WT1-Targeted Dendritic Cell Vaccination as A Post-Remission Treatment to Prevent Full Relapse In Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 16-16 ◽  
Author(s):  
Zwi N. Berneman ◽  
Ann an de Velde ◽  
Sébastien Anguille ◽  
Nathalie Cools ◽  
Ann Van Driessche ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Tumor Marker ◽  
Tumor Antigen ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Post Vaccination ◽  
Clinical Responses ◽  
Acute Myeloid

Abstract Abstract 16 Immunization using tumor antigen-loaded dendritic cells (DC) holds promise for the adjuvant treatment of cancer to control residual disease. In a phase I/II trial, we investigated the effect of autologous DC vaccination in 17 patients with acute myeloid leukemia (AML) in remission but at high risk of full relapse. Wilms’ tumor 1 protein (WT1), a nearly universal tumor antigen, was chosen as an immunotherapeutic target because of its established role in leukemogenesis and superior immunogenic characteristics. Two out of 3 patients, who were in partial remission with morphologically demonstrable disease after chemotherapy, were brought into complete remission following 4 biweekly intradermal injections of WT1 mRNA-electroporated DC. In those 2 patients as well as in 7 other patients who were in complete remission but who had molecularly demonstrable residual disease, there was a return to normal of the AML-associated WT1 mRNA tumor marker following DC vaccination, compatible with clinical and molecular response in 9/17 patients. In 3 patients, the WT1 mRNA tumor marker returned to pathological values following normalization after initial DC vaccination and additional injections of DC were needed to bring back the tumor marker to normal. Of the 9 responders, 3 have relapsed and 2 have died. Of the 8 non-responders, 7 have relapsed and 7 have died. Of the 2 patients in partial remission who were brought into complete remission by the DC vaccination, 1 has relapsed and has died. Median overall survival was 52.0 months in responders as compared to 6.0 months in non-responders (P=0.0007). Median relapse-free survival was 47.0 months in responders and 3.0 months in non-responders (P smaller than 0.0001). Immunomonitoring performed on the first 10 patients, showed a significant increase in WT1-specific interferon-gamma+ CD8+ T cells and signs of general immune stimulation, such as a significant increase of plasma levels of interleukin 2 and of HLA-DR+ CD4+ T-cells. Clinical responses were correlated with elevated levels of activated natural killer cells post-vaccination. Long-term clinical responses, lasting for at least 3 years, were significantly correlated with an increase in polyepitope WT1-specific tetramer+ CD8+ T-cell frequencies. There was no significant change post-vaccination in WT1 antibody levels or of regulatory T lymphocytes. In conclusion, DC-based immunotherapy elicits both innate and adaptive cellular immune responses correlated with clinical benefit. WT1 mRNA-loaded DC emerge as a feasible and effective strategy to control residual disease in AML, in particular as a post-remission treatment to prevent full relapse. Disclosures: Berneman: Argos Therapeutics: Patents & Royalties. Van Tendeloo:Argos Therapeutics: Patents & Royalties.

WT1-targeted dendritic cell vaccination as a postremission treatment to prevent or delay relapse in acute myeloid leukemia.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2506-2506 ◽  
Author(s):  
Zwi N. Berneman ◽  
Ann Van de Velde ◽  
Sebastien Anguille ◽  
Nathalie Cools ◽  
Ann Van Driessche ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Partial Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Wilms Tumor ◽  
Dendritic Cell Vaccination ◽  
Clinical Responses ◽  
Acute Myeloid

