| 1. |
- Albertsen, Birgitte Klug, et al.
(författare)
-
Asparaginase treatment in infants with acute lymphoblastic leukemia; pharmacokinetics and asparaginase hypersensitivity in Interfant-06
- 2019
-
Ingår i: Leukemia and Lymphoma. - : TAYLOR & FRANCIS LTD. - 1042-8194 .- 1029-2403. ; 60:6, s. 1469-1475
-
Tidskriftsartikel (refereegranskat)abstract
- Acute lymphoblastic leukemia (ALL) is a rare disease in infants. Asparaginase is an essential part of the treatment, and there Acute is a need to evaluate the efficiency and safety of this drug in this age group. We evaluated the pharmacokinetics of intramuscularly administered native E. coli asparaginase (Asparaginase Medac((R))) and PEG-asparaginase (Oncaspar((R))) as well as hypersensitivity reactions during treatment in Interfant-06 (www.clinicaltrials.gov: NCT01025804). All patients without hypersensitivity had sufficiently high enzyme activity levels during treatment with both preparations. Patients with hypersensitivity reactions during treatment, characterized by the presence of either or not of clinical symptoms and no measurable enzyme activity, received ineffective therapy. For optimization of the bad prognosis in infant ALL, therapeutic drug monitoring should be performed for identification of patients who should be switched to a different asparaginase preparation because of inactivation of the drug.
|
|
| 2. |
- Thastrup, Maria, et al.
(författare)
-
Flow cytometric analysis of cerebrospinal fluid improves detection of leukaemic blasts in infants with acute lymphoblastic leukaemia
- 2021
-
Ingår i: British Journal of Haematology. - : John Wiley & Sons. - 0007-1048 .- 1365-2141. ; 195:1, s. 119-122
-
Tidskriftsartikel (refereegranskat)abstract
- Infants with acute lymphoblastic leukaemia (ALL) have a high frequency of central nervous system (CNS) involvement. Flow cytometric analysis of cerebrospinal fluid (CSF) was recently demonstrated to be a sensitive method for detecting CNS involvement in childhood ALL. In the present study, CSF from 14 infants was collected at routine lumbar punctures and analysed by multicolour flow cytometry. At initial diagnosis, leukaemic blasts were detected in CSF by flow cytometry in 11 patients (78 center dot 6%) compared to seven patients (50%) by cytospin. Larger studies are needed to determine if CSF flow cytometry has prognostic value in infant ALL.
|
|
| 3. |
- Abrahamsson, Jonas, 1954, et al.
(författare)
-
Associations between neutrophil recovery time, infections and relapse in pediatric acute myeloid leukemia
- 2018
-
Ingår i: Pediatric Blood & Cancer. - : John Wiley & Sons. - 1545-5009 .- 1545-5017. ; 65:9
-
Tidskriftsartikel (refereegranskat)abstract
- BackgroundChildren with acute myeloid leukemia (AML) treated similarly show different toxicity and leukemic responses. We investigated associations between neutrophil recovery time after the first induction course, infection and relapse in children treated according to NOPHO-AML 2004 and DB AML-01. ProcedureNewly diagnosed patients with AML with bone marrow blast<5% between day 15 after the start of the treatment and the start of second induction course, and in complete remission after the second induction course were included (n=279). Neutrophil recovery time was defined as the time from the start of the course to the last day with absolute neutrophil count<0.5x10(9)/l. Linear and Cox regressions were used to investigate associations. ResultsNeutrophil recovery time after the first induction course was positively associated with neutrophil recovery time after the remaining courses, and longer neutrophil recovery time (25 days) was associated with increased risk of grade 3-4 infections (hazard ratio 1.4, 95% confidence interval [CI], 1.1-1.8). Longer neutrophil recovery time after the first induction (>30 days) was associated with the increased risk of relapse (5-year cumulative incidence: 48% vs. 42%, hazard ratio 1.7, 95% CI, 1.1-2.6) for cases not treated with hematopoietic stem cell transplantation in first complete remission. ConclusionLonger neutrophil recovery time after the first induction course was associated with grade 3-4 infections and relapse. If confirmed, this knowledge could be incorporated into risk stratification strategies in pediatric AML.
|
|
| 4. |
|
|
| 5. |
- Abrahamsson, Jonas, 1954, et al.
(författare)
-
Use of granulocyte colony-stimulating factor and risk of relapse in pediatric patients treated for acute myeloid leukemia according to NOPHO-AML 2004 and DB AML-01.
- 2019
-
Ingår i: Pediatric blood & cancer. - : Wiley. - 1545-5017 .- 1545-5009. ; 66:6
-
Tidskriftsartikel (refereegranskat)abstract
- Supportive-care use of granulocyte colony-stimulating factor (G-CSF) in pediatric acute myeloid leukemia (AML) remains controversial due to a theoretical increased risk of relapse and limited impact on neutropenic complications. We describe the use of G-CSF in patients treated according to NOPHO-AML 2004 and DB AML-01 and investigated associations with relapse.Patients diagnosed with de novo AML completing the first week of therapy and not treated with hematopoietic stem cell transplantation in the first complete remission were included (n=367). Information on G-CSF treatment after each course (yes/no) was registered prospectively in the study database and detailed information was gathered retrospectively from each center. Descriptive statistics were used to describe G-CSF use and Cox regression to assess the association between G-CSF and risk of relapse.G-CSF as supportive care was given to 128 (35%) patients after 268 (39%) courses, with a large variation between centers (0-93%). The use decreased with time-the country-adjusted odds ratio was 0.8/diagnostic year (95% confidence interval [CI] 0.7-0.9). The median daily dose was 5 μg/kg (range 3-12 μg/kg) and the median cumulative dose was 75 μg/kg (range 7-1460 μg/kg). Filgrastim was used in 82% of G-CSF administrations and infection was the indication in 44% of G-CSF administrations. G-CSF was associated with increased risk of relapse-the adjusted hazard ratio was 1.5 (95% CI 1.1-2.2).G-CSF as supportive care was used in a third of patients, and use decreased with time. Our results indicate that the use of G-CSF may be associated with an increased risk of relapse.
|
|
| 6. |
|
|
| 7. |
- Arad-Cohen, Nira, et al.
