Early lymphocyte recovery (ELR) impact on disease outcome following autologous hematopoietic stem cell transplantation (HDT/ASCT) for multiple myeloma (MM) in the era of novel agents.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e19539-e19539
Author(s):  
Jeremy Scott McDuffie ◽  
Bipin N. Savani ◽  
Wichai Chinratanalab ◽  
Stacey Goodman ◽  
John P. Greer ◽  
...  
Keyword(s):  
Minimal Residual Disease ◽  
Residual Disease ◽  
Disease Status ◽  
Novel Agents ◽  
Disease Outcome ◽  
Disease Stage ◽  
Response Criteria ◽  
Hematopoietic Stem ◽  
Significant Difference ◽  
Minimal Residual

e19539 Background: Absolute lymphocyte count (ALC) > 500 cells/ µL on day 15 (ELR+) after HDT/ASCT, has been reported to be an independent prognostic indicator, for improved OS and PFS in patients with MM. Novel agents (immunomodulatory drugs (IMiDs) and proteasome inhibitors), mediate there effect through T-cell stimulation, NK cell activation, anti-proliferation, and are now main stay of therapy for MM. We sought to determine their effects on ELR, and correlated to disease outcome. Methods: A retrospective review of all MM patients seen at our institution undergoing HDT/ASCT from January 2008 to December 2012 was performed. Patients were identified from our CIBMTR database. ALC was determined pre-HDT/ASCT (T1), on day15 (T2) and d30 (T3) post-HDC/ASCT. No restrictions on inclusion were made based upon the International Myeloma Working Group response criteria. All had novel agents as part of their initial induction regimen. Disease response was determined by standard clinical and laboratory CIBMTR response criteria, and minimal residual disease status (MRD) by multiparameter flow cytometry. Results: In our study (n= 184), 52/184 patients had ELR+ while 132/184 had ALC < 500 cells/mL (ELR-) at T2. 21% received IMiDs, 33% proteasome inhibitor and 46% combination therapies. 52% of the ELR+ patients were MRD negative (-) at T1, and improved to 74% and 89% at D100, and 1 year post-HDC/ASCT respectively. Similarly 63%, 70%, and 80% of the ELR- patients, were MRD (-) at similar time-points. Chi squared analysis showed no significant difference in rates of MRD (-) based on ELR. ELR also had no impact on disease status as determined by CIBMTR response criteria, or 1 year PFS and OS (p = 0.383), (p = 0.577) respectively. Multivariate analyses, using cox-regression showed no impact of ALC at T1, T2, T3, age, sex, race, cytogenetic risk, or disease stage on disease outcome. Conclusions: Novel agents improve disease control independent of ELR following HDC/ASCT. Understanding their biologic effect on immune-reconstitution will provide a platform for adoptive immunotherapy to better target minimal residual disease.

Moving Beyond Autologous Transplantation in Multiple Myeloma: Consolidation, Maintenance, Allogeneic Transplant, and Immune Therapy

2016 ◽  
pp. 210-221 ◽  
Author(s):  
Amrita Krishnan ◽  
Ravi Vij ◽  
Jesse Keller ◽  
Binod Dhakal ◽  
Parameswaran Hari
Keyword(s):  
Multiple Myeloma ◽  
Disease Control ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
The Other ◽  
Novel Agents ◽  
Patient Specific ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Minimal Residual

For multiple myeloma, introduction of novel agents as part of the front-line treatment followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (ASCT) induces deep responses in a majority of patients with this disease. However, disease relapse is inevitable, and, with each relapse, the remission duration becomes shorter, ultimately leading to a refractory disease. Consolidation and maintenance strategy after ASCT is one route to provide sustained disease control and prevent repeated relapses. Though the consolidation strategy remains largely confined to clinical trials, significant data support the efficacy of consolidation in improving the depth of response and outcomes. There are also increasing rates of minimal residual disease–negativity with additional consolidation therapy. On the other hand, maintenance with novel agents post-transplant is well established and has been shown to improve both progression-free and overall survival. Evolving paradigms in maintenance include the use of newer proteasome inhibitors, immunotherapy maintenance, and patient-specific maintenance—a concept that utilizes minimal residual disease as the primary driver of decisions regarding starting or continuing maintenance therapy. The other approach to overcome residual disease is immune therapeutic strategies. The demonstration of myeloma-specific alloimmunity from allogeneic transplantation is well established. More sophisticated and promising immune approaches include adoptive cellular therapies, tumor vaccines, and immune checkpoint manipulations. In the future, personalized minimal residual disease–driven treatment strategies following ASCT will help overcome the residual disease, restore multiple myeloma–specific immunity, and achieve sustained disease control while minimizing the risk of overtreatment.

