Use of Blood Transfusions In Paroxysmal Nocturnal Hemoglobinuria Patients with and without Aplastic Anemia Enrolled In the Global PNH Registry

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2241-2241
Author(s):  
Hubert Schrezenmeier ◽  
Robert A Brodsky ◽  
Petra Muus ◽  
Monica Bessler ◽  
Jeffrey Szer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Employment Equity ◽  
Advisory Committees ◽  
Clone Size ◽  
History Of ◽  
Equity Ownership ◽  
To Receive

Abstract Abstract 2241 Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disease characterized by complement-mediated hemolysis which can lead to life-threatening complications including thrombosis, kidney disease, pulmonary hypertension, pain, anemia, and severe fatigue. PNH clones occur in a number of patients with concomitant aplastic anemia (AA) and other bone marrow disorders (BMD). Some patients with PNH and/or BMD may require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow hypoplasia. Aims: To characterize the use of RBC transfusions among PNH patients with and without underlying AA. Methods: Enrollment data from 117 clinical sites participating in the observational PNH Registry in 16 countries on 5 continents was analyzed. Patients are included in the Registry regardless of the proportion of cells with deficiency of glycosylphosphatidyl-inositol anchored proteins (GPI-AP), bone marrow pathology, symptoms, or treatments. Sites collect clinical history at enrollment and additional data every 6 months. Demographic data, use of transfusions and other treatments, lab results, and symptoms are summarized for PNH patients with and without AA. Results: As of June 30, 2010 there were 655 enrolled patients in the Registry (53% female, median age 43). At enrollment, 28% of patients had history of AA and 45% had no history of BMD. Patients with underlying AA had lower median GPI-AP deficient granulocytes than those without BMD (median = 53% vs. 86%, respectively, p<.01) and patients in both groups had similar evidence of hemolytic activity when stratified by clone size (median LDH fold above normal upper limit was 0.90 vs. 0.94, p=.39 for patients with and without AA and clone size <10%; median = 3.41 vs. 4.84, p=.08 for AA vs. no BMD and clone size ≥50%). Not all PNH patients required transfusions: 56% of all patients required transfusions in the year prior to enrollment. Although patients with and without AA were equally likely to be treated with blood transfusions in the year prior to study enrollment overall, some differences emerged when stratified by clone size. For patients with clone size <50%, AA patients were almost twice as likely to receive transfusion in the previous year as patients without BMD (39% vs. 20%, p=.08). However, regardless of underlying AA, the proportion of patients receiving transfusions, in the prior year increased as clone size increased (29%, 31%, and 69% for clone sizes <10%, 10–49%, and ≥50%, respectively, p<.01). When patients were stratified by percent reticulocytes at enrollment (below vs. above the median value of 4.16%), 45% vs. 75% received transfusion in the prior year (p<.01). Among patients receiving a transfusion in the year prior to enrollment, the mean number of RBC units transfused was 9.6 for patients with underlying AA and 7.9 for patients with no BMD (p=.10). However, approximately twice as many patients with AA received 20+ RBC units in that year compared to patients without BMD (20% vs. 11%, p=.09). Number of transfused units in that year was similar by clone size (mean 9.5 vs. 8.6 for clone size <50% vs. ≥50%, p=.57). Concomitant treatment with anticoagulants or immunosuppressants was similar among patients who had received a transfusion in the past year compared to patients with no transfusions (39% vs. 33%, p=.13 and 26% vs. 22%, p=.25 respectively). Patients with AA had more bruising and bleeding while patients without BMD had more hemoglobinuria, dysphagia, and abdominal pain. Transfused patients with AA had more fatigue than non-transfused patients with AA (68% vs. 48%, p=.02). Conclusions: A substantial proportion (56%) of patients with PNH, but not all, required at least one transfusion in the year prior to enrolling in the registry, independent of underlying AA. The proportion of patients who had at least one transfusion increased with clone size. Among patients who had at least one transfusion, there was a trend for patients with underlying AA to receive more RBC units than patients without BMD. PNH patients with AA have fewer GPI-AP deficient granulocytes but demonstrate elevated hemolysis similar to patients without history of BMD when patients with similar clone sizes were compared. This Global PNH Registry, which remains open to accrual ([email protected]), should help to redefine prospectively the long-term natural history of PNH, its treatments, and the outcomes of treatment. Disclosures: Schrezenmeier: Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Brodsky: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Muus: Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Bessler: Alexion Pharmaceutical Inc: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Taligen: Consultancy. Szer: Alexion Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees. Maciejewski: Celgene: Research Funding; Eisai: Research Funding; Alexion: Consultancy. Socié: Alexion: Honoraria, Membership on an entity's Board of Directors or advisory committees. Urbano-Ispizua: Alexion: Membership on an entity's Board of Directors or advisory committees. Kanakura: Alexion: Membership on an entity's Board of Directors or advisory committees. Hoechsmann: Alexion: Speakers Bureau. Rosse: Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees. Khursigara: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Karnell: Alexion Pharma International: Employment, Equity Ownership. Bedrosian: Alexion Pharmaceuticals, Inc.: Employment, Equity Ownership. Hillmen: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals EZH2 Mutations and Impact on Clinical Outcome Analyzed in 1604 Patients with Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1528-1528
Author(s):  
Sebastian Stasik ◽  
Jan Moritz Middeke ◽  
Michael Kramer ◽  
Christoph Rollig ◽  
Alwin Krämer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Mutational Status ◽  
Equity Ownership ◽  
Acute Myeloid

