There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylota... more There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m 2 and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of venoocclusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). (Blood. 2012;120(5): 978-984)
High-dose methotrexate (HDMTX) is a central component in the treatment of acute lymphoblastic leu... more High-dose methotrexate (HDMTX) is a central component in the treatment of acute lymphoblastic leukemia, osteosarcoma, and some lymphomas and brain tumors. MTX is given at lethal doses and then is followed by rescue treatment with folinic acid (FA). Despite FA rescue, many patients suffer severe toxicity. The pharmacokinetics of FA rescue have not been sufficiently studied. However, optimization of FA rescue could potentially increase anti-tumor effects, whilst decreasing organ toxicity. Here, we describe our efforts to establish and optimize a liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the simultaneous determination of five essential components of the folate cycle, as well as MTX and its two metabolites. The method was applied to 6 individual patients receiving HDMTX, with 3 or 4 measurements for each patient. The method allows analysis of samples that were initially frozen. This notion, together with the test results in the 6 pilot patients, shows the feasibility of this method to study MTX and FA pharmacokinetics during HDMTX treatment. The method has the potential to optimize HDMTX and FA rescue treatment in individual patients.
British Journal of Clinical Pharmacology, Sep 11, 2022
AimsHigh‐dose methotrexate (HDMTX) is an essential part of the treatment of several adult and pae... more AimsHigh‐dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity.MethodsAnonymized, de‐identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non‐profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite.ResultsA total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three‐compartment model adequately fitted the data. Time‐dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose‐normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence.ConclusionWe developed a population pharmacometric model that considers weight, albumin and time‐dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.
Although gain of 1q occurs in 25% of Burkitt lymphomas (BLs) and 10% of pediatric high hyperdiplo... more Although gain of 1q occurs in 25% of Burkitt lymphomas (BLs) and 10% of pediatric high hyperdiploid acute lymphoblastic leukemias (ALLs), little is known about the origin, molecular genetic characteristics and functional outcome of dup(1q) in these disorders. Ten dup(1q)-positive BLs/ALLs were investigated by tiling resolution (32k) array CGH analysis, which revealed that the proximal breakpoints in all cases were near-centromeric, in eight of them clustering within a 1.4 Mb segment in 1q12-21.1. The 1q distal breakpoints were heterogeneous, being more distal in the ALLs than in the BLs. The minimally gained segments in the ALLs and BLs were 57.4 Mb [dup(1)(q22q32.3)] and 35 Mb [dup(1)(q12q25.2)], respectively. Satellite II DNA on 1q was not hypomethylated, as ascertained by Southern blot analyses of 15 BLs/ALLs with and without gain of 1q, indicating that aberrant methylation was not involved in the origin of dup(1q), as previously suggested for other neoplasms with 1q rearrangements. Global gene expression analyses revealed that five genes in the minimally 57.4 Mb gained region-B4GALT3, DAP3, RGS16, TMEM183A and UCK2-were significantly overexpressed in dup(1q)-positive ALLs compared with high hyperdiploid ALLs without dup(1q). The DAP3 and UCK2 genes were among the most overexpressed genes in the BL case with gain of 1q investigated. The DAP3 protein has been reported to be highly expressed in invasive glioblastoma multiforme cells, whereas expression of the UCK2 protein has been correlated with sensitivity to anticancer drugs. However, involvement of these genes in dup(1q)-positive ALLs and BLs has previously not been reported.
