Angiogenic factors could help us to define patients obtaining complete response with undetectable minimal residual disease in untreated CLL patients treated by FCR: results from the CLL2010FMP, a FILO study

2021 ◽  
pp. 1-10
Author(s):  
Anne Laure Gagez ◽  
Franciane Paul ◽  
Elina Alaterre ◽  
Valérie Gouilleux-Gruart ◽  
Edouard Tuaillon ◽  
...  
2021 ◽  
pp. JCO.21.01045
Author(s):  
Pieter Sonneveld ◽  
Meletios A. Dimopoulos ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Sara Aquino ◽  
...  

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.


Blood ◽  
2019 ◽  
Vol 134 (16) ◽  
pp. 1337-1345 ◽  
Author(s):  
Laura Rosiñol ◽  
Albert Oriol ◽  
Rafael Rios ◽  
Anna Sureda ◽  
María Jesús Blanchard ◽  
...  

Key PointsVRD was effective and well tolerated before ASCT; 33.4% complete response/28.8% minimal residual disease–negative after 6 induction cycles. Responses deepened with VRD throughout induction and over the course of treatment with few discontinuations due to toxicity.


2019 ◽  
Vol 19 (10) ◽  
pp. e185-e186
Author(s):  
Ioannis V. Kostopoulos ◽  
Efstathios Kastritis ◽  
Aristea-Maria Papanota ◽  
Paraskevi Micheli ◽  
Panagiotis Malandrakis ◽  
...  

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2761-2761
Author(s):  
Leslie R. Ellis ◽  
Loic Vincent ◽  
Sergey Shmelkov ◽  
Andrea Hooper ◽  
Scott Avecilla ◽  
...  

Abstract It has already been established that subsets of leukemic cells express receptors for pro-angiogenic factors, such as vascular endothelial growth factor receptor-2 (VEGFR-2). Further studies have shown that these same leukemic cells also produce the ligand for these VEGF receptors, VEGF-A. This autocrine loop supports the invasion and proliferation of these particular leukemic cells. The VEGFR-2 signaling pathway is further dependent upon the co-activation of other pro-angiogenic factors, such as vascular endothelial (VE)-cadherin. VE-cadherin is an endothelial cell-specific transmembrane cellular adhesion protein that when bound results in the dephosphorylation of VEGFR-2 and contributes to neo-vessel formation. Recent studies have suggested that VE-cadherin may be expressed by a unique subset of hematopoietic cells, raising the possibility that leukemic cells may express VE-cadherin as well. We therefore sought to identify the expression of VE-cadherin on leukemic cell lines and primary samples, and further determine its role in the interaction with VE-cadherin-positive endothelial cells. Leukemic cell lines and primary leukemias were screened for the presence of VE-cadherin by both RT-PCR and Western blot analysis. Primary leukemic samples, as well as established cell lines for human erythroblastic leukemia (HEL) and acute myelogenous leukemia (KG-1a) were found to express VE-cadherin. VE-cadherin expression was further confirmed by flow cytometry and immunocytochemistry, which demonstrated that approximately 15% of the total population was VE-cadherin-positive. Proliferation and migration assays utilizing neutralizing monoclonal antibodies to VE-cadherin were performed with no obvious effects. However, immunofluorescent staining of a co-culture performed with the above leukemic cells grown on a layer of human umbilical vein endothelial cells (HUVECs) demonstrated that the leukemic cells and HUVECs interact via VE-cadherin. Furthermore, when these leukemic cells were injected into NOD-SCID mice subcutaneously, the VE-cadherin-positive cells localized around the vessels present within the leukemic chloroma. These data set forth the concept that a subset of leukemic cells expresses the protein VE-cadherin and that VE-cadherin is involved in the cell-to-cell interaction between a subset of leukemic cells and vascular endothelial cells. Heterotypic VE-cadherin interaction between leukemic cells and neo-vessels may increase the survival of leukemic cells and contribute to the generation of minimal residual disease. Therefore, inhibition of VEGFR-2 in conjunction with VE-cadherin may provide a novel strategy to eradicate minimal residual disease.


Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1390-1390
Author(s):  
Annika Dufour ◽  
S. K Bohlander ◽  
Karsten Spiekermann ◽  
Stephanie Schneider ◽  
Jan Braess ◽  
...  