Abstract Purpose: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and key epigenetic regulator involved in transcriptional repression and embryonic development. Loss of EZH2 activity by inactivating mutations is associated with poor prognosis in myeloid malignancies such as MDS. More recently, EZH2 inactivation was shown to induce chemoresistance in acute myeloid leukemia (AML) (Göllner et al., 2017). Data on the frequency and prognostic role of EZH2-mutations in AML are rare and mostly confined to smaller cohorts. To investigate the prevalence and prognostic impact of this alteration in more detail, we analyzed a large cohort of AML patients (n = 1604) for EZH2 mutations. Patients and Methods: All patients analyzed had newly diagnosed AML, were registered in clinical protocols of the Study Alliance Leukemia (SAL) (AML96, AML2003 or AML60+, SORAML) and had available material at diagnosis. Screening for EZH2 mutations and associated alterations was done using Next-Generation Sequencing (NGS) (TruSight Myeloid Sequencing Panel, Illumina) on an Illumina MiSeq-system using bone marrow or peripheral blood. Detection was conducted with a defined cut-off of 5% variant allele frequency (VAF). All samples below the predefined threshold were classified as EZH2 wild type (wt). Patient clinical characteristics and co-mutations were analyzed according to the mutational status. Furthermore, multivariate analysis was used to identify the impact of EZH2 mutations on outcome. Results: EZH2-mutations were found in 63 of 1604 (4%) patients, with a median VAF of 44% (range 6-97%; median coverage 3077x). Mutations were detected within several exons (2-6; 8-12; 14-20) with highest frequencies in exons 17 and 18 (29%). The majority of detected mutations (71% missense and 29% nonsense/frameshift) were single nucleotide variants (SNVs) (87%), followed by small indel mutations. Descriptive statistics of clinical parameters and associated co-mutations revealed significant differences between EZH2-mut and -wt patients. At diagnosis, patients with EZH2 mutations were significantly older (median age 59 yrs) than EZH2-wt patients (median 56 yrs; p=0.044). In addition, significantly fewer EZH2-mut patients (71%) were diagnosed with de novo AML compared to EZH2-wt patients (84%; p=0.036). Accordingly, EZH2-mut patients had a higher rate of secondary acute myeloid leukemia (sAML) (21%), evolving from prior MDS or after prior chemotherapy (tAML) (8%; p=0.036). Also, bone marrow (and blood) blast counts differed between the two groups (EZH2-mut patients had significantly lower BM and PB blast counts; p=0.013). In contrast, no differences were observed for WBC counts, karyotype, ECOG performance status and ELN-2017 risk category compared to EZH2-wt patients. Based on cytogenetics according to the 2017 ELN criteria, 35% of EZH2-mut patients were categorized with favorable risk, 28% had intermediate and 37% adverse risk. No association was seen with -7/7q-. In the group of EZH2-mut AML patients, significantly higher rates of co-mutations were detected in RUNX1 (25%), ASXL1 (22%) and NRAS (25%) compared to EZH2-wt patients (with 10%; 8% and 15%, respectively). Vice versa, concomitant mutations in NPM1 were (non-significantly) more common in EZH2-wt patients (33%) vs EZH2-mut patients (21%). For other frequently mutated genes in AML there was no major difference between EZH2-mut and -wt patients, e.g. FLT3ITD (13%), FLT3TKD (10%) and CEBPA (24%), as well as genes encoding epigenetic modifiers, namely, DNMT3A (21%), IDH1/2 (11/14%), and TET2 (21%). The correlation of EZH2 mutational status with clinical outcomes showed no effect of EZH2 mutations on the rate of complete remission (CR), relapse free survival (RFS) and overall survival (OS) (with a median OS of 18.4 and 17.1 months for EZH2-mut and -wt patients, respectively) in the univariate analyses. Likewise, the multivariate analysis with clinical variable such as age, cytogenetics and WBC using Cox proportional hazard regression, revealed that EZH2 mutations were not an independent risk factor for OS or RFS. Conclusion EZH mutations are recurrent alterations in patients with AML. The association with certain clinical factors and typical mutations such as RUNX1 and ASXL1 points to the fact that these mutations are associated with secondary AML. Our data do not indicate that EZH2 mutations represent an independent prognostic factor. Disclosures Middeke: Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Rollig:Bayer: Research Funding; Janssen: Research Funding. Scholl:Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees. Hochhaus:Pfizer: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding. Brümmendorf:Janssen: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Merck: Consultancy; Pfizer: Consultancy, Research Funding. Burchert:AOP Orphan: Honoraria, Research Funding; Bayer: Research Funding; Pfizer: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Research Funding. Krause:Novartis: Research Funding. Hänel:Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Platzbecker:Celgene: Research Funding. Mayer:Eisai: Research Funding; Novartis: Research Funding; Roche: Research Funding; Johnson & Johnson: Research Funding; Affimed: Research Funding. Serve:Bayer: Research Funding. Ehninger:Cellex Gesellschaft fuer Zellgewinnung mbH: Employment, Equity Ownership; Bayer: Research Funding; GEMoaB Monoclonals GmbH: Employment, Equity Ownership. Thiede:AgenDix: Other: Ownership; Novartis: Honoraria, Research Funding.

Final Results from an International, Multi-Center, Single-Arm Study Evaluating the Safety and Efficacy of Romiplostim in Adults with Primary Immune Thrombocytopenia (ITP),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3279-3279 ◽  
Author(s):  
Ann Janssens ◽  
Michael D. Tarantino ◽  
Robert Bird ◽  
Maria Gabriella Mazzucconi ◽  
Ralph Vincent V. Boccia ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Platelet Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Platelet Production ◽  
Platelet Counts ◽  
Equity Ownership

Abstract Abstract 3279 Background: ITP is an autoimmune disorder characterized by increased platelet destruction and suboptimal platelet production. Romiplostim stimulates platelet production via the TPO-receptor, and is recommended for second- and third-line treatment of chronic ITP in adults. We report final data from a large prospective study of romiplostim in adults with ITP of varying duration and severity. Methods: Eligibility criteria were broad: patients ≥18 years of age, who had received prior ITP therapies (final protocol amendment: ≥1, previous amendments: ≥3), with low platelet counts (final amendment: ≤ 30 × 109/L, previous amendments: ≤ 10, ≤ 20 × 109/L) or experiencing uncontrolled bleeding. The only excluded comorbidities were: hematological malignancy, myeloproliferative neoplasms, MDS and bone marrow stem cell disorder. Romiplostim was initiated at 1 (final amendment) or 3 (previous amendments) μg/kg/week, with dose adjustments allowed to maintain platelet counts ≥50 × 109/L. Patients could continue on study until they had access to commercially available romiplostim. Rescue medications were allowed at any time; concurrent ITP therapies could be reduced when platelet counts were > 50 × 109/L. Primary endpoint was incidence of adverse events (AEs) and antibody formation. Secondary endpoint was platelet response, defined as either (1) doubling of baseline count and ≥ 50 × 109/L or (2) ≥20 × 109/L increase from baseline. Results: A total of 407 patients received romiplostim, 60% of whom were female. Median (Q1, Q3) time since ITP diagnosis was 4.25 (1.20, 11.40) years (maximum 57.1 years), with 51% of patients splenectomised and 39% receiving baseline concurrent ITP therapies. Seventy-one percent of patients completed the study, with requirement for alternative therapy and withdrawn consent the most common reasons for discontinuation (5% each). Median (Q1, Q3) on-study treatment duration was 44.29 (20.43, 65.86) weeks (maximum 201 weeks), with a total of 20,201 subject-weeks on study. Incidence and type of AEs were consistent with previous studies. The most common serious treatment-related AEs were cerebrovascular accident, headache, bone marrow reticulin fibrosis (with no evidence of positive trichrome staining for collagen and no evidence suggesting primary idiopathic myelofibrosis), nausea, deep vein thrombosis, hemorrhage and pulmonary embolism, with each reported in 2 of 407 (0.5%) patients. All other serious treatment-related AEs were each reported in one patient. Eighteen patients died; 3 deaths (hemolysis, intestinal ischaema, aplastic anemia) were considered treatment-related. No neutralizing antibodies to romiplostim or TPO were reported. Approximately 90% of patients achieved each of the platelet response definitions, regardless of splenectomy status. Overall, median (Q1, Q3) time to response was 2 (1, 4) weeks for response definition 1, and 1 (1, 3) week for response definition 2. Median (Q1, Q3) baseline platelet count was 14 (8, 21) × 109/L. After 1 week of treatment median (Q1, Q3) platelet count had increased to 42 (18, 101) × 109/L. From week 8 onwards, and excluding counts within 8 weeks of rescue medication use, median platelet counts were consistently above 100 × 109/L (range 101.0–269.5 × 109/L). Median (Q1, Q3) average weekly romiplostim dose was 3.62 (1.99, 6.08) μg/kg. Summary/conclusions: This is the largest prospective study in adult ITP reported to date. The data reported here are similar to those reported for previous romiplostim studies, with romiplostim able to safely induce a rapid platelet response in adult ITP patients with low platelet counts or bleeding symptoms. Romiplostim is an important, well-tolerated, treatment option for adult ITP patients, which significantly increases and maintains platelet counts. Adverse Event Subject Incidence Platelet Response Disclosures: Janssens: Amgen: Consultancy; Roche: Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Tarantino:Cangene corporation: Research Funding; Baxter: Research Funding; Talecris: Honoraria, Speakers Bureau; Up-to-date: Patents & Royalties; The Bleeding and Clotting Disorders Institute: Board Member. Bird:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Membership on an entity's Board of Directors or advisory committees. Boccia:Amgen: Equity Ownership, Honoraria, Speakers Bureau. Lopez-Fernandez:Amgen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kozak:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Steurer:Amgen: Honoraria. Dillingham:Amgen Limited: Employment, Equity Ownership. Lizambri:Amgen: Employment, Equity Ownership.

