scholarly journals Percentage of Erythroid Cells in Bone Marrow at Diagnosis As a New Prognostic Factor in Patients with Myelodysplastic Syndrome

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4363-4363
Author(s):  
Ana Villalba ◽  
Leonor Senent ◽  
Esther Alonso ◽  
Elvira Mora ◽  
Teresa Bernal Del Castillo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Risk Factor ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Independent Risk Factor ◽  
Multivariable Analysis ◽  
Erythroid Cells ◽  
Advisory Committees ◽  
Erythroid Precursors

Abstract Introduction Risk assessment is essential for guiding therapy in patients with myelodysplastic syndromes (MDS). Currently, the most widely used prognostic scoring models are the International Prognostic Scoring System (IPSS) and the revised IPSS (IPSS-R). The prognostic relevance of the percentage of erythroid precursors (EP) in bone marrow (BM) and its relationship with other biological characteristics has been poorly studied, although it has been proposed that a very low percentage of EP in BM may represent a cohort of patients with potentially adverse outcome. Our main aim was to analyze the biological and clinical features of MDS patients according to the percentage of EP in BM at diagnosis and evaluate its prognostic value on survival. Patients and Methods Data from 4,791 de novo MDS patients from the MDS Spanish Registry with available cytogenetics were collected. All patients included were diagnosed based on the 2008 WHO criteria and risk stratification was performed following the IPSS-R. Patients were distributed, according to the percentage of EP in BM, into three groups: less than 15% (EP<15%), between 15% and 49% (EP 15-49%) and equal or more than 50% (EP>49%). Proportions were compared by the Chi-square test. Survival curves were constructed by Kaplan-Meier method and differences between curves were evaluated by log rank tests. Multivariable analysis of survival was performed using Cox's proportional hazards regression model. P-values <0.05 were considered as statistically significant. All statistical analyses were performed by the R software. Results The 4,791 cases were grouped according to the percentage of erythroid cells in BM at diagnosis. In Table 1 are displayed the clinical and biological characteristics of the patients in the whole series and in the three groups based on the EP percentage in BM. The group with EP<15% in BM showed a significantly greater number of cytopenias at diagnosis, a higher number of peripheral blood (PB) and BM blasts, and a higher percentage of patients classified in MDS subtypes with excess blasts. The EP>49% group presented higher rates of patients with refractory anemia with ring sideroblasts (RARS), lower number of PB and BM blasts, and more frequent high-risk cytogenetics. Conversely, the intermediate EP group with EP 15-49% showed less number of cytopenias, higher frequency of good-prognosis cytogenetics, and lower percentage of patients in higher-risk IPSS-R categories. Survival analyses confirmed that age, blast percentage in PB and BM, and IPSS-R cytogenetics are significantly associated with worse survival. A striking difference in survival within groups according to percentage of EP was also found, recognizing EP percentage as an independent risk factor for survival of MDS patients in multivariate analysis. Patients with EP<15% in BM experienced a significantly shorter OS (median, 28 months) in both univariable (P<0.0001) and multivariable analysis (P<0.0001) (Table 2 and Figure 1). The best survival was found for patients with EP 15-49% with a median survival of 58 months. The group with EP>50% in BM had also worse survival than the intermediate group, showing a median survival of 47 months (hazard ratio, 0.79; 95% CI, 0.67 to 0.93; P < 0.005). Conclusions Our study proves the prognostic impact of the percentage of erythroid precursors in bone marrow in MDS patients, providing evidence that the presence of EP <15% in BM is an independent risk factor for survival. Disclosures Díez-Campelo: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Acute Myeloid Leukemia (AML) Treated with Azacitidine: Survival Outcomes for Patients Who Complete More Than Six Cycles Are Similar to High-Risk Myelodysplastic Syndrome/Low Blast Count AML

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5156-5156
Author(s):  
Jill Fulcher ◽  
Zahra Abdrabalamir Alshammasi ◽  
Nathan Cantor ◽  
Christopher Bredeson ◽  
Grace Christou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Median Survival ◽  
Research Funding ◽  
Survival Outcomes ◽  
Advisory Committees ◽  
Ottawa Hospital ◽  
Funding Agencies ◽  
Progression Of Disease ◽  
Refractory Aml

