Impact Of The Proportion Of Metaphases With Isolated Del(5q) On Clinical Outcomes In Lenalidomide (LEN)-Treated Patients With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) In MDS-003 and MDS-004

Abstract Introduction The proportion of aberrant metaphases is prognostic for overall survival (OS) in MDS patients with trisomy 8 (Mallo M, et al. Leuk Res. 2011;35:834-6). The impact of the proportion of metaphases with del(5q) on clinical outcomes, including OS, disease progression and response to therapy with LEN in MDS remains undefined. In two large multicenter studies of LEN (MDS-003 and MDS-004) in RBC transfusion-dependent patients with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk del(5q) MDS, RBC transfusion independence (TI) ≥ 8 weeks was achieved in 51–67% of patients (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). This retrospective analysis evaluated response to treatment, progression to acute myeloid leukemia (AML) and OS by proportion of del(5q) metaphases in patients with isolated del(5q) from the MDS-003 and 004 studies. Methods In order to allow sufficient patient numbers for analysis, ≥ 16 metaphases were evaluated for del(5q) by standard karyotyping (MDS-003 and MDS-004) and 200 interphase nuclei were evaluated by fluorescence in situ hybridization (FISH; MDS-004 only) using a probe for the commonly deleted region 5q31 (LSI EGR1/D5S721, Abbott, Wiesbaden, Germany). Patients received LEN on days 1–21 of each 28-day cycle (10 mg) or continuously (5 mg or 10 mg), or placebo. In MDS-004, patients randomized to placebo could cross over to LEN 5 mg by week 16. RBC-TI ≥ 26 weeks, time to AML progression and OS were analyzed by the proportion of del(5q) metaphases or interphases (≤ 60% vs > 60%) using standard karyotyping and FISH, respectively. Results Of the 353 patients from MDS-003 and MDS-004, 194 had isolated del(5q) by standard karyotyping; median proportion of del(5q) metaphases was 96% (range 4–100). Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, platelet and absolute neutrophil counts were comparable among patients with ≤ 60% (n = 21) and > 60% (n = 173) del(5q) metaphases. Rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 0.6515). Time to AML progression was comparable for patients in the ≤ 60% group versus the > 60% group (log-rank test P = 0.9802); 2-year rates were 22.2% (95% confidence interval [CI]: 7.7–54.5%) and 14.6% (95% CI: 9.9–21.2%), respectively. Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.5514). OS was longer in the > 60% versus the ≤ 60% group (log-rank test P = 0.0436); median OS was 3.7 years (95% CI: 3.0–4.2) and 2.4 years (95% CI: 1.5–4.9), respectively. In MDS-004, the proportion of del(5q) interphases was analyzed using FISH in 106 patients, including 46 with ≤ 60% and 60 with > 60%. When analyzed by FISH, rates of RBC-TI ≥ 26 weeks were similar across patients in the ≤ 60% and > 60% groups (P = 1.000). Time to AML progression and OS were similar across these groups (log-rank test P = 0.7311 and P = 0.8639, respectively) when analyzed by FISH. In the ≤ 60% and > 60% groups respectively, 2-year AML progression rates were 14.8% (95% CI: 6.9–30.1%) and 18.6% (95% CI: 10.4–32.0%), and median OS was 3.1 years (95% CI: 2.3–4.8) and 2.9 years (95% CI: 2.3–4.4). Time to AML progression was similar when analyzed with death without AML as competing risk (Gray’s test P = 0.8631). Conclusions In IPSS Low- or Int-1-risk MDS patients with isolated del(5q) treated with LEN in MDS-003 and MDS-004 studies, baseline characteristics, RBC-TI ≥ 26 weeks and AML progression were comparable in patients with > 60% versus ≤ 60% del(5q) metaphases. Although similar across groups when analyzed by FISH in a subset of patients, surprisingly, OS was longer in patients with > 60% del(5q) metaphases than in those with ≤ 60% del(5q) metaphases by standard karyotyping. However, the number of patients with ≤ 60% del(5q) metaphases was limited and no adjustment was made for multiple testing. These findings suggest that the number of cells with the isolated del(5q) abnormality measured by FISH does not impact clinical outcome in this RBC transfusion-dependent study population, but this finding could not be confirmed for OS by standard karyotyping. Disclosures: Giagounidis: Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Hellström-Lindberg:Celgene: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Sekeres:Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Mufti:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene: Consultancy. Morrill:Celgene: Employment, Equity Ownership. Wu:Celgene: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Celgene: Honoraria.

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Prevalence and Clinical Impact of Additional Cytogenetic Abnormalities in Patients (Pts) with Myelodysplastic Syndromes (MDS) and Deletion 5q from the MDS-003 and MDS-004 Studies

Blood ◽

10.1182/blood.v124.21.3270.3270 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3270-3270

Author(s):

Aristoteles Giagounidis ◽

Alan F. List ◽

Eva Hellstrom-Lindberg ◽

Ghulam J. Mufti ◽

Brigitte Schlegelberger ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Clinical Impact ◽

