ON 01910.Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients While Decreasing Bone Marrow CD34+ Blast Counts and Aneuploid Clone Size.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 120-120
Author(s):  
Elaine M Sloand ◽  
Matthew J. Olnes ◽  
Naomi Galili ◽  
Aarthi Shenoy ◽  
Loretta Pfannes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Cyclin D1 ◽  
Research Funding ◽  
Treatment Options ◽  
Cell Cycle Control ◽  
Trisomy 8 ◽  
Clone Size ◽  
Monosomy 7

Abstract Abstract 120 Patients with high risk MDS can be successfully treated with 5-azacytidine, or with lenalidomide but non-responding patients have few treatment options. Chemotherapy produces significant morbidity and very short remissions and most patients are too old for bone marrow transplantation. We previously demonstrated up-regulation of c-myc, survivin, and cyclin D1 in CD34+ cells in patients with trisomy 8 (and selected patients with monosomy 7). siRNA-mediated knockdown of survivin or c-myc decreased trisomy 8 cell growth in vitro (Sloand et al, Blood 2007, 110: 822). We postulated that increased cyclin D1 causes upregulation of survivin, resulting in resistance of these cells to apoptosis. The styryl sulfone, ON 01910.Na, decreases cyclin D1 accumulation in cultured bone marrow from patients with high risk trisomy 8 MDS and in some monosomy 7 patients (who also show upregulation of cyclin D1), while selectively decreasing blasts and aneuploidy with this cytogenetic abnormality (ASH Abstracts Nov 2008; 112: 1651). Here we examine the clinical response to ON1910 in an ongoing phase I/II clinical trial in which 13 evaluable patients with intermediate-1(int-1) to high risk MDS and treatment-refractory trisomy 8 AML were enrolled. Patients were treated with escalating doses of ON 01910.Na at 800 mg/m2 × 2 days every 3/4 weeks, 800 mg/m2 × 3 days every 2 weeks, 800 mg/m2 × 5 days every 2 weeks, and 1500 mg/m2 × 2 days every 3/4 weeks at two institutions. No significant toxicity could be ascribed to the drug. Patients with trisomy 8 and monosomy 7 demonstrated significant declines in aneuploidy measured by florescence in situ hybridization (FISH) (mean aneuploidy; 50% before and 24% after 1 cycle of treatment; p=0.02 :Fig below). Rather than becoming cytopenic, many patients showed substantial improvements of blood counts and one patient (01-02; graphic shown below) became red cell transfusion-independent and maintains his remission 14 months after stopping therapy. Cyclin D1 measurement by flow cytometry showed decreases of this protein in both CD34 and CD33 cells during infusion of ON 1910 infusion (example shown in Fig below). Results from individual evaluable patients are shown in table 1. These results indicate that modulation of cell cycle control by cyclin D1 may represent a novel targeted approach for trisomy 8 and monosomy 7 MDS. Disclosures: Sloand: Onconova: Research Funding. Olnes:Onconova: Research Funding. Galili:Onconova: Research Funding. Wilhelm:Onconova: Employment. Groopman:Onconova: Membership on an entity's Board of Directors or advisory committees. Raza:Onconova: Research Funding.

Suppression of Cyclin D 1 (CD1) by on 01910.Na Is Associated with Decreased Survival or Trisomy 8 Myelodysplastic Bone Marrow: A Potential Targetted Therapy for Trisomy 8 MDS.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1651-1651
Author(s):  
Aarthi Shenoy ◽  
Loretta Pfannes ◽  
Francois Wilhelm ◽  
Manoj Maniar ◽  
Neal Young ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cyclin D1 ◽  
Cultured Cells ◽  
Bone Marrow Failure ◽  
Refractory Anemia ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Diploid Cells