INTRODUCTION: Despite accumulating evidence supporting the efficacy of hypomethylating agents in patients with AML and > 30% bone marrow blasts as well as in relapsed/refractory AML, this therapy is not yet funded by National Health Plans / Healthcare Funding Agencies in a number of countries including Canada. The assistance of an industry-sponsored compassionate program has enabled provision of azacitidine for this group of patients at The Ottawa Hospital. We report here our local "real-world" experience of azacitidine efficacy in this diverse group of AML patients and identify a sub-group whose outcomes are equivalent to that of patients with higher-risk Myelodysplastic Syndrome (MDS) and AML with 20-30% blasts for whom azacitidine therapy has funding approval in Canada. METHODS: All patients who received azacitidine at The Ottawa Hospital between 2009 and 2016 were included in this single-center, retrospective analysis. Azacitidine was administered at a dose of 75mg/m2 subcutaneously daily for 7 consecutive days every 28 days. Response was evaluated with a repeat bone marrow aspirate and trephine biopsy after the 6th cycle. In those patients confirmed to have stable or responsive disease, azacitidine was continued until progression of disease, intolerable side-effects of the drug or the patient chose to discontinue therapy. Overall survival curves were generated using the Kaplan-Meier method and log-rank tests were used to compare subgroups of patients. Actuarial median survival months were calculated with 95% confidence intervals (CI). P-values less than 0.05 were considered statistically significant. RESULTS: During the study period, 109 patients received azacitidine: 54 had MDS /AML with 20-30% blasts (the 'funded' group) and 55 had either AML with > 30 % blasts (n=23), AML relapsed post-intensive chemotherapy (n=14), AML relapsed post-allogeneic stem cell transplant (n=10) or primary refractory AML (n=8) (the 'unfunded' group). Median survival of the 'funded' group was 12.2 months while median survival of the 'unfunded' group was 5.6 months (95% CI 3.3-7.7; p=0.0058). Of the AML patients in the 'unfunded' group, 24% completed more than 6 cycles of azacitidine compared to 52% of patients in the 'funded' group. In both the 'funded' and 'unfunded' groups, patients who completed more than 6 cycles of azacitidine had similar survival outcomes (p=0.7277): the 'funded' group had a median survival of 19 months (95% CI 14.4-25.3) while the median survival of this sub-population of the 'unfunded' AML group was 22 months (95% CI 11.7-24.9). Patients in both groups who failed to complete more than 6 cycles of azacitidine also had a similar outcome (p=0.39), with a median survival of 5.7 months (95% CI 4.0-6.3) for patients with MDS/AML 20-30% blasts and 3.6 months (95% CI 2.2-5.1) for AML patients with > 30% blasts or relapsed/refractory disease. Reasons for patients not completing at least 6 cycles of azacitidine included progression of disease (25%), bacterial infections most commonly pneumonia (53%) and patient preference (7%). CONCLUSION: A significant sub-population of AML patients with > 30% blasts or refractory/relapsed AML can achieve a meaningful survival benefit with the hypomethylating agent, azacitidine. A higher proportion of this AML patient population discontinued azacitidine as a result of infective complications. The provision of routine prophylactic antibiotics may enable more patients with AML to receive an adequate amount of azacitidine to achieve therapeutic benefit and warrants further investigation. Our results add to the growing body of 'real-world' evidence that supports healthcare funding agencies to provide coverage of azacitidine for patients with AML who in some countries at present do not fulfill government funding criteria. Disclosures Bredeson: Otsuka: Research Funding. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding.

scholarly journals Minimal Residual Disease (MRD) Detection By Flow Cytometry Complements Molecular MRD Assessment in AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2753-2753
Author(s):  
Veit Bücklein ◽  
Thomas Köhnke ◽  
Frauke Schnorfeil ◽  
Klaus H. Metzeler ◽  
Nikola P Konstandin ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Risk Factor ◽  
Board Of Directors ◽  
Research Funding ◽  
Independent Risk Factor ◽  
Residual Disease ◽  
Specific Treatment ◽  
Patient Specific ◽  
Advisory Committees ◽  
Post Induction

