DOCSLIB.ORG

Minimal Residual Disease in Multiple Myeloma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Minimal Residual Disease in Multiple Myeloma Minimal Residual Disease in Multiple Myeloma Multiple Myeloma – Pathophysiology and Epidemiology Multiple myeloma (MM) is a plasma cell malignancy in which abnormal, clonal plasma cells proliferate and accumulate within the bone marrow. These abnormal cells, referred to as myeloma cells, disrupt normal bone marrow function and invade the surrounding bone. Myeloma cells produce and secrete significant quantities of monoclonal protein (M-protein) into the blood and/or urine.1 This increases M-protein and calcium levels, and leads to renal dysfunction, anemia and bone disease. Bone pain is the most common symptom of MM.2 • MM is the second most common hematologic malignancy and accounts for approximately 17% of all hematologic cancers.3 • Every year, an estimated 159,985 new cases of MM are diagnosed globally and 106,105 deaths can be attributed to the disease.4 • MM predominantly affects elderly people; it is most frequently diagnosed in those aged between 65–74 years. MM is more common in males and African Americans compared to females and Caucasians, respectively.5 • The incidence of MM increased by 126% between 1990 and 2016, with the highest rates in Western Europe, North America and Oceania.6 • Overall, the 5-year survival among adults with MM is 50.7%.5 Complete Response Categories in MM7-10 Minimal Residual Disease – Why Assess It? Improvements in therapeutic agents and regimens have driven The treatment of MM has improved significantly over the last decade, the evolution of the International Myeloma Working Group (IMWG) resulting in many patients exhibiting a CR to front-line therapy.10,11 response criteria to include deeper measures of response. The Unfortunately, the disease course of MM is characterized by a pattern definition of a complete response (CR) was first introduced in1998 of recurrent remissions and relapses.1 After an initial CR, many patients and refined in2006 to include stringent CR.7,8 Definitions for molecular inevitably relapse; therefore, MM remains an incurable disease.6,11 and immunophenotypic CR (not shown) were introduced in 2011.9 In 2016, the IMWG was updated to include measurements of minimal Relapses in MM may be attributed to the persistence of minimal residual residual disease (MRD).10 disease (MRD) below the limits of detection by morphological exami- nation.10,12 MRD refers to the persistence of small numbers of myeloma cells that remain in the body after therapy and contribute to relapse and Negative immunofixation on the serum disease progression.10,13 In recent years, increasingly sensitive assays to and urine and disappearance of any soft detect MRD have been developed.13 CR* tissue plasmacytomas and <5% plasma cells in bone marrow aspirates In a retrospective analysis of 3 clinical trials, 40% of patients with MM relapsed within 4 years of achieving a CR14 CR plus normal FLC ratio and absence of clonal cells in bone marrow biopsy by sCR* immunohistochemistry (κ/λ ratio ≤4:1 or Hypothetical Correlation Between Depth of Response and Risk of Relapse ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells) Presentation Relapse 109 108 TTP short Absence of aberrant clonal plasma cells 107 on bone marrow aspirate, ruled out by 6 MRD-negative‡ an assay† with a minimum sensitivity of 10 1 in 105 nucleated cells or higher 105 -5 (i.e. 10 sensitivity) 4 10 Late relapse due 103 to undetectable levels of MRD MRD negativity as defined by NGF 102 or NGS plus disappearance of every TTP long area of increased tracer uptake found 101 ‡ Total number of malignant cells Imaging-positive MRD-negative at baseline or a preceding PET/CT or 10 Lower risk of relapse decrease to less mediastinal blood pool SUV or decrease to less than that of 0 surrounding normal tissue Diagnosis End of TTP therapy MRD negativity in the marrow (NGF or TTP: time to progression NGS, or both) and by imaging as defined Adapted from Paiva B, et al. Blood. 2015;125:3059-3068. ‡ above, confirmed minimum of 1 year Sustained MRD-negative apart. Subsequent evaluations can be used to further specify the duration of negativity (eg, MRD-negative at 5 years) CR: complete response; sCR: stringent complete response; FLC: free light chain; MRD: minimal residual disease; NGF: next-generation flow; NGS: next-generation sequencing; PET: positron emission tomography; CT: computed tomography; SUV: standardized uptake values *Response categories require two consecutive assessments before starting any new therapy † Based on flow cytometry (EuroFlow standard operating procedure for MRD detection in multiple myeloma or other validated equivalent method) or next-generation sequencing (LymphoSIGHT platform or validated equivalent method) ‡ Requires a complete response, as defined above Overall PFS hazard ratio forest plot15 Overall OS hazard ratio forest plot15 MRD MRD MRD MRD Study Negative Positive Study Negative