Structural Rearrangements ◽

Employment Equity ◽

Advisory Committees ◽

Cytogenetic Abnormalities ◽

Equity Ownership ◽

Baseline Characteristics ◽

Rbc Transfusion

Abstract Introduction: Around 50% of pts with de novo MDS present with chromosomal abnormalities at diagnosis. One of the most common cytogenetic abnormalities in MDS, deletion 5q [del(5q)], occurs in ~15% of pts (Haase et al. Blood 2007;110:4385-95). The presence of cytogenetic abnormalities in addition to del(5q) may be associated with shorter overall survival (OS) and increased risk of progression to acute myeloid leukemia (AML) versus del(5q) alone (Mallo et al. Leukemia 2011;25:110-20). In 2 large multicenter studies (MDS-003 and MDS-004), lenalidomide (LEN) was evaluated in RBC transfusion-dependent pts with IPSS Low/Intermediate (Int)-1-risk MDS and del(5q) (List et al. N Engl J Med 2006;355:1456-65; Fenaux et al. Blood 2011;118:3765-76). This analysis describes the prevalence and clinical impact of the most common cytogenetic abnormalities in pts with del(5q) from MDS-003 and MDS-004. Methods: Of 353 pts enrolled in MDS-003 and MDS-004, 281 pts had available cytogenetic data with ≥ 16 metaphases evaluable, and were included in the analysis. Pts received 10 mg LEN on days 1–21 of each 28-day cycle; LEN 5 mg or 10 mg continuously; or placebo. In MDS-004, placebo pts could crossover to LEN 5 mg by Week (Wk) 16. Centrally reviewed cytogenetic studies were performed at baseline, and wks 24 and 48 (MDS-003); or baseline, Wk 24, and every 24 wks thereafter (MDS-004). RBC-transfusion independence (RBC-TI) ≥ 26 wks, cytogenetic response (CyR), AML progression, and OS were assessed by most common cytogenetic abnormalities in LEN-treated pts with del(5q) plus 1 additional abnormality. Some pts did not fulfill the IPSS lower-risk classification after central pathologic/cytogenetic evaluation. For this analysis outcomes in the del(5q) plus ≥ 2 additional abnormalities group were not evaluated. Results: Of the 281 pts, 70.8% had isolated del(5q), 19.9% del(5q) plus 1 additional abnormality, and 9.3% had del(5q) plus ≥ 2 additional abnormalities. Baseline characteristics including age, time from diagnosis, RBC transfusion burden, hemoglobin level, and platelet and absolute neutrophil counts were comparable across the cytogenetic groups. In pts with del(5q) plus 1 additional abnormality at baseline, the most common numerical abnormalities were +8 (17.9%; n = 10), +21 (14.3%; n = 8), and −7 (3.6%; n = 2); the most common balanced structural rearrangements were translocation 2;11 [t(2;11)] (5.4%; n = 3) and isochromosome 21q [i(21q)] (3.6%; n = 2); and the most common unbalanced structural rearrangements were del(11q) (7.1%; n = 4), del(20q) (5.4%; n = 3), del(9q) (3.6%; n = 2), and del(12p) (3.6%; n = 2) (Figure). In the del(5q) plus 1 additional abnormality group, baseline characteristics were comparable across pts with +8, +21, or other abnormalities (i.e. excluding those with +21 and +8), with the exception of age (P = 0.023). Rates of RBC-TI ≥ 26 wks and CyR did not significantly differ among LEN-treated pts with +8 (n = 9), +21 (n = 8), or other abnormalities (n = 37). Rates of RBC-TI ≥ 26 wks were 66.7%, 50.0%, and 54.1% (P = 0.839), respectively. In pts evaluable for CyR (n = 40), CyR rates were 42.9%, 42.9%, and 65.4% (P = 0.407), respectively. Median time to AML progression was shorter in LEN-treated pts with +21 (2.6 years [yrs]; 95% CI 1.2–4.8) versus +8 (4.8 yrs; 95% CI 1.6–not estimable) or other abnormalities (7.5 yrs; 95% CI 4.1–7.5) (P = 0.0143). The 5-year AML progression rates were 68.8% (95% CI 26.6–98.7), 85.7% (95% CI 53.5–99.3), and 36.3% (95% CI 19.2–61.3) in pts with +8, +21, or other abnormalities, respectively. Median OS was 4.1 yrs (95% CI 0.9–5.3), 3.0 yrs (95% CI 1.1–4.9), and 3.4 yrs (95% CI 2.6–6.5) (P = 0.423), respectively. Of the 2 pts with −7: 1 pt with Int-1-risk MDS had a 92% to 8% reduction of −7-positive metaphases at Day 84 on treatment, but no RBC-TI ≥ 26 wks, and died at Day 709 without AML; the other Int-2-risk pt progressed to AML on Day 147 with clearance of −7 from 8%, and development of new +8 and del(16q) abnormalities. Conclusions:In MDS pts with del(5q) plus 1 additional abnormality from MDS-003 and MDS-004, the most common cytogenetic abnormalities were +8, +21, del(11q), del(20q), and t(2;11), which accounted for 50% of the additional abnormalities at baseline. In the del(5q) plus 1 additional abnormality population, median time to AML progression was shorter in pts with +21 versus either +8 or other abnormalities. Due to small pt numbers, larger prospective analyses are needed to confirm these observations. Figure 1 Figure 1. Disclosures Giagounidis: Celgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. List:Celgene Corporation: Consultancy. Hellstrom-Lindberg:Celgene: Research Funding. Mufti:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schlegelberger:Celgene Corporation: Consultancy. Morrill:Celgene Corporation: Employment, Equity Ownership. Wu:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Fenaux:Novartis: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding.

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Renal Response in Carfilzomib (K)- Versus Bortezomib (V)-Treated Patients (Pts) with Relapsed or Refractory Multiple Myeloma (RRMM) in the Real-World Practice Setting

Blood ◽

10.1182/blood-2018-99-113519 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3253-3253

Author(s):

Shaji K. Kumar ◽

Alan Fu ◽

Khalid Mezzi ◽

Megan Braunlin ◽

Christopher Kim ◽

...

Keyword(s):