Abstract CD34 positive cells from patients with trisomy 8 myelodysplastic syndrome (MDS) have pronounced expression of early apoptotic markers compared to normal hematopoietic cells. However, trisomy 8 clones persist in patients with bone marrow failure and expand following immunosuppression (Sloand EM et al; Blood2005; 106(3):841). We have demonstrated up-regulation of c-myc, survivin, and CD1 in CD34 cells of patients with trisomy 8 (Sloand et al; Blood2007; 109(6):2399). Employing siRNA mediated knockdown of the anti-apoptotic protein survivin, we demonstrated a decrease in trisomy 8 cell growth and postulated that increased Cyclin D1 caused the upregulation of survivin resulting in resistance of these cells to apoptosis. Using fluorescent in situ hybridization (FISH) we showed that the novel styryl sulfone, ON 01910.Na (Vedula MS et al; European Journal of Medicinal Chemistry2003;38:811), inhibits cyclin D1 accumulation and is selectively toxic to trisomy 8 cells while promoting maturation of diploid cells. Flow cytometry of cultured cells demonstrated increased proportions of mature CD15 positive myeloid cells and decreased number of immature CD33+ cells or CD34+ blasts (Sloand EM et al; Blood2007;110:822). These encouraging in vitro data led to a phase I/II trial of ON 01910.Na in MDS patients with refractory anemia with excess blasts who had IPSS =/> int-2. This study was designed to assess the safety, and activity of escalating doses of ON 01910.Na (800 mg/m2/day × 3 days, 800 mg/m2/day × 5 days, 1500 mg/m2/day × 5 days, 1800 mg/m2/day × 5 days every 2 weeks) in MDS patients. To date five MDS patients have been treated with ON 01910.Na for 4 to 16 weeks in the first two dose cohorts. Two patients had isolated trisomy 8, two had complex cytogenetic abnormalities including trisomy 8 in all aneuploid cells, and one had monosomy 7. Three and five day infusions were well tolerated. Pharmakokinetic analysis showed that the half life of the drug is 1.3 ± 0.5 hours without signs of drug accumulation. Four of five patients demonstrated a rapid and significant decrease in the number of peripheral blasts and aneuploid cells after 4 weeks of therapy (see below), concomitantly with increases in neutrophil and/or platelet counts in four patients. All four patients exhibiting a biological effect of drug treatment had trisomy 8 in their aneuploid clone prior to therapy. One monosomy 7 patient, previously refractory to EPO became responsive to Darbopoietin and another trisomy 8 patient became platelet-transfusion independent. In this early safety trial, ON 01910.Na demonstrates efficacy at early timepoints with respect to improved cytopenias and decreased blast counts. Continued enrollment and long term follow-up will further detail clinical efficacy and impact on the long term prognosis of high risk MDS patients treat with this drug. Figure Figure

scholarly journals Clinical Characteristics and Treatment Allocations in Patients with Myelodysplastic Syndromes and Monosomy 7: Results from an International Multicenter Study Suggest That Hypomethylating Agents Significantly Improve Overall- and AML-Free Survival in Patients Classified As Very High Risk By IPSS-R

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4656-4656 ◽  
Author(s):  
Julie Schanz ◽  
Friederike Braulke ◽  
Ghulam J. Mufti ◽  
Elena Crisà ◽  
Austin Kulasekararaj ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Best Supportive Care ◽  
High Risk Group ◽  
Study Cohort ◽  
Monosomy 7 ◽  
Free Survival ◽  
Very High

