Publications by authors named "Cor van den Bos"

45 Publications

Vincristine-Induced Peripheral Neuropathy in Pediatric Oncology: A Randomized Controlled Trial Comparing Push Injections with One-Hour Infusions (The VINCA Trial).

Cancers (Basel) 2020 Dec 12;12(12). Epub 2020 Dec 12.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric oncology, 1081 HV Amsterdam, The Netherlands.

Vincristine (VCR) is a frequently used chemotherapeutic agent. However, it can lead to VCR-induced peripheral neuropathy (VIPN). In this study we investigated if one-hour infusions of VCR instead of push-injections reduces VIPN in pediatric oncology patients. We conducted a multicenter randomized controlled trial in which participants received all VCR administrations through push injections or one-hour infusions. VIPN was measured at baseline and 1-5 times during treatment using Common Terminology Criteria of Adverse Events (CTCAE) and pediatric-modified Total Neuropathy Score. Moreover, data on co-medication, such as azole antifungals, were collected. Overall, results showed no effect of administration duration on total CTCAE score or ped-mTNS score. However, total CTCAE score was significantly lower in patients receiving one-hour infusions concurrently treated with azole antifungal therapy (β = -1.58; = 0.04). In conclusion, generally VCR administration through one-hour infusions does not lead to less VIPN compared to VCR push injections in pediatric oncology patients. However, one-hour infusions lead to less severe VIPN compared to push-injections when azole therapy is administered concurrently with VCR. These results indicate that in children treated with VCR and requiring concurrent azole therapy, one-hour infusions might be beneficial over push injections, although larger trials are needed to confirm this association.
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http://dx.doi.org/10.3390/cancers12123745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764775PMC
December 2020

Parental functioning during maintenance treatment for childhood acute lymphoblastic leukemia: Effects of treatment intensity and dexamethasone pulses.

Pediatr Blood Cancer 2020 11 10;67(11):e28697. Epub 2020 Sep 10.

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands.

Background: During maintenance treatment, Dutch pediatric patients with medium-risk (MR) acute lymphoblastic leukemia (ALL) receive intravenous chemotherapy and cyclic dexamethasone. Dexamethasone affects child's sleep and behavior. Standard-risk (SR) patients only receive oral chemotherapy, without dexamethasone. Effects of stratified therapy on parents are not well known. This study compares parental sleep, distress and quality of life (QoL) with the general population, between MR and SR groups, and on- and off-dexamethasone (MR group).

Procedure: One year after diagnosis, parents of MR patients completed the Medical Outcomes Study (MOS) sleep, distress thermometer for parents and Short Form-12 (SF-12) twice; once on-dexamethasone and once off-dexamethasone. SR parents completed one measurement. Sleep problems, distress and QoL scores (off-dexamethasone) were compared to reference values and between MR and SR. Score differences on- and off-dexamethasone were assessed by multilevel regression analysis.

Results: Parents (80% mothers) of 121 patients (57% males; 75% MR, 25% SR) completed 191 measurements. Compared to reference values, parents reported more sleep disturbances, higher distress, and lower mental QoL. Additionally, MR parents reported clinical distress (score ≥ 4), whereas SR parents (on average) did not (mean 4.8 ± 2.4 vs 3.5 ± 2.4, P = .02). Within the MR group, outcomes did not significantly differ on- and off-dexamethasone.

Conclusions: Parents of ALL patients report sleep problems, high distress, and QoL impairment. Within the MR group, parental functioning did not differ on- and off-dexamethasone. However, MR parents reported clinical distress more often than SR parents, possibly reflecting differences in prognostic estimates and treatment burden. This perhaps includes the overall strain of cyclic dexamethasone. This study highlights the need for psychosocial support throughout treatment, regardless of risk stratification.
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http://dx.doi.org/10.1002/pbc.28697DOI Listing
November 2020

Bone marrow-derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis.

Blood 2020 Nov;136(19):2188-2199

Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk, multisystem, risk-organ-positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO- and single-system LCH would result from driver mutation in a circulating or tissue-resident, DC-committed precursor. We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo's)/macrophages (MΦs), osteoclasts (OCs), and DCs. CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in healthy donors. In one MS-RO+ LCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk LCH patients gave rise to DCs and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo's /MΦs, DCs, LC-like cells, and/or OC-like cells in lesions and/or Mo and DCs in blood of multiple low-risk patients. We therefore hypothesize that in both high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood.
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http://dx.doi.org/10.1182/blood.2020005209DOI Listing
November 2020

Population Pharmacokinetics of Vincristine Related to Infusion Duration and Peripheral Neuropathy in Pediatric Oncology Patients.

Cancers (Basel) 2020 Jul 4;12(7). Epub 2020 Jul 4.

Emma Children's Hospital, Amsterdam University Medical Center, Vrije Universiteit Amsterdam, Pediatric Oncology, 1081 HV Amsterdam, The Netherlands.

Vincristine (VCR) is frequently used in pediatric oncology and can be administered intravenously through push injections or 1 h infusions. The effects of administration duration on population pharmacokinetics (PK) are unknown. We described PK differences related to administration duration and the relation between PK and VCR-induced peripheral neuropathy (VIPN). PK was assessed in 1-5 occasions (1-8 samples in 24 h per occasion). Samples were analyzed using high-performance liquid chromatography/tandem mass spectrometry. Population PK of VCR and its relationship with administration duration was determined using a non-linear mixed effect. We estimated individual post-hoc parameters: area under the concentration time curve (AUC) and maximum concentration (C) in the plasma and peripheral compartment. VIPN was assessed using Common Terminology Criteria for Adverse Events (CTCAE) and the pediatric-modified total neuropathy score (ped-mTNS). Overall, 70 PK assessments in 35 children were evaluated. The population estimated that the intercompartmental clearance (IC-Cl), volume of the peripheral compartment (V), and C were significantly higher in the push group. Furthermore, higher IC-Cl was significantly correlated with VIPN development. Administration of VCR by push led to increased IC-Cl, V, and C, but were similar to AUC, compared to 1 h infusions. Administration of VCR by 1 h infusions led to similar or higher exposure of VCR without increasing VIPN.
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http://dx.doi.org/10.3390/cancers12071789DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7407622PMC
July 2020

Apparent Lack of Derived HLA Class I Presented Neoantigens Hampers Neoplastic Cell Targeting by CD8 T Cells in Langerhans Cell Histiocytosis.

Front Immunol 2019 10;10:3045. Epub 2020 Jan 10.

Immunology Laboratory Willem-Alexander Children's Hospital, Leiden University Medical Center, Leiden, Netherlands.

Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder of hematopoietic origin characterized by inflammatory lesions containing clonal histiocytes (LCH-cells) intermixed with various immune cells, including T cells. In 50-60% of LCH-patients, the somatic driver mutation, which is common in many cancers, is detected in these LCH-cells in an otherwise quiet genomic landscape. Non-synonymous mutations like can be a source of neoantigens capable of eliciting effective antitumor CD8 T cell responses. This requires neopeptides to be stably presented by Human Leukocyte Antigen (HLA) class I molecules and sufficient numbers of CD8 T cells at tumor sites. Here, we demonstrate substantial heterogeneity in CD8 T cell density in = 101 LCH-lesions, with mutated lesions displaying significantly lower CD8 T cell:CD1a LCH-cell ratios ( = 0.01) than wildtype lesions. Because LCH-lesional CD8 T cell density had no significant impact on event-free survival, we investigated whether the intracellularly expressed protein is degraded into neopeptides that are naturally processed and presented by cell surface HLA class I molecules. Epitope prediction tools revealed a single HLA class I binding derived neopeptide (KIGDFGLATK), which indeed displayed strong to intermediate binding capacity to HLA-A03:01 and HLA-A11:01 in an peptide-HLA binding assay. Mass spectrometry-based targeted peptidomics was used to investigate the presence of this neopeptide in HLA class I presented peptides isolated from several expressing cell lines with various HLA genotypes. While the HLA-A02:01 binding wildtype peptide KIGDFGLATV was traced in peptides isolated from all five cell lines expressing this HLA subtype, KIGDFGLATK was not detected in the HLA class I peptidomes of two distinct transduced cell lines with confirmed expression of HLA-A03:01 or HLA-A11:01. These data indicate that the predicted HLA class I binding and proteasome-generated neopeptides derived from the protein are not presented by HLA class I molecules. Given that the mutation is highly prevalent in chemotherapy refractory LCH-patients who may qualify for immunotherapy, this study therefore questions the efficacy of immune checkpoint inhibitor therapy in LCH.
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http://dx.doi.org/10.3389/fimmu.2019.03045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6967030PMC
November 2020

High prevalence of parent-reported sleep problems in pediatric patients with acute lymphoblastic leukemia after induction therapy.

Pediatr Blood Cancer 2020 04 15;67(4):e28165. Epub 2020 Jan 15.

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Objective: To assess sleep problems (prevalence and predictors) in pediatric patients with acute lymphoblastic leukemia (ALL) after the most intensive phase of therapy (induction).

Methods: Patients (≥2 years) treated according to the Dutch ALL-11 protocol were included. Sleep was measured using parent-reports and self-reports (Children's Sleep Habits Questionnaire; CSHQ) and actigraphy. Parental sleep (Medical Outcome Study Sleep Scale) and distress and parenting problems (Distress Thermometer for Parents) were assessed with questionnaires. Z-scores were calculated for total CSHQ scores using age-appropriate scores of healthy Dutch children. The prevalence of sleep problems (defined as a Z-score > 1) in patients with ALL was compared to healthy children (chi-square tests). Actigraphic sleep estimates were collected in healthy Dutch children (n = 86, 2-18 years) for comparison with patients (linear regression). Determinants of parent-reported child sleep (total CSHQ Z-score) were identified with regression models.

Results: Responses were collected for 124 patients (response rate 67%), comprising 123 parent-reports, 34 self-reports, and 69 actigraphy assessments. Parents reported sleep problems in 38.0% of the patients compared to 15.2% in healthy children (P < .001). Patients reported fewer sleep problems themselves: 12.1% compared to 15.8% in healthy children (P = .33). Total time in bed (B (95% CI): 22.89 (9.55-36.22)) and total sleep time (B (95% CI):16.30 (1.40-31.19)), as derived from actigraphy, were significantly longer in patients. More parent-reported child sleep problems were predicted by parenting problems, more parental sleep problems, bedroom sharing, and child's sleep medication use (explained variance: 27.4%).

Conclusions: Systematic monitoring of child and parental sleep and implementation of effective interventions may be a gateway to improve quality of survival in pediatric ALL.
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http://dx.doi.org/10.1002/pbc.28165DOI Listing
April 2020

Individualized Asparaginase Dosing in Childhood Acute Lymphoblastic Leukemia.

J Clin Oncol 2020 03 10;38(7):715-724. Epub 2020 Jan 10.

Pediatric Oncology and Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands.

Purpose: In the DCOG ALL-11 protocol, polyethylene glycol-conjugated asparaginase (PEGasparaginase) and asparaginase treatment of pediatric acute lymphoblastic leukemia are individualized with therapeutic drug monitoring (TDM). The efficacy of TDM and its effect on asparaginase-associated toxicity are reported.

Patients And Methods: After induction with 3 fixed intravenous doses of 1,500 IU/m PEGasparaginase, medium-risk patients (n = 243) received 14 individualized doses that targeted trough levels of 100-250 IU/L, standard-risk patients (n = 108) received 1 individualized dose, and high-risk patients (n = 18) received 2-5 fixed administrations (1,500 IU/m). After a neutralizing hypersensitivity reaction, patients were started with 20,000 IU/m asparaginase 3 times per week, and l-asparagine was measured to monitor asparaginase efficacy. Several asparaginase-associated toxicities were studied.

Results: The final median PEGasparaginase dose was lowered to 450 IU/m. Overall, 97% of all trough levels of nonallergic patients were > 100 IU/L. Asparagine was < 0.5 μM in 96% and 67% of the PEGasparaginase and asparaginase levels > 100 IU/L, respectively. Ten percent developed a neutralizing hypersensitivity reaction to PEGasparaginase, of which 40% were silent inactivations. The cumulative incidence of grade 3-4 pancreatitis, central neurotoxicity, and thromboses was 12%, 4%, and 6%, respectively, and not associated with asparaginase activity levels. During medium-risk intensification, 50% had increased ALT and 3% hyperbilirubinemia (both grade 3/4 and correlated with asparaginase activity levels), and 37% had grade 3/4 hypertriglyceridemia. Hypertriglyceridemia occurred less in intensification compared with ALL-10 (37% 47%), which is similar to ALL-11 but with higher asparaginase levels during intensification.

Conclusion: TDM of asparaginase results in a significant reduction of the PEGasparaginase dose with adequate asparaginase activity levels and sufficient asparagine depletion. In addition, with TDM, silent inactivation and allergic-like reactions were identified. However, the effect of reduced asparaginase activity levels on toxicity is limited.
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http://dx.doi.org/10.1200/JCO.19.02292DOI Listing
March 2020

Sleep-wake rhythm disruption is associated with cancer-related fatigue in pediatric acute lymphoblastic leukemia.

Sleep 2020 Jun;43(6)

Emma Children's Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Oncology, Cancer Center Amsterdam, Amsterdam, The Netherlands.

