Lenalidomide in High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia with Chromosome 5 Abnormalities.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 115-115 ◽  
Author(s):  
Lars Möllgård ◽  
Lars Nilsson ◽  
Lars Kjeldsen ◽  
Ingunn Dybedal ◽  
Inge Hogh Dufva ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Underlying Disease ◽  
Low Risk ◽  
Induction Treatment ◽  
Complex Karyotype ◽  
A Minor

Abstract Abstract 115 Background: Treatment with lenalidomide in patients with low risk MDS with deletion del(5q) has resulted in a high proportion of transfusion independence and also cytogenetic responses. The aim of this study was to evaluate the effect of lenalidomide in high risk MDS and AML patients with del(5q) or monosomy 5 not eligible for induction treatment, primary cases as well as patients relapsing/refractory to intensive treatment. Methods: This investigator-initiated prospective phase II study assessed the effects of continuous lenalidomide treatment during 16 weeks, in increasing doses from 10 to 30 mg, with 8 weeks on the highest level. Dose modifications due to hematologic toxicity were performed according to the clinical judgment of the treating physician. The primary objective was cytogenetic response, assessed by FISH on bone marrow (BM) smears at inclusion and after 8 and 16 weeks. Clinical and morphological BM response was evaluated every 4 weeks. Results: 25 patients were included from October 2007 to July 2009, 22 of which are so far evaluable. Overall, the patient cohort included several patients with very advanced disease and two patients died before treatment was started. Fourteen MDS patients and 11 AML patients have been included. Twenty-two of the patients had 5q- (9 of these had a complex karyotype and 5 had del(5q)+1) and 3 patients had monosomy 5 (all complex karyotype). The median time of treatment was 13 weeks (range 0–16 weeks). The reason for early termination in the patients who started lenalidomide treatment was progressive disease (3) and adverse events (10). Six of 7 patients who completed the study (16 weeks of treatment) had a response: Two MDS patients with del(5q-)+1, and del(5q)+2, respectively, achieved a major cytogenetic response (≥50 % reduction), in one of these patients the blast count decreased from 9.5% to <5%. Two MDS patients with 5q- and complex karyotype had a minor cytogenetic response (≥25% reduction) and a reduction to <5% blasts, respectively. One AML with 5q- and a complex karyotype had a minor cytogenetic response and a complete BM response. Another AML patient with isolated 5q- showed a complete BM, but no cytogenetic response. In total, 6 of the 20 patients (30%) who started treatment had a cytogenetic and/or morphological BM response. Four of 6 responders also experienced hematologic response. Twenty-one serious adverse events (SAE) have been reported in 15 of the patients. The main SAE criterion has been inpatient hospitalization. Fourteen of the SAE:s were infection or febrile neutropenia. In 6 patients the outcome of the SAE has been death. For these patients the causality/relationship to lenalidomide has been judged as not suspected or not related. The cause of death has been the underlying disease or complications to the underlying disease like infections. Conclusion: Lenalidomide as a single agent, but in higher doses than those applied to low-risk MDS patients resulted in cytogenetic and/or morphological bone marrow response in 30% of patients with high-risk MDS or AML with del(5q) or monosomy 5. We considered this a promising response rate, considering the high frequency of very advanced patients, and complex karyotypes. The main serious adverse event was infections. Future combinations with cytostatic or hypometylating agents may further improve these results. Disclosures: Möllgård: Celgene: Research Funding. Hellström-Lindberg:Celgene: Research Funding.

An Effective and Tolerable Chemoimmunotherapy Regimen For Relapsed/Refractory and Very-High Risk Chronic Lymphocytic Leukemia Combining Alemtuzumab With Pentostatin and Low Dose Rituximab

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1641-1641
Author(s):  
Clive S. Zent ◽  
Betsy R LaPlant ◽  
Wenting Wu ◽  
Timothy G. Call ◽  
Deborah Bowen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Phase Ii ◽  
Research Funding ◽  
Low Dose ◽  
Lymphocytic Leukemia ◽  
Bulky Disease ◽  
Purine Analogue ◽  
Very High

