scholarly journals Summary of the 2019 Blood and Marrow Transplant Clinical Trials Network Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling

2020 ◽  
Vol 26 (10) ◽  
pp. e247-e255
Author(s):  
Sarah A. Holstein ◽  
Alan Howard ◽  
David Avigan ◽  
Manisha Bhutani ◽  
Adam D. Cohen ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Marrow Transplant ◽  
Blood And Marrow Transplant ◽  
Immune Profiling ◽  
Minimal Residual

scholarly journals Summary of the Second Annual BMT CTN Myeloma Intergroup Workshop on Minimal Residual Disease and Immune Profiling

2019 ◽  
Vol 25 (3) ◽  
pp. e89-e97 ◽  
Author(s):  
Sarah A. Holstein ◽  
J Christine Ye ◽  
Alan Howard ◽  
Manisha Bhutani ◽  
Nicole Gormley ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Immune Profiling ◽  
Minimal Residual

Minimal residual disease in multiple myeloma: an important tool in clinical trials

2021 ◽  
Vol 16 ◽  
Author(s):  
Alessandro Gozzetti ◽  
Monica Bocchia
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
New Drugs ◽  
Next Generation ◽  
Depth Of Response ◽  
Next Generation Sequencing Ngs ◽  
Future Therapy ◽  
Minimal Residual

: Minimal residual disease (MRD) detection represents a great advancement in multiple myeloma. New drugs are now available that increase depth of response. The International Myeloma Working Group recommends the use of next-generation flow cytometry (NGF) or next-generation sequencing (NGS) to search for MRD in clinical trials. Best sensitivity thresholds have to be confirmed, as well as timing to detect it. MRD has proven as the best prognosticator in many trials and promises to enter also in clinical practice to guide future therapy.

Utility of WT1 as a Reliable Tool for the Detection of Minimal Residual Disease in Children with Leukemia

2002 ◽  
Vol 5 (3) ◽  
pp. 269-275 ◽  
Author(s):  
Morris Kletzel ◽  
Marie Olzewski ◽  
Wei Huang ◽  
Pauline M. Chou
Keyword(s):  
Bone Marrow ◽  
Minimal Residual Disease ◽  
Bone Marrow Transplant ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Marrow Transplant ◽  
Post Transplant ◽  
High Level ◽  
Minimal Residual

WT1 encodes a transcription factor involved in the pathogenesis of Wilms' tumor. A high level of expression has been reported in blasts from patients with various hematological malignancies. The study was performed to evaluate the utility of monitoring WT1 expression in children with leukemia at diagnosis, during therapy, and following bone marrow transplant. We tested a total of 204 samples prospectively. These included samples from patients with the following diagnoses: acute lymphoblastic leukemia (ALL) at diagnosis ( n = 45), at relapse ( n = 14), and in remission ( n = 45); acute non-lymphoblastic leukemia (ANLL) at diagnosis ( n = 14), at relapse ( n = 5), and in remission ( n = 12); and chronic myelogenous leukemia (CML) in blast crisis ( n = 1) and in chronic phase ( n = 1). A total of 33 of these patients were transplanted: 19 ALL, 12 ANLL, and 2 CML. In addition, samples from 5 patients with aplastic anemia and 28 controls were obtained from peripheral blood ( n = 17), cord blood ( n = 3), and bone marrow ( n = 8). Primer pairs were designed to locate specific nucleotide sequences for mRNA of WT1. RT-PCR was performed in all samples and compared with K562 cells from ATCC (defined as 1.0) as positive control. A positive test was arbitrarily defined as WT1/K562 > 0.5. Samples at diagnosis and relapse, including 56 out of 59 ALL (95%), 26 ANLL (100%), and 1 CML in blast crisis, demonstrated high levels of WT1 expression. In contrast, only 5 of 90 samples obtained in remission or post-transplant showed high levels of WT1 expression ( P < 0.0001; 95% CI = 0.66–0.94). The five patients with high WT1 expression during follow-up relapsed within 2 to 6 months. In conclusion, we have found that WT1 is consistently elevated in children with leukemia. Significant differences in the level of WT1 expression were noted between these patients during diagnosis and at relapse, and those during remission. More importantly, following bone marrow transplant, a significant high level of WT1 expression preceded clinical relapse by 2 to 6 months. Therefore, WT1 is a reliable marker for monitoring minimal residual disease during therapy as well as in the post-transplant period.