Abstract 69 Infant (< 1 year of age) acute lymphoblastic leukemia (ALL) is a rare disease ... more Abstract 69 Infant (< 1 year of age) acute lymphoblastic leukemia (ALL) is a rare disease characterized by rearrangements of the Mixed Lineage Leukemia (MLL) gene at 11q23 and a poor prognosis. In an effort to determine the total complement of somatic mutations occurring in this high risk leukemia, we performed paired-end whole genome sequencing (WGS) on diagnostic leukemia blasts and matched germ line samples from 22 infants with MLL rearranged ALL using the Illumina platform. In addition, we sequenced 2 paired relapse samples. Somatic alterations, including single nucleotide variations (SNV), and structural variations (SV) including insertions, deletions, inversion, and inter- and intra-chromosomal rearrangements were detected using complementary analysis pipelines including Bambino, CREST and CONSERTING. Validation of identified somatic mutations was performed using PCR amplification of the leukemia and germ line DNA followed by Sanger or 454-based sequencing, or by array-based capture followed by Illumina-based sequencing. Analysis of the structure of MLL rearrangements at the base pair level revealed that over half had complex rearrangements that involved either three or more chromosomes, or contained at the breakpoints deletions, amplifications, insertions, or inversion of sequences. In five of the complex cases, chromosomal rearrangements were predicted to generate not only a MLL-partner gene fusion, but also novel in-frame fusions including KRAS-MLL; RAD51B-MLL / AFF1-RAD51B; MLLT10-CTNNAP3B; MLLT10-ATP5L / ATP5L-YPEL4; and CRTAM-GNL3. An analysis of the sequence surrounding the breakpoints of MLL and its partner genes suggest that the predominant mechanism of rearrangement involved non-homologous end joining. An analysis of the total number of non-silent mutations revealed infant ALL to have the lowest frequency of non-silent somatic mutations of any cancer sequenced to date. After removal of SVs and CNAs associated with the MLL rearrangements, a mean of only 2 somatic SVs and 2 SNVs affecting the coding region of annotated genes or regulatory RNAs were detected per case, with a range of non-silent mutation of between 0 and 11 per case (0–7 SV and 0–5 SNV). Despite the paucity of mutations several pathways were recurrently targeted. Mutations leading to activation of signaling through the PI3K/RAS pathway was observed in 45% of the cases with mutation of individual components including KRAS (n=4), NRAS (n=2), and non-recurrent mutations in NF1, PTPN11, PIK3R1, and the GTPase activating protein ARHGAP32 (p200Rho/GAP), which mediates cross-talk between RAS and Rho signaling. Other pathways altered include B cell differentiation, with 23% of cases containing mono-allelic deletion or gains of PAX5, 14% with deletions of the CDKN2A/B, and 2 cases with focal deletions of the non-coding RNA genes DLEU1/2. WGS of two infant ALL relapse samples and comparison with the data from their matched diagnostic samples revealed a marked increase in the number of mutations at relapse with additional SVs, SNVs, and CNAs identified. Moreover, an analysis of the allelic ratios of mutated genes revealed clonal heterogeneity at diagnosis with relapse appearing to arise from a minor diagnostic clone. Because of the exceedingly low frequency of mutations detected in infant ALL, we decided to define the frequency of non-silent SNVs in MLL rearranged leukemia occurring in older children (7–19 years of age). Exome sequencing was performed on 13 MLL leukemias (8 ALLs and 5 AMLs). This analysis revealed that non-infant pediatric MLL rearranged leukemias harbor a significantly higher number of non-silent somatic SNVs than infant ALL (mean 8/case in older patients versus 2/case in infants, p<0.001). Although the increased frequency of mutations may be a reflection of the older age, the low number of cooperating mutations in infants raises the possibility that the target cell of transformation differs between infants and older children, with the cells present during early development requiring fewer cooperating mutations to induce leukemia. In summary our analysis demonstrated an exceedingly small number of mutations required to generate infant MLL rearranged leukemia. The number of detected somatic mutations may represent the lower limit of mutations required to transform a normal human cell into cancer. Disclosures: Fioretos: Cantargia AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Qlucore AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Methotrexate (MTX), an anti-folate, is administered at high-doses to treat malignancies in childr... more Methotrexate (MTX), an anti-folate, is administered at high-doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high-dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life-threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 standard deviations above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of lab results that do not directly correspond to the algorithm prove to be a limitat...
Malignant leptomeningeal dissemination poses significant treatment challenges and is difficult to... more Malignant leptomeningeal dissemination poses significant treatment challenges and is difficult to eradicate. The disadvantages of conventional chemotherapy and intrathecal anticancer agents are due to limited drug penetration through the blood-brain barrier, low cytotoxic concentrations in the cerebrospinal fluid (CSF), and rapid metabolism. DepoCyte is a new liposomal, slow-release preparation of cytarabine for intrathecal use that maintains cytotoxic concentrations for as long as 14 days or more and improves the distribution of free cytarabine in the CSF. Here, we report our experience concerning thirteen pediatric patients age 1–13 years who received more than 40 treatment doses with liposomal cytarabine either as a therapeutic or prophylactic agent in doses of either 35 mg or 50 mg (children 11 years and younger or 12 years and older, respectively). There were four patients with refractory/relapsing neuroblastoma stage IV, two of whom had confirmed central nervous system (CNS) i...
Clinical Journal of the American Society of Nephrology, 2022
Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflamm... more Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either “strong” or “weak/conditional”) were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent...
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploi... more Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploidy [51-67 chromosomes] and the t(12;21)(p13;q22) [ETV6/RUNX1 fusion] representing the most frequent abnormalities. Although these arise in utero, there is long latency before overt ALL, showing that additional changes are needed. Gene dysregulation through hypermethylation may be such an event; however, this has not previously been investigated in a detailed fashion. We performed genome-wide methylation profiling using bacterial artificial chromosome arrays and promoter-specific analyses of high hyperdiploid and ETV6/RUNX1-positive ALLs. In addition, global gene expression analyses were performed to identify associated expression patterns. Unsupervised cluster and principal component analyses of the chromosome-wide methylome profiles could successfully subgroup the two genetic ALL types. Analysis of all currently known promoter-specific CpG islands demonstrated that several B-cell-and neoplasia-associated genes were hypermethylated and underexpressed, indicating that aberrant methylation plays a significant leukemogenic role. Interestingly, methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes and the tri-/tetrasomic chromosomes in the high hyperdiploid ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of high hyperdiploid ALL but also for other disorders with acquired or constitutional numerical chromosome anomalies.