Abstract Patients with very-high risk (purine analogue refractory and TP53 defective) CLL have limited treatment options. In these patients alemtuzumab can be effective against CLL cells in the circulation and bone marrow, and in combination therapy with fludarabine can be active in patients with bulky disease, but these regimens have a high risk of serious infections. Addition of rituximab to alemtuzumab can also improve efficacy but has limited activity against bulky disease. We conducted a phase II clinical trial to determine the efficacy and toxicity of therapy with pentostatin, alemtuzumab, and low dose higher frequency rituximab (PAR) in patients with relapsed/refractory or progressive CLL with 17p13 deletion. The rituximab schedule was designed to decrease the loss of CD20 expression by circulating CLL cells. Methods This two-stage phase II trial study (NCT00669318) conducted at the Mayo Clinic Rochester and University of Iowa with IRB approval had an accrual goal of 38 evaluable patients. Eligibility required a diagnosis of progressive CLL by standard criteria and either previous treatment for CLL (<4 purine analogue regimens) or 17p13 deletion (17p13-). Exclusion criteria were organ failure, poor performance status (ECOG >3), infection with HIV, hepatitis B, hepatitis C, active autoimmune cytopenia, or alemtuzumab therapy within the past 2 months. Rituximab 20 mg/m2 IV M-W-F started on day 1, alemtuzumab started on day 3 with an escalation of 3-10-30 mg/d SQ and then 30 mg M-W-F from day 8, and pentostatin 2 mg/m2 IV every 2 weeks started on day 8. Peg-G-CSF or GM-CSF was used after each dose of pentostatin and patients received Pneumocystis and Varicella prophylaxis. CMV PCR assays were done weekly during treatment and viremia was treated with either valganciclovir or ganciclovir. Cycle 1 was 5 weeks and subsequent cycles were 4 weeks. At the end of cycle 2 patients with a clinical CR had a CT scan and a bone marrow study with immunohistochemical (IHC) staining for residual CLL cells, and therapy was stopped if there was no radiological or IHC evidence of residual CLL (stringent CR). Patients with residual disease received a 3rd cycle of therapy. Results Forty-one patients were enrolled (July 2008 - February 2013) and all 39 who started therapy were evaluable for response: Median age 61 years (range 47-78), 30 (77%) males, 36 (92%) relapsed/refractory CLL (median prior regimens = 2, range 1-10), 3 (8%) previously untreated, 23 (59%) advanced stage (Rai III-IV), 16 (41%) intermediate stage (Rai I-II). Prognostic factors: FISH (hierarchical classification) 15 (38%) 17p13-, 6 (15%) 11q22-, 5 (13%) 12+, 3 (8%) no defects, 8 (21%) 13q14-, and 2 (5%) other abnormalities, IGHV analysis (n=38) 27 (71%) unmutated (<2%), ZAP-70 (n=37) 28 (76%) positive (>20%). Thirty (77%) patients completed planned therapy (28 had 3 cycles, 2 had 2 cycles with stringent CR). Nine patients received one (n=4) or two (n=5) cycles of therapy because of disease progression or complications. Grade 3-4 hematological adverse events (n=37) at least possibly related to treatment included neutropenia (n=22), thrombocytopenia (n=11), anemia (n=2) and hemolysis (n=2). Non-hematological adverse events (n=17) included infections/neutropenic fever (n=8), fatigue (n=3), and hemorrhage (n=2). CMV reactivation was detected and treated in 14 patients (grade 1-2). No patients died during treatment or from treatment related complications. The overall response rate was 56% (95% CI 40-72) with 4 (10%) CR, 7 (18%) CRi, 11 (28%) PR, 7 (18%) SD, and 10 (26%) PD. Four patients (3 CR and 1 CRi) had IHC negative bone marrow studies. Thirteen (33%) patients have died due to progressive CLL (n = 11), sepsis (n=1), and pneumonia (n=1). Median follow up for surviving patients is 23 months (range 3-55). Seven (18%) patients proceeding to RIC allogeneic transplant were censored for time to next treatment. Twenty-one (54%) patients required therapy for progressive CLL and 7 (18%) have required no further therapy. Median progression free survival was 7 months (95% CI: 5-16), time to next treatment 9 months (95% CI: 6-27) and median overall survival has not been reached. Discussion PAR was effective and tolerable therapy for high-risk CLL. This study suggests that alemtuzumab can be used safely in combination with a purine analogue in a short-duration regimen. Disclosures: Zent: Genentech : Research Funding; Genzyme: Research Funding; Biothera: Research Funding; GlaxSmithKline: Research Funding; Novartis: Research Funding. Off Label Use: Pentostatin therapy for CLL, use of lower doses of rituximab.

scholarly journals Predictive Factors for Complete Remission and Survival in AML Patients Failing to Achieve Adequate Bone Marrow Day 14 Blast Eradication

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1464-1464
Author(s):  
Rafee Talukder ◽  
Sarvari Venkata Yellapragada ◽  
Hussein Hamad ◽  
Gustavo A. Rivero
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
High Risk ◽  
Complete Remission ◽  
Induction Therapy ◽  
Research Funding ◽  
Complex Karyotype ◽  
Early Assessment ◽  
Secondary Aml ◽  
Impact On Survival

Abstract Introduction: Complete remission (CR) is an important endpoint after cytarabine plus anthracycline [7+3] induction therapy in Acute Myelogenous Leukemia (AML). Even though CR is observed in about 50-90% of unselected European Leukemia Network 2017 (ELN-2017) patients (pt), factors such as age >65 years, complex karyotype, and adverse mutations (RUNX1, ASLX1, TP53, FLT3 ITD high, KMT2A, secondary AML), leads to inadequate blast eradication. Early response to induction is a predictor of subsequent complete remission (CR). Bone marrow day 14 [D14] inform pt with early inadequate leukemia eradication [blast >10%] who are suitable for re-induction, a strategy that seeks to facilitate conversion to CR or CR with incomplete hematologic recovery (CRi), secure potential allogenic transplantation and reproduce superior outcomes. In this study, we investigated the clinical outcome of an unselected ELN-2017 AML cohort with inadequate D14 marrow response. From the subgroup of patients exhibiting sub-optimal response (SOR), we examined the odds and predictors for subsequent achievement of CR/CRi for those patients who did not receiving immediate re-induction therapy. Additionally, we evaluated the effect of subsequent CR/CRi achievement on survival. Methods: With prior IRB approval, 160 AML pt diagnosed with AML from 1995 to 2017 within Baylor College of Medicine institutions were evaluated. Kaplan-Meier method was used to estimate overall survival (OS) among pt achieving D14 <> 10% blast in an unselected ELN-2017 AML cohort and pt exhibiting >10% blast in D14 marrow with and without CR/CRi. Logistic and cox regression analysis in SOR pt [1] attaining subsequent CR/CRi and [2] OS, respectively, was performed to investigate multiple independent variables with predictive value for the 2 above outcomes. Results: 68/160 (42.5%) of pt had available D14 [early assessment] and sequential day 30 marrow for CR/CRi evaluation. Among 68 unselected ELN-2017 AML pt with D14 marrow for CR/CRi assessment, 42/68 (61.7%) and 26/68 (38.2%) had D14 marrow blasts < and > 10%. Median age was 57 y (range 27-73) and 59 y (range 24-89), respectively, p= 0.74. OS was 459 d vs 169 d in pt with D14 marrow <10% and >10%, at day 14 (p=0.001 95% CI 0.2-0.9) [Fig 1A]. CR/CRi was observed in 36/42 (90%) and 10/26 (38.7%) of pt with D14 marrow <10% vs >10%, respectively, p=0.0005. After controlling for traditional high-risk factors including WBC, age, platelet count, RDW, de novo v secondary AML, only ELN-2017 classification [fav vs unfav and intermediate vs unfav, p= 0.0026 and p=0.01] retained impact on survival. In pt with SOR, we performed second analysis to investigate survival among pt with and without subsequent CR/CRi achievement who did not receive re-induction [Fig 1B]. 16/26 (62.5%) of pt with SOR failed to achieved CR/CRi. OS was 333 d vs 109 d for pt with CR/CRi vs those without CR/CRi [p=0.002, 95% CI 2.6-3.4]. Logistic regression identified in pt with CR/CRi vs those without CR/CRi that: [a] age [63.1 vs 43.6 y-p=0.001]; [b] lower platelet count [47.1 vs 83.1 K/uL-p=0.03]; [c] higher absolute monocyte count (AMC) [3.7 vs 0.41 K/uL-p=0.04]; [d] increased RDW [18.3 vs 14.7-p=0.004] and [e] high BMI [31 vs 24.1-p=0.0003] were significantly associated with failure to achieve CR/CRi. Typical complex karyotype and initial marrow blast % were not associated with subsequent CR/CRi achievement. However, in pt with SOR, lack of high-risk mutations [P53, RUNX, FLT3-ITD, U2AF1] was significant associated with CR/CRi, [40% v 62.5%, p= 0.0004]. Cox proportional regression model showed significant impact on survival for high-risk mutations and higher BMI in survival. Conclusion: In our retrospective study, despite 38.7% of patients with detectable D14 residual leukemia achieved CR/CRi without re-induction, failure to attain CR/CRi was frequently observed after SOR. Advanced age, lower platelet count, higher AMC, RDW and BMI predict failure to achieve CR/CRi status in patients exhibiting initial SOR. Lack of high-risk mutation was a strong predictor for CR/CRi achievement. Our study is novel by suggesting that a combination of pre-induction and "early post-induction" variables facilitate recognition of high-risk AML subgroups requiring re-induction or alternative novel therapy via clinical trials. Disclosures Yellapragada: Takeda: Research Funding; Novartis: Employment; Celgene: Research Funding.