Abstract Introduction: Total (-7) or partial (7q-) monosomy 7 is the second frequent abnormality in MDS, occurring in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with -7 or del(7q) in a multicentric, retrospective cohort study. Patients and Methods: 471 patients with MDS/AML following MDS and monosomy 7 were registered and retrospectively analyzed. The median observation time was 3.6 years. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, bone marrow blast count <=30% and presence of -7 or 7q- proved by chromosome banding analysis (CBA) or fluorescence in situ-hybridization (FISH). The data was coalesced from 8 centers in London (n=140; 29.7%), Duesseldorf, (n=120; 25.5%%), Goettingen (n=118; 25.1%), Cologne (n=38; 8.1%), Freiburg (n=29; 6.2%), Munich (n=13; 2.8%), Dresden (n=10; 2.1%) and Mannheim (n=3; 0.6%). The median age in the study cohort was 66 years, 63% of patients were males. MDS/AML was therapy-associated in 53 (11%). According to IPSS-R, 9 (1.9%) were assigned to the low risk group, 39 (8.3%) to the intermediate group, 81 (17.2%) to the high-risk group and 133 (28.2%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), hypomethylating agents (HMA; either 5-azacytidine or decitabine), and others (e.g. valproic acid, steroids, lenalidomide or thalidomide). Survival analyses were performed regarding overall- (OS) as well as AML-free survival (AFS) using the Kaplan-Meier method. Results: 147 patients (31.2%) showed 7q-, 313 (66.5%) -7 and 11 (2.3) patients showed both abnormalities at the first cytogenetic examination. The abnormality was detected by CBA±FISH in 440 (93.4%) and by FISH only in 31 (6.6%). In the latter cases, the CBA was either unsuccessful or showed a normal karyotype. In 182 (38.6%) patients, -7/del7q was detected as a single abnormality, 77 (16.3%) showed two abnormalities and 184 (39.1%) showed a complex karyotype involving -7/7q-. As previously described (Schanz et al., 2012), untreated patients with an isolated 7q- as compared to an isolated -7 show a better prognosis regarding OS (median: 4.0 vs. 0.7 years; p<0.01) as well as AFS (median not reached vs. 2.3 years; p=0.062). Median hemoglobin level in the study cohort was 9.3 g/dl, ANC 0.98*103/μl, platelet count 73*103/μl and the median number of bone marrow blasts was 8%. Regarding the treatment, a best supportive care regimen was chosen in 195 (41%) patients. The remaining 276 (58.6) patients received 1-5 sequential therapies (one therapy: 31.6%; more than 1 therapy: 27.0%). 81 patients received an allogeneic bone marrow transplantation (ATX). Within the group of patients treated with HMA at any time of their disease (n=167), 147 (31.2%) received 5-Azacytidine, 8 (1.7%) Decitabine and 12 (2.5%) patients were treated with both drugs. As the first line therapy, 122 patients (25.9%) received HMA, 50 (10.6%) HDC, 28 (5.9%) ATX, 28 (5.9%) 11 (2.3%) LDC, and 28 (5.9%) were treated with other therapies. Patients eligible for ATX showed a significantly better prognosis as compared to any other therapy strategy: The median OS in was 2.1 years as compared to 1.1 years in non-transplanted patients (p<0.01). In patients not eligible for ATX, treatment with HMA at any course of their disease as compared to a BSC strategy was associated with a better OS (1.4 vs. 0.8 years, p=0.014). By comparing HMA to any other therapy, the OS did not differ significantly (1.4 years in HMA vs. 1.1 years in any other, p n.s.). In patients classified as very high risk according to IPSS-R, the median OS was significantly prolonged in patients receiving HMA as compared to BSC (1.1 vs. 0.6 years, p<0.01). This was also observed for the risk of AML-transformation in this subgroup of patients: The median time to AML was 1.8 years in HMA-treated patients versus 0.6 years in BSC (p=0.012). Conclusions: To our knowledge, the study describes the largest patient cohort with MDS/AML and monosomy 7 published to date. Further data regarding the clinical characteristics of this subgroup of patients and the treatment regimes applied will be presented in detail. The study was supported by research funding from Celgene Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Schanz: Celgene: Honoraria, Research Funding, Travel grants: Celgene, Novartis, Lilly Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Nolte:Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

Early and Sustained Response to Azacytidine in High-Risk MDS Patients with Monosomy 7 Correlates with Increased Apoptosis and Not CDKN2B Demethylation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2530-2530 ◽  
Author(s):  
Kavita K. Raj ◽  
Alison M. John ◽  
Aloysius Ho ◽  
Nicholas Shaun B. Thomas ◽  
Ghulam J. Mufti
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Complete Remission ◽  
Promoter Methylation ◽  
Annexin V ◽  
T Test ◽  
Bone Marrow Mononuclear Cell ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
The Mean

