A von Stackelberg

Standardized MRD quantification in European ALL trials : Proceedings of the Second International Symposium on MRD assessment in Kiel, Germany, 18-20 September 2008

Assessment of minimal residual disease (MRD) has acquired a prominent position in European treatment protocols for patients with acute lymphoblastic leukemia (ALL), on the basis of its high prognostic value for predicting outcome and the possibilities for implementation of MRD diagnostics in treatment stratification. Therefore, there is an increasing need for standardization of methodologies and harmonization of terminology. For this purpose, a panel of representatives of all major European study groups on childhood and adult ALL and of international experts on PCR- and flow cytometry-based MRD assessment was built in the context of the Second International Symposium on MRD assessment in Kiel, Germany, 18–20 September 2008. The panel summarized the current state of MRD diagnostics in ALL and developed recommendations on the minimal technical requirements that should be fulfilled before implementation of MRD diagnostics into clinical trials. Finally, a common terminology for a standard description of MRD response and monitoring was established defining the terms ‘complete MRD response’, ‘MRD persistence’ and ‘MRD reappearance’. The proposed MRD terminology may allow a refined and standardized assessment of response to treatment in adult and childhood ALL, and provides a sound basis for the comparison of MRD results between different treatment protocols.

Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia

Complete remission after blinatumomab-induced donor T-cell activation in three pediatric patients with post-transplant relapsed acute lymphoblastic leukemia

Prognostic value of genetic alterations in children with first bone marrow relapse of childhood B-cell precursor acute lymphoblastic leukemia.

Despite risk-adapted treatment, survival of children with relapse of acute lymphoblastic leukemia (ALL) remains poor compared with that of patients with initial diagnosis of ALL. Leukemia-associated genetic alterations may provide novel prognostic factors to refine present relapse treatment strategies. Therefore, we investigated the clinical relevance of 13 recurrent genetic alterations in 204 children treated uniformly for relapsed B-cell precursor ALL according to the ALL-REZ BFM 2002 protocol. The most common alterations were deletions of CDKN2A/2B, IKZF1, PAX5, ETV6, fusion of ETV6-RUNX1 and deletions and/or mutations of TP53. Multivariate analysis identified IKZF1 deletion and TP53 alteration as independent predictors of inferior outcome (P=0.002 and P=0.001). Next, we investigated how both alterations can improve the established risk stratification in relapsed ALL. Intermediate-risk relapse patients with low minimal residual disease are currently considered to have a good prognosis. In this group, deletion of IKZF1 and alteration of TP53 identify patients with significantly inferior outcome (P<0.001). In high-risk relapse patients, deletion of IKZF1 is strongly predictive of a second relapse after stem cell transplantation (P<0.001). We conclude that IKZF1 and TP53 represent relevant prognostic factors that should be considered in future risk assessment of children with relapsed ALL to indicate treatment intensification or intervention.

KRAS and CREBBP mutations: a relapse-linked malicious liaison in childhood high hyperdiploid acute lymphoblastic leukemia

High hyperdiploidy defines the largest genetic entity of childhood acute lymphoblastic leukemia (ALL). Despite its relatively low recurrence risk, this subgroup generates a high proportion of relapses. The cause and origin of these relapses remains obscure. We therefore explored the mutational landscape in high hyperdiploid (HD) ALL with whole-exome (n=19) and subsequent targeted deep sequencing of 60 genes in 100 relapsing and 51 non-relapsing cases. We identified multiple clones at diagnosis that were primarily defined by a variety of mutations in receptor tyrosine kinase (RTK)/Ras pathway and chromatin-modifying genes. The relapse clones consisted of reappearing as well as new mutations, and overall contained more mutations. Although RTK/Ras pathway mutations were similarly frequent between diagnosis and relapse, both intergenic and intragenic heterogeneity was essentially lost at relapse. CREBBP mutations, however, increased from initially 18–30% at relapse, then commonly co-occurred with KRAS mutations (P<0.001) and these relapses appeared primarily early (P=0.012). Our results confirm the exceptional susceptibility of HD ALL to RTK/Ras pathway and CREBBP mutations, but, more importantly, suggest that mutant KRAS and CREBBP might cooperate and equip cells with the necessary capacity to evolve into a relapse-generating clone.