scholarly journals Baseline and on-Treatment Bone Marrow Microenvironments Predict Myeloma Patient Outcomes and Inform Potential Intervention Strategies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1882-1882 ◽  
Author(s):  
Samuel A Danziger ◽  
Mark McConnell ◽  
Jake Gockley ◽  
Mary Young ◽  
Adam Rosenthal ◽  
...  
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Expression Profiles ◽  
Cell Types ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership

Abstract Introduction The multiple myeloma (MM) tumor microenvironment (TME) strongly influences patient outcomes as evidenced by the success of immunomodulatory therapies. To develop precision immunotherapeutic approaches, it is essential to identify and enumerate TME cell types and understand their dynamics. Methods We estimated the population of immune and other non-tumor cell types during the course of MM treatment at a single institution using gene expression of paired CD138-selected bone marrow aspirates and whole bone marrow (WBM) core biopsies from 867 samples of 436 newly diagnosed MM patients collected at 5 time points: pre-treatment (N=354), post-induction (N=245), post-transplant (N=83), post-consolidation (N=51), and post-maintenance (N=134). Expression profiles from the aspirates were used to infer the transcriptome contribution of immune and stromal cells in the WBM array data. Unsupervised clustering of these non-tumor gene expression profiles across all time points was performed using the R package ConsensusClusterPlus with Bayesian Information Criterion (BIC) to select the number of clusters. Individual cell types in these TMEs were estimated using the DCQ algorithm and a gene expression signature matrix based on the published LM22 leukocyte matrix (Newman et al., 2015) augmented with 5 bone marrow- and myeloma-specific cell types. Results Our deconvolution approach accurately estimated percent tumor cells in the paired samples compared to estimates from microscopy and flow cytometry (PCC = 0.63, RMSE = 9.99%). TME clusters built on gene expression data from all 867 samples resulted in 5 unsupervised clusters covering 91% of samples. While the fraction of patients in each cluster changed during treatment, no new TME clusters emerged as treatment progressed. These clusters were associated with progression free survival (PFS) (p-Val = 0.020) and overall survival (OS) (p-Val = 0.067) when measured in pre-transplant samples. The most striking outcomes were represented by Cluster 5 (N = 106) characterized by a low innate to adaptive cell ratio and shortened patient survival (Figure 1, 2). This cluster had worse outcomes than others (estimated mean PFS = 58 months compared to 71+ months for other clusters, p-Val = 0.002; estimate mean OS = 105 months compared with 113+ months for other clusters, p-Val = 0.040). Compared to other immune clusters, the adaptive-skewed TME of Cluster 5 is characterized by low granulocyte populations and high antigen-presenting, CD8 T, and B cell populations. As might be expected, this cluster was also significantly enriched for ISS3 and GEP70 high risk patients, as well as Del1p, Del1q, t12;14, and t14:16. Importantly, this TME persisted even when the induction therapy significantly reduced the tumor load (Table 1). At post-induction, outcomes for the 69 / 245 patients in Cluster 5 remain significantly worse (estimate mean PFS = 56 months compared to 71+ months for other clusters, p-Val = 0.004; estimate mean OS = 100 months compared to 121+ months for other clusters, p-Val = 0.002). The analysis of on-treatment samples showed that the number of patients in Cluster 5 decreases from 30% before treatment to 12% after transplant, and of the 63 patients for whom we have both pre-treatment and post-transplant samples, 18/20 of the Cluster 5 patients moved into other immune clusters; 13 into Cluster 4. The non-5 clusters (with better PFS and OS overall) had higher amounts of granulocytes and lower amounts of CD8 T cells. Some clusters (1 and 4) had increased natural killer (NK) cells and decreased dendritic cells, while other clusters (2 and 3) had increased adipocytes and increases in M2 macrophages (Cluster 2) or NK cells (Cluster 3). Taken together, the gain of granulocytes and adipocytes was associated with improved outcome, while increases in the adaptive immune compartment was associated with poorer outcome. Conclusions We identified distinct clusters of patient TMEs from bulk transcriptome profiles by computationally estimating the CD138- fraction of TMEs. Our findings identified differential immune and stromal compositions in patient clusters with opposing clinical outcomes and tracked membership in those clusters during treatment. Adding this layer of TME to the analysis of myeloma patient baseline and on-treatment samples enables us to formulate biological hypotheses and may eventually guide therapeutic interventions to improve outcomes for patients. Disclosures Danziger: Celgene Corporation: Employment, Equity Ownership. McConnell:Celgene Corporation: Employment. Gockley:Celgene Corporation: Employment. Young:Celgene Corporation: Employment, Equity Ownership. Schmitz:Celgene Corporation: Employment, Equity Ownership. Reiss:Celgene Corporation: Employment, Equity Ownership. Davies:MMRF: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; TRM Oncology: Honoraria; Abbvie: Consultancy; ASH: Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria. Copeland:Celgene Corporation: Employment, Equity Ownership. Fox:Celgene Corporation: Employment, Equity Ownership. Fitch:Celgene Corporation: Employment, Equity Ownership. Newhall:Celgene Corporation: Employment, Equity Ownership. Barlogie:Celgene: Consultancy, Research Funding; Dana Farber Cancer Institute: Other: travel stipend; Multiple Myeloma Research Foundation: Other: travel stipend; International Workshop on Waldenström's Macroglobulinemia: Other: travel stipend; Millenium: Consultancy, Research Funding; European School of Haematology- International Conference on Multiple Myeloma: Other: travel stipend; ComtecMed- World Congress on Controversies in Hematology: Other: travel stipend; Myeloma Health, LLC: Patents & Royalties: : Co-inventor of patents and patent applications related to use of GEP in cancer medicine licensed to Myeloma Health, LLC. Trotter:Celgene Research SL (Spain), part of Celgene Corporation: Employment, Equity Ownership. Hershberg:Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Dervan:Celgene Corporation: Employment, Equity Ownership. Ratushny:Celgene Corporation: Employment, Equity Ownership. Morgan:Takeda: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Research Funding.