Introduction. Results from St. Jude and M. D. Anderson, USA, suggested that AML children < 10 ... more Introduction. Results from St. Jude and M. D. Anderson, USA, suggested that AML children < 10 years have significantly better outcome than patients aged 10–21 years. Similarly, the Medical Research Council, UK, showed superior survival in children < 10 years due to a lower relapse rate compared to 10 – 15 year olds. We describe the AML outcome by age in the Nordic countries. Patients. Within the population based NOPHO AML protocols (NOPHO-AML 93 and NOPHO-AML 2004) we treated 403 patients aged 0 – 18 years from 1993 – 2007. Patients with Down syndrome and AML-M3 were excluded. The children were divided into three age groups; 0 –1 year (27%), 2 –9 years (41%) and 10+ years (32%). The oldest age group had a male preponderance. MLL-aberrations were more common among the youngest and t(8;21) among the oldest. FAB-type M5 was seen in 35% of 0–1 year olds versus only in 16% of children aged 10+. 0 – 1 year n= 109 2 –9 years n = 165 10 – 18 years n = 129 Boys/girls 44/67 = 0.67 80...
The NOPHO-AML 2004 protocol includes a post-consolidation randomization to Gemtuzumab ozagamicin,... more The NOPHO-AML 2004 protocol includes a post-consolidation randomization to Gemtuzumab ozagamicin, (GO, Mylotarg) or no further therapy. Randomization is offered to all standard-risk patients and to high-risk patients without a donor for SCT. GO is administered as a 2-hour infusion of 5 mg/m2 at least four weeks after the last consolidation including high-dose cytarabine and etoposide (HA2E). GO is repeated following a scheduled interval of three weeks. By August 2007 a total of 45 patients have been randomized (39 with standard-risk and 6 with high-risk AML). An additional nine patients were eligible but not randomized due to clinical decision (n=2), parental refusal (n=6), or administrative error (n=1). Twenty-three were randomized to receive GO. Detailed toxicity data were available from 21 of these patients. The median age was 3 years (six patients less than 2 years of age) at the time of GO. The median interval from HA2E to first GO was 32 days (range 27 – 43). The median interv...
3529 Introduction: High hyperdiploidy (51–67 chromosomes) is one of the most common cytogenetic a... more 3529 Introduction: High hyperdiploidy (51–67 chromosomes) is one of the most common cytogenetic abnormality patterns in childhood B-cell precursor acute lymphoblastic leukemia (ALL) and the clinical and cytogenetic features are well characterized. High hyperdiploidy in pediatric acute myeloid leukemia (AML), however, is a rare cytogenetic finding. It is most often categorized as a complex karyotype, which is considered associated with an unfavorable outcome. The group of complex karyotypes is heterogeneous and the significance of multiple additional chromosomes with or without structural abnormalities among the pediatric hyperdiploid AML patients is relatively unknown. Current knowledge in this field is based on small adult series or case reports. In this descriptive study we describe the clinical - and cytogenetic features in childhood hyperdiploid AML with a modal chromosome number at 50 or more. We report a series of 29 children from the Nordic Countries diagnosed with high hyper...
Introduction The World Health Organization (WHO) classification of myeloid neoplasms and acute le... more Introduction The World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia was revised in 2008 and is based on genetic characteristics and morphology. The classification incorporates newly recognized entities and emphasizes, more than previously, the pivotal role of cytogenetic abnormalities aiming at identifying biological and clinical entities as basis for a stratified treatment. The classification of acute myeloid leukemia (AML) is primarily based on adult studies. However, the frequency of cytogenetic changes varies among children and adults and the relevance of the 2008 revised WHO classification in pediatric AML has not yet been elucidated. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based pediatric AML cohort. Methods We included children 0-18 years of age diagnosed with de novo AML in the Nordic countries (Sweden, Norway, Finland, Iceland and Denmark) and Hong Kong treated accor...