Study Objectives: To compare sleep-wake rhythms, melatonin, and cancer-related fatigue in pediatric patients with acute lymphoblastic leukemia (ALL) to healthy children and to assess the association between sleep-wake outcomes and cancer-related fatigue.

Methods: A national cohort of ALL patients (2-18 years) was included. Sleep-wake rhythms were measured using actigraphy and generated the following variables: Interdaily stability (IS): higher IS reflects higher stability; intradaily variability (IV): lower IV indicates less fragmentation; L5 and M10 counts: activity counts during the five least and 10 most active hours, respectively; and relative amplitude (RA): the ratio of L5 and M10 counts (higher RA reflects a more robust rhythm). The melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), was assessed in urine. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Using regression models sleep-wake rhythms, aMT6s, and cancer-related fatigue were compared to healthy children and associations between sleep-wake outcomes and cancer-related fatigue were assessed in ALL patients.

Results: In total, 126 patients participated (response rate: 67%). IS, RA, and M10 counts were lower in patients compared to healthy children (p < 0.001). aMT6s levels were comparable to healthy children (p = 0.425). Patients with ALL were more fatigued compared to healthy children (p < 0.001). Lower IS, RA and M10 counts and higher IV were significantly associated with more parent-reported cancer-related fatigue. Associations between sleep-wake rhythms and self-reported cancer-related fatigue were not statistically significant.

Conclusions: Sleep-wake rhythm impairment is associated with more cancer-related fatigue in pediatric ALL patients. Interventions aimed to improve sleep hygiene and encourage physical activity may reduce cancer-related fatigue.
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http://dx.doi.org/10.1093/sleep/zsz320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294409PMC
June 2020

Venous Thrombosis in Children with Acute Lymphoblastic Leukemia Treated on DCOG ALL-9 and ALL-10 Protocols: The Effect of Fresh Frozen Plasma.

TH Open 2019 Apr 24;3(2):e109-e116. Epub 2019 Apr 24.

Department of Pediatric Hematology, Erasmus Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.

 Venous thromboembolism (VTE) is an important complication for treatment of acute lymphoblastic leukemia (ALL) in children. Especially, ALL treatment, with therapeutics such as asparaginase and steroids, increases the thrombotic risk by reduction in procoagulant and anticoagulant proteins. Replacement of deficient natural anticoagulants by administration of fresh frozen plasma (FFP) may have a preventive effect on the occurrence of VTE.  We retrospectively analyzed all consecutive children (≤18 years) with ALL, treated on the Dutch Childhood Oncology Group (DCOG) ALL-9 and ALL-10 protocols at the Emma Children's Hospital Academic Medical Center between February 1997 and January 2012, to study the effect of FFP on VTE incidence, antithrombin and fibrinogen plasma levels, and VTE risk factors.  In total, 18/205 patients developed VTE (8.8%; 95% confidence interval [CI]: 4.9-12.7%). In all patients, VTE occurred after asparaginase administration. In total, 82/205 patients (40%) received FFP. FFP supplementation did not prevent VTE or alter plasma levels of antithrombin or fibrinogen. In the multivariate analysis, VTE occurred significantly more frequently in children ≥12 years (odds ratio [OR]: 3.89; 95% CI: 1.29-11.73) and treated according to the ALL-10 protocol (OR: 3.71; 95% CI: 1.13-12.17).  FFP supplementation does not seem to be beneficial in the prevention of VTE in pediatric ALL patients. In addition, age ≥12 years and treatment according to the DCOG ALL-10 protocol with intensive and prolonged administration of asparaginase in combination with prednisone are risk factors. There is a need for effective preventive strategies in ALL patients at high risk for VTE.
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http://dx.doi.org/10.1055/s-0039-1688412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524923PMC
April 2019

The effect of asparaginase therapy on methotrexate toxicity and efficacy in children with acute lymphoblastic leukemia.

Leuk Lymphoma 2019 12 23;60(12):3002-3010. Epub 2019 May 23.

Department of Pediatric Oncology and Hematology, Erasmus MC - Sophia Children's Hospital, Rotterdam, The Netherlands.

Asparaginase and methotrexate (MTX), both essential for pediatric acute lymphoblastic leukemia therapy, are often used concomitantly. Depending on the sequence, , asparaginase inhibits MTX-polyglutamate (MTXPG) formation, and side effects overlap. MTX toxicity and efficacy, reflected by intracellular erythrocyte MTXPG's, were compared between children treated with and without asparaginase during high dose MTX (HD-MTX) courses of the DCOG ALL-11 protocol (NL50250.078.14). Seventy-three patients, of whom 23 received asparaginase during the HD-MTX courses, were included. Grade 3-4 leukopenia and neutropenia occurred more often (59% and 86% vs. 30% and 62%). The number of infections, grade 3-4 hepatotoxicity, nephrotoxicity, and neurotoxicity did not differ. Patients with asparaginase had lower MTXPG levels, although to a lesser extent than studies. Although patients with asparaginase during HD-MTX courses showed more myelosuppression, this had no (serious) clinical consequences. Regarding the MTX efficacy, the schedule-related antagonism seen in seems less important .
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http://dx.doi.org/10.1080/10428194.2019.1613537DOI Listing
December 2019

Risk of solid subsequent malignant neoplasms after childhood Hodgkin lymphoma-Identification of high-risk populations to guide surveillance: A report from the Late Effects Study Group.

Cancer 2019 04 17;125(8):1373-1383. Epub 2018 Dec 17.

Institute for Cancer Outcomes and Survivorship, University of Alabama at Birmingham, Birmingham, Alabama.

Background: Survivors of Hodgkin lymphoma (HL) in childhood have an increased risk of subsequent malignant neoplasms (SMNs). Herein, the authors extended the follow-up of a previously reported Late Effects Study Group cohort and identified patients at highest risk for SMNs to create evidence for risk-based screening recommendations.

Methods: The standardized incidence ratio was calculated using rates from the Surveillance, Epidemiology, and End Results program as a reference. The risk of SMN was estimated using proportional subdistribution hazards regression. The cohort included 1136 patients who were diagnosed with HL before age 17 years between 1955 and 1986. The median length of follow-up was 26.6 years.

Results: In 162 patients, a total of 196 solid SMNs (sSMNs) were identified. Compared with the general population, the cohort was found to be at a 14-fold increased risk of developing an sSMN (95% confidence interval, 12.0-fold to 16.3-fold). The cumulative incidence of any sSMN was 26.4% at 40 years after a diagnosis of HL. Risk factors for breast cancer among females were an HL diagnosis between ages 10 years and 16 years and receipt of chest radiotherapy. Males treated with chest radiotherapy at age <10 years were found to be at highest risk of developing lung cancer. Survivors of HL who were treated with abdominal/pelvic radiotherapy and high-dose alkylating agents were found to be at highest risk of developing colorectal cancer and females exposed to neck radiotherapy at age <10 years were at highest risk of thyroid cancer. By age 50 years, the cumulative incidence of breast, lung, colorectal, and thyroid cancer was 45.3%, 4.2%, 9.5%, and 17.3%, respectively, among those at highest risk.