scholarly journals A Phase II Study of Daratumumab in Patients with High-Risk MGUS and Low-Risk Smoldering Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1649-1649
Author(s):  
Omar Nadeem ◽  
Robert A. Redd ◽  
Michael Z. Koontz ◽  
Jeffrey V. Matous ◽  
Andrew J. Yee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Low Risk ◽  
M Protein ◽  
Advisory Committees ◽  
Bone Marrow Plasma

Abstract Introduction : Daratumumab (Dara) is an anti-CD38 monoclonal antibody that is approved for use in patients with newly diagnosed and relapsed multiple myeloma (MM). We hypothesized that early therapeutic intervention with Dara in patients with high-risk MGUS (HR-MGUS) or low-risk SMM (LR-SMM) would lead to eradication of the tumor clone by achieving deep responses, resulting in prevention of progression to MM. We present results of our phase II, single arm study of Dara in HR-MGUS and LR-SMM. Methods : Patients enrolled on this study met eligibility for either HR-MGUS or LR-SMM. HR-MGUS is defined as &lt;10% bone marrow plasma cells and &lt;3g/dL M protein and at least 2 of the following 3 high-risk criteria: Abnormal serum free light chain ratio (SFLC) of &lt;0.26 or &gt;1.65, M protein ≥ 1.5g/dL or non-IgG M protein. LR-SMM is defined by one of the following 3 criteria: M protein ≥3g/dL, ≥10% bone marrow plasma cells, SFLC ratio &lt;0.125 or &gt;8. Dara (16mg/kg) was administered intravenously on a weekly schedule for cycles 1-2, every other week cycles 3-6, and monthly during cycles 7-20. The primary objective of this study was to determine the proportion of patients who achieve very good partial response (VGPR) or greater after 20 cycles of Dara. Secondary objectives included duration of response, safety, and rates of minimal residual disease (MRD)-negativity in VGPR or greater patients. Correlative studies included assessing changes in immune microenvironment, evaluating clonal heterogeneity using deep sequencing, and determining association of genomic aberrations correlating with either response to therapy or progression of disease. Results : At the time of data cutoff, a total of 42 patients were enrolled on this study from 2018 to 2020 with participation of 5 sites. The median age for all patients at enrolment was 60 years (range 38 to 76), with 22 males (52.4%) and 20 females (47.6%). Majority of patients enrolled were classified as LR-SMM (n = 37, 88.1%) and the remaining 5 patients had HR-MGUS (11.9%). 41 patients have started treatment and are included in toxicity assessment, and 40 patients have at least completed 16 cycles (range 6-20). Grade 3 toxicities were rare and only experienced in 5/41 patients including diarrhea (n =1/41; 2%), flu like symptoms (n = 1/41; 2%), headache (n=1/41; 2%), and hypertension (n=2/41; 5%). Most common toxicities of any grade included fatigue (n = 24/41, 51%), cough (n = 19/41, 46%), nasal congestion (n = 18/41, 44%), headache (n = 14/41, 34%), hypertension (n = 11/41, 27%), nausea (n = 13/41, 32%), and leukopenia (n = 13/41, 32%). No patients have discontinued therapy due to toxicity. Minimal response or better was observed in 82.9% of patients (34/41) and PR or better was observed in 51.2% of patients (21/41). This included overall CR (n = 4, 9.8%), VGPR (n = 1, 2.4%), PR (n = 16, 39.0%), MR (n = 13, 31.7%), and SD (n = 7, 17.1%). In the 40 patients who completed at least 16 cycles, response rates were as follows: MR or better 85% (34/40), PR or better 52.5% (21/40) and VGPR or better 12.5% (5/40). Median time to VGPR was 7 months. Median overall survival and progression-free survival have not been reached and no patients have progressed to overt multiple myeloma while on study. Conclusion : Dara is very well tolerated among patients with HR-MGUS and LR-SMM with minimal toxicities. Responses are seen in majority of patients. Early therapeutic intervention in this precursor patient population appears promising but longer follow up is required to define the role of single agent Dara in preventing progression to MM, therefore avoiding more toxic interventions in this low-risk patient population. Disclosures Nadeem: Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Yee: GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Sanofi: Consultancy; Bristol Myers Squibb: Consultancy; Adaptive: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. Zonder: Caelum Biosciences: Consultancy; Amgen: Consultancy; BMS: Consultancy, Research Funding; Intellia: Consultancy; Alnylam: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy. Rosenblatt: Attivare Therapeutics: Consultancy; Imaging Endpoints: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Wolters Kluwer Health: Consultancy, Patents & Royalties. Mo: AbbVIE: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Consultancy; Epizyme: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sperling: Adaptive: Consultancy. Richardson: Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; AbbVie: Consultancy; Takeda: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Secura Bio: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Oncopeptides: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Ghobrial: AbbVie, Adaptive, Aptitude Health, BMS, Cellectar, Curio Science, Genetch, Janssen, Janssen Central American and Caribbean, Karyopharm, Medscape, Oncopeptides, Sanofi, Takeda, The Binding Site, GNS, GSK: Consultancy.

