searched retrospectively their databases for NT‐ALL patients. Results: We collected data of 36 European children from seven European countries with NT‐ALL diagnosed since 1992. All patients reached complete remission (CR) after induction chemotherapy. Their blasts were negative for peroxidase and BCR‐ABL1. Ten children were diagnosed as T‐cell ALL (T‐ALL) EGIL categories (T‐I n = 2, T‐II n = 2, T‐III n = 3, T‐IV n = 3) and four displayed various structural chromosomal abnormalities. Eight of 10 T‐ALL remained in 1st CR; one died in CR from sepsis and one is alive in 2nd CR. Median survival was 88 (7–213) months. B‐cell precursor (BCP) ALL was diagnosed in 26 children. Thirteen were positive for ETV6‐RUNX1 and are alive in 1st CR for 32–147 months. Ten children were ETV6‐RUNX1 negative and remained in 1st CR for 16–163 months. One girl with hypodiploid and NT metaphases and ETV6‐RUNX1‐negative BCP‐ALL and one of two boys with NT‐BCP‐ALL not examined for ETV6‐RUNX1 died of infection after stem cell transplantation in 2nd/3rd CR. Secondary myelodysplastic syndrome developed in two patients with NT‐BCP‐ALL. Conclusions: Our data demonstrate immunophenotypic, cytogenetic, and molecular heterogeneity of NT‐ALL and favorable prognosis of most NT‐ALL across different immunophenotypic and/or genetic ALL subtypes.     

Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003

The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild‐type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event‐free survival (EFS) between the TPMT genotypes. The 5‐year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild‐type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5‐year EFS 53%) was not seen in ALL2003 (5‐year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high‐risk MRD patients 4·22, 95% confidence interval 2·97–5·99, P < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol.     

Outcomes of treatment for relapsed acute lymphoblastic leukaemia in children with Down syndrome

Children with Down syndrome (DS) have a greater risk for developing both acute lymphoblastic leukaemia (ALL) and significant adverse effects of chemotherapy. We investigated their outcome with, and tolerance of, treatment protocols for relapsed ALL optimized in the paediatric population without DS. Probability of survival and causes of treatment failure were determined for 49 children with DS and a matched cohort of 98 children without DS among 2160 children treated for relapsed ALL in clinical trials conducted by the Berlin‐Frankfurt‐Münster ALL Relapse Study Group between 1983 and 2012. Despite more favourable ALL relapse characteristics, children with DS experienced lower event‐free (EFS) and overall survival (OS) than the control group without DS (EFS 17 ± 08% vs. non‐DS 41 ± 06%, P = 0·006; OS 17 ± 09% vs. non‐DS 51 ± 06%, P < 0·001). Children with DS developed more frequently fatal complications of treatment (34 ± 07% vs. non‐DS 10 ± 04%, P < 0·001). During the last decade, EFS and OS were no longer significantly different in children with and without DS (EFS 31 ± 09% vs. 36 ± 09%, P = 0·399; OS 31 ± 12% vs. 53 ± 09%, P = 0·151). DS proved an independent prognostic factor of outcome after ALL relapse. Induction deaths and treatment‐related mortality but not subsequent relapse were the main barrier to successful outcomes of relapse therapy in children with DS.     

Secondary acute lymphoblastic leukaemia is constitutional and probably not related to prior therapy

Very little is known about secondary acute lymphoblastic leukaemia (s‐ALL). This retrospective analysis studied a cohort of s‐ALL patients treated at a single centre between 1994 and 2013, while comparing therapy‐associated ALL (t‐ALL) and antecedent malignancy ALL (am‐ALL) patients. Thirty‐two patients with s‐ALL were identified. The overall incidence was 9·4% among ALL adults while T‐cell s‐ALL was rare (12% of s‐ALLs). The median time interval between two malignant diagnoses was 5·3 years (range: 0·1–28). In contrast to previous reports, most of the s‐ALLs were CD10 +  and without KMT2A (MLL) abnormalities. The overall survival (OS) rates of the entire cohort at 12 and 24 months from ALL diagnosis was 49% and 25%, respectively. Most patients (n = 23, 72%) received prior chemo‐/radio‐therapy for their first malignancy (t‐ALL) and only 9 (28%) did not (am‐ALL). No significant difference was found in the incidence of B‐/T‐ lineage ALL, extramedullary disease, blood count, and the rate of Philadelphia‐positive ALL, nor in the rates of complete remission (P = 0·55) and OS (P = 0·97). This similarity, together with high incidence of family malignancy in both groups, raise the possibility that s‐ALL patients may have an inherent predisposition to malignancies and a history of previous therapy may be of lesser importance in the pathogenesis of s‐ALL.     

Thiopurine dose intensity and treatment outcome in childhood lymphoblastic leukaemia: the influence of thiopurine methyltransferase pharmacogenetics

The impact of thiopurine methyltransferase (TPMT) genotype on thiopurine dose intensity, myelosuppression and treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia (ALL) trial ALL97. TPMT heterozygotes had significantly more frequent cytopenias and therefore required dose adjustments below target levels significantly more often than TPMT wild‐type patients although the average dose range was similar for both genotypes. Event‐free survival (EFS) for patients heterozygous for the more common TPMT*1/*3A variant allele (n = 99, 5‐year EFS 88%) was better than for both wild‐type TPMT*1/*1 (n = 1206, EFS 80%, P = 0·05) and TPMT*1/*3C patients (n = 17, EFS 53%, P = 0·002); outcomes supported by a multivariate Cox regression analysis. Poor compliance without subsequent clinician intervention was associated with a worse EFS (P = 0·02) and such non‐compliance may have contributed to the poorer outcome for TPMT*1/*3C patients. Patients prescribed escalated doses had a worse EFS (P = 0·04), but there was no difference in EFS by dose intensity or duration of cytopenias. In contrast to reports from some USA and Nordic trials, TPMT heterozygosity was not associated with a higher rate of second cancers. In conclusion, TPMT*1/*3A heterozygotes had a better EFS than TPMT wild‐type patients. Thiopurine induced cytopenias were not detrimental to treatment outcome.     