(författare)
-
Supportive care in pediatric acute myeloid leukemia:Expert-based recommendations of the NOPHO-DB-SHIP consortium
- 2022
-
Ingår i: Expert Review of Anticancer Therapy. - : Taylor & Francis Group. - 1473-7140 .- 1744-8328. ; 22:11, s. 1183-1196
-
Forskningsöversikt (refereegranskat)abstract
- Introduction Pediatric acute myeloid leukemia (AML) is the second most common type of pediatric leukemia. Patients with AML are at high risk for several complications such as infections, typhlitis, and acute and long-term cardiotoxicity. Despite this knowledge, there are no definite supportive care guidelines as to what the best approach is to manage or prevent these complications. Area covered The NOPHO-DB-SHIP (Nordic-Dutch-Belgian-Spain-Hong-Kong-Israel-Portugal) consortium, in preparation for a new trial in pediatric AML patients, had dedicated meetings for supportive care. In this review, the authors discuss the available data and outline recommendations for the management of children and adolescents with AML with an emphasis on hyperleukocytosis, tumor lysis syndrome, coagulation abnormalities and bleeding, infection, typhlitis, malnutrition, cardiotoxicity, and fertility preservation. Expert opinion Improved supportive care has significantly contributed to increased cure rates. Recommendations on supportive care are an essential part of treatment for this highly susceptible population and will further improve their outcome.
|
|
| 8. |
- Bager, Ninna, et al.
(författare)
-
Complex and monosomal karyotype are distinct cytogenetic entities with an adverse prognostic impact in paediatric acute myeloid leukaemia : A NOPHO-DBH-AML study
- 2018
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 183:4, s. 618-628
-
Tidskriftsartikel (refereegranskat)abstract
- Data on occurrence, genetic characteristics and prognostic impact of complex and monosomal karyotype (CK/MK) in children with acute myeloid leukaemia (AML) are scarce. We studied CK and MK in a large unselected cohort of childhood AML patients diagnosed and treated according to Nordic Society for Paediatric Haematology and Oncology (NOPHO)-AML protocols 1993-2015. In total, 800 patients with de novo AML were included. CK was found in 122 (15%) and MK in 41 (5%) patients. CK and MK patients were young (median age 2.1 and 3.3 years, respectively) and frequently had FAB M7 morphology (24% and 22%, respectively). Refractory disease was more common in MK patients (15% vs. 4%) and stem cell transplantation in first complete remission was more frequent (32% vs. 19%) compared with non-CK/non-MK patients. CK showed no association with refractory disease but was an independent predictor of an inferior event-free survival (EFS; hazard ratio [HR] 1.43, P = 0.03) and overall survival (OS; HR 1.48, P = 0.01). MK was associated with a poor EFS (HR 1.57, P = 0.03) but did not show an inferior OS compared to non-MK patients (HR 1.14, P = 0.62). In a large paediatric cohort, we characterized AML with non-recurrent abnormal karyotype and unravelled the adverse impact of CK and MK on prognosis.
|
|
| 9. |
|
|
| 10. |
- Borgstedt-Bendixen, Sofie E., et al.
(författare)
-
Abdominal Complications During Treatment for Pediatric Acute Myeloid Leukemia
- 2022
-
Ingår i: Journal of Pediatric Hematology/Oncology. - : Ovid Technologies (Wolters Kluwer Health). - 1077-4114 .- 1536-3678. ; 44:5, s. 220-229
-
Tidskriftsartikel (refereegranskat)abstract
- Acute myeloid leukemia (AML) accounts for 15% to 20% of childhood leukemias. Because of high-intensive therapy, up to 5% of patients suffer from treatment-related mortality (TRM). Abdominal complications are frequent, however, literature on this subject is sparse. We aimed to characterize severe abdominal pain (AP) and hyperbilirubinemia experienced by pediatric AML patients treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML 2004 protocol (n=313). Patients were censored at hematopoietic stem cell transplantation and relapse. Toxicity information was collected prospectively. Additional information was requested retrospectively from the treating centers. Sixteen episodes of hyperbilirubinemia and 107 episodes of AP were reported. The treating centers deemed infection (30%) and typhlitis (18%) as the most frequent causes of AP. Six patients developed appendicitis (2%). Patients experiencing concurrent AP and sepsis had a high risk of TRM (36%, n=4). Eighty percent of episodes with hyperbilirubinemia fulfilled the European Society for Bone and Marrow Transplantation criteria for sinusoidal obstruction syndrome. In conclusion, abdominal complications were frequent with infection considered the predominate cause. Most patients with hyperbilirubinemia fulfilled the criteria for sinusoidal obstruction syndrome. AML treatment might be associated with appendicitis. Patients suffering from concurrent AP and sepsis had a high risk of TRM indicating that high awareness of abdominal complications is essential to reduce mortality, especially during sepsis.
|
|
| 11. |
- Castor, Anders, et al.
(författare)
-
Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia
- 2005
-
Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 11:6, s. 630-637
-
Tidskriftsartikel (refereegranskat)abstract
- The cellular targets of primary mutations and malignant transformation remain elusive in most cancers. Here, we show that clinically and genetically different subtypes of acute lymphoblastic leukemia (ALL) originate and transform at distinct stages of hematopoietic development. Primary ETV6-RUNX1 (also known as TEL-AML1) fusions and subsequent leukemic transformations were targeted to committed B-cell progenitors. Major breakpoint BCR-ABL1 fusions (encoding P210 BCR-ABL1) originated in hematopoietic stem cells (HSCs), whereas minor BCR-ABL1 fusions (encoding P190 BCR-ABL1) had a B-cell progenitor origin, suggesting that P190 and P210 BCR-ABL1 ALLs represent largely distinct tumor biological and clinical entities. The transformed leukemia-initiating stem cells in both P190 and P210 BCR-ABL1 ALLs had, as in ETV6-RUNX1 ALLs, a committed B progenitor phenotype. In all patients, normal and leukemic repopulating stem cells could successfully be separated prospectively, and notably, the size of the normal HSC compartment in ETV6-RUNX1 and P190 BCR-ABL1 ALLs was found to be unaffected by the expansive leukemic stem cell population.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
- Gregers, Jannie, et al.
(författare)
-
Pharmacogenetic polymorphisms in folate metabolism affect toxicity after high dose methotrexate in childhood acute lymphoblastic leukemia
- 2012
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- We hypothesized that polymorphisms in folate metabolism would affect treatment effects of the folate antagonist methotrexate (MTX). We studied whether ATIC347C>T, MTHFR677C>T, MTHFR1298C>A and SHMT1-1420C>T polymorphisms influence risk of disease or efficacy and toxicity of MTX in a large population of children with acute lymphoblastic leukaemia (ALL). The children were treated after standardized Nordic protocols with 5-8 g/m2 high-dose MTX courses and long term oral maintenance therapy with weekly MTX. Ninety-four percent (n=533) of the children diagnosed during a 16 year time period were included. The study showed that the polymorphisms had no effect on risk of ALL, MTX pharmacokinetics or outcome. However after high-dose MTX treatment, patients with MTHFR677TT/MTHFR677CT had more liver toxicity than patients with MTHFR677CC (alanine transferase: 174/154 versus 115U/L, p=0.049). Patients with MTHFR1298AA had more liver toxicity than patients with MTHFR1298CC (alanine transferase: 144 versus 108 U/L, p=0.04). More bone marrow toxicity was found in patients with MTHFR1298CC compared to MTHFR1298CT / MTHFR1298AA (Nadir means: Platelets 72 versus 109/93*109/L, p=0.0001). In conclusion this study supports that MTHFR1298C>A and MTHFR677C>T are associated with toxicity in MTX treatment and the MTHFR variants should be considered as markers for individualization of treatment in childhood ALL in combination with other pharmacogenetic markers.