Renal Function ◽

Board Of Directors ◽

Research Funding ◽

Post Treatment ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

Renal Response ◽

Log Rank Test ◽

Equity Ownership

Abstract Introduction: Renal impairment (RI) is a classic clinicopathological feature of MM, is associated with poor prognosis and shorter survival (Eleutherakis-Papaiakovou Leuk Lymphoma 2007), and can complicate drug dosing and limit treatment options. In clinical trials, the proteasome inhibitors K and V have demonstrated efficacy in RRMM pts with RI, with superior efficacy observed in K-treated pts (Dimopoulos Blood 2017). K and V have also been observed to improve renal function in RRMM pts (Dimopoulos Clin Lymphoma Myeloma 2009; Dimopoulos Blood Advances 2017). However, few studies have investigated the real-world effectiveness of K- and V-based regimens in renal rescue. This study aimed to describe and compare renal response rates in RRMM pts treated with K + dexamethasone (Kd) and V + dexamethasone (Vd) in oncology clinics. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database (Lau Clin Epidemiol 2011) contains electronic medical records (EMR) from community- and hospital-affiliated oncology clinics in the United States. MM pts aged ≥18 who entered an OSCER clinic Jan 2012‒Feb 2018; initiated Kd or Vd treatment as line 2 (2L), 3L, or 4L; and had baseline renal impairment (Modification of Diet in Renal Disease Study estimated glomerular filtration rate [eGFR] <50 mL/min from the most recent baseline serum creatinine measurement) were included. Index date was the date of Kd or Vd initiation. The baseline period was 60 d prior to index to 30 d post-index. Follow-up was 30 d after index date to 60 d after completion of the same line. Primary outcome was renal response during follow-up. Renal response was defined according to the International Myeloma Working Group criteria (Dimopoulos J Clin Oncol 2016): complete response (RCR; baseline eGFR <50 mL/min and best post-treatment eGFR ≥60 mL/min), partial response (baseline eGFR <15 mL/min and best post-treatment eGFR 30‒59 mL/min), minor response (baseline eGFR <15 mL/min and best post-treatment eGFR 15‒29 mL/min, or baseline eGFR 15‒29 mL/min and best post-treatment eGFR 30‒59 mL/min). Renal response rates in Kd- and Vd-treated pts were evaluated using the Kaplan-Meier method and log-rank test. Incidence rate ratios (IRR) and 95% confidence intervals (CIs) were calculated for renal overall response (ROR) and RCR using multivariate Cox proportional hazard models adjusted for baseline covariates (demographics, Eastern Cooperative Oncology Group Performance Status, International Staging System stage, baseline renal function, V use in 1L, time from MM diagnosis to line initiation, use of intravenous bisphosphonates, and baseline serum calcium, serum free light chain ratio, lactate dehydrogenase, and whole blood hemoglobin measurements). Missing baseline values were estimated by multiple imputations. Results: 543 Kd-treated and 1005 Vd-treated pts were included. Baseline characteristics were similar between cohorts, with no difference in baseline eGFR stages. More Kd pts were <65 yrs of age at MM diagnosis. Median time from diagnosis to line initiation was longer in Kd pts (Kd: 17.1 mos; Vd 16.1 mos). V-based regimens were the most common therapies in 1L. Median (interquartile range) treatment duration was 4.4 (2.3-8.3) mos for Kd and 4.3 (2.1-8.3) mos for Vd. Pts treated with Kd at 2L were more likely than those treated with Vd to achieve both ROR (51.4% [178/346] vs 39.6% [327/825]; log-rank test p<0.0001) and RCR (26.6% [92/346] vs 22.2% [183/825]; log-rank test p=0.0229). This pattern persisted when 3L and 4L pts were included, (ROR: 48.4% [263/543] vs 39.8% [400/1005]; log-rank p<0.0001; RCR: 26% [141/543] vs 22.1% [222/1005]; log-rank p=0.0084) (Figures 1A and 1B). Following adjustment for potential baseline confounders, 2L Kd pts were 45% more likely to achieve ROR (IRR, 95% CI: 1.45, 1.18‒1.78) and 68% more likely to achieve RCR (1.68, 1.24‒2.28) vs 2L Vd pts (Figure 2). Kd pts in 2‒4L were 36% more likely to achieve ROR (1.36, 1.15‒1.62) and 52% more likely to achieve RCR (1.52, 1.19‒1.94). Conclusions: Using one of the most complete oncology EMR databases available, we found that RRMM pts with baseline RI treated with Kd had higher rates of overall and complete renal response, and were more likely to have a renal response, compared with pts treated with Vd. A limitation of the study is that we could not account for all concomitant medications or comorbidities that affect renal function, as some may not be captured in OSCER. Disclosures Kumar: AbbVie: 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, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Fu:Amgen: Employment, Equity Ownership. Mezzi:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Kim:Amgen: Employment, Equity Ownership. Iskander:Amgen: Employment, Equity Ownership. Niesvizky:Amgen Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Jagannath:Celgene: Consultancy; Novartis: Consultancy; Merck: Consultancy; Medicom: Speakers Bureau; Multiple Myeloma Research Foundation: Speakers Bureau; Bristol-Myers Squibb: Consultancy. Boccia:Sandoz: Consultancy; Celgene: Speakers Bureau; Abbvie: Speakers Bureau; Genentech: Research Funding, Speakers Bureau; Amgen: Research Funding, Speakers Bureau; BMS: Research Funding; Pfizer: Consultancy; AstraZeneca: Research Funding, Speakers Bureau. Raje:Celgene: Consultancy; Janssen: Consultancy; Merck: Consultancy; Takeda: Consultancy; AstraZeneca: Research Funding; Research to Practice: Honoraria; Medscape: Honoraria; BMS: Consultancy; Amgen Inc.: Consultancy.

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Imerge: A Study to Evaluate Imetelstat (GRN163L) in Transfusion-Dependent Subjects with IPSS Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS) That Is Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Treatment

Blood ◽

10.1182/blood-2019-127435 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4248-4248 ◽

Cited By ~ 1

Author(s):

Uwe Platzbecker ◽

David P. Steensma ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Phase 3 ◽

Advisory Committees ◽

Equity Ownership ◽

The Impact ◽

Rbc Transfusion

Background: Current treatment options for red blood cell (RBC) transfusion-dependent (TD) patients with lower risk (LR) myelodysplastic syndromes (MDS) relapsed after or refractory to erythropoiesis-stimulating agents (ESAs) have limited efficacy and durability; new approaches are needed. Imetelstat is a 13-mer lipid-conjugated oligonucleotide that targets the RNA template of human telomerase and is a competitive inhibitor of telomerase enzymatic activity (Asai et al, Cancer Res 2003; Herbert et al, Oncogene 2005). Preclinical, in vivo xenograft models (Dikmen et al, Cancer Res 2005; Hochreiter et al, Clin Cancer Res 2006) and preliminary clinical data from a pilot study conducted at Mayo Clinic (Tefferi et al, Blood Cancer Journal 2016) supported initiation of a study in TD LR MDS patients. A Phase 2 study of imetelstat, IMerge, demonstrated an 8-week RBC transfusion independence (RBC-TI) rate of 42%, 24-week RBC-TI rate of 29%, and 68% erythroid hematologic improvement (HI-E) rate in 38 heavily TD patients (median prior RBC transfusion burden 8 units / 8 weeks over the 16 weeks pre-study period) with LR MDS. Responses were durable with median duration of 8-week RBC-TI of 85.9 weeks by Kaplan Meier estimates (range 8.0-140.9) (Steensma ASH 2018, Fenaux EHA 2019). These Phase 2 results provided further evidence of potential clinical benefit of imetelstat treatment in TD LR MDS, and supported initiation of a Phase 3 trial. Methods: IMerge is two-part, Phase 2/3 study (ClinicalTrials.gov: NCT02598661). The Phase 2 portion of the study described above is closed for enrollment. The Phase 3 portion of the study is open for enrollment of adult patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk, non-del(5q) MDS, who are TD, are relapsed after or refractory to ESAs, and have not received treatment with lenalidomide or hypomethylating agents. The study is a randomized (2:1) double-blind, placebo-controlled trial to compare efficacy of imetelstat vs. placebo that will enroll approximately 170 patients and will be conducted at approximately 90 centers in North America, Europe, Asia and Middle East. Imetelstat will be administered as 2-hour IV infusion every 4 weeks at 7.5 mg/kg. The primary endpoint of the study is to assess the rate of RBC-TI lasting ≥8 weeks. Secondary endpoints include safety, rate of RBC-TI ≥24 weeks, time to RBC-TI start, RBC-TI duration, rate of HI-E, the amount and relative change in RBC transfusions, rate of CR or PR, overall survival, progression of MDS, pharmacokinetics and effect of treatment on quality of life. Biomarkers relevant to the mechanism of action of imetelstat will be assessed to demonstrate target inhibition and their association with clinical responses. Cytogenetics and mutation analyses will be performed to evaluate the impact of imetelstat on reduction/depletion of malignant clones leading to disease modification. Disclosures Platzbecker: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria. Steensma:Astex: Consultancy; Arrowhead: Equity Ownership; Summer Road: Consultancy; Onconova: Consultancy; Aprea: Research Funding; Pfizer: Consultancy; Stemline: Consultancy; H3 Biosciences: Other: Research funding to institution, not investigator.. Santini:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria; Acceleron: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Menarini: Membership on an entity's Board of Directors or advisory committees. Germing:Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria. Font:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Patnaik:Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Sherman:Geron Corporation: Employment, Equity Ownership. Dougherty:Geron Corporation: Employment, Equity Ownership. Feller:Geron Corporation: Employment. Sun:Geron Corporation: Employment, Equity Ownership. Wan:Geron Corporation: Employment, Equity Ownership. Huang:Geron Corporation: Employment, Equity Ownership. Rizo:Geron Corporation: Employment, Equity Ownership. Fenaux:Celgene Corporation: Honoraria, Research Funding; Aprea: Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding.

