Most relapses in childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) are not predicted using current prognostic features. Here, we determined the co-occurrence and independent ...prognostic relevance of 3 recently identified prognostic features: BCR-ABL1-like gene signature, deletions in IKZF1, and high CRLF2 messenger RNA expression (CRLF2-high). These features were determined in 4 trials representing 1128 children with ALL: DCOG ALL-8, ALL9, ALL10, and Cooperative ALL (COALL)-97/03. BCR-ABL1-like, IKZF1-deleted, and CRLF2-high cases constitute 33.7% of BCR-ABL1–negative, MLL wild-type BCP-ALL cases, of which BCR-ABL1-like and IKZF1 deletion (co)occurred most frequently. Higher cumulative incidence of relapse was found for BCR-ABL1-like and IKZF1-deleted, but not CRLF2-high, cases relative to remaining BCP-ALL cases, reflecting the observations in each of the cohorts analyzed separately. No relapses occurred among cases with CRLF2-high as single feature, whereas 62.9% of all relapses in BCR-ABL1–negative, MLL wild-type BCP-ALL occurred in cases with BCR-ABL1-like signature and/or IKZF1 deletion. Both the BCR-ABL1-like signature and IKZF1 deletions were prognostic features independent of conventional prognostic markers in a multivariate model, and both remained prognostic among cases with intermediate minimal residual disease. The BCR-ABL1-like signature and an IKZF1 deletion, but not CRLF2-high, are prognostic factors and are clinically of importance to identify high-risk patients who require more intensive and/or alternative therapies.
•BCR-ABL1-like signature and IKZF1 deletions are clinically important to identify high-risk acute lymphoblastic patients.
Abstract Genetic predisposition for childhood cancer is under diagnosed. Identifying these patients may lead to therapy adjustments in case of syndrome-related increased toxicity or resistant disease ...and syndrome-specific screening programs may lead to early detection of a further independent malignancy. Cancer surveillance might also be warranted for affected relatives and detection of a genetic mutation can allow for reproductive counseling. Here we present an easy-to-use selection tool, based on a systematic review of pediatric cancer predisposing syndromes, to identify patients who may benefit from genetic counseling. The selection tool involves five questions concerning family history, the type of malignancy, multiple primary malignancies, specific features and excessive toxicity, which results in the selection of those patients that may benefit from referral to a clinical geneticist.
With the increase of pediatric cancer survival rates, late effects and quality of life (QoL) have received more attention. Disturbed sleep in pediatric cancer is a common clinical observation, but ...research on this subject is sparse. In general, sleep problems can lead to significant morbidity and are associated with impaired QoL. Information on sleep is essential to develop interventions to improve QoL.
Children (2-18 years) with acute lymphoblastic leukemia (ALL) were eligible for this multi-center study. The Children's Sleep Habits Questionnaire (CSHQ), Child Health Questionnaire (CHQ) and Pediatric Quality of Life Inventory 3.0™ Acute Cancer Version (PedsQL) were used to assess sleep and QoL halfway through maintenance therapy. Sleep and QoL were measured during and after dexamethasone treatment (on-dex and off-dex).
Seventeen children participated (age 6.7 ± 3.3 years, 44% boys). Children with ALL had more sleep problems and a lower QoL compared to the norm. There were no differences on-dex and off-dex. Pain (r = -0.6; p = 0.029) and worry (r = -0.5; p = 0.034) showed a moderate negative association with sleep. Reduced overall QoL was moderately associated with impaired overall sleep (r = -0.6; p = 0.014) and more problems with sleep anxiety (r = -0.8; p = 0.003), sleep onset delay (r = -0.5; p = 0.037), daytime sleepiness (r = -0.5; p = 0.044) and night wakenings (r = -0.6; p = 0.017).
QoL is impaired in children during cancer treatment. The results of this study suggest that impaired sleep may be a contributing determinant. Consequently, enhanced counseling and treatment of sleep problems might improve QoL. It is important to conduct more extensive studies to confirm these findings and provide more detailed information on the relationship between sleep and QoL, and on factors affecting sleep in pediatric ALL and in children with cancer in general.