Positive Rawstron et al, 2002 Rawstron et al, 2002 San Miguel et al, 2002 Ferrero et al, 2014 Ferrero et al, 2014 Bakkus et al, 2004 Bakkus et al, 2004 Dal Bó et al, 2013 Dal Bó et al, 2013 Paiva et al, 2011 (CR) Paiva et al, 2011 Paiva et al, 2008 Paiva et al, 2008 Korthals al, 2012 Korthals et al, 2012 Korthals et al, 2013 Korthals et al, 2013 Swedin et al, 1998 (CR) Swedin et al, 1998 (CR) Rawstron et al, 2013 Rawstron et al, 2013 Ludwig et al, 2015 (CR) Roussel et al, 2014 Fukumoto et al, 2016 Fukumoto et al, 2016 Overall HR, 0.57 95% CI, 0.46-0.71, P< .001 Sarasquete et al, 2005 Overall HR, 0.41 95% CI, 0.36-0.48, P< .001 0 0.5 1.0 1.5 2.0 0 1.0 2.0 3.0 4.0 Hazard Ratio for PFS Hazard Ratio for OS Overall PFS by MRD status15 Overall OS by MRD status15 100 100 2 2 χ1 = 134.4 χ1 = 25.27 P<.001 P<.001 80 80 60 60 MRD- n=599 PFS, % 40 40 MRD- n=660 20 Cumulative Surviving, % 20 MRD+ MRD+ n=613 n=501 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Time, y Time, y No. at risk No. at risk MRD Negative 457 214 70 12 1 MRD Negative 508 359 139 26 4 MRD Positive 308 113 28 4 1 MRD Positive 390 250 105 17 5 Hypothetical CorrelationHypothetical Between Correlation MRD Between and Clinical MRD and Outcomes Clincial Outcomes 100 100 MRD- MRD- Overall Survival, % MRD+ Progression-Free Survival, % MRD+ 0 0 Time Time Adapted from Munshi NC, et al. JAMA. 2017;3:28-35 There is a growing body of data that suggests that MRD is prognostic for improved clinical outcomes.15 As such, a patient’s MRD status is now being used as an endpoint in multiple myeloma clinical trials and may potentially guide treatment decisions.10 Features of MRD Detection Methods10,14,16,17 Method Process Sensitivity Important Considerations • Applicability: 90-100% • Fresh sample necessary Differentiates between normal • Widely available • Less expensive and abnormal plasma cells MFC 10-5–10-6 • Quantitative • Not applicable to extramedullary disease through detection of cell-surface (≥ 8-color) • Fast turnaround time • Not yet standardized marker expression • Applicability: 43%-75% • Fresh sample not necessary Analysis of VDJ heavy chain • Intermediate availability • More expensive regions for detection of myeloma 10-5–10-6 ASO–PCR • Indirect quantitation • Not applicable to extramedullary disease specific Ig rearrangements • Longer turnaround time • Standardized (EuroMRD) • More expensive, but costs decreasing • Applicability: ~90% Use of high throughput • Fresh sample not necessary • Limited availability sequencing to detect clonal Ig 10-6 • Not applicable to extramedullary disease NGS • Indirect quantitation VDJ gene rearrangements • Not yet standardized • Longer turnaround time Automatically identifies • Applicability: 100% • More expensive plasma cells by comparing • Limited availability • Fresh sample necessary NGF 10-6 against reference databases of • Quantitative • Not applicable to extramedullary disease bone marrow • Longer turnaround time • Standardized (EuroFlow) Permits detection of lesions • Applicability: ~100% • More expensive demonstrating metabolic activity • Intermediate availability • Detects extramedullary disease together with morphologic Variable sensitivity PET/CT • Fast turnaround time • False-negative and false-positive results information and has advantage of with coexisting infection or inflammation detecting extramedullary disease MRD: minimal residual disease; MFC: Multiparametric flow cytometry; ASO: Allele-specific oligonucleotide; Q-PCR: quantitative polymerase chain reaction; NGS: Next-genera- tion sequencing; PET: positron emission tomography; CT: computed tomography; VDJ: variable diversity joining Future applications and clinical potential Relapses in MM may potentially indicate the presence of residual disease. Recently, technological advances in molecular testing, particu- larly in NGF and NGS, and imaging techniques, such as PET/CT, have enabled the detection of myeloma cells with greater sensitivity14, 15 and provided a means to quantitatively assess MRD in MM. Ongoing studies will continue to define MRD’s value and its role in improving long-term outcomes for patients with MM.10,15,18 Numerous studies have demonstrated the prognostic importance of MRD; however, the standardization of MRD testing, as well as the role of MRD status in driving treatment decisions, is ongoing.15 Large clinical trials that incorporate response-based treatment strategies based on MRD status will be informative and have the potential to define the depth of response required for sustained benefit.10 Future standardized MRD testing tech- niques may therefore become part of the standard of care for patients with MM.18 References 1. Durie BGM. Multiple Myeloma - Concise Review of the Disease and Treatment Options. 2018 Second Edition. 10. Kumar S, Paiva B, Anderson KC, et al. Lancet Oncol. 2016;17:e328-e346. International Myeloma Foundation. https://www.myeloma.org/sites/default/files/resource/ConciseReview.pdf 11. Fernandez de Larrea C, Jiménez R, Rosiñol L, et al.