Conclusions: Survivors of childhood HL remain at an increased risk of developing sSMNs. In the current study, subgroups of survivors of HL at highest risk of specific sSMNs were identified, and evidence for screening provided.
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http://dx.doi.org/10.1002/cncr.31807DOI Listing
April 2019

A multicenter study of patients with multisystem Langerhans cell histiocytosis who develop secondary hemophagocytic lymphohistiocytosis.

Cancer 2019 03 6;125(6):963-971. Epub 2018 Dec 6.

Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.

Background: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasm characterized by the presence of abnormal CD1a-positive (CD1a )/CD207 histiocytes. Hemophagocytic lymphohistiocytosis (HLH) represents a spectrum of hyperinflammatory syndromes typified by the dysregulated activation of the innate and adaptive immune systems. Patients with LCH, particularly those with multisystem (MS) involvement, can develop severe hyperinflammation mimicking that observed in HLH. Nevertheless, to the authors' knowledge, little is known regarding the prevalence, timing, risk factors for development, and outcomes of children and young adults who develop HLH within the context of MS-LCH (hereafter referred to LCH-associated HLH).

Methods: To gain further insights, the authors conducted a retrospective, multicenter study and collected data regarding all patients diagnosed with MS-LCH between 2000 and 2015.

Results: Of 384 patients with MS-LCH, 32 were reported by their primary providers to have met the diagnostic criteria for HLH, yielding an estimated 2-year cumulative incidence of 9.3% ± 1.6%. The majority of patients developed HLH at or after the diagnosis of MS-LCH, and nearly one-third (31%) had evidence of an intercurrent infection. Patient age <2 years at the time of diagnosis of LCH; female sex; LCH involvement of the liver, spleen, and hematopoietic system; and a lack of bone involvement each were found to be independently associated with an increased risk of LCH-associated HLH. Patients with MS-LCH who met the criteria for HLH had significantly poorer 5-year survival compared with patients with MS-LCH who did not meet the criteria for HLH (69% vs 97%; P < .0001).

Conclusions: Given its inferior prognosis, further efforts are warranted to enhance the recognition and optimize the treatment of patients with LCH-associated HLH.
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http://dx.doi.org/10.1002/cncr.31893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786263PMC
March 2019

Peripheral Stem Cell Apheresis is Feasible Post Iodine-Metaiodobenzylguanidine-Therapy in High-Risk Neuroblastoma, but Results in Delayed Platelet Reconstitution.

Clin Cancer Res 2019 02 12;25(3):1012-1021. Epub 2018 Oct 12.

Princess Máxima Center for Pediatric Oncology (PMC), Utrecht, the Netherlands.

Purpose: Targeted radiotherapy with iodine-meta-iodobenzylguanidine (I-MIBG) is effective for neuroblastoma (NBL), although optimal scheduling during high-risk (HR) treatment is being investigated. We aimed to evaluate the feasibility of stem cell apheresis and study hematologic reconstitution after autologous stem cell transplantation (ASCT) in patients with HR-NBL treated with upfront I-MIBG-therapy.

Experimental Design: In two prospective multicenter cohort studies, newly diagnosed patients with HR-NBL were treated with two courses of I-MIBG-therapy, followed by an HR-induction protocol. Hematopoietic stem and progenitor cell (e.g., CD34 cell) harvest yield, required number of apheresis sessions, and time to neutrophil (>0.5 × 10/L) and platelet (>20 × 10/L) reconstitution after ASCT were analyzed and compared with "chemotherapy-only"-treated patients. Moreover, harvested CD34 cells were functionally (viability and clonogenic capacity) and phenotypically (CD33, CD41, and CD62L) tested before cryopreservation ( = 44) and/or after thawing ( = 19).

Results: Thirty-eight patients (47%) were treated with I-MIBG-therapy, 43 (53%) only with chemotherapy. Median cumulative I-MIBG dose/kg was 0.81 GBq (22.1 mCi). Median CD34 cell harvest yield and apheresis days were comparable in both groups. Post ASCT, neutrophil recovery was similar (11 days vs. 10 days), whereas platelet recovery was delayed in I-MIBG- compared with chemotherapy-only-treated patients (29 days vs. 15 days, = 0.037). Testing of harvested CD34 cells revealed a reduced post-thaw viability in the I-MIBG-group. Moreover, the viable CD34 population contained fewer cells expressing CD62L (L-selectin), a marker associated with rapid platelet recovery.

Conclusions: Harvesting of CD34 cells is feasible after I-MIBG. Platelet recovery after ASCT was delayed in I-MIBG-treated patients, possibly due to reinfusion of less viable and CD62L-expressing CD34 cells, but without clinical complications. We provide evidence that peripheral stem cell apheresis is feasible after upfront I-MIBG-therapy in newly diagnosed patients with NBL. However, as the harvest of I-MIBG-treated patients contained lower viable CD34 cell counts after thawing and platelet recovery after reinfusion was delayed, administration of I-MIBG after apheresis is preferred.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-1904DOI Listing
February 2019

Efficacy and safety of recombinant E. coli asparaginase in children with previously untreated acute lymphoblastic leukemia: A randomized multicenter study of the Dutch Childhood Oncology Group.

Pediatr Blood Cancer 2018 08 4;65(8):e27083. Epub 2018 May 4.

Department of Hemato-oncology, Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background: The efficacy and safety of recombinant Escherichia coli-asparaginase (rASNase) was compared to native E.coli asparaginase (Asparaginase medac).

Methods: One hundred and ninety-nine children with newly diagnosed acute lymphoblastic leukemia were randomized to receive one of both agents at a dose of 5,000 U/m² during induction (eight doses) and 10,000 U/m² during the postinduction phase (only high-risk patients; standard- and medium-risk patients received pegaspargase).

Results: Median trough serum asparaginase activity levels were comparable between both groups; they ranged from 143 to 182 U/l during induction and were above the target value of 100 U/l. Complete asparagine depletion in serum was achieved in 97.9% of patients, with no significant differences between both groups. On day 33 (end of induction), only two (2%) evaluable patients in each group had measurable asparagine serum levels, and complete asparagine depletion in the cerebrospinal fluid was achieved in 98.8% and 93.6% of the patients with rASNase and Asparaginase medac, respectively. During induction, 2.1% and 5% of patients developed an allergic reaction to rASNase or Asparaginase medac, respectively. Approximately 41% of the patients in both groups had a clinical allergy or enzyme inactivation to the first dose of any asparaginase preparation in postinduction. A comparable proportion of patients in both groups developed anti-asparaginase antibodies (57%) during repeated administration of asparaginase. Minimal residual disease levels at the end of induction, 5-year event-free survival, and 5-year cumulative incidence of relapse did not differ between both groups.