scholarly journals Rusfertide (PTG-300) Induction Therapy Rapidly Achieves Hematocrit Control in Polycythemia Vera Patients without the Need for Therapeutic Phlebotomy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 390-390
Author(s):  
Yelena Ginzburg ◽  
Kamini Kirubamoorthy ◽  
Sinari Salleh ◽  
Sung-Eun Lee ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Polycythemia Vera ◽  
Research Funding ◽  
Safety Monitoring ◽  
Data Safety Monitoring Board ◽  
Low Risk ◽  
Publicly Traded ◽  
The Mean ◽  
Mean Time

Abstract Background. Polycythemia (PV) patients with hematocrit above 45% are at increased risk of thrombotic complications and are treated with phlebotomy and/or cytoreductive therapy to reach a hematocrit target below 45%. Rusfertide (PTG-300) is a peptidic mimetic of hepcidin that is being developed for treatment of polycythemia vera (PV). A Phase 2 trial has indicated that rusfertide is effective at reducing the number of phlebotomies and maintaining hematocrit below 45% without phlebotomy in PV patients who are either high-risk or low-risk, patients treated with cytoreductive therapy (hydroxyurea, interferon, ruxolitinib) and patients treated with phlebotomy alone (Kremyanskaya, ASH 2020). The current trial (PTG-300-08) tested the ability of rusfertide to normalize hematocrit in PV patients with elevated hematocrit without instituting phlebotomy treatment to normalize hematocrit to below 45% in PV patients without requiring phlebotomy and/or cytoreductive treatment. Methods. Eligible study subjects were diagnosed with PV (in accordance with the WHO 2016 criteria), had baseline hematocrit above 48%, and a history of 3 or more hematocrit values above 48% in the year prior to enrollment. High-risk and low-risk subjects treated with phlebotomy alone or with concurrent cytoreductive therapy were eligible. Rusfertide was added on to each subject's current therapy. The initial rusfertide dose was 40 mg administered subcutaneously twice weekly. When each subject's hematocrit was below 45%, the dosing schedule was changed to weekly and the rusfertide dose was adjusted to maintain hematocrit below 45%. Results. Sixteen subjects (12 male and 4 females) have been enrolled. The mean age is 56.1 years; the mean time since diagnosis is 3.74 years; 10 subjects are low risk PV; 12 subjects are receiving concurrent hydroxyurea and 4 subjects were not receiving cytoreductive therapy. Baseline values (mean, min-max) HCT (51.0%, 47.4 - 59), WBC (12,338/µL, 7,000 - 24,600), RBCs (5.9x10 6/µL, 4.3 - 7.6), platelets (486,500/µL, 242,000 - 904,000). All subjects had rapid decreases in hematocrit to below 45% without the use of phlebotomy (Figure 1a). Hematocrit levels remained well controlled after falling below 45% as investigators reduced rusfertide dose to maintenance once weekly regimen. Hemoglobin (Figure 1b) fell rapidly. Erythrocyte counts (Figure 1c) also fell rapidly, indicating that decreased hematocrit is due to decreased erythrocytosis. For the 11 subjects with adequate follow-up, the mean rate of absolute hematocrit decrease was 1.76% per week (median: 1.81%/week; min - max: 0.65 - 2.69%) and the mean time to reach goal hematocrit below 45% was 4.79 weeks (median: 4.14 weeks, min - max: 3.57 - 8.14). Eight subjects reported adverse events (AEs). Injection site reactions (ISRs) occurred in 7 subjects and were mild or moderate in severity. The most common ISRs were erythema (n=7), induration (n=5) and pruritis (n=2). Adverse events other than ISRs that occurred in 2 or more subjects were hypertension (n=2), pyrexia (n=2) and thrombocytosis (n=2). There were two serious adverse events (worsening migraine and pleuritic chest pain) and both were considered unrelated to rusfertide. Overall, rusfertide was well tolerated. Conclusions. This study demonstrates that induction therapy with twice weekly rusfertide administration was effective in rapidly achieving target hematocrit below 45% without phlebotomy in all PV patients which was then successfully maintained with weekly rusfertide treatment. Moreover, the twice weekly injections of rusfertide used to rapidly lower hematocrit levels were safe and well tolerated. Key words: Hepcidin, Hematocrit, Rusfertide, PTG-300, Polycythemia Vera, PV, Therapeutic Phlebotomy Figure 1 Figure 1. Disclosures Gupta: Protagonist Therapeutics: Current Employment. Valone: Protagonist Therapeutics: Consultancy, Current equity holder in publicly-traded company. Khanna: Protagonist: Current Employment, Current equity holder in publicly-traded company. Modi: Protagonist Therapeutics: Current Employment. Hoffman: Kartos Therapeutics, Inc.: Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Novartis: Other: Data Safety Monitoring Board, Research Funding; AbbVie Inc.: Other: Data Safety Monitoring Board, Research Funding.