Load more

Recommended publications
  • Minimal Residual Disease Detection in Childhood Precursor–B-Cell Acute Lymphoblastic Leukemia: Relation to Other Risk Factors
    Leukemia (2003) 17, 1566–1572 & 2003 Nature Publishing Group All rights reserved 0887-6924/03 $25.00 www.nature.com/leu Minimal residual disease detection in childhood precursor–B-cell acute lymphoblastic leukemia: relation to other risk factors. A Children’s Oncology Group study MJ Borowitz1, DJ Pullen2, JJ Shuster3,4, D Viswanatha5, K Montgomery6, CL Willman5 and B Camitta7 1Johns Hopkins Medical Institutions, USA; 2University of Mississippi, USA; 3University of Florida, Gainesville FL, USA; 4Children’s Oncology Group, Arcadia, CA, USA; 5University of New Mexico, USA; 6Genzyme Genetics, Santa Fe, NM; and 7Milwaukee Childrens Hospital, USA Minimal residual disease (MRD) can be detected in the marrows prognostic significance at several time points. MRD levels at the of children undergoing chemotherapy either by flow cytometry end of induction are highly prognostic. Since intensification of or polymerase chain reaction. In this study, we used four-color therapy after successful induction can improve the outcome of flow cytometry to detect MRD in 1016 children undergoing 33 therapy on Children’s Oncology Group therapeutic protocols many patients with adverse prognostic features, it is possible for precursor–B-cell ALL. Compliance was excellent, with that a similar approach might benefit patients with MRD. For follow-up samples received at the end of induction on nearly these reasons, we have chosen to focus our MRD studies on 95% of cases; sensitivity of detection at this time point was at end-of-induction therapy. least 1/10,000 in more than 90% of cases. Overall, 28.6% of Although MRD and other measures of early response to patients had detectable MRD at the end of induction.
    [Show full text]
  • Effect of the Philadelphia Chromosome on Minimal Residual Disease In
    Leukemia (1997) 11, 1497–1500 1997 Stockton Press All rights reserved 0887-6924/97$12.00 Effect of the Philadelphia chromosome on minimal residual disease in acute lymphoblastic leukemia MJ Brisco1, PJ Sykes1, G Dolman1, S-H Neoh1, E Hughes1, L-M Peng2, G Tauro3, H Ekert3, I Toogood4, K Bradstock5 and AA Morley1 1Department of Haematology, Flinders Medical Centre, Bedford Park, South Australia; 2Department of Laboratory Medicine, School of Medicine, West China University of Medical Sciences, Chengdu, People’s Republic of China; 3Department of Haematology, Royal Childrens Hospital, Parkville, Victoria; 4Department of Haematology/Oncology, Womens and Childrens Hospital, North Adelaide, South Australia; and 5Department of Haematology, Westmead Hospital, Westmead, NSW, Australia The Philadelphia translocation is associated with a poor prog- number of leukemic cells remaining at the end of induction nosis in adults and children with acute lymphoblastic leukemia, provides a good approximation of the degree of drug resist- even though the majority of patients achieve remission. To test ance in vivo. the hypothesis that the translocation leads to drug resistance 6–10 in vivo, we studied 61 children and 20 adults with acute lym- Since the initial reports, a number of groups have phoblastic leukemia and used the level of minimal residual dis- developed sensitive methods to quantify minimal residual dis- ease at the end of induction as the measure of drug resistance ease (MRD) by use of the polymerase chain reaction (PCR). in vivo. In children
    [Show full text]
  • REVIEW Clinical Relevance of Minimal Residual Disease Monitoring in Non