Background. The core-binding factor AMLs, t(8;21)(q22;q22), AML1-ETO or RUNX1-RUNX1T1 and inv(16)... more Background. The core-binding factor AMLs, t(8;21)(q22;q22), AML1-ETO or RUNX1-RUNX1T1 and inv(16)(p13q22), CBFB–MYH11, are considered as favorable risk factors in AML with superior event-free survival (EFS) and overall survival (OS). However, within the AML protocol from the Nordic society of pediatric hematology/oncology (NOPHO) from 2004 we observed a decrease in EFS for t(8;21) AML. Material. We analyzed all children with t(8;21) or inv(16) treated on NOPHO-AML 93 and NOPHO-AML 2004 from Denmark, Finland, Iceland, Norway, and Sweden from 1993 to 2013 and patients from countries later joining the NOPHO-AML 2004 protocol; Estonia (2004), Hong Kong (2007), Belgium and the Netherlands (2010). The choice of anthracycline during induction changed from two courses including doxorubicin (75 mg/m2 in each course), Dox-Dox, in the NOPHO-AML 93 to idarubicin (36 mg/m2) and mitoxantrone (30 mg/m2), Ida-Mitox, in NOPHO-AML 04. After the observation of a decrease in EFS in patients with t(8;21...
BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patient... more BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine best can be used as a predictor for severely delayed MTX elimination thus a guide for therapeutic interventions to minimize renal toxicity.
Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity... more Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is ab...
Journal of pediatric hematology/oncology, Jan 26, 2016
We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate,... more We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received TIT and 9/11 in the liposomal cytarabine arm received liposomal cytarabine. Arachnoiditis occurred in all initial 5 patients given liposomal cytarabine and intrathecal prednisolone succinate. Subsequently liposomal cytarabine was given with systemic dexamethasone. Neurotoxicity occurred at 6/27 liposomal cytarabine administrations with concomitant dexamethasone (22%). More liposomal cytarabine-treated patients experienced neurotoxicity in relation to intrathecal therapy during at least 1 cycle compared with TIT-treated patients (6/9 [67%] vs. 3/28 [11%], P=0.002). Apart from intermittent lower extremity sensory pain in 1 liposomal cytarabine-treated patient, no permanent adverse neurological...
There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylota... more There are no data on the role of postconsolidation therapy with gemtuzumab ozogamicin (GO; Mylotarg) in children with acute myeloid leukemia (AML). The NOPHO-AML 2004 protocol studied postconsolidation randomization to GO or no further therapy. GO was administered at 5 mg/m 2 and repeated after 3 weeks. We randomized 120 patients; 59 to receive GO. Survival was analyzed on an intention-to-treat basis. The median follow-up for patients who were alive was 4.2 years. Children who received GO showed modest elevation of transaminase and bilirubin without signs of venoocclusive disease. Severe neutropenia followed 95% and febrile neutropenia 40% of the GO courses. Only a moderate decline in platelet count and a minor decrease in hemoglobin occurred. Relapse occurred in 24 and 25 of those randomized to GO or no further therapy. The median time to relapse was 16 months versus 10 months (nonsignificant). The 5-year event-free survival and overall survival was 55% versus 51% and 74% versus 80% in those randomized to receive GO or no further therapy, respectively. Results were similar in all subgroups. In conclusion, GO therapy postconsolidation as given in this trial was well tolerated, showed a nonsignificant delay in time to relapse, but did not change the rate of relapse or survival (clinicaltrials.gov identifier NCT00476541). (Blood. 2012;120(5): 978-984)
High-dose methotrexate (HDMTX) is a central component in the treatment of acute lymphoblastic leu... more High-dose methotrexate (HDMTX) is a central component in the treatment of acute lymphoblastic leukemia, osteosarcoma, and some lymphomas and brain tumors. MTX is given at lethal doses and then is followed by rescue treatment with folinic acid (FA). Despite FA rescue, many patients suffer severe toxicity. The pharmacokinetics of FA rescue have not been sufficiently studied. However, optimization of FA rescue could potentially increase anti-tumor effects, whilst decreasing organ toxicity. Here, we describe our efforts to establish and optimize a liquid chromatography tandem mass spectrometric (LC-MS/MS) method for the simultaneous determination of five essential components of the folate cycle, as well as MTX and its two metabolites. The method was applied to 6 individual patients receiving HDMTX, with 3 or 4 measurements for each patient. The method allows analysis of samples that were initially frozen. This notion, together with the test results in the 6 pilot patients, shows the feasibility of this method to study MTX and FA pharmacokinetics during HDMTX treatment. The method has the potential to optimize HDMTX and FA rescue treatment in individual patients.