Abstract Abstract 1390 Introduction: Levels of minimal residual disease (MRD) have been shown to correlate with PFS in previously untreated patients with CLL (CLL8, Boettcher et al. Leukemia, 2009). Patients who remain MRD positive after treatment have a higher risk of relapse. Eradication of MRD is therefore a desirable clinical endpoint of treatment. We were interested to assess this correlation in REACH, a randomized international clinical study in previously treated CLL patients, randomized 1:1 for treatment with rituximab, fludarabine and cyclophosphamide© R-FC (276 patients) or FC alone (276 patients); (Robak et al. JCO 2010). Methods: While MRD quantification by flow cytometry requires an identifiable stable phenotype and fresh blood samples, PCR based methods can be performed centrally on frozen samples. We have therefore developed a Realtime Quantitative (RQ) PCR method, using patient-specific IgVH (immunoglobulin variable heavy chain) gene rearrangements as targets. Briefly, genomic DNA was isolated from CD19 sorted B-cells. ASO (allele-specific oligonucleotide) primers were designed matching the hypervariable N-D-N region of the patient-specific leukemic clone and used with reverse consensus primers and hydrolysis probes annealing to the family-specific joining region of the IGH rearrangement (Brüggemann et al., Leukemia, 2004). Maximum sensitivity and quantitative range were defined for every RQ-PCR. Patients were categorized as molecular responders (MRD negative) if there was no detectable clonal IgH rearrangement, using a sensitivity cut-off of 1×10-4. Molecular response was assessed at the time of CR confirmation and 6 months later (if CR was maintained). Results: Among the 103 patients who achieved CR during the study, 86 patients had at least one MRD assessment in peripheral blood, 92 patients in bone marrow. Since many patients had a CR confirmation at different time points during the follow-up period, we initially analyzed the MRD levels only in patients who had achieved confirmed complete response at end of treatment +/−3 month (“EOT - period”). The rate of MRD negativity in blood (22 pts: 5(15) FC, 6(7)R-FC) at EOT was 33% for patients treated with FC, and 86% for patients treated with R-FC (p=0.06); In bone marrow at the EOT (61 patients: 5(27) FC, 20(34) R-FC) the rates were 19% and 59%, respectively (p= 0,02), indicating higher efficacy of the Rituximab containing regimen in eradication of residual disease; This is in line with the previously reported results using FACS analysis of MRD in the CLL8 trial; the differences in the detection rate in blood versus bone-marrow, suggest a higher sensitivity for detection of MRD in bone marrow. We therefore compared the levels of MRD negativity in samples from blood and bone marrow in patients where both samples were taken at the same time point. Results were concordant in 8/9 patients, one patient had a positive result in bone marrow with no detectable signal in blood. This supports the notion that assessment of MRD in bone marrow of CLL patients may be more sensitive than assessment in blood only. However, for a definitive statement larger sample size would be needed. We then correlated MRD status at EOT, regardless of treatment arm, with PFS: In line with previous reports, there was a clear trend to longer PFS in patients who had reached MRD negativity (median PFS not reached), while patients with residual disease had shorter PFS; however, due to small sample numbers, statistical significance could not be reached. We also analyzed the correlation of MRD negativity reached at any time during and after treatment with PFS, bearing in mind that this sample set is inherently biased, since patients with early progression will be lost from the analysis; the results are consistent with the EOT findings. Summary: ASO IgVH RQ-PCR is a powerful method to detect residual levels of disease in CLL patients with clinical complete response and undetectable MRD correlates with longer PFS. Among patients in REACH achieving clinical CR on either study arm, a higher percentage achieved MRD negativity on the R-FC arm, consistent with the increased efficacy shown for the Rituximab treatment arm by the REACH clinical data. Disclosures: Mundt: Roche: Employment. Smith:Roche: Employment. Lin:Genentech: Employment. Barrett:Roche: Employment. Hurst:Genentech: Employment. Geisler:Roche: Research Funding, Speakers Bureau. Hiddemann:Roche: Research Funding.


Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3339-3339 ◽  
Author(s):  
Dickran Kazandjian ◽  
Neha S Korde ◽  
Mark Roschewski ◽  
Sham Mailankody ◽  
Candis Morrison ◽  
...  