    Leukemia (1999) 13, 1691–1695 1999 Stockton Press All rights reserved 0887-6924/99 $15.00 http://www.stockton-press.co.uk/leu REVIEW Clinical relevance of minimal residual disease monitoring in non-Hodgkin’s lymphomas: a critical reappraisal of molecular strategies P Corradini1, M Ladetto2, A Pileri2 and C Tarella2 1Bone Marrow Transplantation Unit, Istituto Scientifico HS Raffaele, Milan; and 2Divisione Universitaria di Ematologia–Azienda Ospedaliera S Giovanni Battista, Turin, Italy Although current treatments can induce clinical complete neoplasms. In the NHL setting, several studies have been pub- remissions in the vast majority of patients with indolent lym- lished on the prognostic significance of minimal residual dis- phoma, most of them actually relapse, because of the persist- ence of residual tumor cells which are undetectable using con- ease (MRD) detection. Most of these studies focus on indolent ventional diagnostic procedures. Polymerase chain reaction lymphomas: small lymphocytic lymphoma/chronic lympho- (PCR)-based methods are increasingly used for minimal cytic leukemia (SLL/CLL),17,18 follicular (FCL)19–21 and mantle residual disease detection (MRD), and provide useful prognos- cell lymphomas (MCL).20,22 This is mostly because these tic information. In this review, current approaches for MRD tumors, unlike more aggressive NHL histotypes, are dissemi- detection in indolent lymphomas are summarized. In addition, nated disorders with frequent microscopic or submicroscopic the prognostic aspects of molecular monitoring after transplan- tation procedures are discussed. The experience accumulated bone marrow (BM) and peripheral blood (PB) involvement, over the past decade shows that PCR analysis has a prognostic and thus they represent ideal targets for MRD evaluation with impact in several therapeutic programs including conventional PCR-based assays.23,24 and high-dose regimens.
    [Show full text]
  • How Close Are We to Incorporating Measurable Residual Disease Into
    REVIEW ARTICLE How close are we to incorporating Ferrata Storti Foundation measurable residual disease into clinical practice for acute myeloid leukemia? Nicholas J. Short and Farhad Ravandi Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Haematologica 2019 ABSTRACT Volume 104(8):1532-1541 ssessment of measurable residual disease, also called “minimal resid - ual disease,” in patients with acute myeloid leukemia in morpholog - Aical remission provides powerful prognostic information and comple - ments pretreatment factors such as cytogenetics and genomic alterations. Based on data that low levels of persistent or recurrent residual leukemia are consistently associated with an increased risk of relapse and worse long- term outcomes, its routine assessment has been recommended by some experts and consensus guidelines. In addition to providing important prog - nostic information, the detection of measurable residual disease may also theoretically help to determine the optimal post-remission strategy for an individual patient. However, the full therapeutic implications of measurable residual disease are uncertain and thus controversy exists as to whether it should be routinely incorporated into clinical practice. While some evidence supports the use of allogeneic stem cell transplantation or hypomethylating agents for some subgroups of patients in morphological remission but with detectable residual leukemia, the appropriate use of this information in mak - ing clinical decisions remains largely speculative at present. To resolve this pressing clinical issue, several ongoing studies are evaluating measurable Correspondence: residual disease-directed treatments in acute myeloid leukemia and may FARHAD RAVANDI lead to new, effective strategies for patients in these circumstances. This [email protected] review examines the common technologies used in clinical practice and in the research setting to detect residual leukemia, the major clinical studies Received: February 8, 2019.