scholarly journals Minimal residual disease monitoring and immune profiling in multiple myeloma in elderly patients

Blood ◽  
2016 ◽  
Vol 127 (25) ◽  
pp. 3165-3174 ◽  
Author(s):  
Bruno Paiva ◽  
Maria-Teresa Cedena ◽  
Noemi Puig ◽  
Paula Arana ◽  
Maria-Belen Vidriales ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Prognostic Factors ◽  
Elderly Patients ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Disease Monitoring ◽  
Minimal Residual Disease Monitoring ◽  
Key Points ◽  
Immune Profiling ◽  
Minimal Residual

Key Points MRD monitoring is one of the most relevant prognostic factors in elderly MM patients, irrespective of age or cytogenetic risk. Second-generation MFC immune profiling concomitant to MRD monitoring also helped to identify patients with different outcomes.

scholarly journals Minimal Residual Disease (MRD) in Myeloma: Independent Outcome Prediction and Sequential Survival Benefits per Log Tumour Reduction

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3416-3416 ◽  
Author(s):  
Andy C Rawstron ◽  
Walter Gregory ◽  
Ruth M de Tute ◽  
Faith E Davies ◽  
Susan E Bell ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Clinical Trials ◽  
Minimal Residual Disease ◽  
Research Funding ◽  
Outcome Prediction ◽  
Residual Disease ◽  
Surrogate Endpoint ◽  
Cell Transplant ◽  
Minimal Residual