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Effects of Long-Term Ruxolitinib (RUX) on Bone Marrow (BM) Morphology in Patients with Myelofibrosis (MF) Enrolled in the COMFORT-I Study

Blood ◽

10.1182/blood.v128.22.1949.1949 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1949-1949 ◽

Cited By ~ 3

Author(s):

Hans Michael Kvasnicka ◽

Juergen Thiele ◽

Carlos E. Bueso-Ramos ◽

William Sun ◽

Ahmad Naim ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Rank Test ◽

Employment Equity ◽

Advisory Committees ◽

Signed Rank ◽

Signed Rank Test ◽

Equity Ownership ◽

Grade 3

Abstract Background: MF is a life-shortening complication of myeloproliferative neoplasms associated with ineffective hematopoiesis, splenomegaly, cytopenias, debilitating symptoms, and progressive BM fibrosis The 2 phase 3 COMFORT studies have shown that RUX, an oral Janus kinase (JAK) 1/JAK2 inhibitor, improves splenomegaly, constitutional symptoms, and overall survival in patients with MF. Accumulating evidence suggests that RUX may also modulate the BM microenvironment. Aims: We evaluated the effects of long-term RUX treatment on changes in BM fibrosis in patients with intermediate-2 or high-risk primary MF, post-polycythemia vera MF, or post-essential thrombocythemia MF who were enrolled in the phase 3 COMFORT-I study. Methods: BM biopsies were obtained at baseline (BL), Weeks 48 and 72, and approximately every 48 weeks thereafter for up to 5 years of RUX treatment. Biopsies were reviewed independently in a blinded fashion (blinded for patient and treatment) by 3 hematopathologists (HMK, JT, and CEB-R). The final grading was based on consensus; no disagreements were recorded. The WHO grading system was used to grade BM fibrosis density based on a scale of 0-3 (Thiele et al, Haematologica 2005;90). Other details on the patient population and study design for the COMFORT-I study have been published previously (Verstovsek et al, N Engl J Med 2012;366). Biopsies from 59 patients were included in this exploratory analysis; patients who failed screening or received only 1 BM measurement were excluded. Three subgroups were defined for the analysis: 1) originally randomized to RUX (n=36); 2) randomized to placebo with BM measurements at BL and Week 48 (n=15); and 3) crossover to RUX with BM measurements at BL and ≥1 post-BL measurement after crossover (n=21). Changes from BL in BM fibrosis grades at various time points were categorized for each patient as improvement (-1 to -3), stabilization (0), or worsening (1 to 3). Patients with a BL score of 0 for improvement and 3 for worsening were excluded from the analysis. Patients who received placebo for ≥36 weeks were included in the crossover group, with Week 48 used as the BL BM measurement. RUX and crossover groups were combined for evaluation of RUX effect. Placebo effect in the crossover group was assessed by analyzing change from BL to Week 48. Change from BL was evaluated using a signed rank test. Change from BL to last grade, and time to the first occurrence of a ≥1 grade improvement from BL was assessed for RUX and crossover groups. KM analysis was used to estimate time to improvement in BM fibrosis for a subgroup of patients who had a BM fibrosis grade of ≥1 at BL. Results: BL characteristics for age, gender, International Prognostic Scoring System risk, spleen volume, hemoglobin, and platelet counts were similar between the 3 groups. At BL, of 36 patients originally randomized to RUX, 17% (n=6) presented with WHO-defined fibrosis grade 1, 39% (n=14) with grade 2, and 36% (n=13) with grade 3 (3 patients were grade 0). Of the 15 patients randomized to placebo, 20% (n=3) presented with grade 1, 40% (n=6) with grade 2, and 27% (n=4) with grade 3 WHO-defined fibrosis at BL (2 patients were grade 0). Mean exposure to RUX in the RUX and crossover groups was 136.0 (SD, 67.4) weeks and 129.1 (SD, 67.7) weeks, respectively. The proportion of evaluable patients with an improvement in BM fibrosis from BL to Week 48 was 26% (n=27) in the RUX group and 15.4% (n=13) in the placebo group. When evaluating all patients who received RUX (including placebo crossover), a significant shift was observed from BL to the last change in BM fibrosis grade (P=0.0119; signed rank test). For all RUX-treated patients (n=57), 33% (grade -1, n=11; -2, n=7; -3, n=1) had an improvement, 49% had no change or stabilization, and 18% had a worsening in BM fibrosis from BL to the last grade (Figure). At the final grading, 82% (n=47) of patients had improvement or stabilization while on RUX. Median time to a ≥1 grade improvement in BM fibrosis grade was approximately 3.5 years (95% CI, 2.5 to 4.5; n=51). Conclusions: This analysis from the COMFORT-I study showed that treatment with RUX was associated with improvement and stabilization in WHO-defined BM fibrosis in the majority of patients with MF in this study cohort. These results support evidence from other studies, suggesting that RUX treatment may contribute to disease-modifying effects in MF. The clinical effect of improvement and stabilization in BM fibrosis requires further study. Disclosures Kvasnicka: Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; AOP Pharma: Consultancy, Honoraria. Thiele:Novartis: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria. Sun:Incyte Corporation: Employment, Equity Ownership. Naim:Incyte Corporation: Employment, Equity Ownership. Svaraman:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Gotlib:Incyte Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gupta:Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Dao:Incyte Corporation: Research Funding. Talpaz:Incyte Corporation: Other: Travel expense reimbursement, Research Funding; Novartis: Research Funding; Ariad: Other: Expense reimbursement, travel accomodation expenses, Research Funding; Pfizer: Consultancy, Other: travel accomodation expenses, Research Funding. Winton:Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Verstovsek:AstraZeneca: Research Funding; Roche: Research Funding; Celgene: Research Funding; Lilly Oncology: Research Funding; Galena BioPharma: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Geron: Research Funding; Gilead: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Genentech: Research Funding.