scholarly journals Phase 3 Study of Lenalidomide (LEN) Vs Placebo in Non-Transfusion Dependent (TD) Low Risk Del(5q) MDS Patients with Del(5q) — Preliminary Blinded Analysis of the European Sintra-REV Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 468-468 ◽  
Author(s):  
Félix López Cadenas ◽  
Eva Lumbreras ◽  
Blanca Xicoy ◽  
Joaquin Sanchez-Garcia ◽  
Pierre Fenaux ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Low Risk ◽  
Phase Iii ◽  
Investigational Drug ◽  
Blurred Vision ◽  
Advisory Committees ◽  
Grade 3

Abstract Background: Lenalidomide (LEN) is a reference treatment in IPSS low and in1 (lower) risk MDS patients with isolated de(5q) (MDS-del(5q)) and RBC - TD. Most low risk MDS-del(5q) patients with anemia and independent of transfusions develop TD or need of treatment for symptomatic anemia very early after diagnosis (median time to transfusion/treatment of 20 months, López Cadenas et al abstract 3180 ASH, 2016). LEN directly targets the del(5q) clone improving anemia, quality of life and survival in this subset of patients. Limited data also suggest a role of LEN in non-TD patients with del(5q) (Oliva et al Cancer Med 2015). However no prospective randomized study of LEN has been performed in this group of patients. Material: The Sintra-Rev clinical trial is a phase III European multicenter study, in low-risk MDS-del(5q) patients, with anemia (Hb<12g/dL) without TD. Patients were randomized in a double-blind design to LEN (5mg/day) vs placebo (2:1 randomization) for 2 years of treatment and 2y of FU. The primary endpoint was the time to TD, the secondary endpoints included erythroid and cytogenetic response (HI-E -IWG 2006 criteria-; minor HI-ER was defined as Hb increase 1 to 1.5 g/dL), overall survival (OS), event free survival (EFS), time to AML and mutational analysis (TP53 and other myeloid genes). Preliminary blinded results of efficacy of the entire cohort after 12 weeks of treatment are reported. Results: Main clinical characteristics of the 58 patients included are summarized in Table 1: 81% were females, median age was 72 years (37-89), median Hb at inclusion 9.8 g/dL(7.1 - 11.7) g/dL and most patients (86%) had isolated del(5q) cytogenetic abnormality. Three patients were excluded due to screening failures and 58 were finally included in the trial. Seven patients discontinued before 12 weeks: Three developed disease progression (defined as TD), two withdrew consent, one due to changes in patient's status and it was not specified in the remaining patient. Therefore, fifty-four patients were finally evaluable for efficacy and 58 for safety at w12. HI-E was observed in 20/54 patients (37%), minor HI-ER in 6/54 (11%), stable disease in 25/54 (46%) and TD (transfusion dependency) in 3 (6%). In the 26 patients achieving HI-E or minor HI-E, the median Hb level rise was 2.2 g/dL (range 1-4.4) and median Hb level was 12.5 g/dL (9.8-14.2). Cytogenetic response (CyR) was available in 41/54 patients: complete in 16 (30%), partial in 9 (17%), no CyR in 16 (30%) and no available in 13 (23%) patients. 54 patients developed adverse events (AE) in the first 12w, most of them hematological and probably related to the treatment. Hematological toxicity occurred in 74% of patients (neutropenia or thrombocytopenia) and only one third was grade 3/4 (neutropenia 35% or thrombocytopenia 3%). Non-hematological adverse events potentially related to the investigational drug were described in 19 patients (35%) but only 2/19 (11%) were grade 3. Nine serious AE were reported in 7 patients: congestive heart failure (2), vestibular neuritis, polyarthritis, arterial hypertensive crisis, carpal arthritis, respiratory infection, chronic obstructive pulmonary disease exacerbation and blurred vision. Only the last one (blurred vision) was potentially related with the study drug Conclusions: In this preliminary and blinded analysis we confirm a high rate of erythroid and cytogenetic responses early (w12) after study treatment with an adequate safety profile. Unblinded data will be presented at the meeting. Disclosures Platzbecker: Celgene: Research Funding. Götze:JAZZ Pharmaceuticals: Honoraria; Takeda: Honoraria, Other: Travel aid ASH 2017; Novartis: Honoraria; Celgene: Honoraria, Research Funding. Díez-Campelo:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

scholarly journals Pracinostat in Combination with Azacitidine Produces a High Rate and Rapid Onset of Disease Remission in Patients with Previously Untreated Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 947-947 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Ehab Atallah ◽  
Olatoyosi Odenike ◽  
Bruno C Medeiros ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Adverse Events ◽  
Board Of Directors ◽  
Null Hypothesis ◽  
Research Funding ◽  
Progressive Disease ◽  
De Novo ◽  
Phase Ii Study ◽  
Advisory Committees