    [Show full text]
  • Cancer and the Immune System an Overview of Recent Publications Featuring Illumina® Technology 2 Cancer and the Immune System TABLE of CONTENTS
    Cancer and the Immune System An Overview of Recent Publications Featuring Illumina® Technology 2 Cancer and the Immune System TABLE OF CONTENTS 04 Introduction 05 Dendritic cells 07 T-Cell Repertoire 09 Intratumoral T-Cells 11 Single Cells and TCR Sequencing 14 Cancer antigens 18 Cancer Immunoediting 20 Tumor Microenvironment 22 Cancer Immunotherapy 25 Hematological Malignancies 28 Tracking Malignant Lymphocytes 30 Bibliography Cancer and the Immune System 3 INTRODUCTION Advances in high-throughput sequencing have dramatically improved our knowledge of the cancer genome and the intracellular mechanisms involved in tumor progression and response to treatment. While the primary focus to date has been on the cancer cell, this technology can also be used to understand the interaction of the tumor cells and the cells in the surrounding tumor microenvironment. The tumor microenvironment is defined as the cellular environment in which the tumor exists. This includes surrounding blood vessels, immune cells, fibroblasts, other cells, signaling molecules, and the extracellular matrix. Expression analysis of the RNA levels can be used to determine the activation of pathways in the tumor microenvironment. Since common signaling pathways are involved in manifestation of several hallmarks of cancer, including cancer cell proliferation, survival, invasion, metastasis, and immunosuppression, targeting these shared signaling pathways in combination with immunotherapy may be a promising strategy for cancer treatment1. It is important to note that RNA-seq has the potential to track the activation of individual clones, which could ultimately lead to personalized treatment2,3. The human adaptive immune system provides protection against an enormous variety of pathogens and well as tumors.
    [Show full text]
  • Minimal Residual Disease Detection in Mantle Cell Lymphoma
    Original Article Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations Sebastian Böttcher,1 Matthias Ritgen,1 Sebastian Buske,1 Stefan Gesk,2 Wolfram Klapper,3 Eva Hoster,4 Wolfgang Hiddemann,4 Michael Unterhalt,4 Martin Dreyling,4 Reiner Siebert,2 Michael Kneba,1 and Christiane Pott1 on behalf of the EU MCL MRD Group 1University of Schleswig-Holstein, Campus Kiel, 2nd Department of Medicine, Kiel, Germany; 2University of Schleswig-Holstein, Campus Kiel, Institute of Human Genetics, Kiel, Germany; 3Department of Haematopathology and Lymph Node Registry Kiel, University of Schleswig-Holstein, Campus Kiel, Germany and 4Department of Internal Medicine III, University of Munich, Hospital Grosshadern, Munich, Germany Citation: Böttcher S, Ritgen M, Buske S, Gesk S, Klapper W, Hoster E, Hiddemann W, Unterhalt M, Dreyling M, Siebert R, Kneba M and Pott C on behalf of the EU MCL MRD Group. Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations. Haematologica 2008 Apr; 93(4):XXX-XXX. doi: 10.3324/haematol.11267 Treatment protocols as published by the BIOMED-2 Concerted Action.3 FAM- labeled PCR products were size separated on a high-resolu- Untreated patients with Ann Arbor stage II to IV MCL tion polyacrylamide gel and laser-induced fluorescence ana- were eligible for inclusion in the trials. Computed tomogra- lyzed using an ABI 310 genetic analyzer (Applied phy (CT) examinations of neck, chest, abdomen, and pelvis Biosystems, ABI, Darmstadt, Germany) as described previ- as well as bone marrow biopsies for cytology and histology ously (GeneScanning).4 In case of a polyclonal signal after (in general assessed by local pathologists) were mandatory FR1-IGH PCR, FR2- and FR3-IGH primer sets were used in for initial staging.
    [Show full text]
  • Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment Guidance for Industry
    Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Oncology Center of Excellence (OCE) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) January 2020 Clinical/Medical Hematologic Malignancies: Regulatory Considerations for Use of Minimal Residual Disease in Development of Drug and Biological Products for Treatment Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: [email protected] https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs and/or Office of Communication, Outreach, and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010; Email: [email protected] https://www.fda.gov/vaccines-blood-biologics/guidance-compliance-regulatory-information-biologics/biologics- guidances U.S. Department of Health and Human Services Food and Drug Administration Oncology Center of Excellence (OCE) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) January 2020 Clinical/Medical TABLE OF CONTENTS I. INTRODUCTION............................................................................................................. 1 II. BACKGROUND ............................................................................................................... 2 III. DEVELOPMENT OF MRD AS A BIOMARKER FOR REGULATORY USE ........ 3 A. Regulatory Uses of Biomarkers ...................................................................................................