Abstract The prognosis of patients with AML is determined by a multitude of recurrent genetic alterations, and treatment algorithms heavily rely on risk stratification by genetic characterization of the disease at the time of diagnosis. However, this a priori risk stratification does not integrate information on treatment susceptibility of the individual patient. Assessment of Minimal Residual Disease (MRD) aims to implement this information in the patient-specific treatment management. AML cells with aberrant phenotypes can be detected at sensitivities below 1:104 by flow cytometry in the majority of patients. Therefore, flow cytometry MRD assessment (flow MRD) enables determination of MRD status in patients without suitable molecular markers (e.g. NPM1, CBFß-MYH11, and RUNX1-RUNX1T1). Here, we validate the role of flow MRD in AML patients receiving intensive chemotherapy with and without available molecular markers. Flow MRD was analyzed in patients with AML (excluding APL) diagnosed between 2012 and 2017 receiving intensive induction chemotherapy (sHAM or 7+3). Flow MRD analysis was performed during aplasia (on day 16 after treatment initiation) as well as post induction. Presence of ≥0.1% Leukemia-associated immunophenotype (LAIP)-positive cells was defined as flow MRD positivity. Molecular MRD was analyzed post induction for NPM1 and CBF, and post consolidation for RUNX1-RUNX1T1. Kaplan-Meier estimators and log-rank tests were used to analyze survival data. Cox's proportional hazards regression model was used to determine the influence of individual factors in multivariate analyses. A total of 161 patients were included. In 5 cases (3.1% of all cases), no LAIP could be identified, and these patients were excluded from further analyses. Flow MRD assessment during aplasia was available in 145 cases. 122 patients had flow MRD assessments available post induction. 114 patients achieving CR or CRi after induction therapy had flow MRD assessments available at both time points. Flow MRD positivity during aplasia was associated with shorter event free survival (EFS, 6.1 months vs. 19.1 months, p<0.001). Similarly, flow MRD positivity post induction was associated with shorter EFS (11.9 months vs. median not reached, p=0.007). For both timepoints, flow MRD was an independent risk factor in multivariate analysis compared to known risk factors such as age, genetic/molecular risk profile as determined by the ELN2017 risk categories as well as early blast clearance by morphology. Persistent flow MRD positivity at both timepoints (combined flow MRD) identified patients with particularly short EFS (8.2 months), whereas patients with flow MRD negativity at both time points had the best outcome in our cohort (median not reached, p=0.002). Combined flow MRD status was an independent predictor of EFS and RFS (HR 1.9 and 1.8, p=0.001 and p=0.007, respectively), whereas blast clearance by morphology had no significant prognostic impact (p>0.05 for all endpoints). 64/161 patients (39%) had molecular MRD assessment available for analysis. In these patients, molecular MRD positivity predicted a significantly shorter EFS (9.3 months vs. median not reached, p=0.01). Indeed, molecular MRD positivity was an independent risk factor for adverse EFS and RFS (HR 1.7 and 1.6, p=0.008 and p=0.018, respectively). In this subgroup, flow MRD was not an independent prognostic factor. However, for patients without available molecular MRD marker (97/161 patients), flow MRD positivity at aplasia (p=0.004), post induction (p=0.015) or as combined status (p=0.004) was associated with a significantly shorter EFS and remained an independent risk factor in multivariate analysis (HR 2.5 and 2.6, p=0.016 and p=0.012 for EFS and RFS, respectively). Taken together, we demonstrate that both flow MRD as well as molecular MRD strongly correlate with survival. While molecular MRD assessment was only available in 39% of patients, MRD assessment by flow cytometry was feasible in >95% of AML patients. Flow MRD positivity both during aplasia and post induction was an independent risk factor, confirming the superiority of flow MRD compared to early morphologic response assessment. In conclusion, molecular and flow cytometric MRD assessment are complementing methods for the estimation of treatment response, and will be integrated in clinical trials to validate their significance for patient-specific treatment management. Disclosures Metzeler: Celgene: Consultancy, Research Funding; Novartis: Consultancy. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Subklewe:Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche AG: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

Pure Red Cell Aplasia (PRCA) in Chronic Lymphocytic Leukemia (CLL): Etiology, Therapy, and Outcomes

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4169-4169 ◽  
Author(s):  
Mazie Tsang ◽  
Kari Rabe Chaffee ◽  
Timothy G. Call ◽  
Wei Ding ◽  
Jose F. Leis ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Diagnostic Criteria ◽  
Mayo Clinic ◽  
Research Funding ◽  
Normocytic Anemia ◽  
Normal Range ◽  
Advisory Committees ◽  
Significant Difference ◽  
Erythroid Precursors