scholarly journals Prognostic value of minimal residual disease before allogeneic hematopoietic stem cell transplantation in patients with acute leukemia

2021 ◽  
Vol 66 (4) ◽  
pp. 539-555
Author(s):  
Z. V. Konova ◽  
E. N. Parovichnikova ◽  
I. V. Galtseva ◽  
M. Yu. Drokov ◽  
Yu. O. Davydova ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Minimal Residual Disease ◽  
Prognostic Value ◽  
Residual Disease ◽  
Disease Status ◽  
Long Term Results ◽  
Disease Relapse ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Minimal Residual

Introduction. One of the main causes of treatment failure after allogeneic hematopoietic stem cells transplantation (alloHSCT) for acute leukemia (AL) is disease relapse. In recent years, multiparameter fl ow cytometry (MPC) has been widely used to detect minimal residual disease (MRD) because of its capacity to identify patients with a high risk of relapse due to availability and the ability to obtain results in a timely manner.Aim — to evaluate the prognostic value of MRD status before allo-HSCT and the effect of donor type and conditioning intensity on long-term results of allo-HSCT of MOB-positive patients.Patients and methods. The analysis included 107 patients with acute myeloid leukemia (AML) and 63 patients with acute lymphoblastic leukemia (ALL) who underwent allo-HSCT between September 2015 and June 2020. All patients were in complete morphological remission before allo-HSCT. At the time of allo-HSCT 91 patients with AML and 37 patients with ALL were in the first complete remission (CR), in their second and more than two CRs were 16 and 26 patients, respectively. The median follow-up was 18 (1.5–48) months for AML and 14 (1.8–60.1) months for ALL. Immunophenotypic study was performed before allo-HSCT. MRD was detected using a combination of the “different from normal” method and the search for cells with a leukemia-associated immunophenotype.Results. The disease status at the time of transplantation and the presence of MRD before allo-HSCT were independent factors infl uencing the probability of relapse (disease status: HR = 2.911, 95% CI: 1.328–6.379; MRD before allo-HSCT: HR = 7.667, 95% CI: 3.606–16.304) and post-transplant mortality (disease status: HR = 2.911, 95% CI: 1.328–6.379; MRD before allo-HSCT: HR = 7.667, 95% CI: 3.606–16.304). In univariate analysis, the relapse-free survival of MRD+ patients with AL in the first CR was significantly worse than in MRD– (AML: 23 % versus 57 %, p < 0.0001, ALL: 34 % versus 61.7 %, p = 0.0484), and the probability of relapse in MRD+ patients was significantly higher (AML: 75 % versus 12 %, p < 0.0001, ALL: 57 % versus 7 %, p = 0.0072). Pre-transplant MRD status was not prognostically significant for AL-patients in the second and third remission. The development of chronic GVHD reduces post-transplant mortality if it does not require systemic therapy with glucocorticosteroids (HR = 0.006, 95% CI: 0.008–0.446).Conclusion. Testing for MRD of patients with AL in the first CR before allo-HSCT is necessary for risk stratification and identification of patients who will need preventive post-transplant therapy in order to prevent disease relapse.

scholarly journals Monitoring of Post-Transplant MLL-PTD as Minimal Residual Disease Can Predict Relapse After Allogeneic HSCT in Patients With Acute Myeloid Leukemia and Myelodysplastic Syndrome