    [Show full text]
  • Monitoring Minimal Residual Disease and Predicting Relapse in APL By
    Leukemia (2001) 15, 1060–1065 2001 Nature Publishing Group All rights reserved 0887-6924/01 $15.00 www.nature.com/leu Monitoring minimal residual disease and predicting relapse in APL by quantitating PML-RARα transcripts with a sensitive competitive RT-PCR method K Tobal, H Moore, M Macheta and JA Liu Yin Molecular Oncology Group, University Department of Haematology, Manchester Royal Infirmary, Manchester M13 9WL, UK Qualitative RT-PCR methods used for monitoring minimal for diagnosis and in monitoring minimal residual disease residual disease (MRD) in APL patients fail to predict relapse (MRD).5–12 Serial negative tests for the PML-RARα transcripts in up to 25% of patients in remission. We report here the devel- opment and evaluation of a highly sensitive (10−5 and 10−6 with in post-chemotherapy patients are generally associated with one round and two rounds of PCR, respectively) competitive prolonged remission. However, up to 25% of those patients RT-PCR method to quantitate the PML-RARα fusion transcripts. can relapse within a short period of testing negative.10–13 This PML-RARα transcript’s levels were normalised to 105 copies of is due in part to the low level of sensitivity of these methods, ABL transcript. Serial BM and PB samples from 16 patients with approximately 10−4, which is 2 log lower than corresponding APL and t(15;17) were examined. Presentation samples from methods for other fusion genes such as AML1-MTG8.14 These three patients (three BM, one PB) showed levels in the range of 0.7 × 106–3.5 × 106 and 1.2 × 105 molecules in BM and PB methods lack the necessary sensitivity to detect the presence samples respectively.
    [Show full text]
  • Minimal Residual Disease (MRD) AHS-M2175
    Corporate Medical Policy Minimal Residual Disease (MRD) AHS-M2175 File Name: minimal_residual_disease_mrd Origination: 11/2020 Last CAP Review: 8/2021 Next CAP Review: 8/2022 Last Review: 8/2021 Description of Procedure or Service Minimal residual disease, also called measurable residual disease or MRD, refers to the subclinical levels of residual diseases, such as acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM) (Horton & Steuber, 2020; Larson, 2020; Rajkumar, 2020; Stock & Estrov, 2020a, 2020b). MRD is a postdiagnosis, prognostic indicator that can be used for risk stratification and to guide therapeutic options when used alongside other clinical and molecular data (Schuurhuis et al., 2018). Many different techniques have been developed to detect residual disease; however, PCR-based techniques, multicolor flow cytometry, and deep sequencing-based MRD generally provide better sensitivity, specificity, reproducibility, and applicability than other techniques, such as fluorescence in situ hybridization (FISH), Southern blotting, or cell culture (Stock & Estrov, 2020b). Related Policies: Flow Cytometry AHS-F2019 Genetic Testing for Acute Myeloid Leukemia AHS-M2062 Genetic Cancer Susceptibility Using Next Generation Sequencing AHS-M2066 ***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. Policy BCBSNC will provide coverage for minimal residual disease when it is determined to be medically necessary because the medical criteria and guidelines shown below are met. Benefits Application This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits.
    [Show full text]
  • Minimal Residual Disease in Acute Lymphoblastic Leukemia: Current Practice and Future Directions
    cancers Review Minimal Residual Disease in Acute Lymphoblastic Leukemia: Current Practice and Future Directions Gloria Paz Contreras Yametti 1,2 , Talia H. Ostrow 2, Sylwia Jasinski 1,2, Elizabeth A. Raetz 1,2, William L. Carroll 1,2,* and Nikki A. Evensen 2 1 Division of Pediatric Hematology Oncology, NYU Langone Health, New York, NY 10016, USA; [email protected] (G.P.C.Y.); [email protected] (S.J.); [email protected] (E.A.R.) 2 Department of Pediatric and Pathology, Perlmutter Cancer Center, NYU Langone Health, Smillow 1211, 560 First Avenue, New York, NY 10016, USA; [email protected] (T.H.O.); [email protected] (N.A.E.) * Correspondence: [email protected]; Tel.: +1-212-263-9247 Simple Summary: Acute lymphoblastic leukemia minimal residual disease (MRD) refers to the presence of residual leukemia cells following the achievement of complete remission, but below the limit of detection using conventional morphologic assessment. Up to two thirds of children may have MRD detectable after induction therapy depending on the biological subtype and method of detection. Patients with detectable MRD have an increased likelihood of relapse. A rapid reduction of MRD reveals leukemia sensitivity to therapy and under this premise, MRD has emerged as the strongest independent predictor of individual patient outcome and is crucial for risk stratification. However, it is a poor surrogate for treatment effect on long term outcome at the trial level, with impending need of randomized trials to prove efficacy of MRD-adapted interventions. Citation: Contreras Yametti, G.P.; Ostrow, T.H.; Jasinski, S.; Raetz, E.A.; Abstract: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and advances Carroll, W.L.; Evensen, N.A.