Abstract Background: PRCA is characterized by severe normochromic normocytic anemia, reticulocytopenia, and markedly reduced bone marrow erythroid precursors with intact leukocytic and megakaryocytic lineages. There is limited information about the prevalence and outcomes of PRCA in CLL, with the vast majority of information derived from case reports and small series comprising <10 patients. Here, we describe the clinical features, therapy, and outcomes of CLL patients with PRCA seen at our institution. Methods: The Mayo Clinic CLL Database includes all patients with a diagnosis of CLL evaluated at Mayo Clinic Rochester, MN between January 1995 and December 2014. We identified patients diagnosed with PRCA per the following diagnostic criteria: those who presented with normocytic anemia, had decreased erythroid precursors on bone marrow examination, and reticulocytopenia that could not be explained by any other cause besides PRCA. The baseline demographics, clinical characteristics, therapy, and outcomes were abstracted from the electronic medical records. We generated descriptive statistics and calculated overall survival (OS) from diagnosis date (PRCA, autoimmune cytopenia [AID], or CLL) to last known alive or death date. OS was plotted using Kaplan Meier curves and compared between groups using log-rank statistic. The Mayo Clinic IRB approved this study. Results: Of the 3945 CLL patients seen during the study interval, we identified 30 patients who met the diagnostic criteria of PRCA as described in the Methods section. The baseline characteristics, etiology and therapy for PRCA are shown in Table 1. The median time to PRCA from CLL diagnosis was 4.5 years (range-0.1-14 years). Of the 13 patients with IGHV results available, 12 (92%) were IGHV unmutated. Twenty-one (70%) were male and their median age at PRCA diagnosis was 67 years (range 40-81 years). Parvovirus testing was positive in 6 of 24 (25%) patients who were tested; 3 of these patients were treated with IVIG, 2 were treated with prednisone and IVIg, and 1 was treated with prednisone and rituximab. Eight patients (27%) had both PRCA and autoimmune hemolytic anemia (AIHA), and 1 patient (3%) had concomitant PRCA and immune thrombocytopenia (ITP). Of the 27 patients for whom we have treatment data, 10 required only one treatment regimen and 17 required 2-6 treatment regimens, with two patients requiring splenectomy for concomitant AIHA. The median survival of CLL patients after a diagnosis of PRCA was 4.6 years (Figure 1). There was no difference in survival between PRCA cases with and without parvovirus (p=0.92). Compared to newly diagnosed CLL Rai stage III/IV patients, there was no difference in OS (p=0.53). There was no statistically significant difference in survival from an AID cytopenia diagnosis when comparing PRCA, ITP, AIHA, and Evans syndrome (Figure 1; median 5 years for PRCA and 6 years for other groups; p=0.17). Conclusion: PRCA is a rare complication in CLL, occurring in <1% CLL patients seen at our institution over the past 20 years. Parvovirus was the etiologic factor in ~25% of patients and did not influence outcomes. There appears to be no significant difference in outcomes of PRCA patients compared to patients with other AID in CLL. Table 1. Patient Characteristics Characteristic N [range] or (%) Number of patients 30 Males 21 (70) IGHV status* · Unmutated · Mutated 12 (92) 1 (8) FISH results at CLL diagnosis* · 17p- · 11q- · Trisomy 12 · 13q- · Negative 0 (0) 1 (10) 3 (30) 3 (30) 3 (30) At PRCA Diagnosis Median age 67 [40 - 81] Median hemoglobin (gm/dL)* [normal range 12-15.5 gm/dL] 8.2 [3.5 - 10.8] Median absolute reticulocyte count (x 109/L)* [normal range: 38 - 113 x 109/L] 3.5 [0.0 - 25.3] Patients treated for CLL prior to PRCA diagnosis 25 (83) Etiology of PRCA Parvovirus (n = 24) 6 (25) Therapy-related: · Fludarabine · Alemtuzumab/rituximab · Pentostatin/cyclophosphamide/rituximab 3 (10) 1 (3) 1 (3) Autoimmune (neither therapy nor parvovirus related) 19 (63) Initial Therapy of Non-Parvovirus Related PRCA Steroids alone 2 (8) Steroids and Rituximab 3 (13) Steroids in combination with: · IVIG, Chlorambucil · Cyclosporine · Rituximab, IVIg · IVIg, splenectomy 1 (4) 2 (8) 1 (4) 1 (4) Monoclonal Ab alone · Alemtuzumab · Rituximab 1 (4) 4 (17) Cyclosporine 1 (4) Cyclophosphamide 2 (8) RCP (Rituxan, Cyclophosphamide, and prednisone) 2 (8) IVIg 1 (4) Not available 3 (13) *Not available for all patients Figure 1. Figure 1. Disclosures Ding: Merck: Research Funding. Kay:Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Hospira: Research Funding; Tolero Pharma: Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Shanafelt:Cephalon: Research Funding; Hospira: Research Funding; Glaxo-Smith-Kline: Research Funding; Genentech: Research Funding; Jannsen: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding; Pharmacyclics: Research Funding.

scholarly journals The Metabolomic Status of the Differentiating Myeloid Lineage in MDS with Low and High Bone Marrow Blast Counts

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 32-33
Author(s):  
Aikaterini Poulaki ◽  
Theodora Katsila ◽  
Ioanna E Stergiou ◽  
Stavroula Giannouli ◽  
Jose Carlos Gόmez Tamayo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Warburg Effect ◽  
Research Funding ◽  
Metabolic Reprogramming ◽  
Negative Ion ◽  
Advisory Committees ◽  
Myeloid Lineage ◽  
Epigenetic Modifier ◽  
Cellular Fate