2506 Background: Vaccination with tumor antigen-loaded dendritic cells (DC) holds promise for the adjuvant treatment of cancer. Methods: In a phase I/II trial, we investigated the effect of autologous DC vaccination in 17 patients with acute myeloid leukemia (AML) in remission but at very high risk of full relapse. Wilms’ tumor 1 protein (WT1) was chosen as immunotherapeutic target and introduced into the DC by mRNA electroporation. We are continuing a phase II trial, which is still recruiting. Results: Two out of 3 patients, who were in partial remission with chemotherapy-refractory disease, were brought into complete remission following 4 biweekly intradermal injections of WT1 mRNA-electroporated DC. In those 2 patients as well as in 6 other patients who were in complete remission but who had molecularly demonstrable residual disease, there was a return to normal of the AML-associated WT1 mRNA tumor marker following DC vaccination, compatible with reaching clinical and molecular remission in 8/17 patients. Among the 8 responders, there have been 2 relapses and 2 deaths. Of the 9 non-responders, 8 have relapsed and 7 have died. Of the 2 patients in partial remission who were brought into complete remission by DC vaccination, 1 has died following relapse. Median overall survival was 6 months in non-responders and 52 months in responders (p=0.0007). Median relapse-free survival was 3 months in non-responders as compared to 47 months in responders (p<0.0001). Clinical responses overall were correlated with elevated levels of activated natural killer (NK) cells post-vaccination. Long-term clinical responses, lasting for at least 3 years, were significantly correlated with an increase in polyepitope WT1-specific tetramer+ CD8+ T-cell frequencies. Conclusions: DC-based immunotherapy elicits both innate (NK) and adaptive (T cells) cellular responses correlated with clinical benefit. WT1 mRNA-transfected DC emerge as a feasible and effective strategy to control residual disease in AML, in particular as a post-remission treatment to prevent full relapse.

scholarly journals Measurable Residual Disease at Induction Redefines Partial Response in Acute Myeloid Leukemia and Stratifies Outcomes in Patients at Standard Risk Without NPM1 Mutations

2018 ◽  
Vol 36 (15) ◽  
pp. 1486-1497 ◽  
Author(s):  
Sylvie D. Freeman ◽  
Robert K. Hills ◽  
Paul Virgo ◽  
Naeem Khan ◽  
Steve Couzens ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Myeloid Leukemia ◽  
High Risk ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
High Risk Factors ◽  
Risk Patients ◽  
Standard Risk ◽  
Acute Myeloid

Purpose We investigated the effect on outcome of measurable or minimal residual disease (MRD) status after each induction course to evaluate the extent of its predictive value for acute myeloid leukemia (AML) risk groups, including NPM1 wild-type (wt) standard risk, when incorporated with other induction response criteria. Methods As part of the NCRI AML17 trial, 2,450 younger adult patients with AML or high-risk myelodysplastic syndrome had prospective multiparameter flow cytometric MRD (MFC-MRD) assessment. After course 1 (C1), responses were categorized as resistant disease (RD), partial remission (PR), and complete remission (CR) or complete remission with absolute neutrophil count < 1,000/µL or thrombocytopenia < 100,000/μL (CRi) by clinicians, with CR/CRi subdivided by MFC-MRD assay into MRD+ and MRD−. Patients without high-risk factors, including Flt3 internal tandem duplication wt/− NPM1-wt subgroup, received a second daunorubicin/cytosine arabinoside induction; course 2 (C2) was intensified for patients with high-risk factors. Results Survival outcomes from PR and MRD+ responses after C1 were similar, particularly for good- to standard-risk subgroups (5-year overall survival [OS], 27% RD v 46% PR v 51% MRD+ v 70% MRD−; P < .001). Adjusted analyses confirmed significant OS differences between C1 RD versus PR/MRD+ but not PR versus MRD+. CRi after C1 reduced OS in MRD+ (19% CRi v 45% CR; P = .001) patients, with a smaller effect after C2. The prognostic effect of C2 MFC-MRD status (relapse: hazard ratio [HR], 1.88 [95% CI, 1.50 to 2.36], P < .001; survival: HR, 1.77 [95% CI, 1.41 to 2.22], P < .001) remained significant when adjusting for C1 response. MRD positivity appeared less discriminatory in poor-risk patients by stratified analyses. For the NPM1-wt standard-risk subgroup, C2 MRD+ was significantly associated with poorer outcomes (OS, 33% v 63% MRD−, P = .003; relapse incidence, 89% when MRD+ ≥ 0.1%); transplant benefit was more apparent in patients with MRD+ (HR, 0.72; 95% CI, 0.31 to 1.69) than those with MRD− (HR, 1.68 [95% CI, 0.75 to 3.85]; P = .16 for interaction). Conclusion MFC-MRD can improve outcome stratification by extending the definition of partial response after first induction and may help predict NPM1-wt standard-risk patients with poor outcome who benefit from transplant in the first CR.