Abstract Minimal residual disease (MRD), as assessed by flow cytometry is a powerful predictor of outcome in multiple myeloma (MM). We and others have previously demonstrated that such analyses are informative in patients treated with autologous stem cell transplant (ASCT) and non-transplant regimens. It predicts outcome in patients in conventional CR and is applicable to patients with standard and adverse risk cytogenetics. As a consequence MRD assessment is under consideration as a surrogate endpoint for clinical trials. This is urgently needed in MM as >5yrs follow-up is typically required to demonstrate survival differences in trials of upfront therapy. If surrogate end points are to be used in clinical trials it is essential that a reproducible effect is demonstrable using multivariate models. Previous studies have confirmed the effect of MRD on PFS but a consistent effect on OS has been not been definitively shown. This may in part be due to the availability of effective salvage therapy but it is also possible that the traditional threshold of 10-4 for analysis and the categorization of patients as MRD-postive or negative is suboptimal. Flow cytometry does provide a quantitative assessment of residual tumour over a large range and the degree of tumour depletion may be more informative than a positive-negative analysis. 397 patients from the MRC Myeloma IX trial were included in this analysis. Patients were randomly assigned to CTD (cyclophosphamide, thalidomide, and dexamethasone) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) induction for 4-6 cycles followed by standard high-dose melphalan (HDM) ASCT. BM aspirates were obtained at day 100 for MRD analysis. 500,000 cells were evaluated with six-colour antibody combinations including CD138/CD38/CD45/CD19 with CD56/CD27 in all cases and CD81/CD117 in additional cases as required. PFS and OS data analysis was landmarked from the date of the MRD assesment. Of the 397 patients with MRD data available at day 100 after ASCT, 247/397 (62.2%) achieved <0.01% MRD. The level of residual disease varied across four logs in MRD-positive patients (0.01-<0.1% in 49/397, 0.1-<1% in 72/397, 1-<10% in 26/397 and ≥10% in 3/397). The PFS and OS for individuals with ≥1% residual disease was comparable to individuals with a PR/MR/SD confirming that MRD assessment is most relevant in CR. The level of MRD correlated with outcome. The median PFS for patients with ≥10% MRD at day 100 after ASCT was 0.8 years, with 1-<10% MRD was 1.7 years, with 0.1-<1% MRD was 1.9 years, with 0.01-<0.1% MRD was 2.7 years and for patients with <0.01% MRD was 3.1 years (P<0.001). The median OS for these groups was 1 yr, 4 yrs, 5.9 yrs, 6.8 yrs and for patients with <0.01% MRD not reached with >7.5 yrs median follow-up (P<0.001, see figure). A Cox proportional hazards model was used to further evaluate factors influencing outcome. B2M and MRD were log-transformed and along with age were considered as continuous variables. ISS, haemoglobin (<115g/l), platelets (<150x10^9/l) and cytogenetics were used as stratification factors. Cytogenetic groups were classified as unfavourable for patients with gain(1q), del(1p32), t(4;14), t(14;20), t(14;16), and del(17p), or favourable for hyperdiploidy, t(11;14) and t(6;14), or unknown/inevaluable. MRD assessment (χ2 11.8, P=0.0006) and cytogenetics (χ2 35.5, P=<0.0001) were the only factors that retained significance in this multivariate model. Conventional categorical response, ISS and B2M were not predictive of OS (p=0.99, 0.16 and 0.56 respectively). We would conclude that MRD quantitation is more informative than a positive or negative categorization with a 10-4 threshold and independently predicts outcome. In this analysis we were able to demonstrate an approximate 1 year survival benefit per log tumour depletion. A lower cutpoint for predicting improved outcome was not reached and more sensitive assays will likely improve outcome prediction further. This data strongly supports the role of MRD assessment as a surrogate endpoint in clinical trials. Figure 1 Figure 1. Disclosures Rawstron: Celgene: Consultancy; BD Biosciences: Consultancy, Intrasure Patents & Royalties. Gregory:Celgene: Consultancy. Davies:Celgene: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Novartis: Consultancy. Cook:Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria. Jackson:Celgene: Honoraria; Janssen-Cilag: Honoraria. Morgan:Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Owen:Celgene: Consultancy, Honoraria, Research Funding.

scholarly journals A look into the future: can minimal residual disease guide therapy and predict prognosis in chronic lymphocytic leukemia?

Hematology ◽  
2012 ◽  
Vol 2012 (1) ◽  
pp. 97-104 ◽  
Author(s):  
Paolo Ghia
Keyword(s):  
Clinical Trials ◽  
Chronic Lymphocytic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Surrogate Marker ◽  
Leukemic Cell ◽  
Lymphocytic Leukemia ◽  
End Of Treatment ◽  
Line Of Therapy ◽  
Minimal Residual

Abstract Over the past 2 decades, dramatic improvements in the efficacy of treatments for chronic lymphocytic leukemia have led to progressively higher percentages of clinical complete remissions. A molecular eradication of the leukemia has become not only a desirable, but also an achievable, end point that needs to be evaluated within clinical trials. The assessment of complete remission only at the clinical and morphological level is insufficient, at least for physically fit patients. The detection of minimal residual disease (MRD) in chronic lymphocytic leukemia has become feasible using PCR-based or flow cytometric techniques that reproducibly allow reaching the detection level of less than 1 leukemic cell per 10 000 leukocytes (10−4), the level currently defined as MRD− status. Emerging data indicate that the MRD status during and at the end of treatment is one of the most powerful predictors of progression-free and overall survival. This predictor appears to be independent of clinical response, type or line of therapy, and known biological markers. For these reasons, the time is ripe to test the use of MRD as a surrogate marker of clinical end points and as a real-time marker of efficacy and/or resistance to the administered therapies. In the near future, clinical trials will determine whether MRD assessment can be used for guiding therapy, either to improve quality of responses through consolidation or to prevent relapses through preemptive therapies based on the reappearance of MRD.

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