Despite its major role in cellular biology, metabolism has only recently acquired a principal role in the research of the most profound cellular cycle disturbance, cancerous transformation. Myelodysplastic syndromes (MDS), a massively heterogeneous group of Hematopoietic Stem/ Progenitor Cell (HSC/HPC) disorders lie at the interface of normal differentiation and malignant transformation and have thus drew great attention due to their polymorphic presentation and elusive pathophysiology. Failure to establish a direct etiopathogenic relationship with specific genetic aberrations, along with the novel finding of a highly deregulated HIF1 activity by several unrelated research groups worldwide, including ours, urged us to investigate the metabolomic status of human bone marrow derived differentiating myeloid lineage in comparison with one another as well as with control samples. BM aspiration samples collected from 14 previously untreated MDS patients (10 patients with &lt;5% (1 SLD, 8MLD, 1del5q, group 1- G1) and 4 with &gt;5% BM blasts (2 EB1, 2 EB2group 2 - G2)) and 5 age matched controls. Myeloid lineage cells were isolated through ficoll bilayer protocol. All samples contained homogenous myeloid lineage subpopulations, assessedthrough optical microscopy. Two different metabolite extraction protocols were applied. The one with the best metabolites yield (50% MeOH, 30% ACN, 20% H2O) was chosen. LC-MS/MS analysis was performed using UPLC 1290 system (Agilent Technologies) coupled to a TripleTOF 5600+ mass spectrometer (SCIEX) equipped with SWATH acquisition, SelexION technology and an electrospray ionization source (ESI). A threshold of a minimum of three samples expressing a given metabolite was set against data sparsity. Data tables were scaled by data centering and setting unit variance. Log2 Foldcalculation and PLS analysis were performed for the two datasets (positive and negative ion-modes). R2 and Q2 for positive ion-mode and negative-ion mode analyses were determined. Both datasets were merged in a unique data table by taking into account maximum absolute log2 foldvalues, when a metabolite was found in both datasets. Warburg effect was evidently present in both the G1 and G2 vs control comparisons, yet the role of this stem like aerobic glycolysis seems markedly different in the two groups. While in the G2 group it serves to rescue glucose from complete burn in the mitochondrion and thus shuts it towards nucleotide synthesis (Pentose Phosphate Pathway found upregulated) with the added benefit of increased reduced Glutathione synthesis and improved redox state, in the G1 group proves detrimental. This greatly variable effect of the same phenomenon in the cellular fate lies upon the quality and functionality of the cellular mitochondrial content. G2 precursors presented functional mitochondrial (decreased NAD/NADH and FAD/FADH2) contrary to the G1 ones (Table). Failing TCA cycle, with increased NAD/NADH and FAD/FADH2 ratios and markedly increased ADP/ATP levels leads to FAs accumulation due to failure of effective adequate β oxidation. The uncontrolled increase in the NAD/NADH ratio stimulates upper glycolysis into a turbo mode further increasing the ADP/ATP, depleting cellular energy contents, engaging it to a never-ending deadly metabolism. The enormous abundance of upper glycolytic intermediates is relieved through phospholipid and ceramide synthesis, all found massively upregulated in both the MDS vs control yet also in the G1 vs G2 comparisons. FAs, mostly phospholipid and ceramide accumulation, interrupt the mitochondrial membrane lipidome further incapacitating metabolic integrity and inducing their autophagic degradation which further stimulates the Warburg effect. This type of metabolic reprogramming is eventually targeted to epigenetic modifier production, increased S-adenosyl-methionine, the major methyl group donor, 2-HydroxyGlutarate, a potent epigenetic modifier and notorious oncometabolite, Acetyl-Lysine, the major acetyl- group donor, even glutathione. We therefore present a model of an uncontrolled Warburg effect which in the G1 group confers premature death of the hematopoietic precursors, the ineffective hematopoiesis of MDS. Yet, under the pressure of the vastly upregulated epigenetic modifiers cellular fate changes, the G1 precursors adapt and transform to the G2 ones yet eventually to Acute Myeloid Leukemia blasts. Table Disclosures Vassilopoulos: Genesis pharma SA: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

scholarly journals p53 Mediated Bone Marrow Mesenchymal Stem Cell Expansion Supports Acute Myeloid Leukemia Development

