| 1. |
- Gottschalk Højfeldt, Sofie, et al.
(författare)
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Relapse risk following truncation of PEG-asparaginase in childhood acute lymphoblastic leukemia.
- 2021
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 137:17, s. 2373-2382
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Tidskriftsartikel (refereegranskat)abstract
- Truncation of asparaginase treatment due to asparaginase related toxicities or silent inactivation (SI) is common and may increase relapse risk in acute lymphoblastic leukemia (ALL). We investigated relapse risk following suboptimal asparaginase exposure among 1401 children aged 1-17 years, diagnosed with ALL between July 2008 and February 2016, and treated according to the NOPHO ALL2008 protocol including extended asparaginase exposure (1,000 IU/m2 intramuscularly weeks 5 to 33). Patients were included with delayed entry at their last administered asparaginase treatment or detection of SI and followed until relapse, death, secondary malignancy, or end of follow-up (median: 5.71 years, interquartile range: 4.02-7.64). In a multiple Cox model comparing patients with (n=358) and without (n=1043) truncated asparaginase treatment due to clinical toxicity, the adjusted relapse-specific hazard ratio (aHR) was 1.33 (95% confidence interval [CI]: 0.86-2.06, P=0.20). In a substudy including only patients with information on enzyme activity (n=1115), the 7-year cumulative incidence of relapse for the 301 patients with truncation of asparaginase treatment or SI (157 hypersensitivity, 53 pancreatitis, 14 thrombosis, 31 other, 46 SI) was 11.1% (95% CI: 6.9-15.4) versus 6.7% (95% CI: 4.7-8.6) for the 814 remaining patients. The relapse-specific aHR was 1.69 (95% CI: 1.05-2.74, P=0.03). The unadjusted bone-marrow relapse-specific HR was 1.83 (95% CI: 1.07-3.14, P=0.03) and 1.86 (95% CI: 0.90- 3.87, P=0.095) for any CNS relapse. These results emphasize the importance of therapeutic drug monitoring and appropriate adjustment of asparaginase therapy when feasible.
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| 2. |
- Pilheden, Mattias, et al.
(författare)
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Duplex sequencing uncovers recurrent low-frequency cancer-associated mutations in infant and childhood KMT2A-rearranged acute leukemia
- 2022
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Ingår i: HemaSphere. - : Wolters Kluwer. - 2572-9241. ; 6:10
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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.
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| 3. |
- Rank, Cecilie Utke, et al.
(författare)
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Thromboembolism in acute lymphoblastic leukemia : results of NOPHO ALL2008 protocol treatment in patients aged 1 to 45 years
- 2018
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Ingår i: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 131:22, s. 2475-2484
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Tidskriftsartikel (refereegranskat)abstract
- Thromboembolism frequently occurs during acute lymphoblastic leukemia (ALL) therapy. We prospectively registered thromboembolic events during the treatment of 1772 consecutive Nordic/Baltic patients with ALL aged 1 to 45 years who were treated according to the Nordic Society of Pediatric Hematology and Oncology ALL2008 protocol (July 2008-April 2017). The 2.5-year cumulative incidence of thromboembolism (N = 137) was 7.9% (95% confidence interval [CI], 6.6-9.1); it was higher in patients aged at least 10 years (P < .0001). Adjusted hazard ratios (HRas) were associated with greater age (range, 10.0-17.9 years: HRa, 4.9 [95% CI, 3.1-7.8; P < .0001]; 18.0-45.9 years: HRa, 6.06 [95% CI, 3.65-10.1; P < .0001]) and mediastinal mass at ALL diagnosis (HRa, 2.1; 95% CI, 1.0-4.3; P = .04). In a multiple absolute risk regression model addressing 3 thromboembolism risk factors, age at least 10 years had the largest absolute risk ratio (RRage, 4.7 [95% CI, 3.1-7.1]; RRenlarged (lymph nodes), 2.0 [95% CI, 1.2-3.1]; RRmediastinal mass, 1.6 [95% CI, 1.0-2.6]). Patients aged 18.0 to 45.9 years had an increased hazard of pulmonary embolism (HRa, 11.6; 95% CI, 4.02-33.7; P < .0001), and patients aged 10.0 to 17.9 years had an increased hazard of cerebral sinus venous thrombosis (HRa, 3.3; 95% CI, 1.5-7.3; P = .003) compared with children younger than 10.0 years. Asparaginase was truncated in 38/128 patients with thromboembolism, whereas thromboembolism diagnosis was unassociated with increased hazard of relapse (P = .6). Five deaths were attributable to thromboembolism, and patients younger than 18.0 years with thromboembolism had increased hazard of dying compared with same-aged patients without thromboembolism (both P <= .01). In conclusion, patients aged at least 10 years could be candidates for preemptive antithrombotic prophylaxis. However, the predictive value of age 10 years or older, enlarged lymph nodes, and mediastinal mass remain to be validated in another cohort.
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| 4. |
- Tulstrup, Morten, et al.
(författare)
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Individualized 6-mercaptopurine increments in consolidation treatment of childhood acute lymphoblastic leukemia: A NOPHO randomized controlled trial.
- 2018
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 100:1, s. 53-60
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Tidskriftsartikel (refereegranskat)abstract
- This randomized controlled trial tested the hypothesis that children with non-high-risk acute lymphoblastic leukemia could benefit from individualized 6-mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event-free survival.392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6-mercaptopurine (25mg/m(2) /day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25mg/m(2) /day beginning on days 50 and/or 71 unless dose-limiting myelosuppression had occurred.In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty-seven of 387 (15%) patients in the experimental arm were MRD positive at end of consolidation vs 77 of 389 (20%) in the control arm (P=.08). Five-year probability of event-free survival was 0.89 (95% CI: 0.85-0.93) in the experimental arm vs 0.93 (0.90-0.96) in the control arm (P=.13). The median accumulated length of 6-mercaptopurine treatment interruptions was 7 (IQR 2-12) in the experimental arm vs 4 (IQR 0-10) in the control arm (P=.002).This study found no benefit from individualized 6-mercaptopurine increments compared to standard therapy.
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