No impact of high‐dose cytarabine and asparaginase as early intensification with intermediate‐risk paediatric acute lymphoblastic leukaemia: results of randomized trial TCCSG study L99‐15

The Tokyo Children's Cancer Study Group conducted a randomized controlled study to evaluate the effect of experimental early intensification using high‐dose cytarabine and L‐asparaginase in paediatric intermediate‐risk (IR) acute lymphoblastic leukaemia (ALL). A total of 310 IR ALL patients were randomized to receive either experimental early intensification (n = 156) or standard early intensification including standard‐dose cytarabine arm (n = 154) after induction therapy. The experimental arm consisted of high‐dose cytarabine and L‐asparaginase, while the standard arm consisted of standard‐dose cytarabine, oral 6‐mercaptopurine and cyclophosphamide. The probabilities of event‐free survival at 8 years in the experimental and standard arms were 72·3 ± 3·7% and 77·5 ± 3·5%, respectively (P = 0·32). The 8‐year overall survival rates for these two arms were 85·0 ± 3·0% and 86·9 ± 2·8%, respectively (P = 0·72). The frequency of infectious events was significantly higher in the experimental arm (66·4%) than in the standard arm (24·6%) (P < 0·001). In conclusion, experimental early intensification including high‐dose cytarabine followed by L‐asparaginase had no advantage over standard early intensification in paediatric IR ALL patients.     

Outcome of relapse after allogeneic HSCT in children with ALL enrolled in the ALL‐SCT 2003/2007 trial

Relapse remains the major cause of treatment failure in children with high‐risk acute lymphoblastic leukaemia (ALL) undergoing allogeneic haematopoietic stem‐cell transplantation (allo‐SCT). Prognosis is considered dismal but data on risk factors and outcome are lacking from prospective studies. We analysed 242 children with recurrence of ALL after first allo‐SCT enrolled in the Berlin‐Frankfurt‐Munster (BFM) ALL‐SCT‐BFM 2003 and ALL‐SCT‐BFM international 2007 studies. Median time from allo‐SCT to relapse was 7·7 months; median follow‐up from relapse after allo‐SCT until last follow‐up was 3·4 years. The 3‐year event‐free survival (EFS) was 15% and overall survival (OS) was 20%. The main cause of death was disease progression or relapse (86·5%). The majority of children (48%) received salvage therapy without second allo‐SCT, 26% of the children underwent a second allo‐SCT and 25% received palliative treatment only. In multivariate analyses, age, site of relapse, time to relapse and type of salvage therapy were identified as significant prognostic factors for OS and EFS, whereas factors associated with first SCT were not statistically significant. Combined approaches incorporating novel immunotherapeutic treatment options and second allo‐SCT hold promise to improve outcome in children with post allo‐SCT relapse.     

NOTCH1 mutations are associated with favourable long‐term prognosis in paediatric T‐cell acute lymphoblastic leukaemia: a retrospective study of patients treated on BCH‐2003 and CCLG‐2008 protocol in China

Activating mutations of NOTCH1 are a common occurrence in T‐cell acute lymphoblastic leukaemia (T‐ALL), but its impact on T‐ALL treatment is still controversial. In this study, the incidence, clinical features, and prognosis of 92 Chinese children with T‐ALL treated using the Beijing Children's Hospital‐2003 and Chinese Childhood Leukaemia Group‐2008 protocols were analysed. NOTCH1 mutations were found in 42% of T‐ALL patients and were not associated with clinical features, prednisone response, and minimal residual disease (MRD) at day 33 and 78. However, proline, glutamate, serine, threonine (PEST)/transactivation domain (TAD) mutations were associated with younger age (15/16 mutant vs. 48/76 wild‐type, P = 0·018) and more central nervous system involvement (4/16 mutant vs. 3/76 wild‐type, P = 0·016); while heterodimerization domain (HD) mutations were associated with KMT2A‐MLLT1 (MLL‐ENL; 4/30 mutant vs. 1/62 wild‐type, P = 0·037). Furthermore, prognosis was better in patients with NOTCH1 mutations than in those with wild‐type NOTCH1 (5‐year event‐free survival [EFS] 92·0 ± 4·5% vs. 64·0 ± 7·1%; P = 0·003). Long‐term outcome was better in patients carrying HD mutations than in patients with wild‐type HD (5‐year EFS 89·7 ± 5·6% vs. 69·3 ± 6·2%; P = 0·034). NOTCH1 mutations and MRD at day 78 were independent prognostic factors. These findings indicate that NOTCH1 mutation predicts a favourable outcome in Chinese paediatric patients with T‐ALL on the BCH‐2003 and CCLG‐2008 protocols, and may be considered a prognostic stratification factor.