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Results of a Phase I-II Clinical Trial of Oxaliplatin, Fludarabine, Cytarabine, and Rituximab (OFAR) Combination Therapy In Patients with Aggressive, Relapsed/Refractory Chronic Lymphocytic Leukemia (CLL) and Richter Syndrome (RS)

Blood ◽

10.1182/blood.v116.21.923.923 ◽

2010 ◽

Vol 116 (21) ◽

pp. 923-923 ◽

Cited By ~ 2

Author(s):

Apostolia Maria Tsimberidou ◽

William G. Wierda ◽

Sijin Wen ◽

William Plunkett ◽

Susan O'Brien ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Clinical Outcomes ◽

Median Survival ◽

Phase Ii ◽

Research Funding ◽

Response Rate ◽

Rank Test ◽

Advisory Committees ◽

Log Rank Test

Abstract Abstract 923 Background: To enhance the response rate with a decrease in myelosuppression that were observed with oxaliplatin, fluradabine, Ara-C, and rituximab (OFAR1) (Tsimberidou et al, J Clin Oncol, 2008;26:196), the daily dose of oxaliplatin was increased from 25 to 30mg, the daily dose of Ara-C was decreased from 1 g/m2 to 0.5 g/m2 and the optimal number of days of fluradabine and Ara-C administration was explored (OFAR2). Methods: OFAR2 consisted of oxaliplatin 30mg/m2 D1-4; fludarabine 30mg/m2; Ara-C 0.5g/m2; rituximab 375mg/m2 D3; and pelfigrastim 6mg D6. Fludarabine and Ara-C were given on D2-3 (level 1) D2-4 (level 2) or D2-5 (level 3) every 4 weeks. Tumor lysis, DNA virus, and PCP prophylaxis was administered. A “3+3” design was used (Phase I) and and the planned number of patients in the Phase II was 90 (CLL, 60; RS, 30). Results: Overall 102 patients (rel. CLL 67, RS 35) were treated. Twelve patients were treated in the Phase I portion of the study. Dose-limiting toxicities were noted in 2/3 patients at level 3 (G4 diarrhea and G4 sepsis). Level 2 was the maximum tolerated dose. Ninety patients (CLL, 60; RS, 30) were treated in Phase II portion of the study (age > 60 years 67%, 17p del 37.5%, 11q del 15%, 13q del 18%, +12, 17%; neg. 12.5%; unmutated IgVH 81.5%, ZAP70-positive 77%, and CD38 30%, 63%). Response in 80 of 90 patients (Phase II) is shown in Table (too early, n=10). The overall response rates in patients (Phase II) with 17p deletion and 11q deletion were 29% and 41%, respectively. Twenty-nine patients underwent SCT after OFAR2 (response status to OFAR2 at the time of SCT: CR, n=3; nPR, n=2; 15; no response, n=9). With a median follow-up of 20.8 months, the median survival was 19 months (95% CI, 13–37+) and the median FFS was 6 months (95% CI, 3.4 – 8.2). Overall, 238 cycles were administered. G3-4 neutropenia, thrombocytopenia, and anemia were noted in 67%, 74%, and 44% of patients (51%, 64%, and 25% of cycles); and G3-4 infections in 19% of patients. Clinical outcomes of OFAR2 were compared with those of OFAR1. In patients with RS, the overall response rate was 41% (11/27) with OFAR2 and 50% (10/20) with OFAR1 (p = 0.57, Fisher's test); the median survival with OFAR2 and OFAR1 was 8.3 months and 18+ months, respectively (p = 0.92, log-rank test); and the respective median FFS was 3.0 months and 4.1 months (p = 0.40, log-rank test). In patients with CLL, the overall response rate was 55% (29/53) with OFAR2 and 33% (10/30) with OFAR1 (p = 0.36, Fisher's test); the median survival with OFAR2 was 21.4 months and 13.8 months with OFAR1 (p = 0.19, log-rank test); and the respective median FFS was 6.6 months and 4.9 months (p = 0.69, log-rank test). Conclusion: OFAR2 induced response in 41% of patients with RS and 55% of patients with relapsed/refractory CLL in the phase II study. Antileukemic activity was also noted in patients with 17p deletion. Although the numbers of patients are small, OFAR1 was associated with a trend towards superior clinical outcomes in patients with RS compared to OFAR2; and OFAR2 was associated with a trend towards superior clinical outcomes compared to OFAR1 in patients with relapsed/refractory CLL. Disclosures: Tsimberidou: Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; ASCO: Career Development Award, Research Funding. Off Label Use: Drug: Oxaliplatin. Oxaliplatin combined with fludarabine, cytarabine, and rituximab has antileukemic activity in patients with relapsed/refractory Chronic Lymphocytic Leukemia and Richter Syndrome. Wierda:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Micromet: Consultancy, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Research Funding; Abbott Laboratories: Research Funding. O'Brien:Biogen Idec: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Kipps:Sanofi Aventis: Research Funding. Jones:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbott Laboratories: Research Funding.

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Patterns of Care of Aged Chronic Lymphocytic Leukemia Patients in the United States: Systematic Analysis of 457 Patients in the Connect CLL Registry

Blood ◽

10.1182/blood.v124.21.4672.4672 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4672-4672

Author(s):

Chadi Nabhan ◽

Natalie Galanina ◽

Neil E. Kay ◽

Anthony R. Mato ◽

David L. Grinblatt ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

The United States ◽

Initial Therapy ◽

Patterns Of Care ◽

First Line ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Baseline Characteristics

