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- Frandsen, Thomas Leth, et al.
(författare)
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Complying with the European Clinical Trials directive while surviving the administrative pressure : An alternative approach to toxicity registration in a cancer trial
- 2014
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Ingår i: European Journal of Cancer. - : Elsevier BV. - 0959-8049 .- 1879-0852. ; 50:2, s. 251-259
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Tidskriftsartikel (refereegranskat)abstract
- The European Clinical Trials Directive of 2004 has increased the amount of paper work and reduced the number of initiated clinical trials. Particularly multinational trials have been delayed. To meet this challenge we developed a novel, simplified, fast and easy strategy for on-line toxicity registration for patients treated according to the Nordic/Baltic acute lymphoblastic leukaemia protocol, NOPHO ALL 2008, for children and young adults, including three randomisations. We used a risk-assessment based approach, avoiding reporting of expected adverse events and instead concentrating on 20 well-known serious, but rarer events with focus on changes in therapy introduced in the treatment protocol. This toxicity registration strategy was approved by the relevant regulatory authorities in all seven countries involved, as compliant within the EU directive of 2004. The centre compliance to registration was excellent with 98.9% of all patients being registered within 5 weeks from the requested quarterly registration. Currently, four toxicities (thrombosis, fungal infections, pancreatitis and allergic reactions) have been chosen for further detailed exploration due to the cumulative fraction of patients with positive registrations exceeding 5%. This toxicity registration offers real-time toxicity profiles of the total study cohort and provides early warnings of specific toxicities that require further investigation.
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| 2. |
- Levinsen, Mette, et al.
(författare)
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Clinical features and early treatment response of central nervous system involvement in childhood acute lymphoblastic leukemia
- 2014
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Ingår i: Pediatric Blood & Cancer. - : Wiley. - 1545-5009 .- 1545-5017. ; 61:8, s. 1416-1421
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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.
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| 4. |
- Toft, Nina, et al.
(författare)
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Risk group assignment differs for children and adults 1-45 years with acute lymphoblastic leukemia treated by the NOPHO ALL-2008 protocol
- 2013
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 90:5, s. 404-412
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The prognosis of acute lymphoblastic leukemia is poorer in adults than in children. Studies have indicated that young adults benefit from pediatric treatment, although no upper age limit has been defined.DESIGN AND METHODS:We analyzed 749 patients aged 1-45 years treated by the NOPHO ALL-2008 protocol. Minimal residual disease (MRD) on days 29 and 79, immunophenotype, white blood cell count (WBC), and cytogenetics were used to stratify patients to standard, intermediate, or high risk treatment with or without hematopoietic stem cell transplantation.RESULTS: Adults aged 18-45 had significantly lower WBCs at diagnosis compared to children aged 1-9 and 10-17 years, but significantly more adults were stratified to high-risk chemotherapy (8%, 14%, 17%; p < 0.0001) or high risk chemotherapy with transplantation (4%, 13%, 19%; p < 0.0001). This age dependent skewing of risk grouping reflected more T-ALL (11%, 27%, 33%, p < 0.0001), poorer MRD response day 29 (MRD < 0.1%: 75%, 61%, 52%; p < 0.0001), and more MLL gene rearrangements (3%, 3%, 10%; p = 0.005) in older patients.CONCLUSIONS:Even if identical diagnostics, treatment, and risk stratification are implemented, more adults will be stratified to high risk therapy, which should be considered when comparing pediatric and adult outcomes.
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| 5. |
- Toft, Nina, et al.
(författare)
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Toxicity profile and treatment delays in NOPHO ALL2008-comparing adults and children with Philadelphia chromosome-negative acute lymphoblastic leukemia
- 2016
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Ingår i: European Journal of Haematology. - : Wiley. - 0902-4441 .- 1600-0609. ; 96:2, s. 160-169
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Cure rates improve when adolescents and young adults with acute lymphoblastic leukemia (ALL) are treated according to pediatric protocols. Assumed risks of toxicities and associated delays in treatment have played a role in setting upper age limits. The aim of this study was to examine the toxicity profile and treatment delays in NOPHO ALL2008 comparing children and adults.METHODS: We collected information on 19 treatment-related toxicities, systematically captured at 3-month intervals throughout therapy, and time intervals between 12 consecutive treatment phases for 1076 patients aged 1-45 yrs treated according to the Nordic/Baltic ALL2008 protocol.RESULTS: No adults died during induction. The duration of induction therapy and postinduction treatment phases did not differ between children and adults, except for patients 18-45 yrs being significantly delayed during two of nine high-risk blocks (median number of days for patients 1-9, 10-17, and 18-45 yrs; the glucocorticosteroid/antimetabolite-based block B1: 24, 26, and 29 d, respectively, P = 0.001, and Block 5 (in most cases also a B block): 29, 29, and 37 d, respectively, P = 0.02). A higher incidence of thrombosis with increasing age was found; highest odds ratio 5.4 (95% CI: (2.6;11.0)) for patients 15-17 yrs compared with children 1-9 yrs (P < 0.0001). Risk of avascular osteonecrosis was related to age with the highest OR for patients 10-14 yrs (OR = 10.4 (95% CI: (4.4;24.9)), P < 0.0001).CONCLUSION: Adults followed and tolerated the NOPHO ALL2008 protocol virtually as well as children, although thrombosis and avascular osteonecrosis was most common among adolescents.
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