Molecular Minimal Residual Disease After Induction Is Related to ABC Proteins' Activity and Associated with Survival in 26 Patients with NPM1 Mutated Acute Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4909-4909
Author(s):  
Pierre Hirsch ◽  
Ruoping Tang ◽  
Christophe Marzac ◽  
Fanny Fava ◽  
Jean-Yves Perrot ◽  
...  
Keyword(s):  
Overall Survival ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Induction Chemotherapy ◽  
Cytogenetic Analysis ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Abc Proteins ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Abstract 4909 Background: A major issue in the treatment of acute myeloid leukemia (AML) is resistance to chemotherapeutic drugs. The role of ABC proteins, and specially ABCB1 (PgP/mdr1), in this resistance has been well established, and higher ABC proteins' activity, assessed with functional tests, has been associated with poorer complete remission rates and poorer overall prognosis (Marzac et al, Haematologica, 2011). Furthermore, the evaluation of molecular minimal residual disease (MRD), using mutated nucleophosmin (NPM1)expression quantification has been related to patients' global prognosis (Krönke et al, J. Clin. Oncol., 2011), and to response to treatments. In this study, we evaluate the impact of ABC proteins' activity on MRD after one course of induction chemotherapy, in 26 patients with NPM1 mutated AML. Material and methods: We retrospectively identified 26 AML patients with NPM1 mutation treated in our center and with MRD data. MRD was evaluated as the ratio of NPM1 mutated allele and total NPM1, using PCR DNA quantification and the delta delta Ct method. MRD was measured at the time of diagnosis and after one course of anthracycline-based induction chemotherapy. ABC proteins' activity was evaluated at the time of diagnosis using JC1 +/− cyclosporine A assay (Legrand et al, Blood, 2001). Correlations between ABC proteins' activity and the level of post induction MRD were evaluated with the Mann-Whitney test. Survival was evaluated using the Cox model. For all analyses, P values were considered significant when lower than 0. 05. Results: Median age at diagnosis was 53 years old. Twenty-two patients had normal cytogenetic analysis at diagnosis, and the other 4 patients had intermediate prognosis cytogenetic analysis. Nine patients harboured FLT3-ITD mutation. Median ABC proteins' activity was 0. 11 (0 – 0. 77). After one course of induction chemotherapy, 3 patients did not reach cytological complete remission. In 17 patients MRD level after induction therapy was inferior to 1 %, in 11 patients MRD was inferior to 0. 1 % and in 7 patients MRD was inferior to 0. 01 %. Overall, higher MRD level after induction (defined by MRD level higher than 0. 1 %) was associated with poorer prognosis for disease free survival (HR= 4. 25 [95% CI 1. 049–17. 27]; p=0. 04), and for overall survival HR=11. 25 [95% CI 1. 22–103. 23]; p=0. 03). Higher ABC proteins' activity was associated with higher MRD levels post induction, and patients who did not reach MRD level lower than 0. 1 % had significantly higher ABC proteins' activity than other patients (p=0. 008). ABC proteins' activity was also associated with overall survival in our patients (p=0. 04). Conclusion: Higher ABC proteins' activity is associated with higher MRD levels after one course of induction chemotherapy in 26 NPM1 mutated AML patients, and is also associated with poorer overall survival. The poorer prognosis associated with high ABC proteins' activity in AML seems to be in part related to direct resistance to chemotherapy. These data should be confirmed in larger studies. Disclosures: No relevant conflicts of interest to declare.