Conclusion: The efficacy, safety, and immunogenicity of both asparaginase preparations are comparable. This trial was registered at www.clinicaltrials.gov as #NCT00784017; EudraCT number 2006-003180-31.
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http://dx.doi.org/10.1002/pbc.27083DOI Listing
August 2018

Eating behavior during dexamethasone treatment in children with acute lymphoblastic leukemia.

Pediatr Blood Cancer 2017 Dec 9;64(12). Epub 2017 Jun 9.

Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.

Background And Aim: Large prospective studies on dexamethasone-induced changes in eating behavior, energy, and nutrient intake are lacking in pediatric acute lymphoblastic leukemia (ALL). We prospectively studied eating behavior, energy, nutrient intake, and the effect on leptin and adiponectin levels during dexamethasone administration in children with ALL.

Patients: Parents of patients with ALL (3-16 years) completed a dietary diary for their child during 4 days of dexamethasone (6 mg/m ) administration. Energy intake and nutrient intake (energy percentage = E%) were assessed and compared with the recommended intake. The Dutch Eating Behavior Questionnaire for Children was completed before start and after 4 days of dexamethasone administration by patients of 7-12 years of age. Fasting leptin and adiponectin levels were also measured before start and after 4 days of dexamethasone administration.

Results: Energy intake per day(kcal) (N = 44) increased significantly during dexamethasone (median day 1: 1,103 (717-1,572) versus day 4: 1,482 (1,176-1,822), P < 0.01), including an increase in total protein, fat, saturated fat, carbohydrate, and sodium intake. Intake of saturated fat (median day 4: 12 E%) and salt (median day 4: 1.9 g/day) exceeded the healthy range for age and gender. With respect to eating behavior, dexamethasone significantly decreased restrained eating (P = 0.04). Leptin levels as well as adiponectin levels increased significantly during the dexamethasone course.

Conclusions: Four days of dexamethasone treatment significantly increased energy intake, including excessive saturated fat and salt intake, and changed eating behavior in children with ALL. Nutritional and behavioral interventions during dexamethasone treatment are recommended to stimulate a healthy lifestyle.
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http://dx.doi.org/10.1002/pbc.26679DOI Listing
December 2017

Population pharmacokinetics of intravenous Erwinia asparaginase in pediatric acute lymphoblastic leukemia patients.

Haematologica 2017 03 10;102(3):552-561. Epub 2016 Nov 10.

Department of Pediatric Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands

Erwinia asparaginase is an important component in the treatment of pediatric acute lymphoblastic leukemia. A large variability in serum concentrations has been observed after intravenous Erwinia asparaginase. Currently, Dutch Childhood Oncology Group protocols dose alterations are based on trough concentrations to ensure adequate asparaginase activity (≥100 IU/L). The aim of this study was to describe the population pharmacokinetics of intravenous Erwinia asparaginase to quantify and gather insight into inter-individual and inter-occasion variability. The starting dose was evaluated on the basis of the derived population pharmacokinetic parameters. In a multicenter prospective observational study, a total of 714 blood samples were collected from 51 children (age 1-17 years) with acute lymphoblastic leukemia. The starting dose was 20,000 IU/m three times a week and adjusted according to trough levels from week three onwards. A population pharmacokinetic model was developed using NONMEM A 2-compartment linear model with allometric scaling best described the data. Inter-individual and inter-occasion variability of clearance were 33% and 13%, respectively. Clearance in the first month of treatment was 14% higher (<0.01). Monte Carlo simulations with our pharmacokinetic model demonstrated that patients with a low weight might require higher doses to achieve similar concentrations compared to patients with high weight. The current starting dose of 20,000 IU/m might result in inadequate concentrations, especially for smaller, lower weight patients, hence dose adjustments based on individual clearance are recommended. The protocols were approved by the institutional review boards. (Registered at NTR 3379 Dutch Trial Register; www.trialregister.nl).
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http://dx.doi.org/10.3324/haematol.2016.149195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394946PMC
March 2017

Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia.

Psychoneuroendocrinology 2016 10 11;72:190-5. Epub 2016 Jul 11.

Department of Pediatric Oncology, Erasmus MC - Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, The Netherlands; Princess Máxima Center for Pediatric Oncology, P.O. Box 85090, 3508 AB, Utrecht, The Netherlands. Electronic address:

Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3-16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m(2)), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity.
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http://dx.doi.org/10.1016/j.psyneuen.2016.07.006DOI Listing
October 2016

Bisphosphonates in Langerhans Cell Histiocytosis: An International Retrospective Case Series.

Mediterr J Hematol Infect Dis 2016 1;8(1):e2016033. Epub 2016 Jul 1.

Division of Hematology/Oncology and Bone Marrow Transplantation, Department of Pediatrics, The Hospital for Sick Children (SickKids), University of Toronto, Toronto, Ontario, Canada.

Background: Bone is the most common organ of involvement in patients with Langerhans cell histiocytosis (LCH), which is often painful and associated with significant morbidity from pathological fractures. Current first-line treatments include chemotherapy and steroids that are effective but often associated with adverse effects, whereas the disease may reactivate despite an initial response to first-line agents. Bisphosphonates are osteoclast inhibitors that have shown to be helpful in treating bone lesions of LCH. To date, there are no large international studies to describe their role in treating bone lesions of LCH.

Method: We conducted a multicenter retrospective review of 13 patients with histologically proven LCH, who had received bisphosphonates either at diagnosis or at disease reactivation.

Results: Ten patients (77%) had a single system bone disease, and 3 (23%) had bone lesions as part of multisystem disease. Median follow-up time post-bisphosphonate therapy was 4.6 years (range, 0.8 to 8.2 years). Treatment with bisphosphonates was associated with significant pain relief in almost all patients. Twelve (92%) achieved resolution of active bone lesions, and 10 out of them had no active disease for a median of 3.5 years (range, 0.8 to 5 years). One patient did not respond. No major adverse effects were reported in this series.

Conclusion: Bisphosphonates are well-tolerated drugs that can significantly improve bone pain and induce remission in active bone LCH. Future prospective studies evaluating the role of bisphosphonates in LCH are warranted.
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http://dx.doi.org/10.4084/MJHID.2016.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928520PMC
July 2016

Acute Activation of Metabolic Syndrome Components in Pediatric Acute Lymphoblastic Leukemia Patients Treated with Dexamethasone.