IKZF1-deletions occur in 10-15% of patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL) and predict a poor outcome. However, the impact of IKZF1-loss on sensitivity to drugs used in ...contemporary treatment protocols has remained underexplored. Here we show in experimental models and in patients that loss of IKZF1 promotes resistance to AraC, a key component of both upfront and relapsed treatment protocols. We attribute this resistance, in part, to diminished import and incorporation of cytarabine (AraC) due to reduced expression of the solute carrier hENT1. Moreover, we find elevated mRNA expression of Evi1, a known driver of therapy resistance in myeloid malignancies. Finally, a kinase directed CRISPR/Cas9-screen identified that inhibition of either mediator kinases CDK8/19 or casein kinase 2 can restore response to AraC. We conclude that this high-risk patient group could benefit from alternative antimetabolites, or targeted therapies that resensitize the cells to AraC.
The primary objective of this randomized study was to determine whether a continuous dosing schedule (without the asparaginase-free interval) would result in less hypersensitivity reactions to ...PEGasparaginase (PEGasp) compared with the standard noncontinuous dosing schedule.
Eight hundred eighteen patients (age 1-18 years) with ALL were enrolled in the Dutch Childhood Oncology Group-ALL11 protocol and received PEGasp. Three hundred twelve patients stratified in the medium-risk arm were randomly assigned to receive 14 individualized PEGasp doses once every two weeks in either a noncontinuous or continuous schedule after the first three doses in induction (EudraCT: 2012-000067-25). Hypersensitivity reactions were defined as allergies, allergic-like reactions, and silent inactivation. Secondary end points were other asparaginase-related toxicities, asparaginase activity and antibody levels, and outcome.
During induction, 27 of 818 patients (3.3%) experienced hypersensitivity reactions. After random assignment, 4 of 155 (2.6%) in the continuous treatment arm versus 17 of 157 (10.8%) patients in the noncontinuous treatment arm had hypersensitivity reactions (
< .01), of which two (1.3%) versus 13 (8.3%) were inactivating reactions (
< .01). The occurrence of inactivating hypersensitivity reactions was seven times lower in the continuous arm (odds ratio, 0.15 0.032-0.653). In addition, antibody levels were significantly lower in the continuous arm (
< .01). With exception of a lower incidence of increased amylase in the continuous arm, there were no significant differences in total number of asparaginase-associated toxicities between arms. However, the timing of the toxicities was associated with the timing of the asparaginase administrations. No difference in 5-year cumulative incidence of relapse, death, or disease-free survival was found between both treatment arms.
A continuous dosing schedule of PEGasp is an effective approach to prevent antibody formation and inactivating hypersensitivity reactions. The continuous PEGasp schedule did not increase toxicity and did not affect the efficacy of the therapy.
Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development ...of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. Strategies to modulate GD2 expression in neuroblastoma could further improve anti-GD2–targeted immunotherapy. Here, we report that the cellular sialylation pathway, as well as epigenetic reprogramming, strongly modulates GD2 expression in human and mouse neuroblastoma cell lines. Recognition of GD2 by the 14G2a antibody is sialic acid–dependent and was blocked with the fluorinated sialic acid mimetic Ac53FaxNeu5Ac. Interestingly, sialic acid supplementation using a cell-permeable sialic acid analogue (Ac5Neu5Ac) boosted GD2 expression without or with minor alterations in overall cell surface sialylation. Furthermore, sialic acid supplementation with Ac5Neu5Ac combined with various histone deacetylase (HDAC) inhibitors, including vorinostat, enhanced GD2 expression in neuroblastoma cells beyond their individual effects. Mechanistic studies revealed that Ac5Neu5Ac supplementation increased intracellular CMP–Neu5Ac concentrations, thereby providing higher substrate levels for sialyltransferases. Furthermore, HDAC inhibitor treatment increased mRNA expression of the sialyltransferases GM3 synthase (ST3GAL5) and GD3 synthase (ST8SIA1), both of which are involved in GD2 biosynthesis. Our findings reveal that sialic acid analogues and HDAC inhibitors enhance GD2 expression and could potentially be employed to boost anti-GD2 targeted immunotherapy in neuroblastoma patients.
The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients ...were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2·64, 95% CI 1·32, 5·31, p = 0·006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses.
Controlled-Trials.com ISRCTN45724312.