Abstract Background: High-risk smoldering multiple myeloma (HR-SMM) is a plasma cell dyscrasia which has a 5-year risk of progression to symptomatic multiple myeloma (MM) of approximately 75% based on current risk models. With the availability of novel therapies, early treatment may decrease the risk of progression and prolong survival as evidenced by the recent QuiRedex study results. More recently, studies have demonstrated that triplet regimens are superior to doublet in MM and whole exome sequencing in HR-SMM is indicative of treatment susceptible biology in early disease; supporting the use of effective combination therapy as early intervention. Expanding on our initial results using modern CRd-R therapy in HR-SMM patients (Korde et al. JAMA Onc 2015) we show unprecedented high rates of obtained and sustained complete response (CR) and minimal residual disease negativity (MRDneg CR) in an expanded cohort of patients with a median follow-up of ~3 years. Methods: Treatment-na•ve patients with HR-SMM (IMWG 2010 criteria; Mayo or PETHEMA models) were treated for 8 cycles (28-day cycles) with CFZ 20/36 mg/m2 IV days 1, 2, 8, 9, 15, 16; LEN 25 mg PO days 1-21, and DEX 20/10 mg IV/PO days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients underwent stem cell collection after ≥4 cycles of CRd and then continued CRd treatment (i.e. by-default-delayed high-dose melphalan with autologous stem cell transplant; HDM-ASCT). After 8 cycles of combination therapy, patients with SD or better received 2 years of LEN 10 mg PO maintenance. The primary objective was best response (ORR), followed by secondary objectives of progression free survival (PFS) and response duration (DoR) which were assessed after every cycle of induction and every 90 days during maintenance. Correlative studies including assessment of minimal residual disease (MRD) by multi-color flow cytometry (bone marrow aspirate; 10-5 sensitivity) as defined by updated 2016 IMWG response criteria were performed after 8 cycles of induction and 1 and 2 years of maintenance LEN. Results: Eighteen patients meeting eligibility criteria were enrolled (data-lock 7/20/2016). Demographics and disease characteristics are shown in Table 1. Best ORR and >= VGPR rate (n=18) with CRd-R was 100% (Table 2). The proportion of patients who obtained stringent CR/CR after 8 cycles of induction, 1 year of maintenance and 2 years of maintenance was 61%, 89%, and 89%, respectively. Of evaluable patients who achieved at least a CR, the proportion of patients who obtained MRD negativity (MRDneg CR) at the same time-points was 91%, 71%, and 75%, respectively. DoR and PFS at 36 months was 94% and overall survival with a median follow-up duration of 31 months was 100%. Toxicities Grade 3-4 occurring in >1 patient included lymphopenia (39%), neutropenia (28%), anemia (22%), diarrhea (17%), lung infection (17%), hypophosphatemia (11%), and thromboembolic event (11%). Significant serious adverse events included CHF which occurred in one patient. Conclusions: Early treatment of HR-SMM with modern CRd-R combination therapy with by-default-delayed HDM-ASCT resulted in unprecedented high rates of CR and MRDneg CR after 8 cycles of CRd. Following 2 years of additional LEN maintenance therapy, the CR and sustained MRDneg CR rates were 89% and 69%, respectively. Given the significant risk of progression to symptomatic MM and associated life limiting end-organ damage, early intervention for patients with HR-SMM with effective triplet-based therapies may be warranted. This first proof-of-principle study has thus far demonstrated exceptional clinical benefit. Therefore, this study will be re-opened to enrollment and long-term follow up results collected to expand on these promising results. Updated results will be presented at the Annual Meeting. Disclosures Korde: Medscape: Honoraria. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Landgren:BMS: Honoraria; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Takeda: Honoraria.


Blood ◽  
2014 ◽  
Vol 123 (20) ◽  
pp. 3073-3079 ◽  
Author(s):  
Joaquin Martinez-Lopez ◽  
Juan J. Lahuerta ◽  
François Pepin ◽  
Marcos González ◽  
Santiago Barrio ◽  
...  

Key Points MRD assessment by sequencing is prognostic of TTP and OS in multiple myeloma patients. Among patients in complete response, MRD assessment by sequencing enables identification of 2 distinct subgroups with different TTP.


2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 8030-8030
Author(s):  
Marcella Tschautscher ◽  
S. Vincent Rajkumar ◽  
Francis Buadi ◽  
Morie A. Gertz ◽  
Martha Lacy ◽  
...  

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