|
|
| 19. |
- Gregers, Jannie, 1964-
(författare)
-
Pharmacogenetic studies in childhood acute lymphoblastic leukaemia with primary focus on methotrexate
- 2012
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Childhood acute lymphoblastic leukaemia is the most common type of cancer in children. Improvement in treatment has increased survival to approximately 85 per cent. Pharmacogenetics can influence the disposition of anticancer agents and can ideally be used as tool to further improve treatment based on the individual child’s pharmacogenetic profile.The hypothesis in this thesis was that polymorphisms in genes responsible for MTX influx (SLC19A1), efflux (ABCB1, studies with MTX monotherapy have demonstrated effect of variations in this gene) or other MTX pathways (ATIC, MTHFR and SHMT) could have impact on efficacy in childhood acute lymphoblastic leukaemia.The uptake of MTX and impact of SLC19A1 80G>A was investigated in vitro and showed that SLC19A1 80GG had decreased uptake in CD+ T cells and B cells caused by reduced capacity on receptor-to-receptor basis.In more than 500 patients the clinical effect of SLC19A1 80G>A genotype was evaluated and showed that patients with the SLC19A1 80AA had better survival, more bone marrow toxicity, but less liver toxicity than patients with SLC19A1 80GG or 80GA variants. Furthermore, it was demonstrated that SLC19A1 80G>A interacts with chromosome 21 copy number in the leukemic clone.The clinical impact of ABCB1 1199G>A, 1236C>T, 2677GT on the treatment was evaluated. Patients with either the 1199GA or the 3435CC variant had increased risk of relapse compared to patients with the 1199GG or 3435CT/TT variants, respectively. Toxicity was also affected by the ABCB1 polymorphisms.No association between polymorphisms in the ATIC, MTHFR and SHMT genes and outcome was seen. However the 677C>T and 1298 C>A in the MTHFR gene were associated with toxicity.The genotype frequencies between healthy donors and patients were compared, but no association to risk of developing cancer was seen in the investigated polymorphisms.The results in this thesis emphasise the importance of including pharmacogenetic markers in attempts to improve outcome and reduced side effects in childhood ALL.
|
|
| 20. |
- Gregers, Jannie, et al.
(författare)
-
Polymorphisms in the ABCB1 gene affect outcome and toxicity in Childhood Acute Lymphoblastic Leukemia
- 2012
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences pharmacokinetics in several anti-cancer drugs. We hypothesized that 1199G>A, 1236C>T, 2677G>A/T and 3435C>T variants of ABCB1 could affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL), since treatment includes known P-glycoprotein substrates and 3435C/T may affect methotrexate therapy. We studied 522 Danish children with ALL treated according to NOPHO ALL92 and ALL2000 protocols, 93% of all those eligible during 1992-2007. Risk of relapse was 2.9-fold increased for 41 patients with the 1199GA variant compared to 477 with 1199GG (p=0.001), and reduced by 61% and 40%, respectively for 421 patients with the 3435CT or 3435TT variants compared to 96 with 3435CC (overall p=0.02). Degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was higher in 71 patients with 3435TT variant (median nadirs: hemoglobin 3% and platelets 34/37% lower in3435CT/3435CC) compared to 160 patients with 3435CT/3435CC (Hemoglobin p=0.01 and platelets p<0.0001). We observed more liver toxicity after high-dose methotrexate in 109 patients with 3435CC variant versus 3435CT/TT (Median max alanineaminotransferase: 280 versus 142/111 U/L, p=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms and efficacy and toxicity in childhood ALL.
|
|
| 21. |
- Gregers, Jannie, et al.
(författare)
-
The association of reduced folate carrier 80G greater than A polymorphism to outcome in childhood acute lymphoblastic leukemia interacts with chromosome 21 copy number
- 2010
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 115:23, s. 4671-4677
-
Tidskriftsartikel (refereegranskat)abstract
- The reduced folate carrier (RFC) is involved in the transport of methotrexate (MTX) across the cell membrane. The RFC gene (SLC19A1) is located on chromosome 21, and we hypothesized that the RFC80 G greater than A polymorphism would affect outcome and toxicity in childhood leukemia and that this could interact with chromosome 21 copy number in the leukemic clone. A total of 500 children with acute lymphoblastic leukemia treated according to the common Nordic treatment protocols were included, and we found that the RFC AA variant was associated with a 50% better chance of staying in remission compared with GG or GA variants (P = .046). Increased copy numbers of chromosome 21 appear to improve outcome also in children with GA or GG variant. In a subset of 182 children receiving 608 high-dose MTX courses, we observed higher degree of bone marrow toxicity in patients with the RFC AA variant compared with GA/GG variants (platelet 73 vs 99/105 x 10(9)/L, P = .004, hemoglobin 5.6 vs 5.9/6.0 mmol/L, P = .004) and a higher degree of liver toxicity in patients with RFC GG variant (alanine aminotransferase 167 vs 127/124 U/L, P = .05). In conclusion, the RFC 80G greater than A polymorphism interacts with chromosome 21 copy numbers and affects both efficacy and toxicity of MTX.
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
- Hasle, Henrik, et al.
(författare)
-
Gemtuzumab ozogamicin as postconsolidation therapy does not prevent relapse in children with AML : results from NOPHO-AML 2004
- 2012
-
Ingår i: Blood. - : American Society of Hematology. - 0006-4971 .- 1528-0020. ; 120:5, s. 978-984
-
Tidskriftsartikel (refereegranskat)abstract
- 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).
|
|
| 26. |
- Juul-Dam, KL, et al.
