Minimal residual disease and outcome characteristics in infant KMT2A-germline acute lymphoblastic leukaemia treated on the Interfant-06 protocol

Comparison of paired bone marrow and peripheral blood measurable residual disease in pediatric acute lymphoblastic leukemia by next-generation sequencing: A report from the dana farber ALL consortium protocol 16-001.

Prognostic Impact of Peripheral Blood Involvement during Early Time Points of Childhood ALL Treatment.

To evaluate the prognostic power of minimal residual disease (MRD) monitored by polymerase chain reaction at defined time points during early treatment in adult patients with acute lymphoblastic leukemia (ALL). Seventy-one patients were treated according to the GMALL 07/2003 protocol and evaluated for MRD in bone marrow by specific clonal rearrangements of Ig/TCR in BCR-ABL negative ALL or fusion gene transcript in BCR-ABL positive ALL. Three-year overall survival (OS) was 94% in patients with BCR-ABL negative ALL reaching complete molecular response (CMR) after the first course of chemotherapy (vs. 32% if MRD >10(-4) ; P = 0.001). Patients with CMR prior to the start of consolidation chemotherapy at week 11 had 3-yr OS 82% (vs. 18% if MRD >10(-4) ; P = 0.001). Patients with BCR-ABL positive ALL showed slower MRD dynamics. There was a trend to better OS in patients with ≥ 4 log reduction of BCR-ABL transcript prior to HSCT (92% vs. 50%; P = 0.065). None of the patients with detectable MRD (both BCR-ABL positive and negative) after HSCT survived 3 yr. Early MRD kinetics is an important tool for new prognostication models with direct clinical impact irrespective of standard prognostic factors in patients with BCR-ABL negative ALL.

Intensification of Oral Methotrexate Is Not Superior to Standard Methotrexate Dosing during Maintenance in Children with National Cancer Institute (NCI) Standard-Risk B Acute Lymphoblastic Leukemia (SR B-ALL): A Report from Children's Oncology Group (COG) Study AALL0932

Background: Acute lymphoblastic leukemia (ALL) is the most prevalent cancer in children, with continuously improving survival rates. As few studies in Romania have analyzed ALL patients and disease characteristics or survival, we conducted a retrospective study on 158 patients diagnosed with ALL admitted to the Department of Pediatric Oncology and Hematology at the Emergency Hospital for Children, Cluj-Napoca, Romania, from January 2011 until April 2021. The most important objectives of the study are to establish full profiles of the patients and ALL, remission rates, relapses, and deaths, an epidemiology analysis to determine the incidence of ALL for comparison with the standard European population, and also to assess survival by the most important parameters, including minimal residual disease (MRD).Methods: This was a retrospective study that focused on patients with newly diagnosed ALL from January 2011 to April 2021 in the Department of Pediatric Hematology and Oncology of the Emergency Hospital for Children, Cluj-Napoca, Romania. The inclusion criteria were: patients with de novo ALL, patients who were younger than 18 years of age, and patients with signed informed consents. The exclusion criteria included patients who were older than 18 years of age; patients with relapsed ALL; and patients who did not have a signed informed consent. A total of 158 patients were included in the study, aged between 0 and 17 years. The information about patient characteristics and all variables was taken from the patients' files, where informed consent is mandatorily stored. Descriptive statistics were used to evaluate variables such as age, gender, leukocyte number, immunophenotype, prednisone response, risk group assessment, cytogenetics, relapse, and MRD. Kaplan-Meier curves were used to assess survival, for which patients were divided into two subcohorts: a 2011-2015 subcohort and a 2016-2020 subcohort. The statistical analyses used Prism version 10.2.3 (GraphPad Software, La Jolla, CA). For the analysis, we used Kaplan-Meier curves, the log-rank (Mantel-Cox) test, the log-rank test for trends, the Gehan-Breslow-Wilcoxon test, survival proportions, the chi-square test, and correlations.Results: A shift in risk groups was observed after the introduction of MRD testing in 2017, with more patients being stratified in the medium-risk group (MRG) and high-risk group (HRG). At the survival analyses between bone marrow (BM) aspiration and MRD on day 15, we discovered that patients with MRD>10% had much higher overall survival (OS) and event-free survival (EFS) compared to patients with >25% blasts in the BM; 24(11.4%) patients relapsed, of which, nine (3.8%) were very early relapses and 10 (4.1%) were late relapses. The five-year OS and EFS for patients with the T-cell immunophenotype of ALL and those with leukocyte counts >100,000/mm3 were identical to those at one year.Conclusions: The OS of the 2016-2020 subcohort was higher than that of the 2011-2015 subcohort, and more patients were stratified into MRG and HRGs due to the implementation of MRD testing. Minimal residual disease testing helped to improve significantly the survival rates of patients with more than 10% residual disease. None of the patients with very early relapses entered complete remission (CR), but all late relapses achieved CR. All events experienced by patients with the T-cell immunophenotype, or leukocyte counts of >100,000/mm3 occurred in the first year after diagnosis.