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 523-523
Author(s):  
Rasoul Pourebrahimabadi ◽  
Zoe Alaniz ◽  
Lauren B Ostermann ◽  
Hung Alex Luong ◽  
Rafael Heinz Montoya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Osteoblast Differentiation ◽  
Hematopoietic Cells ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Mdm2 Inhibitor ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous disease that develops within a complex microenvironment. Reciprocal interactions between the bone marrow mesenchymal stem/stromal cells (BM-MSCs) and AML cells can promote AML progression and resistance to chemotherapy (Jacamo et al., 2014). We have recently reported that BM-MSCs derived from AML patients (n=103) highly express p53 and p21 compared to their normal counterparts (n=73 p&lt;0.0001) (Hematologica, 2018). To assess the function of p53 in BM-MSCs, we generated traceable lineage specific mouse models targeting Mdm2 or Trp53 alleles in MSCs (Osx-Cre;mTmG;p53fl/fl and Osx-Cre;mTmG;Mdm2fl/+) or hematopoietic cells (Vav-Cre;mTmG;p53fl/fl and Vav-Cre;mTmG;Mdm2fl/+). Homozygote deletion of Mdm2 (Osx-Cre;Mdm2fl/fl) resulted in death at birth and displayed skeletal defects as well as lack of intramedullary hematopoiesis. Heterozygote deletion of Mdm2 in MSCs was dispensable for normal hematopoiesis in adult mice, however, resulted in bone marrow failure and thrombocytopenia after irradiation. Homozygote deletion of Mdm2 in hematopoietic cells (Vav-Cre;Mdm2fl/fl) was embryonically lethal but the heterozygotes were radiosensitive. We next sought to examine if p53 levels in BM-MSCs change after cellular stress imposed by AML. We generated a traceable syngeneic AML model using AML-ETO leukemia cells transplanted into Osx-Cre;mTmG mice. We found that p53 was highly induced in BM-MSCs of AML mice, further confirming our findings in primary patient samples. The population of BM-MSCs was significantly increased in bone marrow Osx-Cre;mTmG transplanted with syngeneic AML cells. Tunnel staining of bone marrow samples in this traceable syngeneic AML model showed a block in apoptosis of BM-MSCs suggesting that the expansion of BM-MSCs in AML is partly due to inhibition of apoptosis. As the leukemia progressed the number of Td-Tomato positive cells which represents hematopoietic lineage and endothelial cells were significantly decreased indicating failure of normal hematopoiesis induced by leukemia. SA-β-gal activity was significantly induced in osteoblasts derived from leukemia mice in comparison to normal mice further supporting our observation in human leukemia samples that AML induces senescence of BM-MSCs. To examine the effect of p53 on the senescence associated secretory profile (SASP) of BM-MSCs, we measured fifteen SASP cytokines by qPCR and found significant decrease in Ccl4, Cxcl12, S100a8, Il6 and Il1b upon p53 deletion in BM-MSCs (Osx-Cre;mTmG;p53fl/fl) compared to p53 wildtype mice. To functionally evaluate the effects of p53 in BM-MSCs on AML, we deleted p53 in BM-MSCs (Osx-Cre;mTmG;p53fl/fl) and transplanted them with syngeneic AML-ETO-Turquoise AML cells. Deletion of p53 in BM-MSCs strongly inhibited the expansion of BM-MSCs in AML and resulted in osteoblast differentiation. This suggests that expansion of BM-MSCs in AML is dependent on p53 and that deletion of p53 results in osteoblast differentiation of BM-MSCs. Importantly, deletion of p53 in BM-MSCs significantly increased the survival of AML mice. We further evaluated the effect of a Mdm2 inhibitor, DS-5272, on BM-MSCs in our traceable mouse models. DS-5272 treatment of Osx-cre;Mdm2fl/+ mice resulted in complete loss of normal hematopoietic cells indicating a non-cell autonomous regulation of apoptosis of hematopoietic cells mediated by p53 in BM-MSCs. Loss of p53 in BM-MSCs (Osx-Cre;p53fl/fl) completely rescued hematopoietic failure following Mdm2 inhibitor treatment. In conclusion, we identified p53 activation as a novel mechanism by which BM-MSCs regulate proliferation and apoptosis of hematopoietic cells. This knowledge highlights a new mechanism of hematopoietic failure after AML therapy and informs new therapeutic strategies to eliminate AML. Disclosures Khoury: Angle: Research Funding; Stemline Therapeutics: Research Funding; Kiromic: Research Funding. Bueso-Ramos:Incyte: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Amgen: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Mdm2 inhibitor-DS 5272

scholarly journals Beta-Blockers Improved Survival Outcomes in Patients with Multiple Myeloma: A Retrospective Evaluation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3306-3306
Author(s):  
Yi L. Hwa ◽  
Qian Shi ◽  
Shaji Kumar ◽  
Martha Q. Lacy ◽  
Morie A. Gertz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Beta Blockers ◽  
Multivariable Analysis ◽  
Advisory Committees ◽  
Risk Of Death ◽  
Cardiac Medication