(författare)
-
Deep Sequencing of Leukemia-specific Mutations in Peripheral Blood Identifies Children with Imminent Relapse of Acute Myeloid Leukemia
- 2019
-
Ingår i: NOPHO Annual Meeting 2019.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Relapse remains the major problem in childhood acute myeloid leukemia (AML). The outcome in children with imminent relapse may improve if preemptive therapy is initiated at first evidence of leukemia regrowth. This requires measurable residual disease (MRD) monitoring after therapy completion, but only 40% of children with AML harbor genetic abnormalities applicable for quantification using standardized qPCR assays. To enable disease surveillance for all patients, we investigated the potential of early relapse detection in peripheral blood (PB) using patient-tailored deep sequencing (DS) MRD analysis. PB samples were collected at monthly intervals during follow-up from 45 children diagnosed with AML and treated according to the NOPHO-DBH AML 2012 protocol between January 2013 and May 2016 in Denmark, Norway, Sweden and Finland (508 samples, median 11 samples/patient, range 3–27). In relapsed patients, MRD-suitable leukemia-specific single nucleotide variants (SNVs) were identified with exome sequencing (ES) in diagnostic samples and verified at relapse. SNVs were analyzed in PB samples obtained during the months before overt relapse using DS with a sensitivity of 0.02% variant allele frequency (VAF). Until October 1st 2017, 14 patients experienced relapse within 18 months from therapy completion, and in 6 patients analysis has been completed. ES identified 37 leukemia-specific SNVs at diagnosis (median 4 SNVs/patient, range 2–12) of which 23 were also present at relapse (median 3 SNVs/patient, range 1–9). Fourteen MRD-suitable SNVs (1–3/patient) were quantified with DS. In all patients, at least one SNV was detected in PB before overt relapse occurred. The first PB sample showing MRD positivity (median error corrected VAF 0.15%, range 0.03–0.85) preceded hematological relapse at a median interval of 2.3 months (range 0.6–4.7). In conclusion, high-sensitivity quantification of leukemia-specific SNVs can facilitate early detection of imminent relapse and provide a chance for initiation of preemptive treatment.
|
|
| 27. |
|
|
| 28. |
- Juul-Dam, KL, et al.
(författare)
-
Patient-Tailored Deep Sequencing of Peripheral Blood Enables Early Detection of Relapse in Childhood Acute Myeloid Leukemia
- 2019
-
Ingår i: Blood Vpl 134 Suppl 1 1456. - : American Society of Hematology. - 0006-4971 .- 1528-0020.
-
Konferensbidrag (refereegranskat)abstract
- Relapse remains a major therapeutic challenge in children with acute myeloid leukemia (AML). Outcome after relapse may improve if preemptive therapy is initiated at first evidence of leukemia regrowth. Early detection of imminent relapse requires molecular measurable residual disease (MRD) monitoring after therapy completion. Today, this is possible only in about 40% of children with AML that harbor genetic abnormalities applicable for quantification using standardized qPCR assays. To enable disease surveillance for all patients, we developed patient-tailored deep sequencing (DS) MRD analysis, which provides highly sensitive detection of leukemia-specific mutations. We investigated the potential of this method for early relapse detection in peripheral blood (PB), the only easily accessible source for MRD sampling in children. PB samples were collected at monthly intervals during follow-up from 45 children diagnosed with AML and treated according to The Nordic Society of Pediatric Haematology and Oncology (NOPHO)-DBH AML 2012 protocol between January 2013 and May 2016 in Denmark, Norway, Sweden and Finland (508 samples, median 11 samples/patient, range 3-27). Nine patients with relapse (median age 5 years, range 0-8) had available diagnostic and relapse material and were included in this study. The patients displayed core binding factor abnormalities (n=3), KMT2A-rearrangements (n=3), monosomy 7 (n=1) or normal karyotype (n=2) at AML diagnosis. Leukemia-specific single nucleotide variants (SNVs) were identified with exome sequencing (ES) of sorted leukemic cells with lymphocytes or remission PB as constitutive DNA template. A variant allele frequency (VAF) with 95% confidence interval including 50% indicates presence of the mutation in all leukemic cells at diagnosis. With the exception of 2 cases with only subclonal mutations at diagnosis, leukemia-specific SNVs with VAF of 50% at diagnosis and persistence at relapse were selected as MRD targets. MRD target mutations were quantified in PB samples preceding overt relapse using patient-tailored DS assays with sensitivity of VAF 0.02%. In diagnostic samples, ES identified 53 leukemia-specific SNVs (median 4 SNVs/patient, range 2-12) of which 33 were also present at relapse (median 2 SNVs/patient, range 1-9). The number of mutations identified at diagnosis increased with age (Rs 0.83, p=0.006). All patients had at least one leukemia-specific SNV detected at both diagnosis and relapse. Twenty-one MRD target mutations (median 2 SNVs/patient, range 1-3) were quantified in PB (55 samples, median sampling interval 28 days, range 11-80) using DS. In 8/9 patients, at least one SNV was detected in PB before overt relapse occurred. The first PB sample showing MRD positivity (median VAF 0.14%, range 0.03-0.44) preceded hematological relapse at a median interval of 3 months (range 0-7.9). In 6 patients not preemptively treated, the median doubling time based on VAF increments was 7 days, with great variability between individuals and genotypes (range 4-28 days). Three patients had molecular relapse diagnosed by qPCR used in clinical diagnostics and received individualized preemptive treatment. In these 3 patients, DS detected mutations in PB for >100 days preceding overt relapse and the doubling times were 14, 25 and 36 days. In conclusion, DS of leukemia-specific mutations at frequent intervals in PB enables early detection of relapse and ES at diagnosis may identify SNVs applicable for such longitudinal MRD monitoring. This approach facilitates molecular disease surveillance and initiation of preemptive therapy in AML patients without established qPCR targets.
|
|
| 29. |
- Karlsson, Lena, 1964, et al.
(författare)
-
Outcome after intensive reinduction therapy and allogeneic stem cell transplant in paediatric relapsed acute myeloid leukaemia
- 2017
-
Ingår i: British Journal of Haematology. - : WILEY. - 0007-1048 .- 1365-2141. ; 178:4, s. 592-602
-
Tidskriftsartikel (refereegranskat)abstract
- Given that 30-40% of children with acute myeloid leukaemia (AML) relapse after primary therapy it is important to define prognostic factors and identify optimal therapy. From 1993 to 2012, 543 children from the Nordic countries were treated according to two consecutive protocols: 208 children relapsed. The influence of disease characteristics, first line treatment, relapse therapy and duration of first remission on outcome was analysed. Second complete remission (CR2) was achieved in 146 (70%) patients. Estimated 5-year overall survival (OS5y) was 39 +/- 4% for the whole group and 43 +/- 4% for the 190 patients given re-induction therapy, of whom 76% received regimens that included fludarabine, cytarabine (FLA) +/- anthracyclines, 18% received Nordic Society for Paediatric Haematology and Oncology (NOPHO) upfront blocks and 5% received other regimens. Late relapse >= 1 year from diagnosis, no allogeneic stem cell transplantation (SCT) in first remission and core binding factor AML were independent favourable prognostic factors for survival. For the 128 children (124 in CR2) that received SCT as consolidation therapy after relapse, OS5y was 61 +/- 5%. Four of 19 children (21%) survived without receiving SCT as part of relapse therapy. Our data show that intensive re-induction followed by SCT can give cure rates of 40% in children with relapsed AML.
|
|
| 30. |
- Laursen, Anne Cathrine Lund, et al.