British Journal of Clinical Pharmacology, Sep 11, 2022
AimsHigh‐dose methotrexate (HDMTX) is an essential part of the treatment of several adult and pae... more AimsHigh‐dose methotrexate (HDMTX) is an essential part of the treatment of several adult and paediatric malignancies. Despite meticulous supportive care during HDMTX administration, severe toxicities, including acute kidney injury (AKI), may occur contributing to patient morbidity. Population pharmacokinetics provide a powerful tool to predict time to clear HDMTX and adjust subsequent doses. We sought to develop and validate pharmacokinetic models for HDMTX in adults with diverse malignancies and to relate systemic exposure with the occurrence of severe toxicity.MethodsAnonymized, de‐identified data were provided from 101 US oncology practices that participate in the Guardian Research Network, a non‐profit clinical research consortium. Modelled variables included clinical, laboratory, demographic and pharmacological data. Population pharmacokinetic analysis was performed by means of nonlinear mixed effects modelling using MonolixSuite.ResultsA total of 693 HDMTX courses from 243 adults were analysed, of which 62 courses (8.8%) were associated with stage 2/3 acute kidney injury (43 stage 2, 19 stage 3). A three‐compartment model adequately fitted the data. Time‐dependent serum creatinine, baseline serum albumin and allometrically scaled bodyweight were clinically significant covariates related to methotrexate clearance. External evaluation confirmed a satisfactory predictive performance of the model in adults receiving HDMTX. Dose‐normalized methotrexate concentration at 24 and 48 hours correlated with AKI incidence.ConclusionWe developed a population pharmacometric model that considers weight, albumin and time‐dependent creatinine that can be used to guide supportive care in adult patients with delayed HDMTX elimination.
Although gain of 1q occurs in 25% of Burkitt lymphomas (BLs) and 10% of pediatric high hyperdiplo... more Although gain of 1q occurs in 25% of Burkitt lymphomas (BLs) and 10% of pediatric high hyperdiploid acute lymphoblastic leukemias (ALLs), little is known about the origin, molecular genetic characteristics and functional outcome of dup(1q) in these disorders. Ten dup(1q)-positive BLs/ALLs were investigated by tiling resolution (32k) array CGH analysis, which revealed that the proximal breakpoints in all cases were near-centromeric, in eight of them clustering within a 1.4 Mb segment in 1q12-21.1. The 1q distal breakpoints were heterogeneous, being more distal in the ALLs than in the BLs. The minimally gained segments in the ALLs and BLs were 57.4 Mb [dup(1)(q22q32.3)] and 35 Mb [dup(1)(q12q25.2)], respectively. Satellite II DNA on 1q was not hypomethylated, as ascertained by Southern blot analyses of 15 BLs/ALLs with and without gain of 1q, indicating that aberrant methylation was not involved in the origin of dup(1q), as previously suggested for other neoplasms with 1q rearrangements. Global gene expression analyses revealed that five genes in the minimally 57.4 Mb gained region-B4GALT3, DAP3, RGS16, TMEM183A and UCK2-were significantly overexpressed in dup(1q)-positive ALLs compared with high hyperdiploid ALLs without dup(1q). The DAP3 and UCK2 genes were among the most overexpressed genes in the BL case with gain of 1q investigated. The DAP3 protein has been reported to be highly expressed in invasive glioblastoma multiforme cells, whereas expression of the UCK2 protein has been correlated with sensitivity to anticancer drugs. However, involvement of these genes in dup(1q)-positive ALLs and BLs has previously not been reported.
Abstract 69 Infant (&lt; 1 year of age) acute lymphoblastic leukemia (ALL) is a rare disease ... more Abstract 69 Infant (&lt; 1 year of age) acute lymphoblastic leukemia (ALL) is a rare disease characterized by rearrangements of the Mixed Lineage Leukemia (MLL) gene at 11q23 and a poor prognosis. In an effort to determine the total complement of somatic mutations occurring in this high risk leukemia, we performed paired-end whole genome sequencing (WGS) on diagnostic leukemia blasts and matched germ line samples from 22 infants with MLL rearranged ALL using the Illumina platform. In addition, we sequenced 2 paired relapse samples. Somatic alterations, including single nucleotide variations (SNV), and structural variations (SV) including insertions, deletions, inversion, and inter- and intra-chromosomal rearrangements were detected using complementary analysis pipelines including Bambino, CREST and CONSERTING. Validation of identified somatic mutations was performed using PCR amplification of the leukemia and germ line DNA followed by Sanger or 454-based sequencing, or by array-based capture followed by Illumina-based sequencing. Analysis of the structure of MLL rearrangements at the base pair level revealed that over half had complex rearrangements that involved either three or more chromosomes, or contained at the breakpoints deletions, amplifications, insertions, or inversion of sequences. In five of the complex cases, chromosomal rearrangements were predicted to generate not only a MLL-partner gene fusion, but also novel in-frame fusions including