Abstract Introduction: A recent study revealed an antiproliferative and apoptotic effect of propranolol on multiple myeloma (MM) cells. Our previous small matched case-control study showed longer survival in patients with propranolol and other beta-blockers (BB) intake than those without. This larger scale study was conducted to confirm the positive association of BB and MM survival. Methods: We identified 1971 newly diagnosed pts seen at Mayo Clinic between 1995 and 2010. Cardiac medication usage after diagnosis of MM was extracted from patient records and categorized based on BB intake. Cause of death was collected with death due to MM as the primary interest event and death due to cardiac disease or other reasons as competing risk events. The primary outcomes were MM disease-specific survival (DSS) and overall survival (OS). Cumulative incidence functions and Kaplan-Meier method were used to estimate the 5-year cumulative incidence rate (CIR) of MM death and OS rate, respectively. DSS and OS were compared by Gray's test and log-rank test, respectively. Multivarable Cox proportional hazard models were used to estimate the adjusted cause-specific HR (HRCSadj.) and hazard ratio (HRadj.) for DSS and OS, respectively, adjusting for demographics, disease characteristics, diagnosis year, and various chemotherapies. Results: 930 (47.2%) of MM patients had no intake of any cardiac medications; 260 (13.2%) had BB only; 343 (17.4%) used both BB / non-BB cardiac medications; and 438 patients (22.2%) had non-BB cardiac drugs. Five-year CIR of MM death and OS rate were shown in table. Superior MM DSS was observed for BB only users, compared to patients without any cardiac drugs (HRCSadj., .53, 95% confidence interval [CI], .42-.67, padj.<.0001) and non-BB cardiac drugs users (HRCSadj., .49, 95% CI, .38-.63, padj.<.0001). Patients received both BB and other cardiac drugs also showed superior MM DSS than non-cardiac drugs users (HRCSadj.., .54, 95% CI, .44-.67, padj.<.0001) and non-BB cardiac drug users. (HRCSadj., .50, 95% CI, .40-.62, padj.<.0001). MM DSS does not differ between BB users with and without other cardiac drugs (padj.=0.90). Multivariable analysis showed the same pattern for OS. None of the MM therapies impacted the differences in DSS and OS among BB intake groups (interaction padj.>.60). Conclusion: MM patients with BB intake showed reduced risk of death due to MM and overall mortality compared to patients who used non-BB cardiac or never used cardiac drugs. The result warrants further investigation for anti-cancer effect of BB in MM. Disclosures Shi: Mayo Clinic: Employment. Kumar:Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; BMS: Consultancy; Kesios: Consultancy. Gertz:NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Alnylam Pharmaceuticals: Research Funding; Novartis: Research Funding; Prothena Therapeutics: Research Funding; Ionis: Research Funding; Annexon Biosciences: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:pfizer: Research Funding; Celgene: Research Funding; Alnylam: Research Funding; Jannsen: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Transplantation for Congenital Sideroblastic Anaemia Is Feasible and Offers Outcomes Comparable to Other Transfusion Dependent Anaemias. a Joint Retrospective Study of the Paediatric Diseases and Severe Aplastic Anaemia Working Parties (PDWP/SAAWP) of EBMT

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-47
Author(s):  
Josu de la Fuente ◽  
Dirk-Jan Eikema ◽  
Paul Bosman ◽  
Robert F Wynn ◽  
Miguel Díaz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Graft Failure ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Response To Treatment ◽  
Variable Response ◽  
Advisory Committees ◽  
Grade Ii

Congenital sideroblastic anaemias (CSA) are a rare group of disorders characterized by the presence of pathologic iron deposits within the mitochondria of erythroid precursors (ring sideroblasts) in the bone marrow due to heterogenous germline mutations leading to defects in mitochondrial heme synthesis, iron-sulfur (Fe-S) cluster biogenesis, or protein synthesis. Patients present with anaemia and relative reticulocytopenia, and systemic iron overload secondary to chronic ineffective erythropoiesis, leading to end-organ damage. The disease is heterogenous underlying the genetic variability and the variable response to treatment. Although a number of CSA patients have received a bone marrow transplant, the outcomes and toxicities are not known. This status makes it very difficult to understand the role of BMT in the management of CSA. A search in the EBMT database identified 28 patients receiving a HSCT for CSA between 1998 to 2018 by 24 participating centres. The median year of transplantation was 2014 (IQR 2004-2016). The distribution was equal between males (n=14) and females (n=14). The median age at transplantation was 7 years of age (3-10 years). Fifteen patients had a sibling HSCT (88%), one a family matched donor HSCT (6%) and one an unrelated matched (6%), the type of transplant being unknown in others (n=11). The source of stem cells was bone marrow in 20 cases (74%), peripheral blood in 4 cases (15%), cord blood in 2 (7%) and combined bone marrow and cord in one (4%). Five cases had a Bu/Cy based conditioning regimen, 4 had Bu/fludarabine based regimen and three fludarabine/treosulfan based conditioning with the rest having a variety of approaches. Eighty-six percent of cases had serotherapy with ATG or alemtuzumab. The median follow-up was 31.6 months (95% CI, 12.2-74.1%). The overall survival at 12 and 24 months was 88% (76-100) and 82% (66-99), respectively (figure 1). The median neutrophil engraftment was 18 (15-21) days and platelet engraftment &gt;20 x 109/L was 29 (20-51) days, with a graft failure incidence of 7% (0-17) at 12 months. Two patients suffered from VOD. There were four deaths, three of which were related to transplant complications. The event free survival (survival without graft failure, relapse and second transplant) at 12 and 24 months was 85% (72-99) (figure 2). Six patients developed acute GvHD grade II and one case grade III; giving a grade II/III incidence of 28% (10-46). There was one case of limited and one of chronic GvHD, giving an incidence of 11% (0-26%) at 12 months and 24 months. In conclusion, whilst HSCT for CSA is a rare occurrence, these data demonstrate that HSCT for this condition is feasible and the outcomes are in keeping with those obtained for transplantation for transfusion dependent anaemias during the same time-period. Disclosures Handgretinger: Amgen: Honoraria. Moraleda:Gilead: Consultancy, Other: Travel Expenses; Jazz Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Other: Travel Expenses; Sandoz: Consultancy, Other: Travel Expenses; Takeda: Consultancy, Other: Travel Expenses. Risitano:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Jazz: Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees; Samsung: Membership on an entity's Board of Directors or advisory committees; Amyndas: Consultancy; RA pharma: Research Funding; Biocryst: Membership on an entity's Board of Directors or advisory committees; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees; Pfizer: Speakers Bureau. Peffault De Latour:Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4496-4496 ◽  
Author(s):  
Luke Eastburg ◽  
David A. Russler-Germain ◽  
Ramzi Abboud ◽  
Peter Westervelt ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Mortality ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant ◽  
Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4396-4396
Author(s):  
Patrick Mellors ◽  
Moritz Binder ◽  
Rhett P. Ketterling ◽  
Patricia Griepp ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Risk Modeling ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

