Jennifer J.G. Welch

Intravenous pegylated asparaginase versus intramuscular native Escherichia coli L-asparaginase in newly diagnosed childhood acute lymphoblastic leukaemia (DFCI 05-001): a randomised, open-label phase 3 trial.

BACKGROUND l-asparaginase is a universal component of treatment for childhood acute lymphoblastic leukaemia, and is usually administered intramuscularly. Pegylated Escherichia coli asparaginase (PEG-asparaginase) has a longer half-life and is potentially less immunogenic than the native Escherichia coli (E coli) preparation, and can be more feasibly administered intravenously. The aim of the Dana-Farber Cancer Institute Acute Lymphoblastic Leukaemia Consortium Protocol 05-001 (DFCI 05-001) was to compare the relative toxicity and efficacy of intravenous PEG-asparaginase and intramuscular native E colil-asparaginase in children with newly diagnosed acute lymphoblastic leukaemia. METHODS DFCI 05-001 enrolled patients aged 1-18 years with newly diagnosed acute lymphoblastic leukaemia from 11 consortium sites in the USA and Canada. Patients were assigned to an initial risk group on the basis of their baseline characteristics and then underwent 32 days of induction therapy. Those who achieved complete remission after induction therapy were assigned to a final risk group and were eligible to participate in a randomised comparison of intravenous PEG-asparaginase (15 doses of 2500 IU/m(2) every 2 weeks) or intramuscular native E colil-asparaginase (30 doses of 25 000 IU/m(2) weekly), beginning at week 7 after study entry. Randomisation (1:1) was unmasked, and was done by a statistician-generated allocation sequence using a permuted blocks algorithm (block size of 4), stratified by final risk group. The primary endpoint of the randomised comparison was the overall frequency of asparaginase-related toxicities (defined as allergy, pancreatitis, and thrombotic or bleeding complications). Predefined secondary endpoints were disease-free survival, serum asparaginase activity, and quality of life during therapy as assessed by PedsQL surveys. All analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00400946. FINDINGS Between April 22, 2005, and Feb 12, 2010, 551 eligible patients were enrolled. 526 patients achieved complete remission after induction, of whom 463 were randomly assigned to receive intramuscular native E colil-asparaginase (n=231) or intravenous PEG-asparaginase (n=232). The two treatment groups did not differ significantly in the overall frequency of asparaginase-related toxicities (65 [28%] of 232 patients in the intravenous PEG-asparaginase group vs 59 [26%] of 231 patients in the intramuscular native E colil-asparaginase group, p=0·60), or in the individual frequency of allergy (p=0·36), pancreatitis (p=0·55), or thrombotic or bleeding complications (p=0·26). Median follow-up was 6·0 years (IQR 5·0-7·1). 5-year disease-free survival was 90% (95% CI 86-94) for patients assigned to intravenous PEG-asparaginase and 89% (85-93) for those assigned to intramuscular native E colil-asparaginase (p=0·58). The median nadir serum asparaginase activity was significantly higher in patients who received intravenous PEG-asparaginase than in those who received intramuscular native E colil-asparaginase. Significantly more anxiety was reported by both patients and parent-proxy in the intramuscular native E colil-asparaginase group than in the intravenous PEG-asparaginase group. Scores for other domains were similar between the groups. The most common grade 3 or worse adverse events were bacterial or fungal infections (47 [20%] of 232 in the intravenous PEG-asparaginase group vs 51 [22%] of 231 patients in the intramuscular E colil-asparaginase group) and asparaginase-related allergic reactions (14 [6%] vs 6 [3%]). INTERPRETATION Intravenous PEG-asparaginase was not more toxic than, was similarly efficacious to, and was associated with decreased anxiety compared with intramuscular native E colil-asparaginase, supporting its use as the front-line asparaginase preparation in children with newly diagnosed acute lymphoblastic leukaemia. FUNDING National Cancer Institute and Enzon Pharmaceuticals.