KRAS-MLL; RAD51B-MLL / AFF1-RAD51B; MLLT10-CTNNAP3B; MLLT10-ATP5L / ATP5L-YPEL4; and CRTAM-GNL3. An analysis of the sequence surrounding the breakpoints of MLL and its partner genes suggest that the predominant mechanism of rearrangement involved non-homologous end joining. An analysis of the total number of non-silent mutations revealed infant ALL to have the lowest frequency of non-silent somatic mutations of any cancer sequenced to date. After removal of SVs and CNAs associated with the MLL rearrangements, a mean of only 2 somatic SVs and 2 SNVs affecting the coding region of annotated genes or regulatory RNAs were detected per case, with a range of non-silent mutation of between 0 and 11 per case (0–7 SV and 0–5 SNV). Despite the paucity of mutations several pathways were recurrently targeted. Mutations leading to activation of signaling through the PI3K/RAS pathway was observed in 45% of the cases with mutation of individual components including KRAS (n=4), NRAS (n=2), and non-recurrent mutations in NF1, PTPN11, PIK3R1, and the GTPase activating protein ARHGAP32 (p200Rho/GAP), which mediates cross-talk between RAS and Rho signaling. Other pathways altered include B cell differentiation, with 23% of cases containing mono-allelic deletion or gains of PAX5, 14% with deletions of the CDKN2A/B, and 2 cases with focal deletions of the non-coding RNA genes DLEU1/2. WGS of two infant ALL relapse samples and comparison with the data from their matched diagnostic samples revealed a marked increase in the number of mutations at relapse with additional SVs, SNVs, and CNAs identified. Moreover, an analysis of the allelic ratios of mutated genes revealed clonal heterogeneity at diagnosis with relapse appearing to arise from a minor diagnostic clone. Because of the exceedingly low frequency of mutations detected in infant ALL, we decided to define the frequency of non-silent SNVs in MLL rearranged leukemia occurring in older children (7–19 years of age). Exome sequencing was performed on 13 MLL leukemias (8 ALLs and 5 AMLs). This analysis revealed that non-infant pediatric MLL rearranged leukemias harbor a significantly higher number of non-silent somatic SNVs than infant ALL (mean 8/case in older patients versus 2/case in infants, p&lt;0.001). Although the increased frequency of mutations may be a reflection of the older age, the low number of cooperating mutations in infants raises the possibility that the target cell of transformation differs between infants and older children, with the cells present during early development requiring fewer cooperating mutations to induce leukemia. In summary our analysis demonstrated an exceedingly small number of mutations required to generate infant MLL rearranged leukemia. The number of detected somatic mutations may represent the lower limit of mutations required to transform a normal human cell into cancer. Disclosures: Fioretos: Cantargia AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Qlucore AB: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Methotrexate (MTX), an anti-folate, is administered at high-doses to treat malignancies in childr... more Methotrexate (MTX), an anti-folate, is administered at high-doses to treat malignancies in children and adults. However, there is considerable interpatient variability in clearance of high-dose (HD) MTX. Patients with delayed clearance are at an increased risk for severe nephrotoxicity and life-threatening systemic MTX exposure. Glucarpidase is a rescue agent for severe MTX toxicity that reduces plasma MTX levels via hydrolysis of MTX into inactive metabolites, but is only indicated when MTX concentrations are > 2 standard deviations above the mean excretion curve specific for the given dose together with a significant creatinine increase (> 50%). Appropriate administration of glucarpidase is challenging due to the ambiguity in the labeled indication. A recent consensus guideline was published with an algorithm to provide clarity in when to administer glucarpidase, yet clinical interpretation of lab results that do not directly correspond to the algorithm prove to be a limitat...
Malignant leptomeningeal dissemination poses significant treatment challenges and is difficult to... more Malignant leptomeningeal dissemination poses significant treatment challenges and is difficult to eradicate. The disadvantages of conventional chemotherapy and intrathecal anticancer agents are due to limited drug penetration through the blood-brain barrier, low cytotoxic concentrations in the cerebrospinal fluid (CSF), and rapid metabolism. DepoCyte is a new liposomal, slow-release preparation of cytarabine for intrathecal use that maintains cytotoxic concentrations for as long as 14 days or more and improves the distribution of free cytarabine in the CSF. Here, we report our experience concerning thirteen pediatric patients age 1–13 years who received more than 40 treatment doses with liposomal cytarabine either as a therapeutic or prophylactic agent in doses of either 35 mg or 50 mg (children 11 years and younger or 12 years and older, respectively). There were four patients with refractory/relapsing neuroblastoma stage IV, two of whom had confirmed central nervous system (CNS) i...