Deletions and mutations affecting lymphoid transcription factor IKZF1 (IKAROS) are associated with an increased relapse risk and poor outcome in B-cell precursor acute lymphoblastic leukemia. ...However, additional genetic events may either enhance or negate the effects of
deletions on prognosis. In a large discovery cohort of 533 childhood B-cell precursor acute lymphoblastic leukemia patients, we observed that single-copy losses of
were significantly enriched in
-deleted B-cell precursor acute lymphoblastic leukemia (
=0.007). While
deletions alone had no impact on prognosis, the combined presence of
and
deletions was associated with a significantly lower 5-year event-free survival (
=0.0003) and a higher 5-year cumulative incidence of relapse (
=0.005), when compared with
-deleted cases without
aberrations. In contrast, other copy number losses commonly observed in B-cell precursor acute lymphoblastic leukemia, such as
or
, did not affect the outcome of
-deleted acute lymphoblastic leukemia patients. To establish whether the combined loss of IKZF1 and BTG1 function cooperate in leukemogenesis,
-deficient mice were crossed onto an
heterozygous background. We observed that loss of
increased the tumor incidence of
mice in a dose-dependent manner. Moreover, murine B cells deficient for
and
displayed increased resistance to glucocorticoids, but not to other chemotherapeutic drugs. Together, our results identify
as a tumor suppressor in leukemia that, when deleted, strongly enhances the risk of relapse in
-deleted B-cell precursor acute lymphoblastic leukemia, and augments the glucocorticoid resistance phenotype mediated by the loss of IKZF1 function.
Current multimodal treatments for patients with neuroblastoma (NBL), including anti‐disialoganglioside (GD2) monoclonal antibody (mAb) based immunotherapy, result in a favorable outcome in around ...only half of the patients with advanced disease. To improve this, novel immunocombinational strategies need to be developed and tested in autologous preclinical NBL models. A genetically well‐explored autologous mouse model for NBL is the TH‐MYCN model. However, the immunobiology of the TH‐MYCN model remains largely unexplored. We developed a mouse model using a transplantable TH‐MYCN cell line in syngeneic C57Bl/6 mice and characterized the immunobiology of this model. In this report, we show the relevance and opportunities of this model to study immunotherapy for human NBL. Similar to human NBL cells, syngeneic TH‐MYCN‐derived 9464D cells endogenously express the tumor antigen GD2 and low levels of MHC Class I. The presence of the adaptive immune system had little or no influence on tumor growth, showing the low immunogenicity of the NBL cells. In contrast, depletion of NK1.1+ cells resulted in enhanced tumor outgrowth in both wild‐type and Rag1−/− mice, showing an important role for NK cells in the natural anti‐NBL immune response. Analysis of the tumor infiltrating leukocytes ex vivo revealed the presence of both tumor associated myeloid cells and T regulatory cells, thus mimicking human NBL tumors. Finally, anti‐GD2 mAb mediated NBL therapy resulted in ADCC in vitro and delayed tumor outgrowth in vivo. We conclude that the transplantable TH‐MYCN model represents a relevant model for the development of novel immunocombinatorial approaches for NBL patients.
What's new?
Natural killer (NK) cells may serve a role in immune defense against neuroblastoma, though limitations in existing models have prevented extensive study of the immunological characteristics of the disease. Here, to better understand the immunobiology of neuroblastoma, the TH‐MYCN mouse model was adapted for immunological investigation. Tumor cells (9464D) derived from immunologically compatible C57Bl/6 TH‐MYCN mice were found to express the tumor antigen GD2. In addition, depletion of NK cells was associated with tumor outgrowth in both wild‐type and Rag1‐/‐ C57Bl/6 mice, whereas immunotherapy targeted against GD2 decreased tumor growth.
In this study, we examined the correlation between muscle ultrasound and muscle structure. Echo intensity (EI) of 14 muscles of two golden retriever muscular dystrophy dogs was correlated to the ...percentage interstitial fibrous tissue and fat in muscle biopsy. A significant correlation between interstitial fibrous tissue and EI was found (r = 0.87; p < 0.001). The separate influence of interstitial fat on muscle EI could not be established as only little fat was present. We conclude that fibrous tissue causes increased muscle EI. The high correlation between interstitial fibrous tissue and EI makes ultrasound a reliable method to determine severity of structural muscle changes.
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