(författare)
-
Trisomy 8 in pediatric acute myeloid leukemia : A NOPHO-AML study
- 2016
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 55:9, s. 719-726
-
Tidskriftsartikel (refereegranskat)abstract
- Trisomy 8 (+8) is a common cytogenetic aberration in acute myeloid leukemia (AML); however, the impact of +8 in pediatric AML is largely unknown. We retrospectively investigated 609 patients from the NOPHO-AML database to determine the clinical and cytogenetic characteristics of +8 in pediatric AML and to investigate its prognostic impact. Complete cytogenetic data were available in 596 patients (98%) aged 0-18 years, diagnosed from 1993 to 2012, and treated according to the NOPHO-AML 1993 and 2004 protocols in the Nordic countries and Hong Kong. We identified 86 patients (14%) with +8. Trisomy 8 was combined with other cytogenetic aberrations in 68 patients (11%) (+8 other) and in 18 patients (3%), it was the sole abnormality (+8 alone). Trisomy 8 was associated with FAB M5 (36%) but otherwise clinically comparable with non-trisomy 8 patients. Trisomy 8 was favorable in patients of young age and with t(9;11). Trisomy 8 alone was associated with older age (median age 10.1 years), FAB M2 (33%), and FLT3-ITD mutations (58%). The 5-year event-free survival for patients with +8 alone was 50% and 5-year overall survival was 75%. In conclusion, +8 is one of the most common cytogenetic aberrations in pediatric AML. Trisomy 8 positive AML is a heterogeneous group and the majority of cases have additional cytogenetic aberrations. Patients with +8 alone differed from patients with +8 other and were associated with older age, FAB M2, and FLT3-ITD aberrations. There were no differences in survival despite the more frequent occurrence of FLT3-ITD in +8 alone.
|
|
| 31. |
- Levinsen, Mette, et al.
(författare)
-
Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia
- 2014
-
Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 61:8, s. 1416-1421
-
Tidskriftsartikel (refereegranskat)abstract
- Background Central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) remains a therapeutic challenge. Procedure To explore leukemia characteristics of patients with CNS involvement at ALL diagnosis, we analyzed clinical features and early treatment response of 744 patients on Nordic-Baltic trials. CNS status was classified as CNS1 (no CSF blasts), CNS2 (<5 leukocytes/mu l CSF with blasts), CNS3 (5 leukocytes/mu l with blasts or signs of CNS involvement), TLP+ (traumatic lumbar puncture with blasts), and TLP- (TLP with no blasts). Results Patients with CNS involvement had higher leukocyte count compared with patients with CNS1 (P<0.002). Patients with CNS3 more often had T-ALL (P<0.001) and t(9;22)(q34;q11)[BCR-ABL1] (P<0.004) compared with patients with CNS1. Among patients with CNS involvement headache (17%) and vomiting (14%) were most common symptoms. Symptoms or clinical findings were present among 27 of 54 patients with CNS3 versus only 7 of 39 patients with CNS2 and 15 of 75 patients with TLP+ (P<0.001). The majority of patients with CNS involvement received additional induction therapy. The post induction bone marrow residual disease level did not differ between patients with CNS involvement and patients with CNS1 (0.15). The 12-year event-free survival for patients with leukemic mass on neuroimaging did not differ from patients with negative or no scan (0.50 vs. 0.60; P=0.7) or between patients with symptoms or signs suggestive of CNS leukemia and patients without such characteristics (0.50 vs. 0.61; P=0.2). Conclusion CNS involvement at diagnosis is associated with adverse prognostic features but does not indicate a less chemosensitive leukemia.
|
|
| 32. |
- Levinsen, Mette, et al.
(författare)
-
Myelotoxicity after high-dose methotrexate in childhood acute leukemia is influenced by 6-mercaptopurine dosing but not by intermediate thiopurine methyltransferase activity
- 2015
-
Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 75:1, s. 59-66
-
Tidskriftsartikel (refereegranskat)abstract
- Through enhancement of 6-mercaptopurine (6MP) bioavailability and inhibition of purine de novo synthesis, high-dose methotrexate (HD-MTX) may increase incorporation into DNA of 6-thioguanine nucleotides, the cytotoxic metabolites of 6MP. Patients with intermediate activity of thiopurine methyltransferase (TPMTIA) have higher cytosol 6-thioguanine nucleotide levels. We investigated toxicity following HD-MTX during MTX/6MP maintenance therapy in relation to 6MP and TPMT. Using linear mixed models, we explored myelo- and hepatotoxicity in relation to 6MP dosage and TPMT phenotype following 1,749 HD-MTX courses to 411 children with acute lymphoblastic leukemia on maintenance therapy. The degree of myelosuppression following HD-MTX was similar for patients with TPMTIA and patients with high TPMT activity (TPMTHA), when HD-MTX started with same blood counts and 6MP doses. However, since TPMTIA had lower blood counts at initiation of HD-MTX compared with TPMTHA patients (median WBC 2.8 vs. 3.3 x 10(9)/L, P = 0.01; median ANC 1.4 vs. 1.7 x 10(9)/L, P = 0.02), TPMTIA continued to have lower WBC and ANC levels compared with TPMTHA during all 28 days after HD-MTX [relative difference 9 % (95 % CI 2-17), P = 0.02 and 21 % (95 % CI 6-39), P = 0.005]. Still, the fractional decrease in WBC and ANC levels after HD-MTX did not differ between TPMTIA and TPMTHA patients (P = 0.47; P = 0.38). The degree of leukopenia, neutropenia, thrombocytopenia and rise in aminotransferases were all significantly related to 6MP dose (P < 0.001 for all analyses). For both TPMTIA and TPMTHA patients, dose of 6MP prior to HD-MTX should be guided by pre-HD-MTX blood counts, but not by TPMT activity.
|
|
| 33. |
- Lohmann, Ditte J. A., et al.
(författare)
-
Effect of age and body weight on toxicity and sur vival in pediatric acute myeloid leukemia : results from NOPHO-AML 2004
- 2016
-
Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:11, s. 1359-1367
-
Tidskriftsartikel (refereegranskat)abstract
- Treatment for pediatric acute myeloid leukemia is very toxic and the association between outcome and age and Body Mass Index is unclear. We investigated effect of age and Body Mass Index on toxicity and survival in pediatric acute myeloid leukemia. We studied all patients who completed first induction course of NOPHO-AML 2004 (n= 318). Toxicity following induction and consolidation courses (n= 6) was analyzed. The probabilities of toxicity and death were determined using time-to-event analyses with Cox multivariate proportional hazard regression for comparative analyses. Age 10-17 years was associated with sepsis with hypotension [hazard ratio 2.3 (95% confidence interval 1.1-4.6)]. Being overweight (> 1 standard deviation) was associated with requiring supplemental oxygen [1.9 (1.0-3.5)]. The 5-year event-free and overall survival were 47% and 71%. Children aged 10-17 years showed a trend for inferior 5-year overall survival compared to children aged 29 (64% vs. 76%; P= 0.07). Infants showed a trend for superior 5-year event-free survival (66% vs. 43%; P= 0.06). Overweight children aged 10-17 years showed a trend for superior survival [5-year event-free survival 59% vs. 40% (P= 0.09) and 5-year overall survival 78% vs. 56% (P= 0.06)] compared to healthy weight children aged 10-17 years. In conclusion, children aged 10-17 years and overweight children had a higher risk of grade 3-4 toxicity. Children aged 10-17 years showed inferior survival, but, unexpectedly, in this age group overweight children tended to have increased survival. This suggests different pharmacokinetics of chemotherapeutic drugs in adolescents and warrants further studies.
|
|
| 34. |
|
|
| 35. |
- Löhmann, Ditte J. A., et al.