Clinical Journal of the American Society of Nephrology, 2022
Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflamm... more Methotrexate is used in the treatment of many malignancies, rheumatological diseases, and inflammatory bowel disease. Toxicity from use is associated with severe morbidity and mortality. Rescue treatments include intravenous hydration, folinic acid, and, in some centers, glucarpidase. We conducted systematic reviews of the literature following published EXtracorporeal TReatments In Poisoning (EXTRIP) methods to determine the utility of extracorporeal treatments in the management of methotrexate toxicity. The quality of the evidence and the strength of recommendations (either “strong” or “weak/conditional”) were graded according to the GRADE approach. A formal voting process using a modified Delphi method assessed the level of agreement between panelists on the final recommendations. A total of 92 articles met inclusion criteria. Toxicokinetic data were available on 90 patients (89 with impaired kidney function). Methotrexate was considered to be moderately dialyzable by intermittent...
Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploi... more Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, with high hyperdiploidy [51-67 chromosomes] and the t(12;21)(p13;q22) [ETV6/RUNX1 fusion] representing the most frequent abnormalities. Although these arise in utero, there is long latency before overt ALL, showing that additional changes are needed. Gene dysregulation through hypermethylation may be such an event; however, this has not previously been investigated in a detailed fashion. We performed genome-wide methylation profiling using bacterial artificial chromosome arrays and promoter-specific analyses of high hyperdiploid and ETV6/RUNX1-positive ALLs. In addition, global gene expression analyses were performed to identify associated expression patterns. Unsupervised cluster and principal component analyses of the chromosome-wide methylome profiles could successfully subgroup the two genetic ALL types. Analysis of all currently known promoter-specific CpG islands demonstrated that several B-cell-and neoplasia-associated genes were hypermethylated and underexpressed, indicating that aberrant methylation plays a significant leukemogenic role. Interestingly, methylation hotspots were associated with chromosome bands predicted to harbor imprinted genes and the tri-/tetrasomic chromosomes in the high hyperdiploid ALLs were less methylated than their disomic counterparts. Decreased methylation of gained chromosomes is a previously unknown phenomenon that may have ramifications not only for the pathogenesis of high hyperdiploid ALL but also for other disorders with acquired or constitutional numerical chromosome anomalies.
Introduction. Results from St. Jude and M. D. Anderson, USA, suggested that AML children < 10 ... more Introduction. Results from St. Jude and M. D. Anderson, USA, suggested that AML children < 10 years have significantly better outcome than patients aged 10–21 years. Similarly, the Medical Research Council, UK, showed superior survival in children < 10 years due to a lower relapse rate compared to 10 – 15 year olds. We describe the AML outcome by age in the Nordic countries. Patients. Within the population based NOPHO AML protocols (NOPHO-AML 93 and NOPHO-AML 2004) we treated 403 patients aged 0 – 18 years from 1993 – 2007. Patients with Down syndrome and AML-M3 were excluded. The children were divided into three age groups; 0 –1 year (27%), 2 –9 years (41%) and 10+ years (32%). The oldest age group had a male preponderance. MLL-aberrations were more common among the youngest and t(8;21) among the oldest. FAB-type M5 was seen in 35% of 0–1 year olds versus only in 16% of children aged 10+. 0 – 1 year n= 109 2 –9 years n = 165 10 – 18 years n = 129 Boys/girls 44/67 = 0.67 80...
The NOPHO-AML 2004 protocol includes a post-consolidation randomization to Gemtuzumab ozagamicin,... more The NOPHO-AML 2004 protocol includes a post-consolidation randomization to Gemtuzumab ozagamicin, (GO, Mylotarg) or no further therapy. Randomization is offered to all standard-risk patients and to high-risk patients without a donor for SCT. GO is administered as a 2-hour infusion of 5 mg/m2 at least four weeks after the last consolidation including high-dose cytarabine and etoposide (HA2E). GO is repeated following a scheduled interval of three weeks. By August 2007 a total of 45 patients have been randomized (39 with standard-risk and 6 with high-risk AML). An additional nine patients were eligible but not randomized due to clinical decision (n=2), parental refusal (n=6), or administrative error (n=1). Twenty-three were randomized to receive GO. Detailed toxicity data were available from 21 of these patients. The median age was 3 years (six patients less than 2 years of age) at the time of GO. The median interval from HA2E to first GO was 32 days (range 27 – 43). The median interv...
3529 Introduction: High hyperdiploidy (51–67 chromosomes) is one of the most common cytogenetic a... more 3529 Introduction: High hyperdiploidy (51–67 chromosomes) is one of the most common cytogenetic abnormality patterns in childhood B-cell precursor acute lymphoblastic leukemia (ALL) and the clinical and cytogenetic features are well characterized. High hyperdiploidy in pediatric acute myeloid leukemia (AML), however, is a rare cytogenetic finding. It is most often categorized as a complex karyotype, which is considered associated with an unfavorable outcome. The group of complex karyotypes is heterogeneous and the significance of multiple additional chromosomes with or without structural abnormalities among the pediatric hyperdiploid AML patients is relatively unknown. Current knowledge in this field is based on small adult series or case reports. In this descriptive study we describe the clinical - and cytogenetic features in childhood hyperdiploid AML with a modal chromosome number at 50 or more. We report a series of 29 children from the Nordic Countries diagnosed with high hyper...