2021 ◽  
Author(s):  
Jun Kong ◽  
Meng-Ge Gao ◽  
Ya-Zhen Qin ◽  
Yu Wang ◽  
Chen-Hua Yan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Significant Difference ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: MLL-PTD is a special MLL rearrangement gene that occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, including AML and MDS, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation.Methods: We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People’s Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL>0.08% was defined as MLL-PTD positive in this study.Results: The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7%±5.2%, 67.8%±6.9%, 68.1%±6.8% and 20.3%±6.1%, respectively. ROC curve showed that post-transplant MLL-PTD≥1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD≥1.0% and MLL-PTD<1.0% groups (3-year CIR: 75%±15.3% vs. 0%, P<0.001; 3-year OS: 25.0±15.3% vs. 80.7%±6.6%, P<0.001; 3-year DFS: 25.0±15.3% vs. 80.7%±6.6%, P<0.001; 3-year TRM: 0 vs. 19.3±6.6%, P=0.277). However, whether MLL-PTD≥1% or MLL-PTD<1% before transplantation has no significant difference on the prognosis. Conclusions: Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

scholarly journals Monitoring of post-transplant MLL-PTD as minimal residual disease can predict relapse after allogeneic HSCT in patients with acute myeloid leukemia and myelodysplastic syndrome

BMC Cancer ◽  
2022 ◽  
Vol 22 (1) ◽  
Author(s):  
Jun Kong ◽  
Meng-Ge Gao ◽  
Ya-Zhen Qin ◽  
Yu Wang ◽  
Chen-Hua Yan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndrome ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Significant Difference ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background The mixed-lineage leukemia (MLL) gene is located on chromosome 11q23. The MLL gene can be rearranged to generate partial tandem duplications (MLL-PTD), which occurs in about 5-10% of acute myeloid leukemia (AML) with a normal karyotype and in 5-6% of myelodysplastic syndrome (MDS) patients. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently one of the curative therapies available for AML and MDS with excess blasts (MDS-EB). However, how the prognosis of patients with high levels of MLL-PTD after allo-HSCT, and whether MLL-PTD could be used as a reliable indicator for minimal residual disease (MRD) monitoring in transplant patients remains unknown. Our study purposed to analyze the dynamic changes of MLL-PTD peri-transplantation and the best threshold for predicting relapse after transplantation. Methods We retrospectively collected the clinical data of 48 patients with MLL-PTD AML or MDS-EB who underwent allo-HSCT in Peking University People’s Hospital. The MLL-PTD was examined by real-time quantitative polymerase chain reaction (RQ-PCR) at the diagnosis, before transplantation and the fixed time points after transplantation. Detectable MLL-PTD/ABL > 0.08% was defined as MLL-PTD positive in this study. Results The 48 patients included 33 AML patients and 15 MDS-EB patients. The median follow-up time was 26(0.7-56) months after HSCT. In AML patients, 7 patients (21.2%) died of treatment-related mortality (TRM), 6 patients (18.2%) underwent hematological relapse and died ultimately. Of the 15 patients with MDS-EB, 2 patients (13.3%) died of infection. The 3-year cumulative incidence of relapse (CIR), overall survival (OS), disease-free survival (DFS) and TRM were 13.7 ± 5.2, 67.8 ± 6.9, 68.1 ± 6.8 and 20.3% ± 6.1%, respectively. ROC curve showed that post-transplant MLL-PTD ≥ 1.0% was the optimal cut-off value for predicting hematological relapse after allo-HSCT. There was statistical difference between post-transplant MLL-PTD ≥ 1.0% and MLL-PTD < 1.0% groups (3-year CIR: 75% ± 15.3% vs. 0%, P < 0.001; 3-year OS: 25.0 ± 15.3% vs. 80.7% ± 6.6%, P < 0.001; 3-year DFS: 25.0 ± 15.3% vs. 80.7 ± 6.6%, P < 0.001; 3-year TRM: 0 vs. 19.3 ± 6.6%, P = 0.277). However, whether MLL-PTD ≥ 1% or MLL-PTD < 1% before transplantation has no significant difference on the prognosis. Conclusions Our study indicated that MLL-PTD had a certain stability and could effectively reflect the change of tumor burden. The expression level of MLL-PTD after transplantation can serve as an effective indicator for predicting relapse.

