ABSTRACT
INTRODUCTION: Follow-up after allogeneic transplantation in acute myeloid leukaemia (AML) is guided by measurable residual disease (MRD) testing. Quantitative polymerase chain reaction (qPCR) is the preferred MRD platform but unfortunately, 40%-60% of AML patients have no high-quality qPCR target. This study aimed to improve MRD testing by utilising droplet digital PCR (ddPCR). ddPCR offers patient-specific monitoring but concerns of tracking clonal haematopoiesis rather than malignant cells prompt further validation. METHODS: Retrospectively, we performed MRD testing on blood and bone marrow samples from AML patients transplanted by reduced-intensity conditioning. RESULTS: The applicability of ddPCR was 39/42 (92.9%). Forty-five ddPCR assays were validated with a 0.0089% median sensitivity. qPCR targeting NPM1 mutation detected relapse 46 days before ddPCR (p = .03). ddPCR detected relapse 34.5 days before qPCR targeting WT1 overexpression (p = .03). In non-relapsing patients, zero false positive ddPCR MRD relapses were observed even when monitoring targets associated with clonal haematopoiesis such as DNMT3A, TET2, and ASXL1 mutations. CONCLUSION: These results confirm that qPCR targeting NPM1 mutations or fusion transcripts are superior in MRD testing. In the absence of such targets, ddPCR is a promising alternative demonstrating (a) high applicability, (b) high sensitivity, and (c) zero false positive MRD relapses in non-relapsing patients.
Subject(s)
Leukemia, Myeloid, Acute , Nucleophosmin , Humans , Retrospective Studies , Neoplasm Recurrence, Local , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Polymerase Chain Reaction/methods , Chronic Disease , Recurrence , Neoplasm, Residual/diagnosis , Neoplasm, Residual/geneticsABSTRACT
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.
Subject(s)
Antigens, Neoplasm/genetics , Leukemia, Myeloid, Acute/genetics , Microtubule Proteins/genetics , Repressor Proteins/genetics , Adolescent , Antigens, Neoplasm/blood , Biomarkers, Tumor/blood , Biomarkers, Tumor/genetics , Case-Control Studies , Child , Child, Preschool , Female , Gene Expression Regulation, Leukemic , Humans , Infant , Infections/blood , Infections/genetics , Leukemia, Myeloid, Acute/pathology , Leukemia, Myeloid, Acute/therapy , Male , Microtubule Proteins/blood , Neoplasm, Residual , Repressor Proteins/bloodABSTRACT
Longitudinal molecular measurable residual disease (MRD) sampling after completion of therapy serves as a refined tool for identification of imminent relapse of acute myeloid leukaemia (AML) among patients in long-term haematological complete remission. Tracking of increasing quantitative polymerase chain reaction MRD before cytomorphological reappearance of blasts may instigate individual management decisions and has paved the way for development of pre-emptive treatment strategies to substantially delay or perhaps even revert leukaemic regrowth. Traditionally, MRD monitoring is performed using repeated bone marrow aspirations, albeit the current European LeukemiaNet MRD recommendations acknowledge the use of peripheral blood as an alternative source for MRD assessment. Persistent MRD positivity in the bone marrow despite continuous morphological remission is frequent in both core binding factor leukaemias and nucleophosmin 1-mutated AML. In contrast, monthly assessment of MRD in peripheral blood superiorly separates patients with imminent haematological relapse from long-term remitters and may allow pre-emptive therapy of AML relapse.
Subject(s)
Biomarkers, Tumor/blood , Leukemia, Myeloid, Acute/blood , Neoplastic Cells, Circulating , RNA, Messenger/blood , RNA, Neoplasm/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bone Marrow/pathology , Early Diagnosis , Humans , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/pathology , Neoplasm, Residual , Nucleophosmin/genetics , Oncogene Proteins, Fusion/genetics , Predictive Value of Tests , RNA, Long Noncoding/genetics , Real-Time Polymerase Chain Reaction/methods , Recurrence , Remission Induction , Sensitivity and SpecificityABSTRACT
BACKGROUND: As more children survive acute myeloid leukemia (AML) it is increasingly important to assess possible late effects of the intensive treatment. Hearing loss has only sporadically been reported in survivors of childhood AML. We assessed hearing status in survivors of childhood AML treated with chemotherapy alone according to 3 consecutive NOPHO-AML trials. PROCEDURE: A population-based cohort of children treated according to the NOPHO-AML-84, NOPHO-AML-88, and NOPHO-AML-93 trials included 137 eligible survivors among whom 101 (74%) completed a questionnaire and 99 (72%) had otologic and audiologic examination performed including otoscopy (72%), pure tone audiometry (70%), and tympanometry (60%). Eighty-four of 93 (90%) eligible sibling controls completed a similar questionnaire. RESULTS: At a median of 11 years (range, 4 to 25) after diagnosis, hearing disorders were rare in survivors of childhood AML and in sibling controls, with no significant differences. None had severe or profound hearing loss diagnosed at audiometry. Audiometry detected a subclinical hearing loss ranging from slight to moderate in 19% of the survivors, 5% had low-frequency hearing loss, and 17% had high-frequency hearing loss. CONCLUSIONS: The frequency of hearing disorders was low, and hearing thresholds in survivors of childhood AML were similar to background populations of comparable age.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Hearing Disorders , Hearing/drug effects , Leukemia, Myeloid, Acute , Adolescent , Adult , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Cancer Survivors , Child , Child, Preschool , Female , Follow-Up Studies , Hearing Disorders/chemically induced , Hearing Disorders/epidemiology , Humans , Infant , Infant, Newborn , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/epidemiology , Male , Retrospective Studies , SiblingsABSTRACT