Abstract Disease progression in MDS is associated with CDKN2B (encodes p15INK4b) promoter methylation and an inhibition of apoptosis. We therefore studied predominantly high-risk MDS patients treated with azacitidine in order to determine whether clinical responses correlated with changes in CDKN2B promoter methylation and bone marrow apoptosis. In all, 24 patients (19 male) with a median age of 66.7 years were treated with azacitidine (75mg/m2/day x 7 days, every 28 days). Patients were FAB RA (n=2), RAEB (n=7), RAEB-T (n=13) and AML (n=2) with 18/24 having an IPSS risk of Int-2 or High. Cytogenetic abnormalities were present in 17 patients (4 patients with monosomy 7; 1 with der(7) as the sole cytogenetic abnormality and 1 as part of a complex karyotype; 4 with trisomy 8; 1 with 11q abnormalities; 1 with 5q-, 1 with 20q, 1 with iso 17p; and the remaining -y or misc). A median of 5 courses of azacitidine was administered (range: 1–13). Complete remission was achieved in 6 patients: 2 with trisomy 8, 3 with monosomy 7, and 1 with der(7). Haematological Improvement (HI) in Platelets occurred in 6 patients, HI-E in 2 patients, and HI-N in 3 patients. Five patients had a reduction in blast percentage. Importantly, even in complete cytogenetic remission bone marrow dysplasia persisted. All patients with monosomy 7/der(7) are in complete remission (median follow up of 10 months) whereas those with trisomy 8 relapsed their response at 2 and 5 months. CDKN2B promoter methylation in patients pre-treatment and at hematological remission was studied by bisulfite genomic sequencing (region: −263 to +243). There was no difference in CDKN2B methylation in CD34+ or CD33+ cells of responders and non-responders (both had low level, heterogeneous methylation patterns). However, CDKN2B was unmethylated in lymphocytes of responders and methylated in non-responders. Demethylation was not evident following treatment. Baseline bone marrow mononuclear cell apoptosis of 16 patients (12 RAEB, 2 RAEB T, 2 AML) analysed by PI/Annexin V staining (6% mean, 4.06% median); was not significantly different from normal controls (2%: mean, 0.77%; median, n=3) (2 sample T-test 0.103). From 12 treated patients, 8 patients responding to azacitidine (6 CR; 2 blast reduction with HI-E major and HI-N major, regardless of cytogenetic subtype), the mean apoptosis at the time of remission (11.61% mean; 9% median) was significantly higher than the mean apoptosis of 1.82% (median, 1.095%) in 4 non- responders (2 sample t-test p = 0.006). Azacitidine treatment induced sustained responses in all patients with monosomy 7, in whom the CDKN2B promoter is unmethylated. We propose that increased bone marrow apoptosis disrupts the leukaemic clone and leads to disease regression to an earlier stage.

scholarly journals Identification of Dual PI3K/mTOR and BCL2 Inhibitors for the Treatment of High Risk Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 646-646
Author(s):  
Raija Silvennoinen ◽  
Muntasir Mamun Majumder ◽  
David Tamborero ◽  
Pekka Anttila ◽  
Samuli Eldfors ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Risk Stratification ◽  
Research Funding ◽  
Drug Sensitivity ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Treatment Options ◽  
Risk Markers ◽  
Nras Mutation