Weight Status of Children With Sickle Cell Disease

OBJECTIVE: Historically, many children and adolescents with sickle cell disease (SCD) were underweight. Treatment advances like hydroxyurea have been associated with improved growth. We hypothesized that increased hemoglobin (Hb) levels would be associated with increased weight status of children with SCD. METHODS: Investigators at 6 institutions conducted a retrospective chart review of all patients aged 2 to 19 years of age for the calendar years 2007–2009. Height, weight, baseline Hb levels, demographic information, and select comorbidities were recorded from the most recent clinic visit. Overweight and obesity were defined as ≥85th and ≥95th BMI percentiles for age and gender, respectively, and underweight was defined as <5th BMI percentile. RESULTS: Data were collected on 675 children and adolescents in 3 New England states. In this sample, 22.4% were overweight or obese, whereas only 6.7% were underweight. Overweight or obese status was associated with sickle genotypes other than Hb SS or Hb Sβ0 disease, and were associated with higher baseline Hb levels. Underweight individuals were more likely to be male, older, and have had at least 1 SCD-related complication. After adjusting for demographic factors, any SCD-related complication, SCD-directed treatments, and obesity-related conditions, there was a 36% increased odds of overweight/obesity for each 1 g/dL increase in baseline Hb levels. CONCLUSIONS: Nearly one-quarter of children and adolescents with SCD in New England are overweight or obese. Longitudinal studies are needed to determine the impact of elevated BMI on the morbidity and mortality of both children and adults with SCD.

Rare Pediatric Non-Hodgkin Lymphomas: A Report From Children's Oncology Group Study ANHL 04B1.

Non‐Hodgkin lymphoma (NHL) is a relatively common malignancy in pediatric patients; however, a small subgroup have unusual lymphoma subtypes for the pediatric population.

Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia

Pediatric patients receiving induction chemotherapy for newly diagnosed acute lymphoblastic leukemia (ALL) are at high risk of developing life‐threatening infections. We investigated whether uniform antibacterial guidelines, including mandatory antibacterial prophylaxis in afebrile patients during induction, decreases the incidence of microbiologically documented bacteremia.

How Variable Is Our Delivery of Information? Approaches to Patient Education About Oral Chemotherapy in the Pediatric Oncology Clinic

In pediatric patients with acute lymphoblastic leukemia, adherence to oral chemotherapy relies largely on a parents comprehension of the drugs indication and administration guidelines. We assessed how pediatric oncology providers educate families about oral chemotherapy. We conducted a cross-sectional survey of 68 physicians and nurses from 9 institutions in the Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium. The inter-individual approach to patient education is variable and may consist of handouts, treatment calendars, and discussions. The extent of teaching often varies depending on a providers subjective assessment of a familys needs. Twenty-five percent of providers suggested standardizing patient teaching. When developing educational models, care teams should consider approaches that (a) objectively identify families in need of extensive teaching, (b) designate allotted teaching time by nursing staff during clinic visits, and (c) maintain the variation and dynamism that informs a successful provider-patient relationship.

Epstein-Barr virus DNA in serum as an early prognostic marker in children and adolescents with Hodgkin lymphoma

Assay of cell-free DNA in blood offers an approach to assessment of tumor DNA. We sought to determine whether Epstein-Barr virus (EBV) DNA in cell-free blood is also a good surrogate for the presence of tumor DNA in children with Hodgkin lymphoma, as it is in adults, and whether it correlates with pediatric outcomes. Pediatric patients enrolled in a Childrens Oncology Group trial (AHOD0031) were studied at baseline and at 8 days after the initiation of treatment. At baseline, EBV DNA in cell-free blood correlated with the presence of EBV in tumor, and EBV DNA 8 days after the initiation of therapy predicted inferior event-free survival. EBV DNA in cell-free blood warrants further investigation as a marker of inadequate tumor response in Hodgkin lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00025259.

An investigation of toxicities and survival in Hispanic children and adolescents with ALL: Results from the Dana-Farber Cancer Institute ALL Consortium protocol 05-001

This study compared the relative incidence of treatment‐related toxicities and the event‐free and overall survival between Hispanic and non‐Hispanic children undergoing therapy for acute lymphoblastic leukemia (ALL) on Dana‐Farber Cancer Institute ALL Consortium protocol 05‐001.

Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia

Recurrent chromosomal rearrangements carry prognostic significance in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). Recent genome-wide analyses identified a high-risk B-ALL subtype characterized by a diverse spectrum of genetic alterations activating kinases and cytokine receptor genes. This subtype is associated with a poor prognosis when treated with conventional chemotherapy but has demonstrated sensitivity to the relevant tyrosine kinase inhibitors. We sought to determine the frequency of kinase-activating fusions among National Cancer Institute (NCI) high-risk, Ph-negative, B-ALL patients enrolled on Dana-Farber Cancer Institute ALL Consortium Protocol 05-001 and to describe their associated clinical characteristics and outcomes. Among the 105 patients screened, 16 (15%) harbored an ABL-class fusion (ETV6-ABL1: n = 1; FOXP1-ABL1: n = 1; SFPQ-ABL1: n = 1; ZC3HAV1-ABL2: n = 1) or a fusion activating the JAK-STAT pathway (P2RY8-CRLF2: n = 8; PAX5-JAK2: n = 4). Sixty-nine percent of patients with an identified fusion had a concomitant IKZF1 deletion (n = 11). In univariate analysis, fusion-positivity and IKZF1 deletion were each associated with inferior event-free survival; IKZF1 deletion retained statistical significance in multivariable analysis (hazard ratio, 2.64; P = .019). Our findings support therapy intensification for IKZF1-altered patients, irrespective of the presence of a kinase-activating fusion.

Reply to comment on: Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia

To the Editor: We thank Dr. Saxena, Dr. Jain, and Dr. Gupta for their Letter to the Editor1 regarding our paper entitled “Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia”.2 Saxena et al. point out that continuous improvement in supportive care and availability of more potent antibiotics could have contributed to the decreased incidence of bacteremia during induction chemotherapy for acute lymphoblastic leukemia (ALL) observed on Dana–Farber Cancer Institute (DFCI) ALL Consortium Protocol 11-001 compared to the predecessor, DFCI 05-001. We certainly concur with this comment and recognize that the use of historical controls limits our ability to draw a definitive conclusion on the role of fluoroquinolone prophylaxis during induction chemotherapy. However, we had previously observed that rates of bacterial and fungal infections during induction chemotherapy remained constant across different DFCI ALL trials conducted between 2000 and 2011, despite changes in the intensity of chemotherapy and presumed improvement in supporting care; we believe that this observation supports that uniform use of antibiotics during induction chemotherapy is the main cause of the decreased incidence of bacteremia noted in Protocol 11-001. Dr. Saxena et al. suggest that the increase in fungal infections observed in Protocol 11-001 could be related to the prolonged exposure to fluoroquinolones and that the use of routine antifungal prophylaxis adopted by two institutions could have falsely decreased the incidence of fungemia. We absolutely concur with the authors that prolonged antibacterial prophylaxis represents a risk factor for the development of fungal infections; fortunately, we did not observe a significant increase in the incidence of invasive fungal infection in 11-001, compared to 05-001 (4.8% vs. 3.6%, P = 0.34); additionally, the same two institutions used antifungal prophylaxis during induction chemotherapy in 05-001 and 11-001. Saxena et al. suggest that obtaining blood cultures routinely prior to initiation of antibacterial prophylaxis in afebrile patients could have identified bacteremias eventually suppressed by the use of prophylactic antibiotics. We believe that routine blood cultures in patients with no signs or symptoms of infection could generate a significant rate of false positive results and lead to subsequent unnecessary investigations and use of antibiotics; we would therefore discourage this practice. Lastly, Dr. Saxena et al. suggest that additional clinical information regarding the children with ALL who received antibacterial prophylaxis would have been useful, such as the number of febrile days and the severity of the infections.We thank the authors for this comment and agree that more detailed clinical informationwould havebeenuseful for the reader; in ourmanuscript,wedo provide information on the severity of the infections in patients who received fluoroquinolone prophylaxis (n = 66), noting that six (9.1%) developed bacteremia and one (1.5%) developed a fungal infection and bacteremia, of which six were Grade 3 and onewas Grade 4. In summary, we concur with Saxena et al. that large, randomized, and controlled trials are needed to confirm the efficacy of antibacterial prophylaxis during induction chemotherapy for childrenwith ALL.

Outcome of children and adolescents with Down syndrome treated on Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia Consortium protocols 00-001 and 05-001

Children and adolescents with Down syndrome (DS) and acute lymphoblastic leukemia (ALL) are reported to have increased relapse rates and therapy‐related mortality (TRM). Treatment regimens for DS‐ALL patients often include therapy modifications. Dana‐Farber Cancer Institute (DFCI) ALL Consortium protocols have used same risk‐stratified treatment for patients with and without DS.