Abstract Background: Pracinostat is a potent oral inhibitor of histone deacetylases (HDAC’s), selective for class I, II and IV isoforms. In-vitro cytotoxicity assays in AML cell lines revealed an IC50 of <0.1µM, and the combination with azacitidine was synergistic (CI=0.44). A Phase I study of single agent pracinostat showed activity in AML and a pilot Phase II study of pracinostat in combination with azacitidine in higher risk MDS demonstrated a complete response (CR)/CR with incomplete blood count recovery (CRi) rate of 89% (Proc ASH:3821, 2012). We report initial results from a Phase II study of pracinostat with azacitidine in previously untreated, elderly AML. Methods: Eligibility includes previously untreated AML (≥ 20% bone marrow blasts), age ≥65 years, deemed inappropriate for intensive induction therapy, with intermediate or high risk cytogenetics based on SWOG criteria. De-novo, treatment-related, or AML evolved from an antecedent hematologic disorder (AHD) are allowed. Pracinostat is administered orally (60 mg) 3 days a week (e.g., Monday, Wednesday, Friday) for 3 weeks followed by a 1 week break. Azacitidine is administered subcutaneously or intravenously (75 mg/m2) day 1-7 or day 1-5 and 8-9 of each 28-day cycle. The primary endpoint is CR+CRi+ morphologic leukemia free state (MLFS) according to IWG criteria. Response assessments occur at the end of cycle 1 or 2 followed by every other cycle or when clinically indicated. A Simon 2-stage statistical design is utilized with the following assumptions: null=0.10, alternate=0.25, α=0.10, power=0.90. Transition from stage 1 to 2 requires ≥ 3/27 response events; the null hypothesis will be rejected if ≥ 7 response events are observed in the total planned sample of 40 patients. Results: As of August 01, 2014, 21 patients have been enrolled from 12 study sites and are evaluable for safety; 14 are evaluable for efficacy (Table 1), and 7 are ‘too early’ for response assessment. Baseline disease characteristics include: median age 77 (range 69-84); 16 de novo AML, 4 evolved from AHD, 1 treatment related; 11 intermediate-risk, 8 high-risk cytogenetics, and 2 are pending; baseline bone marrow blast counts ranged from 22% to 89%. The primary endpoint of CR +CRi+MLFS was observed in 8 of 14 evaluable patients (57%), the majority after 1 or 2 cycles. No responders have progressed. The most common treatment emergent adverse events (TEAE) were neutropenia/neutropenic fever (n=15), thrombocytopenia (n=12), nausea (n=10), fatigue (n=8), and anemia (n=7). Serious adverse events include febrile neutropenia (n=6) and pulmonary infiltrate/pneumonia (n=2). Three patients discontinued study therapy due to a TEAE, including one each with cellulitis, bacteremia, and subdural hematoma after a fall. There have been 3 deaths on study: 1 bacteremia, 1 subdural hematoma, and 1 progressive disease. Abstract 947. Table 1 Patient Number Days on Study Baseline BM Blast % 1st On-Study BM Blast % Subsequent On-Study BM Blast % Best Response on Study 2 172+ 22 1 (C2) --- CR 3 165+ 24 4 (C1) 0 (C4) CRi 5 162+ 27 9 (C1) 1 (C4) CRi 6 156+ 81 9 (C1) 0 (C4) CRi 7 148+ 78 44 (C1) 17 (C3), 0 (C5) CR 8 114+ 89 4 (C1) --- CR 10 86+ 45 3 (C1) --- CRi 12 81+ 41 2 (C2) --- CRi 4 90 22 43 (C2) Off due to SAE SD 11 56 37 60 (C2) --- PD 15 28 70 --- Patient Withdrew 17 28 60 --- PD 1 26 70 --- Off due to AE 9 26 38 --- Off due to AE +=Patients continue on study; C=cycle; SD=Stable Disease; PD=Progressive Disease Conclusions: The study has achieved the primary goal of rejecting the null hypothesis. The CR+CRi +MLFS response rate estimate of 57% is high compared to historical results with hypomethylating agents alone in this population, and the responses occur rapidly, most within the first 2 cycles. The combination appears tolerable with no unexpected toxicities. Recruitment continues to the final planned sample size of 40 to further define the tolerability and efficacy of the regimen, including remission duration. Updated data will be presented at the meeting. Disclosures Garcia-Manero: MEI Pharma, Inc.: Consultancy. Off Label Use: Azacitidine is not approved for use in acute myelogenous leukemia.. Odenike:Sanofi-Aventis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Algeta Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Suneisis Pharmaceuticals : Honoraria, Membership on an entity's Board of Directors or advisory committees. Medeiros:MEI Pharma, Inc: Research Funding. Cortes:Celgene: Research Funding. Esquibel:MEI Pharma, Inc.: Employment. Cha:MEI Pharma, Inc.: Employment. Khaled:Sequenom: Research Funding.

Initial Results of a Phase 2 Study of Guadecitabine (SGI-110), a Novel Subcutaneous (sc) Hypomethylating Agent, for Patients with Previously Untreated Intermediate-2 or High Risk Myelodysplastic Syndromes (MDS) or Chronic Myelomonocytic Leukemia (CMML)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 346-346 ◽  
Author(s):  
Guillermo Montalban-Bravo ◽  
Prithviraj Bose ◽  
Yesid Alvarado ◽  
Naval Daver ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Phase 2 ◽  
Complex Karyotype ◽  
Sequencing Data ◽  
Free Survival ◽  
Biological Features ◽  
Grade 3