Plasma Exosomes As Markers of Residual Disease in Patients with Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2357-2357
Author(s):  
Michael Boyiadzis ◽  
Chang Sook Hong ◽  
Theresa L Whiteside
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Protein Content ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Molecular Profile ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Acute Myeloid

Abstract Background: Exosomes are virus-size (30–100 nm in diameter) membrane-bound microvesicles that are formed within the endocytic compartments and via fusion of multivesicles bodies are released into extracellular space. The exosomal cargo includes proteins/glycoproteins expressed on the cell membrane as well as molecules and soluble factors present in the cytosol of parental cells. While exosome secretion occurs under physiologic conditions, and all cells are capable of their release, tumor cells are avid exosome producers. Patients newly diagnosed with acute myeloid leukemia (AML) prior to any therapy have higher levels of exosomes compared to normal controls (NC). We hypothesize that the molecular content of isolated exosomes, which are thought to mimic that of leukemic blasts, could be informative about the presence in the bone marrow of leukemic blasts that might avoid detection by conventional hematopathological assays. Methods: Samples of venous blood (20-50 mL) were obtained from patients newly diagnosed with AML prior to any treatment (n=13), after completion of initial induction chemotherapy in patients who achieved complete remission (n=8), during consolidation therapy and age-matched healthy volunteers. Exosome fractions were isolated from plasma by exclusion chromatography on Sephadex G50 columns followed by ultracentrifugation. Exosome protein content was determined and expressed in µg protein/mL plasma. Isolated exosomes were characterized by western blots for expression of classical exosomal markers and for expression of novel myeloid cell surface markers associated with AML, interleukin-3 receptor a chain (CD123) and C-type lectin-like molecule-1 (CLL-1). Results: The exosome fractions isolated from AML patients’ plasma at diagnosis had a considerably greater mean protein content (81.5 ± 10.8 μg protein/mL plasma) than did exosome fractions isolated from the plasma of NC (13.1 ± 2.4 μg protein/mL plasma) with p < 0.005. The molecular profile of exosomes isolated from plasma of AML patients at diagnosis was distinct from that of exosomes isolated from plasma of NC. In addition to classical exosomal markers (MHC class I molecules, LAMP-1, CD81) exosomes isolated from AML patients at diagnosis contained CD34, CD117, CD123 and CLL-1. The exosome fractions isolated from the patients’ plasma who achieved complete remission (n=8) remained elevated, similar to the levels at the time of AML diagnosis (78.5 vs 77.5 μg protein/mL plasma). Exosomes in AML patients who achieved complete remission and in patients receiving consolidation therapy when leukemic blasts are undetectable in the bone marrow by conventional hematopathological methods contained CD123 and CLL-1. Conclusions: Exosomes in AML patients have a unique and distinctive molecular profile. The exosomal profile suggest the presence of residual disease in patients considered to have achieved complete remission by conventional hematopathologic assays. Disclosures No relevant conflicts of interest to declare.