    [Show full text]
  • Molecular Detection of Minimal Residual Disease Is a Strong Predictive Factor of Relapse in Childhood B-Lineage Acute Lymphoblastic Leukemia with Medium Risk Features
    Leukemia (2000) 14, 1939–1943 2000 Macmillan Publishers Ltd All rights reserved 0887-6924/00 $15.00 www.nature.com/leu Molecular detection of minimal residual disease is a strong predictive factor of relapse in childhood B-lineage acute lymphoblastic leukemia with medium risk features. A case control study of the International BFM study group A Biondi1, MG Valsecchi2, T Seriu3, E D’Aniello1, MJ Willemse4, K Fasching5, A Pannunzio1, H Gadner5, M Schrappe3, WA Kamps6, CR Bartram3, JJM van Dongen4 and ER Panzer-Gru¨mayer5 1Clinica Pediatrica Universita` di Milano-Bicocca, Ospedale S Gerardo, Monza, Italy; 2Department of Medicine and Public Health, Universita` di Verona, Italy; 4Department of Immunology, Erasmus University Rotterdam, Rotterdam, The Netherlands; 3Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; 5Children’s Cancer Research Institute, St Anna Kinderspital, Vienna, Austria; and 6Dutch Childhood Leukemia Study Group (DCLSG), The Hague, The Netherlands The medium-risk B cell precursor acute lymphoblastic leuke- abnormalities) features at diagnosis3,4 and the evaluation of mia (ALL) accounts for 50–60% of total childhood ALL and early response to pre-phase treatment.5,6 comprises the largest number of relapses still unpredictable with diagnostic criteria. To evaluate the prognostic impact of The medium-risk group (MRG) represents a rather hetero- 1,7 minimal residual disease (MRD) in this specific group, a case genous cohort of patients. In the recently closed national control study was performed in patients classified and treated studies of the Austrian and German Berlin–Frankfurt–Mu¨nster as medium (or intermediate)-risk according to the criteria of (BFM) group (ALL-BFM 90),8 the Associazione Italiana di national studies (ALL-BFM 90, DCLSG protocol ALL-8, Ematologia e Oncologia Pediatrica (AIEOP-ALL 91)9 or the AIEOP-ALL 91), which includes a good day 7 treatment response.
    [Show full text]
  • Genomics, Transcriptomics, and Minimal Residual Disease Detection
    VIEWS IN THE SPOTLIGHT Genomics, Transcriptomics, and Minimal Residual Disease Detection: The Winning Team to Guide Treatment of Acute Lymphoblastic Leukemia Heidi Segers1,2 and Jan Cools3,4 Summary: Cytogenetics supported by additional molecular analyses and minimal residual disease detection have been successfully combined to improve the outcome of childhood acute lymphoblastic leukemia (ALL). Results from the St. Jude Total Therapy Study 16 demonstrate that some of the recently identified ALL subtypes can further guide risk stratification. See related article by Jeha et al. (8). Childhood acute lymphoblastic leukemia (ALL) is the that outcomes of patients with ALL with intermediate or high most common pediatric cancer and is now associated with levels of MRD at end of induction and consolidation could good treatment response and long-term survival for most be improved with therapy intensification (3). These findings patients. Over the past 50 years, the 5-year overall survival were also confirmed in the UKALL 2003 study, which showed has increased from less than 50% to more than 90% (1). This that therapy reduction could be done safely in patients with major improvement has been achieved by optimizing chemo- ALL with favorable MRD at end of induction, while children therapy regimens, improved supportive care, and better risk with persistent MRD at the end of induction had benefit stratification based on genetics, clinical characteristics at from intensified postremission therapy (4). Importantly, the diagnosis, and early treatment response measured by mini- UKALL 2003 study demonstrated that the relapse risk associ- mal residual disease (MRD). However, despite this success, ated with a specific MRD level varied according to the genetic there are still subtypes of ALL with less favorable outcome.
    [Show full text]