Abstract INTRODUCTION: Guadecitabine (SGI-110) is a next generation hypomethylating agent (HMA) formulated as a dinucleotide of decitabine and deoxyguanosine, with an increased length of exposure compared to decitabine due to reduced metabolism by cytidine deaminase. Previous phase 1 and phase 2 clinical trials of guadecitabine demonstrated clinical activity both in untreated and previously treated patients with MDS, with good tolerance. Improving the current response and survival outcomes of patients with higher risk MDS and CMML, particularly in the presence of very high risk biological features, is fundamental. In the current clinical trial we assessed the activity of guadecitabine in patients with higher-risk MDS and CMML as front-line therapy. METHODS: We are conducting a single arm, non-randomized phase 2 clinical trial of guadecitabine for patients with newly diagnosed MDS or CMML classified as Intermediate-2 or High risk by IPSS. Treatment consisted of guadecitabine at a dose of 60mg/m2 sc daily for 5 days (days 1-5) every 28 days. The primary endpoint was complete response (CR). Secondary objectives included overall response rate (ORR), survival and transfusion independence. Responses were evaluated following the revised 2006 International Working Group (IWG) criteria. Sequencing data was obtained at the time of pre-treatment evaluation by the use of a 28-gene next generation sequencing platform. Study included stopping rules for response and toxicity whereby the study would stop if the CR rate was unlikely (chance <2.5%) to improve over standard of care azacitidine (10% CR rate) by more than 15%, or if at any given time the chance of related grade ≥3 non-hematological toxicity being >30% was >95%, respectively. Adverse events (AEs) were assessed and graded according to the CTCAE v4 criteria. Overall survival (OS) was censored at the time of transplant. Event-free survival (EFS) was defined as the time interval between treatment start and date of resistance, progression or death. RESULTS: A total of 40 patients were enrolled between November 2014 and June 2016. Thirty-seven (93%) were evaluable for toxicity and 36 (90%) for response at the time of analysis. Patient characteristics are shown in Table 1. Median age was 67 years (range 48-86). A total of 34 (85%) patients had MDS and 6 (15%) had CMML. Thirty-six (90%) were classified as int-2 risk and 4 (10%) as high risk by IPSS. A total of 9 (23%) had normal karyotype and 18 (45%) had complex karyotype. Sequencing data was available in 38 (95%) patients. Identified mutations are shown in Figure 1A, with TP53 mutations being the most frequently detected in 15 (38%) patients. Following a median of 6 treatment cycles (range 1-17), 10 (28%) subjects met the primary endpoint by achieving CR. ORR was observed in 22 (61%) subjects, with 4 (10%) hematologic improvement (HI) and 9 (23%) CRi defined as mCR+HI. Median best response occurred by 3 cycles (range 1-6). Of subjects evaluable for cytogenetic response, (n-26; 72%), 6 (21%) achieved a complete cytogenetic response (CCyR). Seven (19%) subjects responded sufficiently to be removed from the study and proceed to allogeneic stem cell transplantation. Only one (3%) patient had transformation to acute myeloid leukemia. Median follow up was 4 months (range 0-19 months). Median OS was 15.2 months (95% CI 12.13-18.25 months) (Figure 1B) and median EFS was 10.8 months (95% CI 6.9-14.76 months) (Figure 1C). At the present time of follow up, no significant differences in survival were observed based on achievement of response (NR vs 15 months, p=0.142) or CR (13.6 vs 15.1 months, p=0.474). A total of 31 (84%) patients experienced at least one AE during therapy with 4 (11%) patients having related grade ≥3 non-hematologic AEs including fatigue, febrile neutropenia and oral mucositis. Therefore, stopping rule for toxicity was not met. Most common grade 1-2 AEs included fatigue (35%), nausea (24%) and dyspnea (24%). Dose reductions due to cytopenias were required in 12 (33%) patients. Early 8-week mortality occurred in 2 (5%) patients, one due to non-related cardiac arrest and one due to sepsis. CONCLUSION: Guadecitabine is a well-tolerated and active new HMA for patients with higher-risk MDS and CMML even in the presence of adverse biological features such as high frequency of complex karyotype, therapy related disease and TP53 mutations. Further follow up is required to assess survival benefit in terms of OS and leukemia-free survival. Table 1. Table 1. Figure 1. Figure 1. Disclosures Daver: Pfizer: Consultancy, Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Ariad: Research Funding; BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Otsuka: Consultancy, Honoraria. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. DiNardo:Novartis: Research Funding; Celgene: Research Funding; Daiichi Sankyo: Research Funding; Agios: Research Funding; Abbvie: Research Funding. Jabbour:ARIAD: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy.

scholarly journals Modified STOP-Bang for predicting perioperative adverse events in the Thai population

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Lisa Sangkum ◽  
Chama Wathanavaha ◽  
Visasiri Tantrakul ◽  
Munthana Pothong ◽  
Cherdkiat Karnjanarachata
Keyword(s):  
High Risk ◽  
Adverse Events ◽  
Oxygen Therapy ◽  
Elective Surgery ◽  
Low Risk ◽  
Perioperative Outcomes ◽  
P Value ◽  
Icu Admission ◽  
Obstructive Sleep ◽  
Postanesthetic Care Unit

Abstract Background Undiagnosed obstructive sleep apnea (OSA) is associated with adverse perioperative outcomes. The STOP-Bang questionnaire is a validated screening tool for OSA. However, its precision may vary among different populations. This study determined the association between high-risk OSA based on the modified STOP-Bang questionnaire and perioperative adverse events. Methods This cross-sectional study included patients undergoing elective surgery from December 2018 to February 2019. The modified STOP-Bang questionnaire includes a history of Snoring, daytime Tiredness, Observed apnea, high blood Pressure, Body mass index > 30 kg/m2, Age > 50, Neck circumference > 40 cm, and male Gender. High risk for OSA was considered as a score ≥ 3. Results Overall, 400 patients were included, and 18.3% of patients experienced perioperative adverse events. On the basis of modified STOP-Bang, the incidence of perioperative adverse events was 23.2 and 13.8% in patients with high risk and low risk (P-value 0.016) (Original STOP-Bang: high risk 22.5% vs. low risk 14.7%, P-value 0.043). Neither modified nor original STOP-Bang was associated with perioperative adverse events (adjusted OR 1.91 (95% CI 0.99–3.66), P-value 0.055) vs. 1.69 (95%CI, 0.89–3.21), P-value 0.106). Modified STOP-Bang ≥3 could predict the incidence of difficult ventilation, laryngoscopic view ≥3, need for oxygen therapy during discharge from postanesthetic care unit and ICU admission. Conclusions Neither modified nor original STOP-Bang was significantly associated with perioperative adverse events. However, a modified STOP-Bang ≥3 can help identify patients at risk of difficult airway, need for oxygen therapy, and ICU admission. Trial registrations This study was registered on Thai Clinical Trials Registry, identifier TCTR20181129001, registered 23 November 2018 (Prospectively registered).