scholarly journals Allogeneic Transplantation for Minimal Residual Disease Negative Acute Lymphoblastic Leukemia According to 2016 Who Classification: A Single Center Retrospective Analysis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5786-5786
Author(s):  
Xingyu Cao ◽  
Deyan Liu ◽  
Jianping Zhang ◽  
Zhijie Wei ◽  
Min Xiong ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Who Classification ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Disease Status ◽  
Unrelated Donor ◽  
Hematopoietic Stem ◽  
Minimal Residual

Abstract The level of minimal residual disease (MRD) is one of the most important prognostic indicators for acute lymphoblastic leukemia (ALL). In this study, the data about 390 cases of ALL patients who obtained MRD negative after chemotherapy or CART therapy underwent allogenic hematopoietic stem cell transplantation (HSCT) in our center were retrospectively analyzed. The MRD was detected by flow cytometry or molecular methods such as fusion genes or gene mutations. 235 were males and 155 were females. Median age was 15 years old (range 2-64). According to 2016 WHO classification, the diagnosis were Pro-B-ALL(n=24), Common B-ALL(n=113), Pre-B-ALL(n=17), Hyperdiploid (n=8), BCR-ABL positive B-ALL(n=51), MLL rearranged B-ALL (n=19), TEL-AML positive B-ALL (n=13), E2A-PBX B-ALL (n=16), BCR-ABL1-like B-All (n=4), Pro-T-ALL(n=8), Pre-T-AL(n=21), Cortical T-ALL(n=17), Medullary T-ALL (n=6) and ETP T-ALL(n=1). Other 5 patients have complex karyotypes and 67 patients cannot be grouped because of absence complete information about immunophenotypes or genetic profiles. Total number of B-ALL was 295 (54 of which received CART therapy before transplant.) and T-ALL was 92. Another one was T-B mixed lineage and remaining two's lineages was unknown. 14% of the patients had sibling identical donors (n=54), 66% of the patients had haplo-identical relative donors (n=258) and others are unrelated donor (n=77) or cord blood (n=1) transplantation. Disease status before transplant are CR1 (n=228), CR2(n=134) and ≥CR3(n=28). MNC dose was 8.30(2.50-22.60)×108/kg, CD34+cells dose was 4.51(0.89-19.61) ×106/kg and CD3+cells was 1.58(0.01-37.63) ×108/kg. Preparative regimens were based on TBI (n=352) or Bu (n=38). The median time to neutrophil and platelets engraftment was 14 and 12 days. Five-years OS and disease-free survival (DFS) for all patients were 71.7% and 71.1% . Univariate analysis showed difference of impact on overall survival about the patient' gender, age, T or B immunotype, WHO classification, whether or not receiving CART therapy before transplant, conditioning regimen based on TBI or Bu, years of transplant, and time from diagnosis to transplant (≤1year, >1year, ≤2year, >2year, ≤3year, >3year) was not statistically significant. 5-ys OS for CR1, CR2, >CR2 were 77.4%, 60.9%, 67.8% (p=0.0018). Five-years OS for sibling-identical , unrelated donor and haplo-identical transplant were 74.8%, 68.8% and 79.6% (p=0.026). The incidence of gradeⅠ-Ⅱ aGVHD and grade Ⅲ-ⅣaGVHD within 100 days were 1.5% and 2.1%. Limited cGVHD was 10.3% and extensive cGVHD was 9.2%. 5 years cumulative relapse rate was 12.2%. In summary, when MRD were negative before transplantation, the result of allo-HSCT for ALL is good. The factors affecting the survival rate are disease status and interval between diagnosis and transplant time rather than gender, age, WHO classification, immunotype, whether or not receiving CART therapy and conditioning regimen. Disclosures No relevant conflicts of interest to declare.

scholarly journals Serum Peptidome Based Biomarkers Searching for Monitoring Minimal Residual Disease in Adult Acute Monocytic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5233-5233
Author(s):  
Ju Bai ◽  
Yun Yang ◽  
Jianli Wang ◽  
Wanggang Zhang ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Correlation Analysis ◽  
Minimal Residual Disease ◽  
Molecular Diagnosis ◽  
Residual Disease ◽  
Acute Monocytic Leukemia ◽  
Healthy Controls ◽  
Monocytic Leukemia ◽  
Disease States ◽  
Significant Difference ◽  
Minimal Residual