An Update on Outcomes Using the USC ALL Frontline Regimen (based on CCG-1882) after Further Modification of Protocol in the Era of Novel Agents in Ph-Negative ALL Patients; A Retrospective Study

Objective: To summarize the clinical data and prognosis of children with Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) common genes. Methods: This was a retrospective cohort study.Clinical data of 56 children with Ph-like ALL common gene cases (Ph-like ALL positive group) treated from January 2017 to January 2022 in the First Affiliated Hospital of Zhengzhou University, Henan Children's Hospital, Henan Cancer's Hospital and Henan Provincial People's Hospital were collected, 69 children with other high-risk B cell acute lymphoblastic leukemia (B-ALL) at the same time and the same age were selected as the negative group. The clinical characteristics and prognosis of two groups were analyzed retrospectively. Comparisons between groups were performed using Mann-Whitney U test and χ2 test. Kaplan-Meier method was used for survival curve, Log-Rank test was used for univariate analysis, and the Cox regression model was used for multivariate prognosis analysis. Results: Among 56 Ph-like ALL positive patients, there were 30 males and 26 females, and 15 cases were over 10 years old. There were 69 patients in Ph-like ALL negative group. Compared with the negative group, the children in positive group were older (6.4 (4.2, 11.2) vs. 4.7 (2.8, 8.4) years), and hyperleukocytosis (≥50×109/L) was more common (25% (14/56) vs. 9% (6/69)), the differences were statistically significant (both P<0.05). In the Ph-like ALL positive group, 32 cases were positive for IK6 (1 case was co-expressed with IK6 and EBF1-PDGFRB), 24 cases were IK6-negative, of which 9 cases were CRLF2 positive (including 2 cases with P2RY8-CRLF2, 7 cases with CRLF2 high expression), 5 cases were PDGFRB rearrangement, 4 cases were ABL1 rearrangement, 4 cases were JAK2 rearrangement, 1 case was ABL2 rearrangement and 1 case was EPOR rearrangement. The follow-up time of Ph-like ALL positive group was 22 (12, 40) months, and 32 (20, 45) months for negative group. The 3-year overall survival (OS) rate of positive group was significantly lower than the negative group ((72±7) % vs. (86±5) %, χ2=4.59, P<0.05). Compared with the 24 IK6-negative patients, the 3-year event free survival (EFS) rate of 32 IK6 positive patients was higher, the difference was statistically significant ((88±9) % vs. (65±14) %, χ2=5.37, P<0.05). Multivariate Cox regression analysis showed that the bone marrow minimal residual disease (MRD) not turning negative at the end of first induction (HR=4.12, 95%CI 1.13-15.03) independent prognostic risk factor for patient with Ph-like ALL common genes. Conclusions: Children with Ph-like ALL common genes were older than other high-risk B-ALL patients at diagnosis, with high white blood cells and lower survival rate. The bone marrow MRD not turning negative at the end of first induction were independent prognostic risk factor for children with Ph-like ALL common gene.

Minimal Residual Disease (MRD) Assessment after Induction Chemotherapy in Children and Adults with Acute Lymphoblastic Leukemia (ALL): A Valuable Strategy in Resource Constraint Settings in the Indian Subcontinent

Minimal Residual Disease following Allogeneic Hematopoietic Stem Cell Transplantation

Background Monitoring of minimal residual disease (MRD) has become a frontline clinical practice in the treatment of virtually all childhood acute lymphoblastic leukemia (ALL) cases and in many cases of adult patients with ALL. The MRD diagnostics has proven to be the strongest prognostic factor allowing for risk group assignment into different treatment arms. The MRD techniques need to be sensitive (≤10–4), which means, the ability to detect one malignant cell among 10 000 normal cells; broadly applicable; accurate; reliable; fast; and affordable. Aim The objective of this study is to evaluate the analysis of immunoglobulin heavy chain (IGH) or T-cell receptor (TCR) gene rearrangements as targets for MRD assessment in ALL, allowing early detection of relapsed cases, compare with the results of morphological evaluation of the same cases and to risk stratify patients with ALL according to the MRD assessment as a prognostic marker independent and superior to other conventional risk factors. Patients and methods Overall, 30 patients (15 males and 15 females) with age ranged from 1 to 25 years old were included in this study. Patients were subjected to full medical history, clinical examination, laboratory examinations such as complete blood count, bone marrow aspirate smear examination, cytochemistry, and immunophenotyping. The molecular studies done by real-time PCR were performed using consensus primers and allele-specific primers for (IGH) or (TCR) gene rearrangements as targets to detect MRD. The ALL cases were assessed by real-time quantitative PCR at the time of diagnosis and at the end of induction chemotherapy, and comparative cycle threshold (Ct) relative quantification method was used for quantitative gene expression. Results The results showed discrepancy between the morphologic examination for ALL assessment depending on the 5% blast index as an indicator of remission or nonremission; morphological nonremissions (>5% blast) were detected in eight (26.7%) cases whereas 22 (73.3%) cases showed morphological remissions ( Conclusion Approximately 81% of ALL cases previously diagnosed as being in the remission state depending on the morphologic assessment only tend to harbor MRD as evident by positive MRD assessment using real-time PCR. The molecular assessment of MRD allows early detection of relapse with chance of intervention and tailoring of treatment according to the patients' need. It was found that there was no relation between MRD results and risk stratification in ALL according to age and white blood cell at diagnosis; this confirms that detection of MRD of leukemic cells can be considered a superior prognostic marker of relapse, independent from conventional prognostic factors. The risk classification in ALL based on MRD results could be used to guide the final treatment strategy and predict early relapse; this should allow prediction of response and relapse while patients are still in the state of clinical remission and morphological remission too.