Abstract Introduction Multiple myeloma (MM) is an incurable malignant plasma cell disease with the highest incidence occurring at 65-70 years of age while 10% of patients are diagnosed below 55 years of age. The International Myeloma Working Group recently proposed new risk stratification standards for MM patients: high-risk (HR), standard (SR) and low-risk (LR) groups (Leukemia 2014, 28, 269−77). Although a median overall survival of LR patients is > 10 years from the diagnosis, new drugs and therapeutic innovations are urgently needed for HR patients (20%) who have a median overall survival of only two years. To identify new treatment options for MM patients, we compared ex vivo drug sensitivity data from primary CD138+ cells to standard risk stratification markers. Ex vivo responses indicated a number of investigational drugs as potential novel options for HR MM patients with links to risk markers. Methods Bone marrow aspirates were collected from newly diagnosed (n=14) and relapsed/refractory (n=21) MM patients. Cytogenetics were determined by fluorescence in situ hybridization (FISH) and the patients stratified based on the presence or absence of adverse FISH markers (t(4;14) and 17p del). Plasma cells (CD138+) were enriched from freshly isolated bone marrow samples and exome sequencing performed using DNA extracted from the CD138+ cells and matched skin biopsies. Ex vivo drug sensitivity was assessed by measuring the viability of the cells after 3-day incubation with 306 different oncology drugs in a 10,000-fold concentration range. Drug sensitivity scores were calculated based on the normalized area under the dose response curve (Scientific Reports 2014, 4, 5193) and select sensitivities determined by comparing results to healthy bone marrow cells. Based on drug sensitivities, the patients were classified in four different groups (sensitive, moderately sensitive, resistant and highly resistant). Results Of the 35 patients included in this study, 11 were classified as HR (31%) and 24 as SR/LR (69%). In the HR group 6/11 (55%) had t(4;14) and 5/11 patients (45%) had 17p13 del. In the SR/LR group common abnormalities included 13 monosomy/13q del (10/24), 1q gain (10/24) and K/NRAS mutation (11/24). Within the HR group, other co-occurring abnormalities included 1q gain (9/11), 13 monosomy/13q del (6/11), K/NRAS mutation (5/11), and TP53 mutation (2/11). Based on overall ex vivo drug sensitivity profiles of all patients, the majority of HR patients were classified as moderately sensitive (8/11; 73%) while SR/LR patients had diverse responses from sensitive to highly resistant. In the HR group, the highest select sensitivities were to BH3 mimetics and PI3K/mTOR inhibitors. While the t(4;14) is predicted to lead to upregulation and increased activity of the FGFR3, which could be targeted by FGFR inhibitors, none of the t(4;14) samples showed sensitivity to these drugs. However, with the exception of one t(4;14) sample, the rest all showed good sensitivity to dual PI3K/mTOR inhibitors, but not to rapalogs, suggesting that inhibition of PI3K and the mTORC1/2 complexes is required to inhibit t(4;14) cell growth rather than mTORC1 alone. Of the 17p del patients, 3/5 were classified as moderately sensitive, 1/5 sensitive and 1/5 highly resistant based on ex vivo drug response of CD138+ cells. All showed select sensitivity to BH3 mimetics/BCL2 inhibitors (navitoclax/ABT-263 and venetoclax/ABT-199/GDC-0199), while response to other drugs varied. Therefore, blocking cell survival signaling is likely essential for this group of HR MM patients. Conclusion By assessing the ex vivo sensitivity of primary plasma cells to a large collection of oncology drugs and comparing these data to standard risk stratification markers for MM, we have been able to identify potential new treatment options for high risk MM patients including dual PI3K/mTOR and BCL2- inhibitors. Although a larger cohort of patients is required to support the correlation between specific drug sensitivities and risk markers, these preliminary data indicate that currently used risk markers may be useful to predict the use of novel treatments. Disclosures Silvennoinen: Janssen-Cilag: Research Funding; Celgene: Research Funding; Janssen-Cilag: Honoraria; Sanofi: Honoraria; Celgene: Honoraria. Porkka:BMS: Honoraria; BMS: Research Funding; Novartis: Honoraria; Novartis: Research Funding; Pfizer: Research Funding. Heckman:Celgene: Research Funding.

scholarly journals APTO-253 Induces KLF4 to Promote Potent in Vitro Pro-Apoptotic Activity in Hematologic Cancer Cell Lines and Antitumor Efficacy As a Single Agent and in Combination with Azacitidine in Animal Models of Acute Myelogenous Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4813-4813 ◽  
Author(s):  
William G Rice ◽  
Avanish Vellanki ◽  
Yoon Lee ◽  
Jeff Lightfoot ◽  
Robert Peralta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Animal Models ◽  
Antitumor Activity ◽  
Single Agent ◽  
Xenograft Model ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Xenograft Models

