Kjeld Schmiegelow1,2, Jacob Nersting3, Stine Nygaard Nielsen3, Mats Heyman4, Finn Wesenberg5, Jon Kristinsson6, Kim Vettenranta7, Henrik Schrøeder8, Richard Weinshilboum9, Katrine Lykke Jensen10, Kathrine Grell10, Susanne Rosthoej10. 1. Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark. kschmiegelow@rh.dk. 2. Faculty of Medicine, Institute of Clinical Medicine, University of Copenhagen, Denmark. kschmiegelow@rh.dk. 3. Department of Pediatrics and Adolescent Medicine, The University Hospital Rigshospitalet, Copenhagen, Denmark. 4. Astrid Lindgrens Barnsjukhus, Stockholm, Sweden. 5. Department of Pediatric Oncology, The University Hospital Rikshospitalet, Oslo, Norway. 6. Department of Pediatric Oncology, The National Hospital, Reykjavik, Iceland. 7. Department of Pediatric Oncology, The University Hospital, Helsinki, Finland. 8. Department of Pediatric Oncology, Århus University Hospital, Denmark. 9. Department of Pharmacology, Mayo Clinic, Rochester, Minnesota. 10. Section of Biostatistics, Department of Public Health, The University of Copenhagen, Copenhagen, Denmark.
Abstract
BACKGROUND: 6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. PROCEDURE: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 109 /l. RESULTS: After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 109 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, rs = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. CONCLUSIONS: This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.
BACKGROUND:6-Mercaptopurine (6MP) and methotrexate (MTX) based maintenance therapy is a critical phase of childhood acute lymphoblastic leukemia treatment. Wide interindividual variations in drug disposition warrant frequent doses adjustments, but there is a lack of international consensus on dose adjustment guidelines. PROCEDURE: To identify relapse predictors, we collected 28,255 data sets on drug doses and blood counts (median: 47/patient) and analyzed erythrocyte (Ery) levels of cytotoxic 6MP/MTX metabolites in 9,182 blood samples (median: 14 samples/patient) from 532 children on MTX/6MP maintenance therapy targeted to a white blood cell count (WBC) of 1.5-3.5 × 109 /l. RESULTS: After a median follow-up of 13.8 years for patients in remission, stepwise Cox regression analysis did not find age, average doses of 6MP and MTX, hemoglobin, absolute lymphocyte counts, thrombocyte counts, or Ery levels of 6-thioguanine nucleotides or MTX (including its polyglutamates) to be significant relapse predictors. The parameters significantly associated with risk of relapse (N = 83) were male sex (hazard ratio [HR] 2.0 [1.3-3.1], P = 0.003), WBC at diagnosis (HR = 1.04 per 10 × 109 /l rise [1.00-1.09], P = 0.048), the absolute neutrophil count (ANC; HR = 1.7 per 109 /l rise [1.3-2.4], P = 0.0007), and Ery thiopurine methyltransferase activity (HR = 2.7 per IU/ml rise [1.1-6.7], P = 0.03). WBC was significantly related to ANC (Spearman correlation coefficient, rs = 0.77; P < 0.001), and only a borderline significant risk factor for relapse (HR = 1.28 [95% CI: 1.00-1.64], P = 0.046) when ANC was excluded from the Cox model. CONCLUSIONS: This study indicates that a low neutrophil count is likely to be the best hematological target for dose adjustments of maintenance therapy.
Authors: Hee Young Ju; Ji Won Lee; Hee Won Cho; Ju Kyung Hyun; Youngeun Ma; Eun Sang Yi; Keon Hee Yoo; Ki Woong Sung; Rihwa Choi; Hong Hoe Koo; Soo-Youn Lee Journal: PLoS One Date: 2021-01-22 Impact factor: 3.240
Authors: Linea Natalie Toksvang; Bodil Als-Nielsen; Christopher Bacon; Ruta Bertasiute; Ximo Duarte; Gabriele Escherich; Elín Anna Helgadottir; Inga Rinvoll Johannsdottir; Ólafur G Jónsson; Piotr Kozlowski; Cecilia Langenskjöld; Kristi Lepik; Riitta Niinimäki; Ulrik Malthe Overgaard; Mari Punab; Riikka Räty; Heidi Segers; Inge van der Sluis; Owen Patrick Smith; Marion Strullu; Goda Vaitkevičienė; Hilde Skuterud Wik; Mats Heyman; Kjeld Schmiegelow Journal: BMC Cancer Date: 2022-05-02 Impact factor: 4.638