Effective childhood cancer treatment: The impact of large scale clinical trials in Germany and Austria

In Germany and Austria, more than 90% of pediatric cancer patients are enrolled into nationwide disease‐specific first‐line clinical trials or interim registries. Essential components are a pediatric cancer registry and centralized reference laboratories, imaging review, and tumor board assistance. The five‐year overall survival rate in countries where such infrastructures are established has improved from <20% before 1950 to >80% since 1995. Today, treatment intensity is tailored to the individual patients risk to provide the highest chances of survival while minimizing deleterious late effects. Multicenter clinical trials are internationalized and serve as platforms for further improvements by novel drugs and biologicals. Pediatr Blood Cancer 2013;60:1574–1581.

TEL-AML1 POSITIVITY IN RELAPSED B CELL PRECURSOR ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDHOOD

TEL-AML1 positivity in relapsed B cell precursor acute lymphoblastic leukemia in childhood

Results of the first randomized multicentre trial on childhood acute lymphoblastic leukaemia in Russia

Until 1990, the survival of children with acute lymphoblastic leukaemia (ALL) in Russia was below 10%. To establish a protocol feasible under conditions there, ALL-MB 91 was designed to avoid prolonged bone marrow aplasia, thereby reducing needs for extensive supportive care, blood transfusions, long-lasting hospitalization and costs. High-dose therapies were avoided, anthracycline use was limited and CNS radiation therapy only foreseen in high-risk patients (about 30%). This was randomized against a modified BFM protocol. From 1995 to 2002, 834 patients of age up to 18 years were registered in 10 centres and 713 received after central randomization the allocated risk-stratified treatment. After a median follow-up of 7 years, the event-free survival (EFS) was 67±3% on ALL-MB 91 (N=358) vs 68±3% on ALL-BFM 90m (N=355). The overall survival (OS) was 71±3% vs 74±2%, respectively. Anaemia, thrombocytopenia, agranulocytosis >10 days and hospitalization (median 35 vs 68 days) were lower on ALL-MB 91 (P<0.01, N=197). While EFS and OS were similar with both protocols, ALL-MB 91 significantly incurred fewer toxicity and resource requirements and, therefore, has been increasingly used across Russia.

Monitoring minimal residual disease in children with high-risk relapses of acute lymphoblastic leukemia: prognostic relevance of early and late assessment

The prognosis for children with high-risk relapsed acute lymphoblastic leukemia (ALL) is poor. Here, we assessed the prognostic importance of response during induction and consolidation treatment prior to hematopoietic stem cell transplantation (HSCT) aiming to evaluate the best time to assess minimal residual disease (MRD) for intervention strategies and in future trials in high-risk ALL relapse patients. Included patients (n=125) were treated uniformly according to the ALL-REZ BFM (Berlin-Frankfurt-Münster) 2002 relapse trial (median follow-up time=4.8 years). Patients with MRD ⩾10−3 after induction treatment (76/119, 64%) or immediately preceding HSCT (19/71, 27%) had a significantly worse probability of disease-free survival 10 years after relapse treatment begin, with 26% (±6%) or 23% (±7%), respectively, compared with 58% (±8%) or 48% (±7%) for patients with MRD <10−3. Conventional intensive consolidation treatment reduced MRD to <10−3 before HSCT in 63% of patients, whereas MRD remained high or increased in the rest of this patient group. Our data support that MRD after induction treatment can be used to quantify the activity of different induction treatment strategies in phase II trials. MRD persistence at ⩾10−3 before HSCT reflects a disease highly resistant to conventional intensive chemotherapy and requiring prospective controlled investigation of new treatment strategies and drugs.