Abstract APTO-253, a small molecule that mediates anticancer activity through induction of the Krüppel-like factor 4 (KLF4) tumor suppressor, is being developed clinically for the treatment of acute myelogenous leukemia (AML) and high risk myelodysplastic syndromes (MDS). APTO-253 was well tolerated in a Phase I study in patients with solid tumors using a dosing schedule of days 1, 2, 15, 16 of a 28 day cycle (2T-12B-2T-12B), but recent scientific observations guided APTO-253 toward AML and high risk MDS. Indeed, suppression of KLF4 was reported as a key driver in the leukemogenesis of AML and subsets of other hematologic diseases. The vast majority (~90%) of patients with AML aberrantly express the transcription factor CDX2 in human bone marrow stem and progenitor cells (HSPC) (Scholl et al., J Clin Invest. 2007, 117(4):1037-48). The CDX2 protein binds to CDX2 consensus sequences within the KLF4 promoter, thereby suppressing KLF4 expression in HSPC (Faber et al., J Clin Invest. 2013, 123(1):299-314). Based on these observations, the anticancer activity of APTO-253 was examined in AML and other hematological cancers. APTO-253 showed potent antiproliferative activity in vitro against a panel of blood cancer cell lines, with ηM IC50values in AML (6.9 - 305 ηM), acute lymphoblastic leukemia and chronic myeloid leukemia (39 – 250 ηM), non-Hodgkin’s lymphoma (11 – 190 ηM) and multiple myeloma (72 – 180 ηM). To explore in vivo efficacy, dose scheduling studies were initially conducted in the H226 xenograft model in mice. In the H226 model, APTO-253 showed improved antitumor activity when administered for two consecutive days followed by a five day break from dosing (2T-5B) each week, i.e. on days 1,2, 8,9, 15,16, 22,23, compared to the 2T-12B-2T-12B schedule. The 2T-5B schedule was used to evaluate antitumor activity of APTO-253 in several AML xenograft models in mice. In Kasumi-1 AML and KG-1 AML xenograft models, APTO-253 showed significant antitumor activity (p = 0.028 and p=0.0004, respectively) as a single agent when administered using the 2T-5B schedule each week for four weeks compared to control animals. Mice treated with APTO-253 had no overt toxicity based on clinical observations and body weight measurements. Mice bearing HL-60 AML xenograft tumors were treated with APTO-253 for one day or two consecutive days per week for three weeks, either as a single agent or combined with azacitidine, or with azacitidine alone twice per week (on days 1,4, 8, 11, 15 and 18). APTO-253 as a single agent inhibited growth of HL-60 tumors to approximately the same extent as azacitidine. Furthermore, both once weekly and twice weekly dosing of APTO-253 in combination with azacitidine resulted in significantly enhanced antitumor activity relative to either single agent alone (p = 0.0002 and p = 0.0006 for 1X and 2X weekly APTO-253 treatment, respectively, compared to control). Likewise, using a THP-1 AML xenograft model, APTO-253 administered as a single agent using the 2T-5B per week schedule showed significant efficacy, similar to that of azacitidine, while the combination of APTO-253 and azacitidine demonstrated greatly improved antitumor effects relative to either drug alone. APTO-253 was effective and well tolerated as a single agent or in combination with azacitidine in multiple AML xenograft models, plus APTO-253 does not cause bone marrow suppression in animal models or humans. Taken together, our results indicate that APTO-253 may serve as a targeted agent for single agent use and may provide enhanced efficacy to standard of care chemotherapeutics for AML and other hematological malignancies. Disclosures Rice: Lorus Therapeutics Inc.: Employment. Vellanki:Lorus Therapeutics Inc.: Employment. Lee:Lorus Therapeutics Inc.: Employment. Lightfoot:Lorus Therapeutics Inc.: Employment. Peralta:Lorus Therapeutics Inc.: Employment. Jamerlan:Lorus Therapeutics Inc.: Employment. Jin:Lorus Therapeutics Inc.: Employment. Lum:Lorus Therapeutics Inc.: Employment. Cheng:Lorus Therapeutics Inc.: Employment.

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.

scholarly journals Autologous transplantation of bone marrow purged in vitro with anti-CD7- (WT1-) ricin A immunotoxin in T-cell lymphoblastic leukemia and lymphoma

Blood ◽  
1989 ◽  
Vol 74 (3) ◽  
pp. 1152-1158 ◽  
Author(s):  
FW Preijers ◽  
T De Witte ◽  
JM Wessels ◽  
GC De Gast ◽  
E Van Leeuwen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
High Risk ◽  
Tumor Cells ◽  
Lymphoblastic Leukemia ◽  
T Cell Response ◽  
Growth Potential ◽  
Ricin A ◽  
Immunologic Reconstitution