Abstract Introduction: The median age at diagnosis for CLL pts in the US is 72 years. As clinical trials in CLL have largely enrolled younger pt populations, data on disease and pts' characteristics, patterns of care, prognosis, and molecular features in aged CLL pts are limited. With this in mind, we conducted a prospective study to update critical demographic data and patterns of care for aged CLL pt. Patients and Methods: Connect®-CLL is a US-based prospective, longitudinal, multi-center, observational registry that is aimed at understanding patterns of CLL management without a study-specific intervention. We enrolled pts treated at an academic (n=155) or community (n=1340) setting between 2010 and 2014. Eligible pts were adults with a clinical diagnosis of CLL who required therapy 2 or less months after enrollment. Data on demographics, baseline characteristics, and treatment selection are presented here using descriptive statistics. Continuous variables are reported using appropriate measures of dispersion and central tendency (means, medians, ranges and standard deviations) while categorical variables are summarized as number and percentage of the analysis population. Results: Of 1495 enrolled pts, 457 (30.5%) were ≥75 years (57.3% males, 94.2% white). Rai stage III/IV was noted in 33% and B symptoms (predominantly fatigue (58.4%)) were observed in 68.1%. These and other clinical baseline characteristics appeared similar to pts younger than 75 years except that older pts had more prior malignancies (33.5% vs. 19.8%) and co-morbidities (69.3% vs. 53.6%). Cardiac, neurologic, and renal disorders were the most common morbidities in pts ≥75 years (11.5%, 8.8%, and 4.6% respectively). Imaging studies were performed in 157 (60.2%) older pts and in 416 (65.7%) pts less than 75 years prior to initial therapy. Percentage of pts with bulky nodes (> 5 cm) by imaging was similar in the two groups, 19.3% overall. Prognostic biomarker data were available on 247 pts (178 (72%) <75 years; 69 (28%) ≥75 years). While a higher proportion of older pts had CD38+ CLL (55.1% vs. 40.5%, P=0.038), the proportions of patients with ZAP-70+ CLL were similar between the two groups. In total, 137 (9%) older and 378 (25%) younger pts had 17p and 11q analysis by FISH at enrollment prior to first-line therapy. Of these, 27.0% of pts ≥75 years and 20.6% of pts <75 years had a deletion of either 17p or 11q (P=0.125). Out of all pts enrolled in the registry, 894 (60%) received first-line treatment (261 (29%) pts ≥75 years and 633 (71%) <75 years) as their indication for study entry. Amongst these treated pts, interim analysis shows (data cutoff date: 25 June 2014) progressive marrow failure was more commonly used as the indication for therapy in older pts compared to younger pts (52.1% vs. 38.5%; P<0.001), while splenomegaly was a more common cause for therapy in younger pts (16% vs. 9%; P<0.01). Rai stage III/IV at time of first therapy was 46% and 49% for younger and older pts, respectively. Progressive lymphocytosis was used as the indication for therapy in one third of pts regardless of age. Seventy-four percent of older CLL pts received first-line therapies containing rituximab (R) vs. 85% in pts <75 years (P<0.0001). R-bendamustine was the most common first-line regimen for CLL pts ≥75 (23.4%) while FCR was more commonly given to pts <75 years (32.5%). R-monotherapy was used in 18.8% of older pts versus 9.5% in pts <75 years (P<0.0001). Of note, approximately 25% of CLL pts ≥75 years did not receive R-based regimens for initial therapy. Conclusions: Connect®-CLL is the largest prospective, multicenter CLL registry in the United States. CLL Pts ≥75 years more frequently overexpress CD38 and may more commonly demonstrate high risk cytogenetics by FISH, although the difference did not reach statistical significance. Pts ≥75 years also more commonly had co-morbid diseases, and surprisingly 25% did not receive first-line R-based therapy. CLL pts are rarely included in front-line clinical trials (<3%). Given that novel therapies are increasingly available for CLL patients a continued analysis is warranted to determine their use in elderly vs younger patients as well. A longer follow up is needed to evaluate the impact of these findings on outcomes. Disclosures Nabhan: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide in CLL. Kay:Celgene: Research Funding. Mato:Genentech, Celgene, Millenium: Speakers Bureau. Grinblatt:Celgene: Honoraria, Speakers Bureau. Kipps:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lamanna:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Weiss:Celgene: Consultancy. Flinn:Celgene: Research Funding. Swern:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Kristen:Celgene: Employment, Equity Ownership. Flowers:Celgene, Prescription Solutions, Seattle Genetics, Millennium (unpaid), Genentech (unpaid) : Consultancy; Gilead, Spectrum, Millennium, Janssen: Research Funding.

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Imetelstat Treatment Leads to Durable Transfusion Independence (TI) in RBC Transfusion-Dependent (TD), Non-Del(5q) Lower Risk MDS Relapsed/Refractory to Erythropoiesis-Stimulating Agent (ESA) Who Are Lenalidomide (LEN) and HMA Naive

Blood ◽

10.1182/blood-2018-99-114877 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 463-463 ◽

Cited By ~ 5

Author(s):

David P. Steensma ◽

Uwe Platzbecker ◽

Koen Van Eygen ◽

Azra Raza ◽

Valeria Santini ◽

...

Keyword(s):

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

Equity Ownership ◽

Grade 3 ◽

Rbc Transfusion

Abstract BACKGROUND: Patients with TD lower-risk (LR)-MDS relapsed or refractory to ESA have limited treatment options. Imetelstat is a first-in-class telomerase inhibitor that targets cells with short telomere lengths and active telomerase, characteristics observed in some MDS patients. IMerge is an ongoing global study of imetelstat in RBC TD patients with LR-MDS (IPSS Low or Int-1). In the first 32 patients enrolled, 8-week TI rate was 34%, with 24-week TI of 16%, and HI-E of 59%. The most frequently reported adverse events were reversible grade ≥3 cytopenias (Fenaux et al EHA 2018 Abstr S1157). Higher response rates were observed in patients (n=13) who were LEN and HMA naïve without del(5q). We report here results in an additional 25 LEN and HMA naïve patients without del(5q), with longer term follow-up of the 13 initial patients meeting the same criteria. METHODS: IMerge is a phase 2/3 trial (NCT02598661) that includes LR-MDS patients with a high transfusion burden (≥4 units / 8 weeks) who are relapsed/refractory to ESA or have sEPO >500 mU/mL. The additional 25 were required to be LEN and HMA naïve and lack del(5q). Imetelstat 7.5 mg/kg was administered IV every 4 weeks. In addition to the key endpoints noted above, secondary endpoints include safety, time to and duration of TI. Biomarkers are also being explored, including telomerase activity, hTERT, telomere length, and genetic mutations. RESULTS: Overall, for the 38 LEN/HMA naïve and non-del(5q) patients, median age was 71.5 years and 66% were men. 63% of patients were IPSS Low and 37% Int-1. Median prior RBC transfusion burden was 8.0 (range 4-14) U, and 71% had WHO 2008 RARS or RCMD-RS. 9/37 (24%) patients with evaluable sEPO levels had baseline level >500 mU/mL. As of July 2018, with a median follow-up of 25.8 months for the initial 13 patients, and 5.2 months for the 25 recently included patients, the 8-week RBC-TI rate was 37% (14/38). Durability of 24-week TI responses was demonstrated, with a median duration of 10 months and the longest ongoing response now >2 years. Among the patients achieving durable TI, all showed a Hb rise of ≥3.0 g/dL compared to baseline during the transfusion-free interval. Response rates were similar in RARS/RCMD-RS (33% [9/27]) and other patients (27% [3/11]), and those with baseline EPO levels >500 mU/mL (33% [3/9]) and ≤500 mU/mL (32% [9/28]). Reversible grade ≥3 neutropenia and thrombocytopenia were each reported in 58% of the patients. Liver function test (LFT) elevations were mostly grade 1/2. Reversible grade 3 LFTelevations were observed in 3 (8%) patients on study. An independent Hepatic Review Committee deemed the observed LFT elevations were not imetelstat-related hepatic toxicities. SUMMARY / CONCLUSIONS: In this cohort of 38 non-del(5q) LR-MDS patients with a high RBC transfusion burden who were ESA relapsed/refractory and naïve to LEN/HMA, single-agent imetelstat yielded a TI rate of 37%, with a median duration of 10 months and limited side effects. Durable responses were characterized by transfusion independence >24 weeks and accompanied by Hb rise. Updated data will be presented. Disclosures Steensma: Takeda: Consultancy; Syros: Research Funding; Otsuka: Membership on an entity's Board of Directors or advisory committees; Onconova: Consultancy; Novartis: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Janssen: Consultancy, Research Funding; H3 Biosciences: Research Funding; Celgene: Research Funding; Amphivena: Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy. Platzbecker:Celgene: Research Funding. Van Eygen:Janssen: Consultancy, Research Funding; Roche: Research Funding; Amgen: Research Funding. Raza:Kura Oncology: Research Funding; Onconova: Research Funding, Speakers Bureau; Celgene: Research Funding; Novartis: Speakers Bureau; Geoptix: Speakers Bureau; Janssen: Research Funding; Syros: Research Funding. Santini:Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Font:Celgene: Membership on an entity's Board of Directors or advisory committees. Samarina:Janssen: Research Funding. Díez-Campelo:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Bussolari:Janssen: Employment, Equity Ownership. Sherman:Janssen: Employment, Equity Ownership. Sun:Janssen: Employment, Equity Ownership. Varsos:Janssen: Employment, Equity Ownership. Rose:Janssen: Employment, Equity Ownership. Fenaux:Roche: Honoraria; Otsuka: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