Copy number genome alterations are associated with treatment response and outcome in relapsed childhood ETV6/RUNX1-positive acute lymphoblastic leukemia

The clinical heterogeneity among first relapses of childhood ETV6/RUNX1-positive acute lymphoblastic leukemia indicates that further genetic alterations in leukemic cells might affect the course of salvage therapy and be of prognostic relevance. To assess the incidence and prognostic relevance of additional copy number alterations at relapse of the disease, we performed whole genome array comparative genomic hybridization of leukemic cell DNA from 51 patients with first ETV6/RUNX1-positive relapse enrolled in and treated according to the relapse trials ALL-REZ of the Berlin-Frankfurt-Münster Study Group. Within this cohort of patients with relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia, the largest analyzed for genome wide DNA copy number alterations to date, alterations were present in every ETV6/RUNX1-positive relapse and a high proportion of them occurred in recurrent overlapping chromosomal regions. Recurrent losses affected chromosomal regions 12p13, 6q21, 15q15.1, 9p21, 3p21, 5q and 3p14.2, whereas gains occurred in regions 21q22 and 12p. Loss of 12p13 including CDKN1B was associated with a shorter remission duration (P=0.009) and a lower probability of event-free survival (P=0.001). Distribution of X-chromosomal copy number alterations was gender-specific: whole X-chromosome loss occurred exclusively in females, gain of Xq only in males. Loss of the glucocorticoid receptor gene NR3C1 (5q31.3) was associated with a poor response to induction treatment (P=0.003), possibly accounting for the adverse prognosis of some of the ETV6/RUNX1-positive relapses.

Phase II study of gemcitabine in children with relapsed leukemia.

To the Editor: Read with interest the paper by Angiolillo et al. [1] on the role of gemcitabine in childhood leukemia. We would like to add an additional experience of a German study on gemcitabine in pediatric leukemia. To determine the efficacy of gemcitabine in children with relapsed leukemia, we conducted a prospective openlabel multicenter phase II study of gemcitabine between May 2003 and December 2004. The drug was given by intravenous short term infusion over 30 min at a dose of 1,200 mg/m weekly on days 1, 8, 15 (in 3 of 4 weeks each), and the repetition of the cycle started on day 29. The treatment was to be continued until tumor progression or other reasons led to termination. Eligiblity included childrenwith first or subsequent recurrence of leukemia or lymphoma after standard therapy had failed. The primary study objective was the response rate while, secondary study objectives were the time to tumor progression and toxicity using the NCI Common Toxicity Criteria. Six patients (4 ALL, 2 AML) between 3 and 18 years old (median age: 14,7 years) were enrolled until the trial was stopped. Mean duration of therapy was 40.3 days, equalling 4.8 courses of gemcitabine. Progression of disease defined as an increase of at least 25%of circulating blasts or an M3 bone marrow aspirate led to early completion of study therapy in all patients. Time to progression therefore corresponded exactly to the time on study. No response to gemcitabine was documented. The mean dosage per course was 899 mg/m. In 15/30 evaluable courses the dosage had to be reduced or omitted mostly for grade 3–4 hematotoxicity. In our patients, hepatotoxicitywas not as frequently observed as described in the paper of Angiolillo et al. The 13 serious adverse events in five patients were more or less commonly observed with the use of such treatment modalities and at least possibly associated to gemcitabine. Fever in absence of neutropenia within 24 hr after treatment administration was observed in 9/30 courses, febrile neutropenia in 7/30 courses (in 4/6 courses with symptoms of pneumonia). One patient died from recurrent GI bleeding due to thrombocytopenia. Our observations are in agreement with Angiolillo et al. and confirm that gemcitabine at this dose and schedule is not effective in children with refractory leukemia. Secondary, the toxicity observed was at least as high as described before even though only one third of the dose was administered in our study (1,200 mg/m vs. 3,600 mg/m weekly). Additionally, we observed febrile reactions within 24 hr after gemcitabine administration in several patients and one fatal event. The high toxicity does not seem to be correlated with a more intensive pre-treatment, which was comparable in both studies. We agree with the conclusion that further evaluation of gemcitabine as single treatment in childhood leukemia does not appear to be warranted and, therefore, prematurely closed our trial although defined stopping criteria were not yet met.