scholarly journals Interim Results from Fight-203, a Phase 2, Open-Label, Multicenter Study Evaluating the Efficacy and Safety of Pemigatinib (INCB054828) in Patients with Myeloid/Lymphoid Neoplasms with Rearrangement of Fibroblast Growth Factor Receptor 1 (FGFR1)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 690-690 ◽  
Author(s):  
Srdan Verstovsek ◽  
Alessandro M. Vannucchi ◽  
Alessandro Rambaldi ◽  
Jason R. Gotlib ◽  
Adam J. Mead ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Phosphate Binders ◽  
Phase 2 ◽  
Open Label ◽  
Employment Equity ◽  
Advisory Committees ◽  
Lymphoid Neoplasms ◽  
Equity Ownership

Abstract Introduction: Myeloid/lymphoid neoplasms (MLNs) with rearrangement of FGFR1 on chromosome band 8p11 are rare but aggressive neoplasms characterized by heterogeneous presentation with myeloid and/or lymphoid proliferation, extramedullary involvement, and rapid progression to blast phase (Strati P, et al., Leuk Lymphoma. 2018;59:1672-1676). FGFR1 gets constitutively activated through fusion genes involving various partner genes, most frequently ZMYM2-FGFR1 or BCR-FGFR1 as consequence of a t(8;13)(p11;q12) or a t(8;22)(p11;q11), respectively. Chemotherapy is usually ineffective, effective targeted treatment has not been described, and allogeneic hematopoietic stem cell transplant (alloHSCT) is the only potentially curative option. Pemigatinib, a selective, potent, oral inhibitor of FGFR1, 2, and 3, has shown efficacy in patients with FGF/FGFR-activated tumors, including cholangiocarcinoma and urothelial carcinoma. We report interim results from the ongoing fight-203 study (NCT03011372) of pemigatinib in patients with FGFR1-rearranged MLNs. Methods: Fight-203 is a phase 2, open-label study enrolling patients ≥ 18 years of age with FGFR1-rearranged MLN. Patients enrolled in the study must have progressed on ≥ 1 prior treatment and be ineligible for alloHSCT. Patients receive a daily oral dose of pemigatinib 13.5 mg on a 21-day cycle (2 weeks on, 1 week off) until disease progression or unacceptable toxicity. The primary endpoint is overall clinical benefit rate, which includes complete clinical (CR) or partial clinical response (PR), and either complete or partial cytogenetic response (CCyR, PCyR). Secondary endpoints include duration of response/benefit, progression-free survival, overall survival, and safety/tolerability. Efficacy is assessed by evaluation of bone marrow histomorphology changes, standard cytogenetic and FISH evaluation of the FGFR1 rearrangement, and PET/CT scan. Results: At data cutoff (July 23, 2018), 14 patients were enrolled. Ten patients who had ≥ 1 response assessment were included in the analysis (Table). Patients received an average of 6.9 cycles of pemigatinib (range, 2-12 cycles). Median number of prior lines of therapy was 3 (range, 0-5), including 2 patients who received alloHSCT. Eight patients (80%) had a major CyR, including 6 patients with CCyR and 2 with PCyR. Eight patients (80%) had a CR or PR in bone marrow, peripheral blood, and extramedullary disease. One patient died of progression to myeloid blast crisis, 2 patients were bridged to alloHSCT, and 7 patients are ongoing. The most common treatment-emergent adverse events (AEs) were hyperphosphatemia (n=7 [70%]), diarrhea (n=5 [50%]) and anemia (n=5 [50%]); hyperphosphatemia was managed with diet and phosphate binders. Nine events in 4 patients (40%) were grade 3/4; 2 of these events (diarrhea and leukopenia) in 2 patients were related to pemigatinib. There were no drug-related AEs leading to dose interruption, dose reduction, or discontinuation. Conclusions: Pemigatinib showed promising efficacy, with an 80% major CyR rate accompanied by complete or partial remission, and was generally well tolerated by patients with FGFR1-rearranged MLN. The protocol was amended to allow continuous dosing, and the study is currently enrolling. Disclosures Verstovsek: Celgene: Membership on an entity's Board of Directors or advisory committees; Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gotlib:Blueprint Medicines: Consultancy, Honoraria, Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Promedior: Research Funding; Kartos: Consultancy; Incyte: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Mead:Celgene: Research Funding; Bristol-Myers Squibb: Consultancy; Evotek: Research Funding; ARIAD: Consultancy; Cell Therapeutics: Consultancy; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elstar: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Incyte: Research Funding; Takeda: Research Funding; Pfizer: Research Funding. Kiladjian:AOP Orphan: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: 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. Hernandez Boluda:Incyte: Consultancy; Novartis: Consultancy. Asatiani:Incyte: Employment, Equity Ownership. Lihou:Incyte: Employment, Equity Ownership. Zhen:Incyte: Employment, Equity Ownership. Reiter:Incyte: Consultancy, Honoraria.

scholarly journals An Open-Label Phase I/IIa Study to Evaluate the Safety and Efficacy of CCS1477, a First in Clinic Inhibitor of the p300/CPB Bromodomains, As Monotherapy in Patients with Advanced Haematological Malignancies

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1266-1266 ◽  
Author(s):  
Tomasz Knurowski ◽  
Karen Clegg ◽  
Nigel Brooks ◽  
Fay Ashby ◽  
Neil A Pegg ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Proliferation ◽  
Board Of Directors ◽  
Research Funding ◽  
Haematological Malignancies ◽  
Loss Of Function ◽  
Employment Equity ◽  
Advisory Committees ◽  
Measurable Disease ◽  
Equity Ownership