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Clinical Outcomes with Ruxolitinib (RUX) in Patients with Myelofibrosis (MF) Stratified By Transfusion Status: A Pooled Analysis of the COMFORT-I and -II Trials

Blood ◽

10.1182/blood.v128.22.3118.3118 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3118-3118 ◽

Cited By ~ 1

Author(s):

Vikas Gupta ◽

Srdan Verstovsek ◽

Ronald Paquette ◽

Jason R. Gotlib ◽

Alessandro M. Vannucchi ◽

...

Keyword(s):

Board Of Directors ◽

Clinical Outcomes ◽

Research Funding ◽

Control Group ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Transfusion Independence ◽

First Occurrence ◽

Equity Ownership

Abstract Background: The phase 3 COMFORT trials demonstrated that the Janus kinase (JAK)1/JAK2 inhibitor RUX reduces spleen volume, prolongs overall survival (OS), and improves MF−related symptoms and measures of quality of life in patients with intermediate-2 or high-risk MF, compared with either placebo (COMFORT-I) or best available treatment (BAT; COMFORT-II). Many patients with MF are anemic or transfusion-dependent; the impact of these features on clinical outcomes is unknown. We evaluated the relationship between transfusion requirement and clinical outcomes in patients treated with RUX in the COMFORT studies. Methods: Analyses of data pooled from COMFORT-I and -II were stratified by baseline anemia status (defined as receiving ≥2 units of red blood cells [RBCs] within the 12 weeks before baseline or baseline hemoglobin [Hb] <10 g/dL). Transfusion independence was defined as the absence of RBC transfusions and maintenance of Hb levels ≥8 g/dL for ≥12 weeks; transfusion dependence was defined as a requirement for ≥4 units of RBCs or Hb levels <8 g/dL during an 8-week interval (Gupta V, et al. JCO [ASCO Abstracts]. 2015;33[s15]:abstract TPS7102). Patients achieving transfusion independence during Weeks 13-24 were considered responders for independence by Week 24; those developing transfusion dependence during Weeks 17-24 were considered dependent by Week 24. Effects of transfusion status at Week 24 on MF Symptom Assessment Form total symptom scores (TSS), spleen volume, and body weight were assessed descriptively. The effect on OS was evaluated using the landmark approach (including patients completing ≥24 weeks of study treatment) with stratified log-rank tests for responder vs nonresponder comparisons. Times to first occurrence of transfusion independence and first occurrence of transfusion dependence in the ITT population (censored at last clinical visit), and time to discontinuation among patients in the RUX group who were anemic at baseline (censored at Week 240) were analyzed using the Kaplan-Meier method. Results: Overall, 301 patients were randomized to RUX (baseline anemia, n=138 [45.8%]) and 227 to the control group (placebo or BAT; baseline anemia, n=113 [49.8%]). In the RUX group, a greater proportion of patients who were nonanemic at baseline (range, 73.4%-73.8%) achieved transfusion independence compared with those who had anemia at baseline (range, 15.5%-22.4%). Week 24 transfusion independence vs nonindependence status did not significantly affect OS in the RUX group (P=0.1322; Figure A), whereas it was significant (P=0.0004; Figure B) in the control group. Similarly, Week 24 transfusion dependence vs nondependence status did not significantly affect OS in the RUX group (P=0.4547; Figure C), whereas it was significant (P=0.0323; Figure D) in the control group. Median OS was significantly longer in the RUX vs control group for patients who were not transfusion independent (baseline anemia, 200 vs 137 weeks; nonanemic, 271 vs 166 weeks; overall P=0.002) or became transfusion dependent (baseline anemia, 210 vs 127 weeks; nonanemic, 292 vs 90 weeks; overall P=0.0323). Changes from baseline in spleen volume, body weight, and TSS at Week 24 were not affected by transfusion or anemia status in the RUX group; however, TSS worsened in the control group among patients who did not achieve transfusion independence vs those who did. Risk of transfusion dependence decreased after Week 24 in the RUX group. The probability of becoming transfusion independent after 1 year of treatment was similar in both treatment groups (approximately 0.75); median time to transfusion independence for the RUX and control groups was 16.6 and 12.0 weeks, respectively. For patients in the RUX group who became transfusion dependent, the mean monthly units of RBCs peaked at Week 20 (2.82 units), decreasing thereafter to 0.52 units at Week 240. Transfusion dependence did not affect RUX discontinuation rates or dosage. Conclusion: Transfusion requirement had little impact on clinical outcomes or treatment discontinuation within the RUX group but was associated with reduced OS and worsened TSS in the control group. The risk of becoming transfusion dependent, units of RBCs administered, and the monthly proportion of patients requiring transfusions decreased rapidly after 24 weeks of RUX treatment. Disclosures Gupta: Novartis: Consultancy, Honoraria, Research Funding; Incyte Corporation: Consultancy, Research Funding. Verstovsek:Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; CTI BioPharma Corp: Research Funding; Galena BioPharma: Research Funding; Gilead: Research Funding; NS Pharma: Research Funding; Promedior: Research Funding; Seattle Genetics: Research Funding; Celgene: Research Funding; Geron: Research Funding; Lilly Oncology: Research Funding; AstraZeneca: Research Funding; Roche: Research Funding; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Paquette:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Kiladjian:AOP Orphan: Research Funding; Novartis: Research Funding. Cervantes:AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sun:Incyte Corporation: Employment, Equity Ownership. Gao:Incyte Corporation: Employment, Equity Ownership. Langmuir:Incyte Corporation: Employment, Equity Ownership. Gopalakrishna:Novartis Pharma AG: Employment, Equity Ownership. Harrison:Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Shire: Honoraria, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Baxaltra: Consultancy, Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau.