Abstract Seven patients with high-risk acute T-cell lymphoblastic leukemia (T- ALL) and six with T cell lymphoma (T-LL) were treated with autologous bone marrow transplantation (ABMT) after in vitro purging of their bone marrow with WT1 (CD7)-ricin A-chain immunotoxin. CD7 expression on the tumor cells showed large variations between the individual patients and was highly related to the specific cytotoxicity of WT1-ricin A. Incubation of bone marrow with up to 10(-8)mol/L WT1-ricin A in the presence of 6 mmol/L NH4Cl did not compromise the growth potential of the hematopoietic progenitors CFU-GM, CFU-GEMM, and BFU-E. Hematologic engraftment (greater than 10(9) leukocytes/L) occurred within a normal time period (median, 17 days). Seven patients are alive and in complete remission (CR) at 48+, 44+, 40+, 26+, 11+, 7+, and 6+ months after ABMT. Four patients relapsed within 6 months after ABMT. Two of them had the lowest CD7 expression on their tumor cells, the other two were transplanted in CR2 and CR3. Two patients died from transplantation related infections. The immunologic reconstitution was delayed, although the numbers of T cells reached normal levels within 1 month. The number of CD7+ cells remained low up to 1 year after transplantation. The T4/T8-ratio was decreased for at least 6 months. The T-cell response to mitogens recovered to normal levels after 1 year. This study shows that ABMT with WT1-ricin A purged bone marrow in high-risk T-cell malignancies results in a complete hematopoietic and a delayed immunologic reconstitution. The actuarial relapse free survival is 61% at 3 years.

Partially matched bone marrow transplantation in patients with myelodysplastic syndromes.

1988 ◽  
Vol 6 (12) ◽  
pp. 1851-1855 ◽  
Author(s):  
N J Bunin ◽  
J T Casper ◽  
C Chitambar ◽  
J Hunter ◽  
R Truitt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Rabbit Serum ◽  
Normal Rabbit Serum ◽  
Trisomy 8 ◽  
Monosomy 7 ◽  
Patients Âgés ◽  
Curative Therapy ◽  
Unrelated Donors

Six patients with a myelodysplastic syndrome (MDS) were treated with bone marrow transplantation (BMT) using partially-matched related (3) or unrelated (3) donors. Patients' ages ranged from 7 to 31 years (median, 10 years). Bone marrow karyotype abnormalities were present in five patients included four with monosomy 7 and one with trisomy 8. One patient was in complete remission before transplant; the remaining five had excess of blasts or were undergoing leukemic transformation. Donor, and recipient were mismatched at the DR locus (2), A locus (2), B locus (1), or A and B loci (1). Conditioning included busulfan, cytarabine, cyclophosphamide, methylprednisolone, and total body irradiation. Cyclosporine was started on day -1. Marrows were T-cell depleted using a monoclonal antibody (MoAb) (CD3) and normal rabbit serum. Four patients engrafted routinely. One patient died of aspergillosis before engraftment (day 12) and one patient failed to engraft on first attempt, but engrafted following additional preparation. Median time to neutrophils greater than 500/microL and platelets greater than 25,000/microL were 16 and 19 days, respectively. Acute graft-v-host disease (GVHD) was less than or equal to grade II in all patients. One patient died with recurrent disease (day 257). One patient died at day 515 of pancreatitis and respiratory failure. Three patients are alive and disease-free at 240, 395, and 560 days post-BMT including two patients with unrelated donors. Partially matched T-depleted bone marrow from related or unrelated donors may be effective, and possibly curative therapy for patients with MDS who lack a histocompatibility locus antigen (HLA)-identical sibling donor.

Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients

2012 ◽  
Vol 48 (15) ◽  
pp. 2442-2450 ◽  
Author(s):  
Ferdinand Wagner ◽  
Bente Henningsen ◽  
Christine Lederer ◽  
Melanie Eichenmüller ◽  
Jan Gödeke ◽  
...  
Keyword(s):  
High Risk ◽  
Treatment Options ◽  
High Risk Patients ◽  
Risk Patients ◽  
New Treatment

Combination Therapy with Entinostat (MS-275) and GM-CSF to Enhance Differentiation In Myeloid Malignancies

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3312-3312 ◽  
Author(s):  
Cho Eunpi ◽  
William Matsui ◽  
Jeanne Kowalski ◽  
Hua-Ling Tsai ◽  
Richard J. Jones ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Combination Therapy ◽  
Research Funding ◽  
Allogeneic Bone ◽  
Differentiation Potential ◽  
Appreciable Change ◽  
Platelet Counts ◽  
Gm Csf