Background CCS1477 is a first in class potent, selective and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in haematological malignancies. In pre-clinical studies, CCS1477 was found to be a potent inhibitor of cell proliferation in acute myeloid leukaemia (AML) multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines. In primary patient AML blast cells CCS1477 inhibited proliferation through a combination of cell cycle arrest at the G1/S transition and an induction of differentiation (up-regulation of CD11b and CD86). CCS1477 has significant anti-tumour activity, inducing tumour regressions in xenograft models of AML and MM. These effects were accompanied by significant reductions in tumour MYC and IRF4 expression. Additionally, there are molecular features of certain haematological malignancies that are likely to increase the sensitivity to p300/CBP inhibition with CCS1477. For example, in B-cell lymphomas there are frequent loss of function mutations in CBP that are associated with heightened sensitivity to pre-clinical inhibition of corresponding non-mutated p300. CCS1477 represents a novel and differentiated approach to inhibiting cell proliferation and survival and offers a potential new therapeutic option for patients who have relapsed or are refractory to current standard of care therapies in AML, MM or NHL. Study Design and Methods This study is the first time that CCS1477 is being dosed in patients with haematological malignancies. The Phase I/IIa study aims to determine the maximum tolerated dose (MTD) and/or recommended Phase II dose (RP2D) and schedule(s) of CCS1477 and investigate clinical activity of CCS1477 monotherapy in patients with haematological malignancies. This study will also characterise the pharmacokinetics (PK) of CCS1477 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers. The trial aims to enrol approximately 90 patients and is currently recruiting in the UK with plans to open additional sites in the USA. Key inclusion criteria include patients with confirmed (per standard disease specific diagnostic criteria), relapsed or refractory haematological malignancies (AML, MM and NHL). Patients must have received standard therapy which for the majority of therapeutic indications is at least 2 prior lines of therapy. Single dose and steady state pharmacokinetics will be determined in all patients. AML response will be measured in bone marrow samples. Myeloma response will be evaluated according to the 'International Myeloma Working Group Response Criteria' based on changes in M protein in blood and/or urine, changes in serum free light chains if measurable, and changes on imaging and/or bone marrow if applicable and according to the guidelines. In NHL patients, tumour assessments will be done for measurable disease, non-measurable disease, and new lesions on CT (or magnetic resonance imaging [MRI]) and/or combined with visual assessment of [18F]2-fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) for response assessment per recent International Working Group consensus criteria (RECIL 2017), until progression The study will begin with two parallel monotherapy dose-escalation arms; Arm 1: Relapsed or refractory NHL and MM; Arm2: Relapsed or refractory AML/high-risk MDS. Once a recommended phase 2 dose/schedule is reached, three monotherapy expansion arms will be opened in AML/high-risk MDS (15 patients), MM (15 patients) and NHL (30 patients). Blood samples along with bone marrow biopsies and aspirates will be collected for exploratory biomarker analysis to understand mechanisms of response to treatment or disease progression. This will include the analysis of tumour-specific and circulating biomarkers, such as tumour DNA, mRNA, proteins or metabolites. In NHL patients, analysis of CBP (and p300) mutations will be undertaken to allow retrospective correlation with tumour response and to determine if loss of function mutations in the genes for either proteins can be utilised as response predictive biomarkers in future studies. Disclosures Clegg: CellCentric Ltd: Employment, Equity Ownership. Brooks:CellCentric Ltd: Employment, Equity Ownership. Ashby:CellCentric Ltd: Employment, Equity Ownership. Pegg:CellCentric Ltd: Employment, Equity Ownership. West:CellCentric Ltd: Employment, Equity Ownership. Somervaille:Novartis: Consultancy. Knapper:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Tolero: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees. Davies:ADCT Therapeutics: Honoraria, Research Funding; MorphoSys AG: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioInvent: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Honoraria, Research Funding; GSK: Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Nascent Transcript and Single Cell Rnaseq Analysis Defines the Mechanism of Action of the LSD1 Inhibitor INCB059872 in Myeloid Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2509-2509
Author(s):  
Gretchen Johnston ◽  
Haley E. Ramsey ◽  
Kristy Stengel ◽  
Shilpa Sampathi ◽  
Pankaj Acharya ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Treatment ◽  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Myeloid Differentiation ◽  
Employment Equity ◽  
Advisory Committees ◽  
Equity Ownership ◽  
Upregulated Genes

Drugs targeting chromatin-modifying enzymes have entered clinical trials for myeloid malignancies, including INCB059872, a selective irreversible inhibitor of Lysine-Specific Demethylase 1 (LSD1). LSD1 is a component of the CoREST complex, in which it associates with histone deacetylases 1 and 2, the transcriptional co-repressor, mSin3A or mSin3B, and the REST corepressor (RCOR1), so a role in gene expression was expected. While initial studies of LSD1 inhibitors have suggested these compounds may be used to induce differentiation of acute myeloid leukemia, the mechanisms underlying this effect and dose-limiting toxicities are not well understood. Here, we have used precision nuclear run-on sequencing (PROseq) and single-cell RNA-sequencing (scRNAseq) to show that INCB059872 de-represses GFI1/GFI1B-regulated genes to promote a myeloid differentiation gene signature in AML cells while stalling maturation of megakaryocyte progenitor cells. Within 3 days of treatment with INCB059872, the majority of THP-1, which contain an the MLL-translocation, undergo myeloid differentiation. RNAseq analysis indicated that 24h drug treatment upregulated genes involved in hematopoietic cell lineage, which is consistent with the differentiation. In addition, PROseq was used to measure the effects of INCB059872 on nascent transcription at genes and enhancers, as this is one of the best methods to define enhancer activity. In THP-1 cells after 24h treatment, there were 203 genes with at least a 1.5-fold increase in transcription, while there are nearly 1300 enhancers meeting this threshold. Upregulated genes include those associated with myeloid cell differentiation, such as CSF1R and CD86. Given that LSD1 catalyzes the removal of mono- and di-methyl marks from histone H3, we expected that INCB059872 would cause a buildup of histone methylation. Surprisingly, ChIPseq for H3K4me2 and H3K4me1 showed only subtle changes in these marks after 48h drug treatment in THP-1. Only a handful of LSD1i-induced enhancers overlapped with detectable changes in H3K4 methylation. However, our PROseq data is consistent with the increases in H3K27 acetylation seen with OG86 (a compound that disrupts the LSD1:GFI1 interaction) at GFI1 binding sites (PMID: 29590629). Indeed, motif analysis of INCB059872-upregulated enhancers identified the GFI1 recognition sequence as the most highly enriched. Moreover, siRNA inhibition of key components of LSD1-containing chromatin remodeling complexes pinpointed the CoREST complex as mediating the THP-1 myeloid differentiation effects of INCB059872. To investigate on-target thrombocytopenia seen with LSD1 inhibitors in preclinical studies, we analyzed the bone marrow of wild-type mice treated daily with INCB059872 for 0, 4, or 6 days before harvesting and sorting lin-bone marrow cells for scRNA-seq. Notably, one of the most highly upregulated genes in treated cells was Gfi1b. Unsupervised clustering identified 22 clusters, corresponding to unique subpopulations (Fig. 1A). While the distribution of cells into different progenitor populations was mostly unaffected by drug treatment, these data revealed a striking increase in the proportion of cells from treated mice assigned to a megakaryocyte stem/progenitor cluster. Cells within this expanded cluster expressed stem cell markers such as MYCN and PBX1, but also expressed VWF (Fig. 1B). Thus, LSD1 inhibition caused accumulation of megakaryopoiesis-biased stem cells that failed to mature into efficient platelet producers. Finally, we used scRNAseq to analyze bone marrow from an AML patient who responded to treatment with INCB059872 plus azacytidine (AZA). A pre-treatment bone marrow sample was divided into separate cultures to study the effects of INCB059872, AZA, or the combination. Remarkably, unsupervised clustering of patient cells assigned the majority of INCB059872 and combination-treated cells to clusters that were not found in control- or AZA-treated samples. Cells exposed to INCB059872 had upregulated GFI1 and GFI1B, as well as differentiation-related genes that were also observed in AML cell lines. Overall, these data indicate that INCB059872 affects gene expression with kinetics consistent with a loss of CoREST activity to stimulate differentiation of AML blasts, but the inactivation of GFI1/GFI1B impairs megakaryocyte maturation likely explaining thrombocytopenia seen in preclinical models. Disclosures Stubbs: Incyte Corporation: Employment, Equity Ownership. Burn:Incyte: Employment, Equity Ownership. Hiebert:Incyte Corporation: Research Funding. Savona:Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Selvita: 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; Sunesis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer Ingelheim: Patents & Royalties; AbbVie: Membership on an entity's Board of Directors or advisory committees.