(författare)
-
Associations between pretherapeutic body mass index, outcome, and cytogenetic abnormalities in pediatric acute myeloid leukemia
- 2019
-
Ingår i: Cancer Medicine. - : WILEY. - 2045-7634. ; 8:15, s. 6634-6643
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Associations between body mass index (BMI), outcome, and leukemia-related factors in children with acute myeloid leukemia (AML) remain unclear. We investigated associations between pretherapeutic BMI, cytogenetic abnormalities, and outcome in a large multinational cohort of children with AML.Methods: We included patients, age 2-17 years, diagnosed with de novo AML from the five Nordic countries (2004-2016), Hong Kong (2007-2016), the Netherlands and Belgium (2010-2016), and Canada and USA (1995-2012). BMI standard deviations score for age and sex was calculated and categorized according to the World Health Organization. Cumulative incidence functions, Kaplan-Meier estimator, Cox regression, and logistic regression were used to investigate associations.Results: In total, 867 patients were included. The median age was 10 years (range 2-17 years). At diagnosis, 32 (4%) were underweight, 632 (73%) were healthy weight, 127 (15%) were overweight, and 76 (9%) were obese. There was no difference in relapse risk, treatment-related mortality or overall mortality across BMI groups. The frequency of t(8;21) and inv(16) increased with increasing BMI. For obese patients, the sex, age, and country adjusted odds ratio of having t(8;21) or inv(16) were 1.9 (95% confidence interval (CI) 1.1-3.4) and 2.8 (95% CI 1.3-5.8), respectively, compared to healthy weight patients.Conclusions: This study did not confirm previous reports of associations between overweight and increased treatment-related or overall mortality in children. Obesity was associated with a higher frequency of t(8;21) and inv(16). AML cytogenetics appear to differ by BMI status.
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
- Oskarsson, Trausti, et al.
(författare)
-
Relapsed childhood acute lymphoblastic leukemia in the Nordic countries : prognostic factors, treatment and outcome
- 2016
-
Ingår i: Haematologica. - Pavia, Italy : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:1, s. 68-76
-
Tidskriftsartikel (refereegranskat)abstract
- Relapse is the main reason for treatment failure in childhood acute lymphoblastic leukemia. Despite improvements in the up-front therapy, survival after relapse is still relatively poor, especially for high-risk relapses. The aims of this study were to assess outcomes following acute lymphoblastic leukemia relapse after common initial Nordic Society of Paediatric Haematology and Oncology protocol treatment; to validate currently used risk stratifications, and identify additional prognostic factors for overall survival. Altogether, 516 of 2735 patients (18.9%) relapsed between 1992 and 2011 and were included in the study. There were no statistically significant differences in outcome between the up-front protocols or between the relapse protocols used, but an improvement over time was observed. The 5-year overall survival for patients relapsing in the period 2002-2011 was 57.5 +/- 3.4%, but 44.7 +/- 3.2% (P<0.001) if relapse occurred in the period 1992-2001. Factors independently predicting mortality after relapse included short duration of first remission, bone marrow involvement, age ten years or over, unfavorable cytogenetics, and Down syndrome. T-cell immunophenotype was not an independent prognostic factor unless in combination with hyperleukocytosis at diagnosis. The outcome for early combined pre-B relapses was unexpectedly poor (5-year overall survival 38.0 +/- 10.6%), which supports the notion that these patients need further risk adjustment. Although survival outcomes have improved over time, the development of novel approaches is urgently needed to increase survival in relapsed childhood acute lymphoblastic leukemia.
|
|
| 41. |
|
|
| 42. |
- Pilheden, Mattias, et al.
(författare)
-
Duplex sequencing uncovers recurrent low-frequency cancer-associated mutations in infant and childhood KMT2A-rearranged acute leukemia
- 2022
-
Ingår i: HemaSphere. - : Wolters Kluwer. - 2572-9241. ; 6:10
-
Tidskriftsartikel (refereegranskat)abstract
- Infant acute lymphoblastic leukemia (ALL) with KMT2A-gene rearrangements (KMT2A-r) have few mutations and a poor prognosis. To uncover mutations that are below the detection of standard next-generation sequencing (NGS), a combination of targeted duplex sequencing and NGS was applied on 20 infants and 7 children with KMT2A-r ALL, 5 longitudinal and 6 paired relapse samples. Of identified nonsynonymous mutations, 87 had been previously implicated in cancer and targeted genes recurrently altered in KMT2A-r leukemia and included mutations in KRAS, NRAS, FLT3, TP53, PIK3CA, PAX5, PIK3R1, and PTPN11, with infants having fewer such mutations. Of identified cancer-associated mutations, 62% were below the resolution of standard NGS. Only 33 of 87 mutations exceeded 2% of cellular prevalence and most-targeted PI3K/RAS genes (31/33) and typically KRAS/NRAS. Five patients only had low-frequency PI3K/RAS mutations without a higher-frequency signaling mutation. Further, drug-resistant clones with FLT3D835H or NRASG13D/G12S mutations that comprised only 0.06% to 0.34% of diagnostic cells, expanded at relapse. Finally, in longitudinal samples, the relapse clone persisted as a minor subclone from diagnosis and through treatment before expanding during the last month of disease. Together, we demonstrate that infant and childhood KMT2A-r ALL harbor low-frequency cancer-associated mutations, implying a vast subclonal genetic landscape.
|
|
| 43. |
- Sandahl, Julie Damgaard, et al.
(författare)
-
Ploidy and clinical characteristics of childhood acute myeloid leukemia : A NOPHO-AML study
- 2014
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 53:8, s. 667-675
-
Tidskriftsartikel (refereegranskat)abstract
- We report the first large series (n=596) of pediatric acute myeloid leukemia (AML) focusing on modal numbers (MN) from the population-based NOPHO-AML trials. Abnormal karyotypes were present in 452 cases (76%) and numerical aberrations were present in 40% (n=237) of all pediatric AML. Among patients with an abnormal karyotype, the MN 46 was most common (n=251; 56%) of which 36 (8%) were pseudodiploid with numerical aberrations, followed by MN 47 (n=80; 18%) and MN 43-45 (n=48; 8%). No cases had MN less than 43. Hyperdiploid AML with MN 48-65 comprised 11% of all cases and was associated with early onset (median age 2 years), female sex (57%), and a dominance of acute megakaryoblastic leukemia (AMKL) (29%). Hypodiploidy constituted 8% of all AML and was associated with older age (median age 9 years), male predominance (60%), FAB M2 (56%), and t(8;21)(q22;q22) (56%) with loss of sex chromosomes. Inferior outcome was observed for hypodiploid cases (5-year event-free survival 40% and 5-year overall survival 40%) but did not reach statistical significance. Chromosomes were gained in a nonrandom pattern, where chromosomes 8, 21, 19, and 6 were the most commonly gained. In conclusion, based on MNs, two cytogenetic subgroups with characteristic clinical features are described; hypodiploidy found in 8% and associated with high median age, male sex, t(8;21)(q22;q22), and FAB M2 and possibly associated with inferior outcome (P=0.13), and hyperdiploidy with MN 48-65 in 11% associated with early onset, female sex, and AMKL.
|
|
| 44. |
- Sandahl, Julie D., et al.