Short-term risk stratification using CADILLAC risk score in patients with ST elevation myocardial infarction

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
T Satou ◽  
H Kitahara ◽  
K Ishikawa ◽  
T Nakayama ◽  
Y Fujimoto ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
High Risk ◽  
Adverse Events ◽  
Risk Score ◽  
Risk Group ◽  
Risk Groups ◽  
Low Risk ◽  
Short Term ◽  
Recurrent Myocardial Infarction ◽  
St Elevation

Abstract Background The recent reperfusion therapy for ST-elevation myocardial infarction (STEMI) has made the length of hospital stay shorter without adverse events. CADILLAC risk score is reportedly one of the risk scores predicting the long-term prognosis in STEMI patients. Purpose To invenstigate the usefulness of CADILLAC risk score for predicting short-term outcomes in STEMI patients. Methods Consecutive patients admitted to our university hospital and our medical center with STEMI (excluding shock, arrest case) who underwent primary PCI between January 2012 and April 2018 (n=387) were enrolled in this study. The patients were classified into 3 groups according to the CADILLAC risk score: low risk (n=176), intermediate risk (n=87), and high risk (n=124). Data on adverse events within 30 days after hospitalization, including in-hospital death, sustained ventricular arrhythmia, recurrent myocardial infarction, heart failure requiring intravenous treatment, stroke, or clinical hemorrhage, were collected. Results In the low risk group, adverse events within 30 days were significantly less observed, compared to the intermediate and high risk groups (n=13, 7.4% vs. n=13, 14.9% vs. n=58, 46.8%, p&lt;0.001). In particular, all adverse events occurred within 3 days in the low risk group, although adverse events, such as heart failure (n=4), recurrent myocardial infarction (n=1), stroke (n=1), and gastrointestinal bleeding (n=1), were substantially observed after day 4 of hospitalization in the intermediate and high risk groups. Conclusions In STEMI patients with low CADILLAC risk score, better short-term prognosis was observed compared to the intermediate and high risk groups, and all adverse events occurred within 3 days of hospitalization, suggesting that discharge at day 4 might be safe in this study population. CADILLAC risk score may help stratify patient risk for short-term prognosis and adjust management of STEMI patients. Initial event occurrence timing Funding Acknowledgement Type of funding source: None

scholarly journals Mutational Characteristics and Changing Pattern from Idiopathic Cytopenia of Undetermined Significance to High-Risk Myelodysplastic Syndrome Stratified By IPSS-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3009-3009
Author(s):  
Eun-Ji Choi ◽  
Young-Uk Cho ◽  
Seongsoo Jang ◽  
Chan-jeoung Park ◽  
Han-Seung Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Rna Splicing ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Intermediate Risk ◽  
Sequencing Data ◽  
Undetermined Significance

Background: Unexplained cytopenia comprises a spectrum of hematological diseases from idiopathic cytopenia of undetermined significance (ICUS) to myelodysplastic syndrome (MDS). Revised International Prognostic Scoring System (IPSS-R) is the standard tool to assess risk in MDS. Here, we investigated the occurrence, characteristics, and changing pattern of mutations in patients with ICUS and MDS stratified by IPSS-R score. Methods: A total of 211 patients were enrolled: 73 with ICUS and 138 with MDS. We analyzed the sequencing data of a targeted gene panel assay covering 141 genes using the MiSeqDx platform (Illumina). The lower limit of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Bone marrow components were assessed for the revised diagnosis according to the 2016 WHO classification. Lower-risk (LR) MDS was defined as those cases with very low- or low-risk MDS according to the IPSS-R. Higher-risk (HR) MDS was defined as those cases with high- or very high-risk MDS according to the IPSS-R. Results: Patients with ICUS were classified as very low-risk (39.7%), low-risk (54.8%), and intermediate-risk (5.5%) according to the IPSS-R. Patients with MDS were classified as LR (35.5%), intermediate-risk (30.4%), and HR (34.1%). In the ICUS, 28 (38.4%) patients carried at least one mutation in the recurrently mutated genes in MDS (MDS mutation). The most commonly mutated genes were DNMT3A (11.0%), followed by TET2 (9.6%), BCOR (4.1%), and U2AF1, SRSF2, IDH1 and ETV6 (2.7% for each). IPSS-R classification was not associated with mutational VAF and the number of mutations in ICUS. In the 49 LR MDS, 28 (57.1%) patients carried at least one MDS mutation. The most commonly mutated genes were SF3B1 (20.4%), followed by TET2 (12.2%), U2AF1 (10.2%), DNMT3A (10.2%), ASXL1 (10.2%), and BCOR (6.1%). Higher VAF and number of mutations were observed in LR MDS compared to ICUS patients. In the 42 intermediate-risk MDS, 27 (64.3%) patients carried at least one MDS mutation. The most commonly mutated genes were ASXL1 (23.8%), followed by TET2 (21.4%), RUNX1 (16.7%), U2AF1 (14.3%), DNMT3A (14.3%), SF3B1 (9.5%), and SRSF2, BCOR, STAG2 and CBL (7.1% for each). In the 47 HR MDS, 36 (76.6%) patients carried at least one MDS mutation. The most commonly mutated genes were TET2 (25.5%), followed by DNMT3A (14.9%), TP53 (14.9%), RUNX1 (12.8%), U2AF1 (10.6%), ASXL1 (10.6%), and SRSF2 and KRAS (6.4% for each). As the disease progressed, VAF and number of the MDS mutations gradually increased, and mutations involving RNA splicing, histone modification, transcription factor or p53 pathway had a trend for increasing frequency. Specifically, ASXL1, TP53, and RUNX1 mutations were the most striking features in patients with advanced stage of the disease. Cohesin mutations were not detected in ICUS, whereas these mutations were detected at a relatively high frequency in HR MDS. Our data were summarized in Table 1. Conclusions: We demonstrate that on disease progression, MDS mutations are increased in number as well as are expanded in size. Furthermore, a subset of mutations tends to be enriched for intermediate- to HR MDS. The results of this study can aid both diagnostic and prognostic stratification in patients with unexpected cytopenia. In particular, characterization of MDS mutations can be useful in refining bone marrow diagnosis in challenging situations such as distinguishing LR MDS from ICUS. Disclosures No relevant conflicts of interest to declare.

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