The Kinetic of Reduction of Minimal Residual Disease Impacts on duration of Response snd Survival of Patients with Acute Myeloid Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 399-399
Author(s):  
Francesco Buccisano ◽  
Luca Maurillo ◽  
Giovanni Del Poeta ◽  
Anna Tamburini ◽  
Maria Christina Cox ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multivariate Analysis ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Consolidation Therapy ◽  
Post Induction ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract In acute myeloid leukemia (AML) patients achieving complete remission, the levels of minimal residual disease (MRD) as determined by flow cytometry have been shown to impact on remission duration and survival. However, some issues such as the most suitable source (BM or PB) or the most appropriate timing (early or delayed evaluation) for MRD determination are still a subject of debate. In our experience, we observed that MRD negativity, as defined by a number of bone marrow residual leukemic cells (BMRLC) <3.5x10−4, after consolidation cycle was associated with a significantly longer disease free survival (DFS) and overall survival (OS). Based on this, the present study was designed to analyze the kinetic of MRD reduction during the post-induction phase, and therefore to determine to what extent post-induction chemotherapy might impact on the outcome of patients with AML. Eighty-nine adult patients with AML were entered into the EORTC/GIMEMA protocols AML10/AML12 (age <61 yrs) or AML13/AML15 (age >61 yrs), all consisting in intensive induction and consolidation cycles, and allogeneic or autologous stem cell transplantation for patients aged < 61 years. Median age was 53 years (range 17–78), all FAB subtypes were represented with the exception of APL cases which were not included. Eighty-one of 89 patients maintained complete remission after consolidation (8/89 had early relapse after induction) and were suitable for the analysis. After consolidation cycle, 32 of 81 (39%) patients had <3.5x10−4 BMRLC and were considered MRD neg. The remaining 49 (61%), were MRD pos since the measured levels of MRD were ≥3.5x10−4 BMRLC. Among these MRD pos patients, in 16 the levels of MRD, although still above the value of 3.5x10−4 BMRLC, were significantly reduced as compared to the post-induction levels (median reduction 6x10−4 BMRLC, range 0–643). Therefore, these 16 patients were considered as having a “chemosensitive MRD” and in fact, within this MRD pos category, they had a superior duration of DFS and OS (P=.010 and .004, respectively) as compared to MRD pos patients with “chemoresistant MRD”, namely those not showing improvement in the level of MRD between the induction and consolidation course. Therefore, we identified 3 discrete categories of patients: 1) 32 patients MRD neg at the end of consolidation therapy (BMRLC <3.5x10−4); 2) 16 patients MRD pos at the end of consolidation therapy (BMRLC ≥3.5x10−4) but with “chemosensitive MRD”; 3) 33 patients MRD pos at the end of consolidation therapy (BMRLC ≥3.5x10−4) but with “chemoresistant MRD”. These 3 groups differed significantly in terms of relapse rate (84% vs. 75% vs. 28%, respectively) both in univariate and multivariate analysis (P<.001). Accordingly, DFS and OS (at 5-years, 66%, 50 % and 12%, respectively) (P<.001) duration also differed; the multivariate analysis confirmed the independent prognostic role of MRD status at the end of consolidation (P<.001). In conclusion, 1) at variance with previous reports emphasizing the prognostic value of an early flow-cytometric determination of MRD, we have found that a delayed (post-consolidation) MRD evaluation provides the best predictive information on patients outcome; 2) the quantitative determination of MRD at specific time-points may also allow the identification of MRD pos patients with variable prognosis (chemosensitive vs chemoresistant MRD).

Towards individualized follow-up in adult acute myeloid leukemia in remission

Blood ◽  
2011 ◽  
Vol 117 (9) ◽  
pp. 2577-2584 ◽  
Author(s):  
Peter Hokland ◽  
Hans Beier Ommen
Keyword(s):  
Acute Myeloid Leukemia ◽  
Complete Remission ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Disease Recurrence ◽  
Clinical Implementation ◽  
Rt Pcr ◽  
Traditional Concept ◽  
Promising Alternative ◽  
Acute Myeloid

Abstract An increasing body of data has demonstrated that the traditional concept of morphologic complete remission in acute myeloid leukemia, in which less than 5% myeloblasts is regarded as a sufficient response criterion, is not biologically sound. Fortunately, the quantitative reverse-transcribed polymerase chain reaction (RT-PCR) method seems to be a promising alternative because of its high degree of preclinical standardization and extreme sensitivity on the background of an accurate day-to-day estimate of sample quality. Widespread implementation of this has, however, to some extent been hampered by the lack of knowledge of how and when to measure minimal residual disease levels and, even more importantly, how to react preemptively on a molecular relapse defined by a PCR reversal. Thus, only few prospective studies have been published to date to clinically validate this assay. Here, we discuss outstanding issues in the clinical implementation of RT-PCR for fusion transcripts, mutated and overexpressed genes in acute myeloid leukemia patients in complete remission, and propose a set of guidelines, which can be used when designing prospective trials aimed at validating the use of RT-PCR as well as for following these patients based on mathematical models for disease recurrence recently developed in our laboratory.

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