(författare)
-
The applicability of the WHO classification in paediatric AML. A NOPHO-AML study
- 2015
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 169:6, s. 859-867
-
Tidskriftsartikel (refereegranskat)abstract
- The World Health Organization (WHO) classification of myeloid leukaemia was revised in 2008. It incorporates newly recognized entities and emphasizes the pivotal role of cytogenetic abnormalities. The aim of this study was to evaluate the usability of the WHO classification when applied to a large population-based paediatric acute myeloid leukaemia (AML) cohort. We included children diagnosed with de novo AML, 0-18years of age from the Nordic countries and Hong Kong from 1993 to 2012. Data were retrieved from the Nordic Society for Paediatric Haematology and Oncology AML database and patients classified according to the WHO 2008 classification. A successful karyotype was available in 97% of the cases. AML with recurrent genetic abnormalities were present in 262 (41%) and 94 (15%) were classified as AML with myelodysplasia-related changes (AML-MDS). WHO classifies patients with monosomy 7 and del(7q) into one group. We found that -7 (n=14) had significantly poorer outcome than del(7q) (n=11); 5-year event-free survival 26% vs. 67%, (P=002), and 5-year overall survival 51% vs. 90%, (P=004). The largest group was the highly heterogeneous AML not otherwise specified (NOS) (n=280) (44%). In conclusion, the WHO classification allocated 15% to AML-MDS, 44% to NOS and grouped together entities with clearly different outcome, therefore limiting the applicability of the current WHO classification in children with AML.
|
|
| 45. |
- Skou, Anne-Sofie, et al.
(författare)
-
Measurable Residual Disease Monitoring of SPAG6, ST18, PRAME, and XAGE1A Expression in Peripheral Blood May Detect Imminent Relapse in Childhood Acute Myeloid Leukemia
- 2021
-
Ingår i: Journal of Molecular Diagnostics. - : Elsevier. - 1525-1578 .- 1943-7811. ; 23:12, s. 1787-1799
-
Tidskriftsartikel (refereegranskat)abstract
- Overexpressed genes may be useful for monitoring of measurable residual disease (MRD) in patients with childhood acute myeloid leukemia (AML) without a leukemia-specific target. The normal expression of five leukemia-associated genes (SPAG6, ST18, MSLN, PRAME, XAGE1A) was defined in children without hematologic disease (n = 53) and children with suspected infection (n = 90). Gene expression at AML diagnosis (n=50) and during follow-up (n = 21) was compared with child-specific reference values. At diagnosis, 34/50 children (68%) had high expression of at least one of the five genes, and so did 16/31 children (52%) without a leukemia-specific target. Gene expression was quantified in 110 peripheral blood (PB) samples (median, five samples/patient; range, 1 to 10) during follow-up in 21 patients with high expression at diagnosis. All nine patients with PB sampling performed within 100 days of disease recurrence displayed overexpression of SPAG6, ST18, PRAME, or XAGE1A at a median of 2 months (range, 0.6 to 9.6 months) before hematologic relapse, whereas MSLN did not reach expression above normal prior to hematologic relapse. Only 1 of 130 (0.8%) follow-up analyses performed in 10 patients in continuous complete remission had transient expression above normal. SPAG6, ST18, PRAME, and XAGE1A expression in PB may predict relapse in childhood AML patients and facilitate MRD monitoring in most patients without a leukemia-specific target.
|
|
| 46. |
- Stove, Heidi Kristine, et al.
(författare)
-
Extramedullary leukemia in children with acute myeloid leukemia : A population-based cohort study from the Nordic Society of Pediatric Hematology and Oncology (NOPHO)
- 2017
-
Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 64:12
-
Tidskriftsartikel (refereegranskat)abstract
- Background: The prognostic significance of extramedullary leukemia (EML) in childhood acute myeloid leukemia is not clarified. Procedure: This population-based study included 315 children from the NOPHO-AML 2004 trial. Results: At diagnosis, 73 (23%) patients had EML: 39 (12%) had myeloid sarcoma, 22 (7%) had central nervous system disease, and 12 (4%) had both. EML was associated with young age (median age: 2.6 years), a high white blood cell count (median: 40 x 10(9)/l), M5 morphology (40%), and 11q23/MLL (KMT2A) rearrangements (34%). No patient received involved field radiotherapy. Five-year event-free survival did not differ significantly between the EML and the non-EML patients (54% vs. 45%, P = 0.57), whereas 5-year overall survival (OS) was significantly lower in the EML group (64% vs. 73%, P = 0.04). The risk of induction death was significantly higher for EML patients (8% vs. 1%, P = 0.002). There was a trend toward a lower risk of relapse for EML patients (5-year cumulative incidence of relapse 33% vs. 49%, P = 0.16). Traumatic lumbar puncture did not adversely affect survival in this cohort. Conclusions: EML was associated with increased risk of induction death impacting the OS. No patients relapsed at the primary site of the myeloid sarcoma despite management without radiotherapy.
|
|
| 47. |
- Tierens, Anne, et al.