Abstract Abstract 3312 Background: Histone actylases (HAC and histone deacetylases (HDAC) are two important enzymes in epigenetic control that can affect transcription of important regulatory transcription factors. Entinostat is a HDAC inhibitor that has been shown in vivo and in vitro to have anti-proliferative effects on many cancer cell types (Abujamra Leukemia Res 2009). When administered at low concentration to leukemic cell lines, entinostat induced p21-mediated growth arrest and expression of differentiation markers; higher concentrations led to marked increase in reactive oxygen species, mitochondrial damage, caspase activation and apoptosis (Rosato Cancer Res 2003). A Phase I study using entinostat as a single agent in relapsed and refractory leukemia showed in vivo differentiation potential with several patients showing significant increases in their mature granulocyte population and increased acetylation of the CD34+ blast population (Gojo Blood 2006). GM-CSF has been shown to enhance the differentiation potential of various agents such as interferon-alpha, all-trans-retinoic acid, bryostatin, and numerous other anti-neoplastic agents. The effects of combination therapy with GM-CSF and entinostat in patients with high-risk MDS or refractory and/or relapsed AML are presented here. Methods: A Phase II study was conducted to assess the safety and efficacy of combination therapy with GM-CSF and entinostat in patients with high-risk MDS and relapsed or refractory AML who are not eligible for allogeneic bone marrow transplant (BMT). The combination of entinostat and GM-CSF was administered in 6-week (42 day) cycles for at least 2 cycles. Entinostat was originally give at 8 mg/m2 weekly but was eventually adjusted to 4 mg/m2 weekly for the first 4 out of 6 weeks due to toxicity. GM-CSF was given at a single dose of 125 micrograms/m2/day for days 1–35 in the cycles 1, 2, 4 and 6 and days 1–42 in cycles 3 and 5. Patients who tolerated two cycles of 4 mg/m2 were assessed for response through measurements of peripheral blood, bone marrow aspirate and biopsies. Transfusion requirements and adverse events (AE) were recorded on all subjects throughout the study period. Clinical responses for AML and MDS were measured according to International Working Group definitions of complete response (CR), partial response (PR), stable disease (SD), hematologic improvement, and progressive disease (PD). Results: A total of 24 patients met the eligibility criteria for response assessment. Median age was 71 (range 52–84) years and 15 (63%) were male. Of the 19 patients with AML, 8 had relapsed/refractory disease, 7 had AML arising from MDS, 3 had therapy-related AML, and 1 had de novo AML. The remaining 5 patients had a primary diagnosis of MDS. 10 patients (42%) completed 2 or more cycles at the 4 or 6 mg/m2 dose of MS-275. These patients completed a total of 33 cycles, 1 resulting in CR, 4 in PR, 24 in SD, and 4 in PD. In addition to these standard endpoints, improvements were also noted in peripheral neutrophil counts (p<0.019) and platelet counts (p<0.001), without an appreciable change in blast count as a result of treatment (p<0.50). These results were achieved with few toxicities at the noted dosing. A total of 38 cycles at the 4-mg/m2-dose were analyzed for Grade 3 or 4 toxicities, which included febrile neutropenia (n=3), neutropenic infection (n=3), bone pain (n=2), fatigue (n=1), pericardial effusion (n=1), and weakness (n=1). Conclusion: Although treatment with entinostat and GM-CSF did not result in durable remissions, there were notable improvements in absolute neutrophil and platelet counts without negatively impacting the blast percentage. These findings suggests that therapy with entinostat and GM-CSF differentially promotes growth of mature myeloid cells and appears associated with better marrow function by minimizing the need for platelet transfusions. Such strategies may be most effective when applied to patients with low disease burdens or as maintenance therapy for patients with high risk disease in remission. Disclosures: Matsui: Pfizer: Consultancy; Bristol-Meyers Squibb: Consultancy; Infinity Phamaceuticals: Consultancy, Patents & Royalties; Merck: Consultancy, Research Funding; Geron Corporation: Research Funding.

Sign in / Sign up

Export Citation Format

Share Document