BACKGROUND: We investigated the spectrum, frequency, and risk factors for renal, gastrointestinal, and hepatic late adverse effects in survivors of childhood acute myeloid leukemia (AML) without relapse treated with chemotherapy alone according to three consecutive AML trials by the Nordic Society of Pediatric Hematology and Oncology (NOPHO). METHODS: A population-based cohort of children treated for AML according to the NOPHO-AML-84, -88, and -93 trials included 138 eligible survivors of whom 102 (74%) completed a questionnaire and 104 (75%) had a clinical examination and blood sampling performed. Eighty-five of 94 (90%) eligible sibling controls completed a similar questionnaire. Siblings had no clinical examination or blood sampling performed. RESULTS: At a median of 11 years (range 4-25) after diagnosis, renal, gastrointestinal, and hepatic disorders were rare both in survivors of childhood AML and in sibling controls, with no significant differences. Ferritin was elevated in 21 (21%) AML survivors but none had biochemical signs of liver damage. Viral hepatitis was present in three and cholelithiasis in two AML survivors. One adult survivor had hypertension, two had slightly elevated systolic blood pressure, and eight survivors had slightly elevated diastolic blood pressure. These persons all had normal creatinine and cystatin C levels. Marginal abnormalities in potassium, magnesium, calcium, or bicarbonate levels were found in 34 survivors. CONCLUSION: Survivors of childhood AML treated with chemotherapy only experienced few renal, gastrointestinal, and hepatic late effects.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Gastrointestinal Diseases/chemically induced , Kidney Diseases/chemically induced , Leukemia, Myeloid, Acute/drug therapy , Liver Diseases/etiology , Survivors/statistics & numerical data , Adolescent , Adult , Child , Child, Preschool , Female , Follow-Up Studies , Gastrointestinal Diseases/diagnosis , Gastrointestinal Diseases/mortality , Humans , Infant , Infant, Newborn , Kidney Diseases/diagnosis , Kidney Diseases/mortality , Liver Diseases/diagnosis , Liver Diseases/mortality , Male , Prognosis , Survival Rate , Young AdultABSTRACT
A 19-month-old girl with the A1555G mitochondrial mutation in the 12S ribosomal RNA gene and acute myelogenous leukemia developed dilated cardiomyopathy and bilateral sensorineural hearing loss before undergoing allogeneic stem cell transplantation. She had received gentamicin during episodes of febrile neutropenia. Testing for the A1555G mutation is recommended in patients frequently treated with aminoglycosides.
Subject(s)
Aminoglycosides/adverse effects , Cardiomyopathies/chemically induced , Hearing Loss, Sensorineural/chemically induced , Mutation , RNA, Ribosomal/genetics , Aminoglycosides/therapeutic use , Cardiomyopathies/genetics , Female , Hearing Loss, Sensorineural/genetics , Humans , Infant , Leukemia, Myeloid, Acute/drug therapy , PedigreeABSTRACT
BACKGROUND: More than 60% of children with acute myeloid leukemia (AML) become long-term survivors. Most are cured using chemotherapy without hematopoietic stem cell transplantation (HSCT). We report on pubertal development and compare self-reported parenthood among AML survivors and their siblings. PROCEDURE: We included 137 children treated for AML according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO)-AML-84, -88, and -93 trials, who were alive by June 2007. Patients with relapse or treated with HSCT were excluded. AML survivors participated in a physical and biochemical examination (n = 102) and completed a questionnaire (n = 101). One of their siblings completed an identical questionnaire (n = 84). RESULTS: At a median follow-up of 11 years (range 5-25) after diagnosis of AML the survivors (median age 16 years, range 5-36) were either prepubertal or had entered puberty normally. Serum levels of FSH, LH, testosterone, estradiol, sex hormone binding globulin (SHBG), inhibin A and B, and testicular volumes were within normal ranges. Anti-Müllerian hormone (AMH) levels were decreased in 5 of 40 postpubertal females. Mean reported age at menarche was 13.1 (range 11-17) years. Among survivors 15 years of age or older 31% of females reported pregnancies and 9% of males reported pregnancies in their partners, rates comparable with the frequency reported by their siblings. CONCLUSIONS: Most AML survivors treated with chemotherapy had normal pubertal development and fertility, however, AMH levels were decreased in 13% of postpubertal females. Longer follow-up is necessary to evaluate possible risk of premature ovarian failure.