PLoS One 2016 30;11(6):e0158225. Epub 2016 Jun 30.

Department of Pediatric Oncology, Erasmus MC- Sophia Children's Hospital, Rotterdam, The Netherlands.

Although dexamethasone is highly effective in the treatment of pediatric acute lymphoblastic leukemia (ALL), it can cause serious metabolic side effects. Because studies regarding the effects of dexamethasone are limited by their small scale, we prospectively studied the direct effects of treating pediatric ALL with dexamethasone administration with respect to activation of components of metabolic syndrome (MetS); in addition, we investigated whether these side effects were correlated with the level of dexamethasone. Fifty pediatric patients (3-16 years of age) with ALL were studied during a 5-day dexamethasone course during the maintenance phase of the Dutch Childhood Oncology Group ALL-10 and ALL-11 protocols. Fasting insulin, glucose, total cholesterol, HDL, LDL, and triglycerides levels were measured at baseline (before the start of dexamethasone; T1) and on the fifth day of treatment (T2). Dexamethasone trough levels were measured at T2. We found that dexamethasone treatment significantly increased the following fasting serum levels (P<0.05): HDL, LDL, total cholesterol, triglycerides, glucose, and insulin. In addition, dexamethasone increased insulin resistance (HOMA-IR>3.4) from 8% to 85% (P<0.01). Dexamethasone treatment also significantly increased the diastolic and systolic blood pressure. Lastly, dexamethasone trough levels (N = 24) were directly correlated with high glucose levels at T2, but not with other parameters. These results indicate that dexamethasone treatment acutely induces three components of the MetS. Together with the weight gain typically associated with dexamethasone treatment, these factors may contribute to the higher prevalence of MetS and cardiovascular risk among survivors of childhood leukemia who received dexamethasone treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0158225PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928792PMC
July 2017

Hydrocortisone as an Intervention for Dexamethasone-Induced Adverse Effects in Pediatric Patients With Acute Lymphoblastic Leukemia: Results of a Double-Blind, Randomized Controlled Trial.

J Clin Oncol 2016 07 9;34(19):2287-93. Epub 2016 May 9.

Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Femke K. Aarsen, Saskia M.F. Pluijm, Christian M. Zwaan, Rob Pieters, and Erica L.T. van den Akker, Erasmus MC-Sophia Children's Hospital, Rotterdam; Cor van den Bos, Academic Medical Center-Emma Children's Hospital; Margreet A. Veening, Vrije Universiteit Medical Center; Helene H. Thygesen, Netherlands Cancer Institute, Amsterdam; Marc B. Bierings, University Medical Center Utrecht-Wilhelmina Children's Hospital; Lidewij T. Warris, Marry M. van den Heuvel-Eibrink, Marc B. Bierings, and Rob Pieters, Princess Máxima Center for Pediatric Oncology, Utrecht; Wim J.E. Tissing, University Medical Center Groningen, Groningen, the Netherlands.

Purpose: Dexamethasone is a key component in the treatment of pediatric acute lymphoblastic leukemia (ALL), but can induce serious adverse effects. Recent studies have led to the hypothesis that neuropsychological adverse effects may be a result of cortisol depletion of the cerebral mineralocorticoid receptors. We examined whether including a physiologic dose of hydrocortisone in dexamethasone treatment can reduce neuropsychologic and metabolic adverse effects in children with ALL.

Patients And Methods: We performed a multicenter, double-blind, randomized controlled trial with a crossover design. Of 116 potentially eligible patients (age 3 to 16 years), 50 were enrolled and were treated with two consecutive courses of dexamethasone in accordance with Dutch Childhood Oncology Group ALL protocols. Patients were randomly assigned to receive either hydrocortisone or placebo in a circadian rhythm (10 mg/m(2)/d) during both dexamethasone courses. Primary outcome measure was parent-reported Strength and Difficulties Questionnaire in Dutch, which assesses psychosocial problems. Other end points included questionnaires, neuropsychological tests, and metabolic parameters.

Results: Of 48 patients who completed both courses, hydrocortisone had no significant effect on outcome; however, a more detailed analysis revealed that in 16 patients who developed clinically relevant psychosocial adverse effects, addition of hydrocortisone substantially reduced their Strength and Difficulties Questionnaire in Dutch scores in the following domains: total difficulties, emotional symptoms, conduct problems, and impact of difficulties. Moreover, in nine patients who developed clinically relevant, sleep-related difficulties, addition of hydrocortisone reduced total sleeping problems and disorders of initiating and maintaining sleep. In contrast, hydrocortisone had no effect on metabolic parameters.

Conclusion: Our results suggest that adding a physiologic dose of hydrocortisone to dexamethasone treatment can reduce the occurrence of serious neuropsychological adverse effects and sleep-related difficulties in pediatric patients with ALL.
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http://dx.doi.org/10.1200/JCO.2015.66.0761DOI Listing
July 2016

[A boy with a painful tumour of his skull].

Ned Tijdschr Geneeskd 2016 ;160:A9939

Ziekenhuis Gelderse Vallei, afd. Kindergeneeskunde, Ede.

A 12-year-old boy presented with an increasing painful swelling of the skull. Physical examination revealed in the left parieto-occipital region a skin-coloured solid mass of 2-3 cm in diameter. The X-ray of the skull was highly suspicious for Langerhans cell histiocytosis. Histopathology of a biopsy of the lesion confirmed the diagnosis.
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May 2017

Executive Dysfunction 25 Years after Treatment with Cranial Radiotherapy for Pediatric Lymphoid Malignancies.

J Int Neuropsychol Soc 2015 Oct 22;21(9):657-69. Epub 2015 Sep 22.

4Department of Pediatrics,Division of Pediatric Hematology/Oncology,VU University Medical Center,Amsterdam,The Netherlands.

The first cohorts to survive childhood lymphoid malignancies treated with cranial irradiation are now aging into adulthood, and concerns are growing about the development of radiotherapy-induced cognitive deficits in the aging brain. These deficits are hypothesized to increase over time. Their impact on daily functioning of older survivors, and the accompanying need for interventions, should be anticipated. By describing a detailed profile of executive function deficits and their associations with age, specific targets for neuropsychological intervention can be identified. Fifty survivors of childhood lymphoid malignancies and 58 related controls were assessed with the Amsterdam Neuropsychological Tasks program. The survivors were on average 31.1 (4.9) years old, treated with 22.5 (6.8) Gy cranial irradiation, and examined on average 25.5 (3.1) years after diagnosis. The survivors showed significantly decreased response speed, irrespective of the task at hand. Furthermore, we found deficits in working memory capacity, inhibition, cognitive flexibility, executive visuomotor control, attentional fluctuations, and sustained attention. Older age was associated with poorer performance on executive visuomotor control and inhibition. On executive visuomotor control, 50% of female survivors performed more than 1.5 SD below average, versus 15.4% of male survivors. The combination of visuospatial working memory problems and decreasing executive visuomotor control could result in difficulty with learning new motor skills at older ages, like walking with a cane. Deterioration of executive control and inhibition may result in decreased behavioral and emotional regulation in aging survivors. Especially the deficiency in executive visuomotor control in female survivors should be considered for (prophylactic) intervention.
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http://dx.doi.org/10.1017/S1355617715000788DOI Listing
October 2015

The presence of CXCR4 CD1a cells at onset of Langerhans cell histiocytosis is associated with a less favorable outcome.