A Longitudinal Prospective Study Evaluating the Effects of Eltrombopag Treatment On Bone Marrow in Patients with Chronic Immune Thrombocytopenia: Interim Analysis At 1 Year.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2195-2195 ◽  
Author(s):  
Russell K. Brynes ◽  
Attilio Orazi ◽  
Raymond S.M. Wong ◽  
Kalpana Bakshi ◽  
Christine K Bailey ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Trabecular Bone ◽  
Board Of Directors ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Employment Equity ◽  
Advisory Committees ◽  
Study Results ◽  
Equity Ownership ◽  
Chronic Immune Thrombocytopenia

Abstract Abstract 2195 Introduction: Eltrombopag (epag), a thrombopoietin receptor agonist (TPO-RA), increases platelet counts in patients with chronic immune thrombocytopenia (cITP). TPO-RAs have been associated with varying degrees of increases in bone marrow reticulin (Brynes 2011; Ghanima 2011). Due to lack of pretreatment evaluations, the incidence and clinical significance of these findings have not been established. Inconsistencies in specimen preparation, staining, and analysis across institutions further confound conclusions. The purpose of this 2-year (y) study (NCT01098487) is to assess for bone marrow fibrosis (reticulin and/or collagen) in patients treated with epag for cITP. Baseline and 1y findings are presented. Methods: Bone marrow biopsies are being collected at baseline (before treatment with epag) and at 1 and 2y of treatment. Specimens are centrally processed and stained for reticulin (silver) and collagen (trichrome) and undergo central independent pathology review of cellularity; megakaryocyte, erythroid, and myeloid quantity and appearance; trabecular bone quality; reticulin grade; and presence of collagen (European Consensus scale-MF; Thiele 2005). Results: Baseline and 1y (10–14 months) data are available for 101 patients. Median age is 42y (18–78); 70 patients are female; 50% are Caucasian/European, 22% are East Asian, and 29% are Central South Asian. Median time since ITP diagnosis is 4.2y (0.2–45.7). All patients had received prior ITP therapy, and 8 patients had received prior TPO-RA treatment (epag [7], romiplostim [1]), the last dose ≥6 months before enrollment. At baseline, 91 patients had reticulin grade 0 (MF-0), 10 MF-1, and 0 MF≥2. At 1y, 59 patients had MF-0, 38 MF-1, 3 MF-2, and 1 MF-3 (Figure). Compared with baseline, there was no change at 1y in MF grade in 61 patients, a decrease by 1 grade in 3, an increase by 1 grade in 35, and an increase in 2 or 3 grades in 1 patient each (Table). Three patients had collagen at 1y (1 patient each with MF-1, MF-2, and MF-3). None of the 4 patients with MF≥2 had adverse events or hematologic abnormalities considered related to impaired bone marrow function, and none withdrew due to bone marrow findings. Among the 8 patients with prior TPO-RA treatment, all had baseline reticulin of MF-0 and none had collagen; at 1y, 6 remained MF-0, 1 was MF-1, and 1 MF-3 (collagen demonstrated). Cellularity was normal in 83% and 80% of patients at baseline and 1y, respectively. Other than normalization of erythroid lineage numbers, no changes occurred in marrow cellular composition. In 3 of 4 patients with MF≥2, cellularity was increased at 1y. Trabecular bone thinning was found at baseline in 28 patients (the majority with prior steroid use) and 51 patients at 1y. Discussion: 10% of patients had MF-1 at baseline. After 1y of treatment, no increase or a mild increase in reticulin was observed in 63% and 35% of patients. No patient with MF≥2 (n=4) had clinical signs or symptoms indicative of bone marrow dysfunction and none withdrew from the study. Results were similar to those reported for EXTEND, an eltrombopag extension study (median treatment duration >2 years; Brynes 2011). Conclusion: These data suggest that treatment with epag is generally not associated with clinically relevant increases in bone marrow reticulin or collagen. The potential association of TPO-RAs and increased bone marrow reticulin needs further study. Disclosures: Brynes: GlaxoSmithKline: Research Funding. Orazi:GlaxoSmithKline: Research Funding. Wong:Roche: Research Funding; MSD: Research Funding; Johnson & Johnson: Research Funding; Bayer: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Biogen-Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; GlaxoSmithKline: Research Funding; Bristol-Myers Squibb: Research Funding. Bakshi:GlaxoSmithKline: Employment, Equity Ownership. Bailey:GlaxoSmithKline: Employment, Equity Ownership. Brainsky:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties.

Characterization of the Mutational Landscape of Multiple Myeloma Using Comprehensive Genomic Profiling

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3418-3418 ◽  
Author(s):  
Christoph Heuck ◽  
Donald Johann ◽  
Brian A Walker ◽  
Caleb K Stein ◽  
Yogesh Jethava ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Mutant Allele ◽  
Genomic Profiling ◽  
Employment Equity ◽  
Advisory Committees ◽  
Comprehensive Genomic Profiling ◽  
Equity Ownership