Introduction The World Health Organization (WHO) classification of myeloid neoplasms and acute le... more Introduction The World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia was revised in 2008 and is based on genetic characteristics and morphology. The classification incorporates newly recognized entities and emphasizes, more than previously, the pivotal role of cytogenetic abnormalities aiming at identifying biological and clinical entities as basis for a stratified treatment. The classification of acute myeloid leukemia (AML) is primarily based on adult studies. However, the frequency of cytogenetic changes varies among children and adults and the relevance of the 2008 revised WHO classification in pediatric AML has not yet been elucidated. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based pediatric AML cohort. Methods We included children 0-18 years of age diagnosed with de novo AML in the Nordic countries (Sweden, Norway, Finland, Iceland and Denmark) and Hong Kong treated accor...
Background. The core-binding factor AMLs, t(8;21)(q22;q22), AML1-ETO or RUNX1-RUNX1T1 and inv(16)... more Background. The core-binding factor AMLs, t(8;21)(q22;q22), AML1-ETO or RUNX1-RUNX1T1 and inv(16)(p13q22), CBFB–MYH11, are considered as favorable risk factors in AML with superior event-free survival (EFS) and overall survival (OS). However, within the AML protocol from the Nordic society of pediatric hematology/oncology (NOPHO) from 2004 we observed a decrease in EFS for t(8;21) AML. Material. We analyzed all children with t(8;21) or inv(16) treated on NOPHO-AML 93 and NOPHO-AML 2004 from Denmark, Finland, Iceland, Norway, and Sweden from 1993 to 2013 and patients from countries later joining the NOPHO-AML 2004 protocol; Estonia (2004), Hong Kong (2007), Belgium and the Netherlands (2010). The choice of anthracycline during induction changed from two courses including doxorubicin (75 mg/m2 in each course), Dox-Dox, in the NOPHO-AML 93 to idarubicin (36 mg/m2) and mitoxantrone (30 mg/m2), Ida-Mitox, in NOPHO-AML 04. After the observation of a decrease in EFS in patients with t(8;21...
BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patient... more BACKGROUND: Severely delayed elimination of methotrexate (MTX) is difficult to predict in patients treated with high-dose MTX (HD-MTX), but may cause life-threatening toxicity. It has not been defined how an increase in plasma creatinine best can be used as a predictor for severely delayed MTX elimination thus a guide for therapeutic interventions to minimize renal toxicity.
Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity... more Acute kidney injury due to high-dose methotrexate (HDMTX) is a serious, life-threatening toxicity that can occur in pediatric and adult patients. Glucarpidase is a treatment approved by the Food and Drug Administration for high methotrexate concentrations in the context of kidney dysfunction, but the guidelines for when to use it are unclear. An expert panel was convened to provide specific, expert consensus guidelines for the use of glucarpidase in patients who develop HDMTX-induced nephrotoxicity and delayed methotrexate excretion. The guideline provides recommendations to identify the population of patients who would benefit from glucarpidase rescue by more precisely defining the absolute methotrexate concentrations associated with risk for severe or life-threatening toxicity at several time points after the start of an HDMTX infusion. For an HDMTX infusion ≤24 hours, if the 36-hour concentration is above 30 µM, 42-hour concentration is above 10 µM, or 48-hour concentration is ab...
Journal of pediatric hematology/oncology, Jan 26, 2016
We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate,... more We investigated efficacy and toxicity of replacing conventional triple (cytarabine, methotrexate, and hydrocortisone) intrathecal therapy (TIT) with liposomal cytarabine during maintenance therapy among 40 acute lymphoblastic leukemia patients. Twenty-eight of 29 patients in the TIT arm received TIT and 9/11 in the liposomal cytarabine arm received liposomal cytarabine. Arachnoiditis occurred in all initial 5 patients given liposomal cytarabine and intrathecal prednisolone succinate. Subsequently liposomal cytarabine was given with systemic dexamethasone. Neurotoxicity occurred at 6/27 liposomal cytarabine administrations with concomitant dexamethasone (22%). More liposomal cytarabine-treated patients experienced neurotoxicity in relation to intrathecal therapy during at least 1 cycle compared with TIT-treated patients (6/9 [67%] vs. 3/28 [11%], P=0.002). Apart from intermittent lower extremity sensory pain in 1 liposomal cytarabine-treated patient, no permanent adverse neurological...
Uploads
Papers by Jesper Heldrup