scholarly journals Phase II Trial of the Combination of Ixazomib, Lenalidomide, and Dexamethasone in High-Risk Smoldering Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 804-804 ◽  
Author(s):  
Mark Bustoros ◽  
Chia-jen Liu ◽  
Kaitlen Reyes ◽  
Kalvis Hornburg ◽  
Kathleen Guimond ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Disease Progression ◽  
Board Of Directors ◽  
Rna Sequencing ◽  
Research Funding ◽  
Response Rate ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Background. This study aimed to determine the progression-free survival and response rate using early therapeutic intervention in patients with high-risk smoldering multiple myeloma (SMM) using the combination of ixazomib, lenalidomide, and dexamethasone. Methods. Patients enrolled on study met eligibility for high-risk SMM based on the newly defined criteria proposed by Rajkumar et al., Blood 2014. The treatment plan was designed to be administered on an outpatient basis where patients receive 9 cycles of induction therapy of ixazomib (4mg) at days 1, 8, and 15, in combination with lenalidomide (25mg) at days 1-21 and Dexamethasone at days 1, 8, 15, and 22. This induction phase is followed by ixazomib (4mg) and lenalidomide (15mg) maintenance for another 15 cycles. A treatment cycle is defined as 28 consecutive days, and therapy is administered for a total of 24 cycles total. Bone marrow samples from all patients were obtained before starting therapy for baseline assessment, whole exome sequencing (WES), and RNA sequencing of plasma and bone marrow microenvironment cells. Moreover, blood samples were obtained at screening and before each cycle to isolate cell-free DNA (cfDNA) and circulating tumor cells (CTCs). Stem cell collection is planned for all eligible patients. Results. In total, 26 of the planned 56 patients were enrolled in this study from February 2017 to April 2018. The median age of the patients enrolled was 63 years (range, 41 to 73) with 12 males (46.2%). Interphase fluorescence in situ hybridization (iFISH) was successful in 18 patients. High-risk cytogenetics (defined as the presence of t(4;14), 17p deletion, and 1q gain) were found in 11 patients (61.1%). The median number of cycles completed was 8 cycles (3-15). The most common toxicities were fatigue (69.6%), followed by rash (56.5%), and neutropenia (56.5%). The most common grade 3 adverse events were hypophosphatemia (13%), leukopenia (13%), and neutropenia (8.7%). One patient had grade 4 neutropenia during treatment. Additionally, grade 4 hyperglycemia occurred in another patient. As of this abstract date, the overall response rate (partial response or better) in participants who had at least 3 cycles of treatment was 89% (23/26), with 5 Complete Responses (CR, 19.2%), 9 very good partial responses (VGPR, 34.6%), 9 partial responses (34.6%), and 3 Minimal Responses (MR, 11.5%). None of the patients have shown progression to overt MM to date. Correlative studies including WES of plasma cells and single-cell RNA sequencing of the bone microenvironment cells are ongoing to identify the genomic and transcriptomic predictors for the differential response to therapy as well as for disease evolution. Furthermore, we are analyzing the cfDNA and CTCs of the patients at different time points to investigate their use in monitoring minimal residual disease and disease progression. Conclusion. The combination of ixazomib, lenalidomide, and dexamethasone is an effective and well-tolerated intervention in high-risk smoldering myeloma. The high response rate, convenient schedule with minimal toxicity observed to date are promising in this patient population at high risk of progression to symptomatic disease. Further studies and longer follow up for disease progression are warranted. Disclosures Bustoros: Dava Oncology: Honoraria. Munshi:OncoPep: Other: Board of director. Anderson:C4 Therapeutics: Equity Ownership; Celgene: Consultancy; Bristol Myers Squibb: Consultancy; Takeda Millennium: Consultancy; Gilead: Membership on an entity's Board of Directors or advisory committees; Oncopep: Equity Ownership. Richardson:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ghobrial:Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; BMS: Consultancy.

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