(författare)
-
Mitoxantrone Versus Liposomal Daunorubicin in Induction of Pediatric AML With Risk Stratification Based on Flow Cytometry Measurement of Residual Disease
- 2024
-
Ingår i: Journal of Clinical Oncology. - : Lippincott Williams & Wilkins. - 0732-183X .- 1527-7755. ; 42:18, s. 2174-2185
-
Tidskriftsartikel (refereegranskat)abstract
- PURPOSE Measurable residual disease (MRD) by using flow cytometry after induction therapy is strongly prognostic in pediatric AML, and hematopoietic stem-cell transplant (hSCT) may counteract a poor response. We designed a phase III study with intensified response-guided induction and MRD-based risk stratification and treated poor induction response with hSCT. The efficacy of liposomal daunorubicin (DNX) in induction was compared with mitoxantrone.METHODS The study planned to randomly assign 300 patients, but the production of DNX ceased in 2017. One hundred ninety-four patients were randomly assigned to mitoxantrone or experimental DNX in induction 1. Ninety-three non–randomly assigned patients served as an observation cohort. Primary end point was fraction of patients with MRD <0.1% on day 22 after induction 1. Patients with MRD ≥15% after induction 1 or ≥0.1% after induction 2 or FLT3-ITD with NPM1 wildtype were stratified to high-risk therapy, including hSCT.RESULTS Outcome for all 287 children was good with 5-year event-free survival (EFS5y) 66.7% (CI, 61.4 to 72.4) and 5-year overall survival (OS5y) 79.6% (CI, 75.0 to 84.4). Overall, 75% were stratified to standard-risk and 19% to high-risk. There was no difference in the proportion of patients with MRD <0.1% on day 22 after induction 1 (34% mitoxantrone, etoposide, araC [MEC], 30% DNX, P 5 .65), but the proportion increased to 61% for MEC versus 47% for DNX (P 5 .061) at the last evaluation before induction 2. EFS5y was significantly lower, 56.6% (CI, 46.7 to 66.5) versus 71.9% (CI, 63.0 to 80.9), and cumulative incidence of relapse (CIR) was higher, 35.1% (CI, 25.7 to 44.7) versus 18.8% (CI, 11.6 to 27.2) for DNX. The inferior outcome for DNX was only in standard-risk patients with EFS5y 55.3% (CI, 45.1 to 67.7) versus 79.9% (CI, 71.1 to 89.9), CIR 39.5% (CI, 28.4 to 50.3) versus 18.7% (CI, 10.5 to 28.7), and OS5y 76.2% (CI, 67.2 to 86.4) versus 88.6% (CI, 81.4 to 96.3). As-treated analyses, including the observation cohort, supported these results. For all high-risk patients, 85% received hSCT, and EFS5y was 77.7 (CI, 67.3 to 89.7) and OS5y was 83.0 (CI, 73.5 to 93.8).CONCLUSION The intensification of induction therapy with risk stratification on the basis of response to induction and hSCT for high-risk patients led to improved outcomes. Mitoxantrone had a superior anti-leukemic effect than liposomal daunorubicin.
|
|
| 48. |
- Tierens, Anne, et al.
(författare)
-
Residual disease detected by flow cytometry is an independent predictor of survival in childhood acute myeloid leukaemia; results of the NOPHO-AML 2004 study
- 2016
-
Ingår i: British Journal of Haematology. - : Wiley. - 0007-1048 .- 1365-2141. ; 174:4, s. 600-609
-
Tidskriftsartikel (refereegranskat)abstract
- Early response after induction is a prognostic factor for disease outcome in childhood acute myeloid leukaemia (AML). Residual disease (RD) detection by multiparameter flow cytometry (MFC) was performed at day 15 and before consolidation therapy in 101 patients enrolled in the Nordic Society of Paediatric Haemato-Oncology AML 2004 study. A multicentre laboratory approach to RD analysis was used. Event-free survival (EFS) and overall survival (OS) was significantly different in patients with and without RD at both time points, using a 0.1% RD cut-off level. RD-negative and -positive patients after first induction showed a 5-year EFS of 65.7% and 22.7%, respectively (P < 0.001) and an OS of 77.6% (P = 0.025) and 51.8%. RD-negative and -positive patients at start of consolidation therapy had a 5-year EFS of 57.7% and 11.7%, respectively (P < 0001) and an OS of 786% and 2811%) (P < 0001). In multivariate analysis only RD was significantly correlated with survival. RD before consolidation therapy was the strongest independent prognostic factor for EFS [hazard ratio (HR): 5.0; 95% confidence interval (CI): 1.9-133] and OS (HR: 7.0; 95% CI: 20-245). In conclusion, RD before consolidation therapy identifies patients at high risk of relapse in need of intensified treatment. In addition, RD detection can be performed in a multicentre setting and can be implemented in future trials.
|
|
| 49. |
- Wareham, Neval E., et al.
(författare)
-
Outcome of poor response paediatric AML using early SCT
- 2013
-
Ingår i: European Journal of Haematology. - : Wiley. - 1600-0609 .- 0902-4441. ; 90:3, s. 187-194
-
Tidskriftsartikel (refereegranskat)abstract
- Background Children with poor response acute myeloid leukaemia (AML) generally have a very poor outcome. Allogeneic stem cell transplantation (SCT) is often recommended for these children but the benefit is unclear. The aim of this study was to investigate survival for poor response AML patients treated with SCT. Material and Methods Treatment was given according to the NOPHO-AML 2004 protocol. All patients received AIET (Cytarabine, Idarubicin, Etoposide, Thioguanine) and AM (Cytarabine, Mitoxantrone) as induction. We included poor response defined as > 15% blasts on day 15 after AIET (n=17) or > 5% blasts after AM (n=14, refractory disease). Poor response patients received intensively timed induction and proceeded to SCT when a donor was available. Results Thirty-one of 267 evaluable patients (12%) had a poor response. SCT was performed in 25; using matched unrelated donors in 13, matched sibling donors in 6, cord blood donor in 4, and haploidentical donor in two. The median follow-up for the 31 poor responding patients was 2.6 years (range 0.4 - 8.1 years) and 3-year probability of survival 70% (95% CI 59-77%). Conclusions The poor responders in the NOPHO-AML 2004 protocol had a favourable prognosis treated with time-intensive induction followed by SCT.
|
|
| 50. |
- Wennström, Lovisa, et al.
(författare)
-
Acute Myeloid Leukemia in Adolescents and Young Adults Treated in Pediatric and Adult Departments in the Nordic Countries
- 2016
-
Ingår i: Pediatric Blood & Cancer. - : Wiley-Blackwell. - 1545-5009 .- 1545-5017. ; 63:1, s. 83-92
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Studies on adolescents and young adults with acute lymphoblastic leukemia suggest better results when using pediatric protocols for adult patients, while corresponding data for acute myeloid leukemia (AML) are limited. Procedure: We investigated disease characteristics and outcome for de novo AML patients 10-30 years old treated in pediatric or adult departments. We included 166 patients 10-18 years of age with AML treated according to the pediatric NOPHO-protocols (1993-2009) compared with 253 patients aged 15-30 years treated in hematology departments (1996-2009) in the Nordic countries. Results: The incidence of AML was 4.9/million/year for the age group 10-14 years, 6.5 for 15-18 years, and 6.9 for 19-30 years. Acute promyelocytic leukemia (APL) was more frequent in adults and in females of all ages. Pediatric patients with APL had similar overall survival as pediatric patients without APL. Overall survival at 5 years was 60% (52-68%) for pediatric patients compared to 65% (58-70%) for adult patients. Cytogenetics and presenting white blood cell count were the only independent prognostic factors for overall survival. Age was not an independent prognostic factor. Conclusions: No difference was found in outcome for AML patients age 10-30 years treated according to pediatric as compared to adult protocols.
|
|