Oncoimmunology 2016 Mar 31;5(3):e1084463. Epub 2015 Aug 31.

Immunology Laboratory, Willem Alexander Children's Hospital/Leiden University Medical Center, Leiden, the Netherlands; Division of Hematology/Oncology, Hospital for Sick Children/University of Toronto, Toronto, Canada.

Purpose: Langerhans Cell Histiocytosis (LCH) is a neoplastic disorder characterized by tissue accumulating CD1a histiocytes which frequently carry somatic mutations. Irrespective of mutation status, these LCH-cells display constitutively active kinases belonging to the MAPK pathway. We evaluated, in retrospect, the contribution of individual components of the MAPK-activating and chemotaxis-promoting TNF-CXCR4-CXCL12 axis to LCH manifestation and outcome.

Experimental Design: CXCR4, CXCL12 and TNF protein expression was immunohistochemically analyzed in 70 LCH-affected biopsies. The presence of CXCR4CD1a cells in peripheral blood (PB) and/or bone marrow (BM) samples was evaluated by flowcytometry in 13 therapy-naive LCH-patients.

Results: CXCL12 was detected in 68/70 (97%) biopsies. CXCR4LCH-cells were present in 50/70 (71%) biopsies; their presence was associated with higher levels of intralesional TNF. Circulating CD1aCXCR4 cells were detected in 4/13 (31%) therapy-naïve LCH-patients which displayed BRAF (2/4), MAP2K1 (1/4) or no (1/4) mutations in their tissues. These CD11c co-expressing CD1aCXCR4cells migrated to CXCL12 in chemotaxis assays. Lesional CXCR4LCH-cells were detected in 18/20 cases who presented with LCH manifestation at multiple sites and in 5/23 (22%) patients who developed additional lesions after initially presenting with a single lesion. The CXCR4 status at onset proved to be an independent risk factor for LCH reactivation in multivariate analysis (odds ratio 10.4, = 0.034).

Conclusions: This study provides the first evidence that CXCR4 is involved in the homing and retention of LCH-cells in CXCL12-expressing tissues and qualifies CXCR4 as a candidate prognostic marker for less favorable disease outcome.
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http://dx.doi.org/10.1080/2162402X.2015.1084463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323006PMC
March 2016

Cladribine and cytarabine in refractory multisystem Langerhans cell histiocytosis: results of an international phase 2 study.

Blood 2015 Sep 20;126(12):1415-23. Epub 2015 Jul 20.

Department of Pediatric Oncology, Emma Children's Hospital/Academic Medical Center, Amsterdam, The Netherlands.

An international phase 2 study combining cladribine and cytarabine (Ara-C) was initiated for patients with refractory, risk-organ-positive Langerhans cell histiocytosis (LCH) in 2005. The protocol, comprising at least two 5-day courses of Ara-C (1 g/m(2) per day) plus cladribine (9 mg/m(2) per day) followed by maintenance therapy, was administered to 27 patients (median age at diagnosis, 0.7 years; median follow-up, 5.3 years). At inclusion, all patients were refractory after at least 1 course of vinblastine (VBL) plus corticosteroid, all had liver and spleen involvement, and 25 patients had hematologic cytopenia. After 2 courses, disease status was nonactive (n = 2), better (n = 23), or stable (n = 2), with an overall response rate of 92%. Median disease activity scores decreased from 12 at the start of therapy to 3 after 2 courses (P < .0001). During maintenance therapy, 4 patients experienced reactivation in risk organs. There were 4 deaths; 2 were related to therapy toxicity and 2 were related to reactivation. All patients experienced severe toxicity, with World Health Organization grade 4 hematologic toxicity and 6 documented severe infections. The overall 5-year survival rate was 85% (95% confidence interval, 65.2%-94.2%). Thus, the combination of cladribine/Ara-C is effective therapy for refractory multisystem LCH but is associated with high toxicity.
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http://dx.doi.org/10.1182/blood-2015-03-635151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624454PMC
September 2015

Management and Outcome of Patients With Langerhans Cell Histiocytosis and Single-Bone CNS-Risk Lesions: A Multi-Institutional Retrospective Study.

Pediatr Blood Cancer 2015 Dec 14;62(12):2162-6. Epub 2015 Jul 14.

Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.

Background: Children with Langerhans cell histiocytosis (LCH) and single-bone CNS-risk lesions have been reported to be at increased risk of diabetes insipidus (DI), central nervous system neurodegeneration (CNS-ND), and recurrence of disease. However, it is unknown whether the addition of chemotherapy or radiotherapy changes outcomes in these patients.

Methods: Ten pediatric institutions across North America and Europe contributed data of their patients with LCH and single-bone CNS-risk lesions. Clinical information on age, sex, specific craniofacial site involvement, and intracranial extension at diagnosis, therapy, and disease course was collected for all eligible patients.

Results: The final analysis included 93 eligible children who were either treated with systemic therapy (chemotherapy, chemo-radiotherapy, or radiotherapy) or local therapy (biopsy, curettage, and/or intralesional steroids). Fifty-nine patients had systemic and 34 had local therapy. The 5-year event-free survival (EFS) and overall survival (OS) were 80 ± 5% and 98 ± 2% in the systemic therapy group versus 85 ± 6% and 95 ± 5% in the local therapy group. There was no statistically significant difference between either group with regard to EFS (P = 0.26) and OS (P = 0.78). On multivariable analysis, there was no significant difference among the two treatment groups after adjusting for site and intracranial soft tissue extension, nor any trend favoring systemic therapy (HR = 2.26, 95% CI = 0.77-6.70; P = 0.14).

Conclusion: Systemic therapy may not reduce the risk of recurrence or late sequelae in children with LCH and single-bone CNS-risk lesions as compared to local treatment.
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http://dx.doi.org/10.1002/pbc.25645DOI Listing
December 2015

MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis.