Abstract Background: Acute monocytic leukemia (M5) is one common type in acute myeloid leukemia (AML). The present study found that a few M5 had special reproducible chromosomal abnormalities and molecular abnormalities. The heterogeneity and complexity of M5 lead to lack of specific tumor-associated markers for molecular diagnosis and targeted therapy. CLINPROT system, with unique advantages, is a firenew and distinctive proteomics technology and has been widely used in the researches of solid tumor and hemopathic malignancies. This study was to screen a panel of serum peptides associated with M5 different disease states for molecular diagnosis and monitoring minimal residual disease. Methods: 92 M5 were enrolled for the study from those who were newly diagnosed (ND) in the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2009 to July 2014. The median age was 45 years old (range 18-73) and 57.6% were male. Diagnosis was made according to bone marrow cell morphology, cytochemical staining and cellular immune phenotype. 90 healthy cases (HC) (age range 19-70, median age 43 years old, male/female 51/39) were recruited from those who came to our hospital to undergo healthy physical examination and had no any abnormal symptoms and results. Sera of 92 M5 were gained pre- and post-treatment of chemotherapy. Weak cation exchange magnetic bead combined with matrix assisted laser desorption/ ionization time of flight mass spectrometry were used to compare and analyze serum peptidome of M5 with different disease states. Spearman method was used to do correlation analysis of two variables. Statistical significance was defined as p<0.05. Results: A total of 42 peptides in the molecular weight range of 700-10000 Da were detected using ClinProt system and statistically different between adult M5 and healthy controls. Among them, 9 peptides were elevated and 33 were decreased in M5. Genetic algorithm (GA) was used to obtain a diagnostic model consisting of 6 peptides that could discriminate M5 from controls with a high sensitivity (100%) and specificity (96.67%). Mass charge ratios (m/z) were 6041.91, 4662.15, 7823.02, 9210.97, 1108.91 and 3263.37 respectively. Blind test verified that this model correctly identified 60 cases out of total 62 M5 and 57 cases from 60 healthy controls. The relative intensities of peptides with m/z of 6041.91 and 4662.15 were increased in the ND group and non-complete remission (CR) group, when comparing with the CR group and HC group(p=0.002; p<0.001), but there was no significant difference between the two groups for any of the peptides (p=0.27, p=0.31). No significant difference was found between the CR group and HC group (p=0.22, p=0.41). The relative intensities of peptides with m/z of 7823.02, 9210.97, 1108.91 and 3263.37 were reduced in the ND group and non-CR group when comparing with the CR group and HC group (p<0.001, p=0.0023, p=0.004, p<0.001), and the two groups had no significant difference (p=0.26, p=0.09, p=0.32, p=0.61). No significant difference was observed between the HC group and CR group (p=0.52, p=0.35, p=0.17, p=0.73). Spearman correlation analysis showed that relative intensities of peptides with m/z of 4662.15, 7823.02 and 9210.97 were correlated with high white blood cells (r=0.88, p<0.001; r=-0.89, p<0.001; p=-0.87, p<0.001), FLT3 mutation (r=0.90, p<0.001; r=-0.87, p<0.001; r=-0.88, p<0.001) , extramedullary disease (r=0.80, p<0.001; r=-0.86, p<0.001; r=- 0.82, p<0.001). The relative intensities of the other three peptides had weak correlation with the unfavorable clinical features of M5 at diagnosis. Conclusion: This panel of peptides has encouraging efficiency in discriminating M5 from HCs and potential value in monitoring M5 minimal residual disease. Disclosures No relevant conflicts of interest to declare.

Early peripheral blast cell clearance predicts minimal residual disease status and refines disease prognosis in acute myeloid leukemia

2020 ◽  
Vol 95 (11) ◽  
pp. 1304-1313
Author(s):  
Francesco Mannelli ◽  
Giacomo Gianfaldoni ◽  
Sara Bencini ◽  
Matteo Piccini ◽  
Ilaria Cutini ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Status ◽  
Blast Cell ◽  
Disease Prognosis ◽  
Cell Clearance ◽  
Minimal Residual ◽  
Acute Myeloid
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