Abstract Introduction: Multiple myeloma (MM) is a neoplastic disease of the bone marrow characterized by a malignant transformation of plasma cells. Many patients relapse after initial treatment and require additional therapies. Impaired cell cycle regulation and DNA repair mechanisms as well as exposure to genotoxic drugs leads to accumulation of genomic alterations with progressive disease. Pressure from antineoplastic agents, including novel agents, eventually leads to the selection of resistant clones. Assessing acquired somatic mutations in MM patients can identify key genomic drivers and guide the development of a rational, individualized therapy plan for each patient with advanced disease. Here we report on the mutational landscape of cancer-associated genes in 214 patients who underwent comprehensive genomic profiling. Methods: Review of this data was approved by the UAMS institutional review board. DNA and RNA were extracted from CD138+ selected cells from bone marrow aspirates. Adaptor ligated sequencing libraries from extracted nucleic acids were captured by solution hybridization using bait sets targeting 405 cancer-related and 265 frequently rearranged genes (FoundationOne Heme®; Foundation Medicine ). For samples with low cell yield only the DNA portion was performed. All samples were sequenced in a CLIA-certified, CAP-accredited laboratory to an average depth >500x. Results We identified 147 clinically relevant alterations with an average of 3 alterations per patient ranging from 1 to 8. The most frequently altered genes were KRAS (29% of cases), NRAS (23%), TP53 (19%), RB1 (10%), BRAF (8%), TRAF3(8%), CDKN2C (7%), DNMT3A (5%), NF1, FAF1 and TET2 (4% each). While RAS, RAF, RB1 and TP53 mutations are also found in previously untreated patients, albeit in lower frequencies, mutations of DNTM3A and TET2 are rarely reported in the early phase of the disease, arguing for the accumulation of genomic alterations over time. We found concomitant alterations in KRAS and BRAF in 5, KRAS and NRAS in 3, and NRAS and BRAF in 2 patients. The vast majority of RAS alterations occurred at hotspots resulting in activating alterations at codons 12, 13 or 61 with mutant allele frequencies ranging from 0.01 to 0.92 with an average of 0.30. In the 17 patients with BRAF alterations the hotspot mutation V600E was found in 7 with mutant allele frequencies ranging from 0.01 to 0.48 with an average of 0.32. Overall the MAPK pathway was affected in 128 of 214 patients. 61 patients had alterations of genes associated with DNA damage repair. Among the 10 patients with DNMT3A alterations 2 also had alterations of TET2 suggesting significant epigenetic deregulation in a subset of patients. Data on subclonal structure and correlation of mutation status with paired gene expression profiles will be presented as well, as will be selected responses of patients treated on the basis of these results. Conclusion Subjecting CD138 selected bone marrow cells to comprehensive genomic profiling allows for the identification of clinically relevant alterations, which deregulate critical pathways in multiple myeloma. Small molecule inhibitors that target key genes in these affected pathways (MEK, BRAF) have recently been approved for therapy in other cancers or are being actively developed (PI3K, AKT, PARP). This comprehensive genomic characterization allows rational development of individualized clinical strategies using molecular targets for MM patients who are refractory to standard of care therapies. Disclosures Walker: Onyx Pharmaceuticals: Consultancy, Honoraria. van Rhee:Senesco: PI Other. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. Ali:Foundation Medicine, Inc.: Employment, Equity Ownership. Stephens:Foundation Medicine: Employment, Equity Ownership. Miller:Foundation Medicine, Inc: Employment. Morgan:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Membership on an entity's Board of Directors or advisory committees; MMRF: Membership on an entity's Board of Directors or advisory committees. Barlogie:Celgene: Consultancy, Patents & Royalties, Research Funding; Millenium: Consultancy, Patents & Royalties, Research Funding.

Ruxolitinib Efficacy By Hematocrit Control in Patients with Polycythemia Vera: An Analysis of the RESPONSE Trial

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3201-3201
Author(s):  
Srdan Verstovsek ◽  
Jean-Jacques Kiladjian ◽  
Ruben Mesa ◽  
Mark M Jones ◽  
Shui He ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Employment Equity ◽  
Advisory Committees ◽  
Jak2 Inhibitor ◽  
Equity Ownership ◽  
To Receive ◽  
Response Trial

Abstract Background: Polycythemia vera (PV) is characterized by erythrocytosis and overactive JAK/STAT activity. The RESPONSE trial compared ruxolitinib (RUX), a JAK1/JAK2 inhibitor, with best available therapy (BAT) in patients (pts) with PV intolerant of or resistant to hydroxyurea according to modified European LeukemiaNet criteria. RUX was superior to BAT in achieving the primary endpoint (21% vs 1%; P<0.0001), and 60% of pts randomized to RUX achieved protocol-defined hematocrit (HCT) control through Wk 32 vs 20% of pts randomized to BAT (J Clin Oncol32:5s, 2014; suppl, abstract 7026). However, the actual phlebotomy rate between Wks 8−32 was only 20% in pts randomized to RUX compared with 62% in pts randomized to BAT, and 85% of pts in the RUX arm continued to receive treatment at the median 81-wk follow-up, suggesting most pts derived some benefit from RUX. Therefore, an analysis was conducted to evaluate the clinical efficacy of RUX in pts who did and did not achieve protocol-defined HCT control. Methods: Phlebotomy-dependent PV pts with splenomegaly, aged ≥18 years, and resistant to or intolerant of HU were enrolled. Pts were required to have HCT between 40%−45% 14 days prior to randomization; those who did not could enter a phlebotomy control period to achieve a HCT in this range within 14 days of randomization. Eligible pts were randomized 1:1 to RUX or BAT. BAT pts could cross over to receive RUX from Wk 32 if they had not met the primary endpoint, or after Wk 32 due to protocol-defined disease progression. The primary composite endpoint comprised HCT control and a ≥35% reduction from baseline in spleen volume (SV) at Wk 32. HCT control was defined as lack of phlebotomy eligibility between Wks 8−32 with no more than 1 phlebotomy eligibility between randomization and Wk 8. Phlebotomy eligibility was based on protocol-defined HCT values (regardless of receipt of phlebotomy), and pts with missing data or assessments outside of protocol-defined time windows were considered non-responders. In pts who were HCT control non-responders (HCT-N) as defined by protocol, time to second phlebotomy eligibility was evaluated. For this analysis, pts without phlebotomy eligibility were excluded and phlebotomies in the first 8 wks were not considered. Patient-reported outcomes were evaluated in both HCT control responders (HCT-R) and HCT-N, including the 14-item modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) and the Patient Global Impression of Change (PGIC). Results: Of 222 randomized pts (RUX, n=110; BAT, n=112), most were male (RUX, 60%; BAT, 71%) and the median age (range) was similar between treatment arms (RUX, 62.0 [34.0–90.0]; BAT, 60.0 [33.0–84.0]). Although pts had a HCT between 40% and 45% within 14 days prior to randomization (with or without phlebotomy), 24% of pts had a HCT >45% on Day 1 (similar between treatment arms) illustrating that many pts have poor HCT control over short intervals of observation. RUX treatment resulted in long-term benefits on HCT levels, even in pts who did not achieve protocol-defined HCT control through Wk 32. Among the RUX HCT-R group, the probability of maintaining HCT response was 97% at 48 wks and 87% at 80 wks. Most BAT pts crossed over to receive RUX immediately after the Wk 32 visit (84% between Wks 32 and 48). In the RUX HCT-N pts, the median time to subsequent phlebotomy eligibility was 52 wks, compared with 21 wks for BAT HCT-N pts (Figure). Compared with the entire BAT group, more RUX-R and RUX-N pts had a ≥50% improvement in the MPN-SAF total symptom score at Wk 32 (RUX-N, 38%; RUX-R, 40%; BAT, 4%). Median changes from baseline at Wk 32 in key symptoms such as tiredness (RUX-N; −50%; RUX-R, −49%; BAT, −4%), itching (RUX-N, −88%; RUX-R, −97%; BAT, −2%), and night sweats (RUX-N, −100%; RUX-R, −97%; BAT, 4%) were also greater among RUX-R and RUX-N pts than BAT pts. RUX-N and RUX-R pts were also more likely to consider their symptoms to be “much improved” or “very much improved” on the PGIC compared with BAT pts (RUX-N, 57%; RUX-R, 74%; BAT, 13%). Conclusion: Among pts receiving RUX who did not achieve protocol-defined HCT control, the median time to subsequent phlebotomy eligibility was 1 year. In contrast, pts on BAT had a median time to subsequent phlebotomy eligibility of 21 wks. Furthermore, pts in the RUX arm achieved meaningful improvements in PV-related symptoms, regardless of meeting the endpoint of HCT control, while pts treated with BAT showed worsening or no improvement. Figure 1 Figure 1. Disclosures Verstovsek: Incyte Corporation: Research Funding. Off Label Use: Ruxolitinib is a JAK1/JAK2 inhibitor approved for the treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post polycythemia vera myelofibrosis, and post-essential thrombocythemia myelofibrosis. Kiladjian:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Mesa:Incyte Corporation: Research Funding; CTI: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Eli Lilly: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Sanofi: Research Funding; Celgene: Research Funding. Jones:Incyte Corporation: Employment, Equity Ownership. He:Incyte Corporation: Employment, Equity Ownership. Li:Novartis Pharmaceuticals: Employment, Equity Ownership. Habr:Novartis Pharmaceuticals: Employment, Equity Ownership. Vannucchi:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Transfusion Requirements in Adult Patients with Paroxysmal Nocturnal Hemoglobinuria with or without a History of Bone Marrow Disorder Receiving Ravulizumab and Eculizumab: Results from a Phase 3 Non-Inferiority Study Extension