Genes Chromosomes Cancer 2015 Jun 31;54(6):361-8. Epub 2015 Mar 31.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

Langerhans cell histiocytosis (LCH) is now understood to be a neoplastic disease in which over 50% of cases have somatic activating mutations of BRAF. However, the extracellular signal-related (ERK) pathway is activated in all cases including those with wild type BRAF alleles. Here, we applied a targeted massively parallel sequencing panel to 30 LCH samples to test for the presence of additional genetic alterations that might cause ERK pathway activation. In 20 BRAF wild type samples, we found 3 somatic mutations in MAP2K1 (MEK1) including C121S and C121S/G128D in the kinase domain, and 56_61QKQKVG>R, an in-frame deletion in the N-terminal regulatory domain. All three variant proteins constitutively phosphorylated ERK in in vitro kinase assays. The C121S/G128D and 56_61QKQKVG>R variants were resistant to the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib in vitro. Within the entire sample set, we found 3 specimens with mutations in MAP3K1 (MEKK1), including two truncation mutants, T779fs and T1481fs; T1481fs encoded an unstable and nonfunctional protein when expressed in vitro. T779fs was present in a specimen carrying BRAF V600E. The third variant was a single nucleotide substitution, E1286V, which was fully functional and is likely a germline polymorphism. These results indicate that LCH cells can harbor additional genetic alterations in the RAS-RAF-MEK pathway which, in the case of MAP2K1, may be responsible for ERK activation in a wild type BRAF setting. The resistance of some of these variants to trametinib may also have clinical implications for the combined use of RAF and MEK inhibitors in LCH.
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http://dx.doi.org/10.1002/gcc.22247DOI Listing
June 2015

Somatic activating ARAF mutations in Langerhans cell histiocytosis.

Blood 2014 May 20;123(20):3152-5. Epub 2014 Mar 20.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA;

The extracellular signal-regulated kinase (ERK) signaling pathway is activated in Langerhans cell histiocytosis (LCH) histiocytes, but only 60% of cases carry somatic activating mutations of BRAF. To identify other genetic causes of ERK pathway activation, we performed whole exome sequencing on purified LCH cells in 3 cases. One patient with wild-type BRAF alleles in his histiocytes had compound mutations in the kinase domain of ARAF. Unlike wild-type ARAF, this mutant was a highly active mitogen-activated protein kinase kinase in vitro and was capable of transforming mouse embryo fibroblasts. Mutant ARAF activity was inhibited by vemurafenib, a BRAF inhibitor, indicating the importance of fully evaluating ERK pathway abnormalities in selecting LCH patients for targeted inhibitor therapy.
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http://dx.doi.org/10.1182/blood-2013-06-511139DOI Listing
May 2014

A prospective study on drug monitoring of PEGasparaginase and Erwinia asparaginase and asparaginase antibodies in pediatric acute lymphoblastic leukemia.

Blood 2014 Mar 21;123(13):2026-33. Epub 2014 Jan 21.

Department of Pediatric Oncology/Hematology, Erasmus MC-Sophia Children's Hospital, Rotterdam, The Netherlands;

This study prospectively analyzed the efficacy of very prolonged courses of pegylated Escherichia coli asparaginase (PEGasparaginase) and Erwinia asparaginase in pediatric acute lymphoblastic leukemia (ALL) patients. Patients received 15 PEGasparaginase infusions (2500 IU/m(2) every 2 weeks) in intensification after receiving native E coli asparaginase in induction. In case of allergy to or silent inactivation of PEGasparaginase, Erwinia asparaginase (20 000 IU/m(2) 2-3 times weekly) was given. Eighty-nine patients were enrolled in the PEGasparaginase study. Twenty (22%) of the PEGasparaginase-treated patients developed an allergy; 7 (8%) showed silent inactivation. The PEGasparaginase level was 0 in all allergic patients (grade 1-4). Patients without hypersensitivity to PEGasparaginase had serum mean trough levels of 899 U/L. Fifty-nine patients were included in the Erwinia asparaginase study; 2 (3%) developed an allergy and none silent inactivation. Ninety-six percent had at least 1 trough level ≥100 U/L. The serum asparagine level was not always completely depleted with Erwinia asparaginase in contrast to PEGasparaginase. The presence of asparaginase antibodies was related to allergies and silent inactivation, but with low specificity (64%). Use of native E coli asparaginase in induction leads to high hypersensitivity rates to PEGasparaginase in intensification. Therefore, PEGasparaginase should be used upfront in induction, and we suggest that the dose could be lowered. Switching to Erwinia asparaginase leads to effective asparaginase levels in most patients. Therapeutic drug monitoring has been added to our ALL-11 protocol to individualize asparaginase therapy.
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http://dx.doi.org/10.1182/blood-2013-10-534347DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3968389PMC
March 2014

Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies.

J Clin Oncol 2013 Sep 19;31(27):3378-88. Epub 2013 Aug 19.

Ilse Schuitema and Leo M.J. de Sonneville, Leiden University, Leiden; Ilse Schuitema, Marita Daams, Frederik Barkhof, Eline van Dulmen-den Broeder, and Anjo J.P. Veerman, Vrije Universiteit University Medical Center; Helena J. van der Pal and Cor van den Bos, Academic Medical Center, Amsterdam, the Netherlands; Sabine Deprez, Anne Uyttebroeck, and Stefan Sunaert, University Hospitals Leuven; Wim Van Hecke, icoMetrix, Leuven, Belgium.

Purpose: CNS-directed chemotherapy (CT) and cranial radiotherapy (CRT) for childhood acute lymphoblastic leukemia or lymphoma have various neurotoxic properties. This study aimed to assess their impact on the maturing brain 20 to 30 years after diagnosis, providing a much stronger perspective on long-term quality of life than previous studies.

Patients And Methods: Ninety-three patients treated between 1978 and 1990 at various intensities, with and without CRT, and 49 healthy controls were assessed with magnetic resonance diffusion tensor imaging (DTI) and neuropsychological tests. Differences in fractional anisotropy (FA)-a DTI measure describing white matter (WM) microstructure-were analyzed by using whole brain voxel-based analysis.

Results: CRT-treated survivors demonstrated significantly decreased FA compared with controls in frontal, parietal, and temporal WM tracts. Trends for lower FA were seen in the CT-treated survivors. Decreases in FA correlated well with neuropsychological dysfunction. In contrast to the CT group and controls, the CRT group showed a steep decline of FA with age at assessment. Younger age at cranial irradiation and higher dosage were associated with worse outcome of WM integrity.

Conclusion: CRT-treated survivors show decreased WM integrity reflected by significantly decreased FA and associated neuropsychological dysfunction 25 years after treatment, although effects of CT alone seem mild. Accelerated aging of the brain and increased risk of early onset dementia are suspected after CRT, but not after CT.
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http://dx.doi.org/10.1200/JCO.2012.46.7050DOI Listing
September 2013