Sex-Based Disparities in Outcome in Childhood Acute Lymphoblastic Leukemia (ALL): A Children's Oncology Group (COG) Report

Simple SummaryNeuroblastoma (NB) is a common pediatric tumor, and less than 50% of children with high-risk (HR)-NB can achieve long-term survival. This is mainly due to a tumor relapse caused by the activation of therapy-resistant minimal residual disease (MRD). Several assays measuring different sets of MRD markers by quantitative PCR (qPCR) or droplet digital PCR (ddPCR) were reported to have a significant prognostic value for MRD in HR-NB patients. The 7NB-mRNAs ddPCR assay was reported to outperform other qPCR assays by a retrospective in-house observational study. In the present study, the Japan Children’s Cancer Group (JCCG) Neuroblastoma Committee conducted a prospective multicenter observational study to evaluate a prognostic value of MRD in bone marrow (BM-MRD) and peripheral blood (PB-MRD) measured by the 7NB-mRNAs ddPCR assay. A total of 19 BM and 19 PB samples were collected from seven HR-NB patients. BM-MRD and PB-MRD estimated area under curve (AUC) of 0.767 and 0.800 with a significant accuracy (AUC > 0.7), validating a prognostic value of BM-MRD obtained by a previous study (AUC 0.723). The present study will pave the way to introduce a MRD assay into HR-NB patients’ clinical practice.High-risk neuroblastoma (HR-NB) patients remain far from obtaining optimal outcomes, with more than 50% relapse/regrowth rate despite current intensive multimodal therapy. This originated from the activation/proliferation of chemoresistant minimal residual disease (MRD). MRD with a significant prognostic was reported by several quantitative PCR (qPCR) or droplet digital PCR (ddPCR) assays quantitating different sets of NB-associated mRNAs (NB-mRNAs). The 7NB-mRNAs ddPCR assay quantitating CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs was reported to outperform other qPCR assays by a retrospective in-house observational study. In the present study, the Japan Children’s Cancer Group (JCCG) Neuroblastoma Committee conducted a prospective multicenter observational study aimed at evaluating a prognostic value of MRD in bone marrow (BM-MRD) and peripheral blood (PB-MRD) detected by 7NB-mRNAs ddPCR assay. Between August 2018 and August 2022, 7 HR-NB patients who registered for JCCG clinical trials (JN-H-11 and JN-H-15) were enrolled. A total of 19 BM and 19 PB samples were collected, and 4/15 BM and 4/15 PB samples were classified as progressive disease (PD)/non-PD samples. BM-MRD and PB-MRD estimated area under curve (AUC) of 0.767 and 0.800 with a significant accuracy (AUC > 0.7). The present study validated a prognostic value of BM-MRD obtained by a previous study (AUC 0.723) and revealed the significant accuracy of PB-MRD as well as BM-MRD.

Introduction: Despite the approval of novel agents that have significantly improved long-term survival rates for multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), most patients eventually relapse. The failure to achieve or maintain bone marrow (BM) minimal residual disease (MRD) negativity is a recognised adverse prognostic factor for progression-free survival (PFS) and overall survival (OS). Contamination of stem cell apheresis by clonal plasma cells may also affect prognosis, though data remain limited. Methods: We conducted a prospective, single-centre observational study including 100 newly diagnosed MM patients eligible for ASCT and treated with bortezomib-based triplet induction. MRD was assessed both on BM and apheresis samples using multiparameter flow cytometry (MFC-MRD) with a sensitivity of 10-5. Results: Clonal plasma cells were detected in 22 apheresis samples (aMRD+), all of which were associated with BM MRD positivity. Patients with aMRD+ had inferior pre-ASCT responses (≥VGPR: 10% vs. 63%, p = 0.005) and worse post-ASCT BM MRD negativity rates (4% vs. 49%, p = 0.048). After a median follow-up of 52.4 months, aMRD+ was associated with shorter progression-free survival (median 38.5 vs. not reached, p = 0.007) and overall survival (median 60 months vs. not reached, p = 0.003). Conclusions: Contamination of the apheresis product is associated with persistent BM disease and poorer outcomes. Combined MRD assessment in both bone marrow and apheresis may improve risk stratification in MM patients undergoing ASCT.

Minimal Residual Disease Negative Status At the End of Induction Therapy Is a Potent Prognostic Marker in Adult Non-Ph Acute Lymphoblastic Leukemia: Results of the ALL MRD2002 Study

The Significance of Flow Cytometry and Positron Emission Tomography and Computed Tomography (PET-CT) in the Assessment of the Minimum Residual Disease in Patients with Multiple Myeloma