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 31-33
Author(s):  
Antonio Risitano ◽  
Jun-Ho Jang ◽  
Lee Gyeong-Won ◽  
Wanchai Wanachiwanawin ◽  
Hubert Schrezenmeier ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Sample Size ◽  
Board Of Directors ◽  
Research Funding ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Complement Inhibitor ◽  
Phase 3 ◽  
Advisory Committees ◽  
Treatment Groups ◽  
History Of

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and life-threatening hematologic disorder leading to hemolytic anemia, which can occur concomitantly with bone marrow disorders (BMD), such as aplastic anemia (AA) and myelodysplastic syndrome (MDS). Accordingly, patients with PNH often require red blood cell (RBC) transfusions to treat anemia due to hemolysis or bone marrow failure. After demonstrating a non-inferior efficacy and safety profile in two of the largest clinical trials to date, ravulizumab was approved as a treatment for adults with PNH, including patients with an underlying history of bone marrow disease, who are transfusion dependent or independent. Aims: To assess the efficacy of ravulizumab in patients with PNH with or without an underlying pathology of AA or MDS, and to investigate the impact of ravulizumab on transfusion burden as measured by number of transfusions and total packed RBC (pRBC) units transfused over a 52-week period. Methods: This phase 3 multicenter, randomized, active-controlled, open-label study (study 301, NCT02946463) enrolled complement-inhibitor-naïve patients with PNH. Patients were aged ≥ 18 years with a confirmed diagnosis of PNH by flow cytometry and lactate dehydrogenase (LDH) level ≥ 1.5x the upper limit of normal (ULN; 246 U/L). Patients received either ravulizumab or eculizumab for 26 weeks; after which all patients received ravulizumab from week 26 to week 52. Efficacy outcomes included the proportion of patients achieving transfusion avoidance (TA), number of pRBC units transfused and the number of pRBC or whole blood transfusions (WBT) received from baseline to 26 and 52 weeks of treatment. In this retrospective analysis, outcomes were analysed for the following subgroups: AA, MDS or no BMD (medical history of AA or MDS was determined by the investigator at screening). Descriptive statistics were calculated for continuous (means) and categorical variables (numbers and percentages). Formal hypothesis testing for significance between treatment groups was not performed. Results: Of the 246 patients included in the study, 79 had a history of AA (32.1%) and 13 (5.3%) had a history of MDS. Baseline characteristics were comparable between treatment groups. From baseline to week 26, a comparable proportion of patients with AA achieved TA to those with no BMD; 75.6% for patients with AA and no BMD receiving ravulizumab, and 60.5% and 73.7% for patients with AA and no BMD receiving eculizumab, respectively (Table 1). Importantly, TA was maintained through 52 weeks, with similar proportions of patients with AA (87.1‒91.3%) maintaining TA to patients without BMD (85.7‒91.5%). More specifically, 65.9% of patients with AA and 69.2% of patients without BMD achieved TA through 52 weeks of ravulizumab treatment, and 55.3% and 63.2% of patients with AA and without BMD, respectively, achieved TA on eculizumab followed by ravulizumab. The proportion of patients with MDS who achieved TA appeared numerically lower compared with patients with AA or no BMD, however, this subgroup sample size was small. Furthermore, a lower proportion of patients on ravulizumab with AA or MDS received any transfusion from baseline to weeks 26 and 52 compared with those treated with eculizumab followed by ravulizumab: for week 26, 24.4% and 57.1% for ravulizumab versus 39.5% and 100.0% for eculizumab in patients with AA and MDS, respectively, and for week 52, 29.3% and 57.1% for patients with AA and MDS receiving ravulizumab for 52 weeks versus 44.7% and 100.0% for patients with AA and MDS treated with eculizumab followed by ravulizumab. In addition, ravulizumab-treated patients with AA or MDS had numerally fewer transfusions and units of pRBC/WBT compared with those who received eculizumab followed by ravulizumab. Overall, the exploratory nature of the analysis and small sample size means that interpretation of the data is limited. Conclusions: This analysis demonstrates that majority of patients with PNH and AA who received ravulizumab avoided the need for transfusion up to 52 weeks of treatment. Patients treated with ravulizumab for the 52-week period had numerically fewer transfusions and units of pRBC/WBT transfused compared with patients who received eculizumab followed by ravulizumab. Overall, these findings support the use of ravulizumab in complement-inhibitor-naïve patients with PNH, with or without a history of BMD. Disclosures Risitano: Amyndas: Consultancy; Samsung: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; RA pharma: Research Funding; Pfizer: Speakers Bureau; Apellis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Biocryst: Membership on an entity's Board of Directors or advisory committees; Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Alnylam: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Achillion: Membership on an entity's Board of Directors or advisory committees. Schrezenmeier:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Yonemura:Alexion Pharmaceuticals: Honoraria, Research Funding. Munir:Alexion: Honoraria; F. Hoffmann-La Roche: Consultancy, Other: Medical writing support, furnished by Scott Battle, PhD, of Health Interactions, was funded by F. Hoffmann-La Roche Ltd, Basel, Switzerland. Pavani:Alexion Pharmaceuticals: Current Employment. Wang:Alexion Pharmaceuticals Inc.: Current Employment. Kulagin:Alexion Pharmaceuticals Inc.: Consultancy, Research Funding. Kulasekararaj:Alexion Pharmaceuticals Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sicre de Fontbrune:Alexion Pharmaceuticals Inc.: Honoraria, Research Funding. Röth:Novartis: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Biocryst: Consultancy, Honoraria; Apellis: Consultancy, Honoraria; Alexion Pharmaceuticals Inc.: Consultancy, Honoraria, Research Funding.

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