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Hepcidin Suppression By Momelotinib Is Associated with Increased Iron Availability and Erythropoiesis in Transfusion-Dependent Myelofibrosis Patients

Blood ◽

10.1182/blood-2018-99-111349 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4282-4282 ◽

Cited By ~ 3

Author(s):

Stephen T Oh ◽

Moshe Talpaz ◽

Aaron T. Gerds ◽

Vikas Gupta ◽

Srdan Verstovsek ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Serum Iron ◽

Iron Availability ◽

Spleen Volume ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

La Jolla ◽

Rbc Transfusion

Abstract Introduction: Patients develop anemia as a result of myelofibrosis (MF) or its treatment, including Janus kinase (JAK) inhibitors. However, momelotinib (MMB), a JAK1/2 and Activin A receptor type I (ACVR1) inhibitor with demonstrated clinical activity in MF, improved anemia in prior clinical trials. JAK1/2 and ACVR1 respond to inflammation and iron stores to control iron availability through hepcidin, the key regulator of the entry of iron into circulation. Like other inflammatory diseases, MF is characterized by high hepcidin. MMB inhibited ACVR1 to modulate hepcidin and ameliorate anemia in a rodent model (Asshoff, Blood 2017). The impact of MMB was investigated on blood hepcidin, along with markers of iron storage and availability, erythropoiesis, and inflammation to explore mechanisms of the favorable effects of MMB on MF-associated anemia. Methods: In a phase 2 open-label study, MMB 200 mg once daily was given for 24 weeks to transfusion-dependent (TD; ≥4 units red blood cells [RBC] transfusion in the 8 weeks prior to first dose of MMB) patients with primary or post-ET/PV MF (age ≥18 yrs, required MF therapy, CrCl ≥ 60 mL/min, platelets ≥50 K, and absence of Gr ≥2 peripheral neuropathy, baseline palpable spleen was not required, patients with prior splenectomy were excluded). Patients were evaluated for MMB efficacy and safety. Total symptom score (TSS) was based on a modified Myeloproliferative Neoplasm Symptom Assessment Form. Transfusion-independent response/non-response (TI-R/NR) was defined as RBC transfusion-independence ≥12 weeks at any time on study. Serial blood samples were analyzed for a panel of biomarkers and liver iron content (LIC) was measured by MRI. Blood hepcidin was evaluated at every study visit in the morning (8-10am) pre-dose and 6 hours post-dose using a mass spectrometry assay and, prior to first dose, the normal daily increase of blood hepcidin was observed in half the population. Results: 41 patients (mean age 70, 63% male, 88% white) received MMB. By week 24, 14 (34.1%, 90% CI: 22.0-48.1%) patients had a TI-R and 39.0% had no RBC transfusion for ≥8 weeks at any time (90% CI: 26.2-53.1%). Six patients (15.8%, 90% CI: 7.1-28.8%) had a ≥50% reduction from baseline to week 24 in TSS and 5 patients (12.2%, 90% CI: 4.9-23.9%) had a ≥35% reduction in spleen volume; in those patients with week 24 data, the TSS and splenic response rates were 28.6% and 19.2% respectively. TSS and spleen volume assessments were not available for 17 (44.5%) and 15 (36.6%) patients, respectively, and these patients were considered non-responders. Adverse events were consistent with previous studies of MMB in MF, with cough, diarrhea, nausea, and fatigue as the most common. AEs ≥Gr 3 were experienced by 21 patients, most commonly anemia and neutropenia. At every study visit, median blood hepcidin decreased 6 hours after dosing with MMB (Fig. 1). Daily inhibition of hepcidin did not lead to an increase in serum iron for the entire population. However, serum iron, transferrin, hemoglobin, reticulocytes, and hematocrit increased at week 2 in patients with TI-R. Following this peak, serum iron decreased while hemoglobin, hematocrit and platelet count increased through week 24. At baseline, TI-R was associated with lower hepcidin, LIC, serum iron, reduced inflammation (C-reactive protein and ferritin), and higher hematocrit, erythrocytes, reticulocytes, platelets, and hemoglobin than TI-NR (Fig. 2). In multivariable analysis, TI-R was strongly associated with baseline hemoglobin ≥8g/dL (p=0.036) and lower morning hepcidin (p=0.013), weakly associated with younger age (p=0.070) and lower DIPSS score (p=0.075), but not with gender, type of MF (primary vs post-ET/PV), spleen volume, TSS, or JAK2V617F mutation. Conclusion: Safety findings and rate of TI-R were similar to TD MF patients in other MMB trials. Consistent with preclinical data, daily MMB treatment led to a transient decrease in blood hepcidin. In patients with TI-R, hepcidin suppression was associated with increased iron availability and markers of erythropoiesis. At baseline, TI-R associated with reduced inflammation, lower hepcidin, and increased markers of erythropoiesis and bone marrow function. Overall, the study suggests that transient modulation of hepcidin by MMB is sufficient to boost erythropoiesis in those transfusion-independent MF patients with lower baseline inflammation and greater erythropoietic potential. Disclosures Oh: Takeda: Research Funding; Janssen: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gerds:Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees. Mesa:Novartis: Consultancy; Celgene: Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; Incyte Corporation: Research Funding; Promedior: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Gilead: Research Funding; UT Health San Antonio - Mays Cancer Center: Employment. Miller:Gilead Sciences, Inc.: Consultancy, Research Funding; Incyte: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Heaney:Decipheral: Research Funding; Novartis: Research Funding; Blueprint: Research Funding; Incyte: Research Funding; Roche: Consultancy, Research Funding. O'Connell:Incyte: Research Funding. Arcasoy:Gilead Sciences, Inc.: Research Funding; Incyte: Research Funding; CTI BioPharma: Research Funding; Samus Therapeutics: Research Funding. Zhang:Gilead Sciences, Inc.: Employment. Kawashima:Gilead Sciences, Inc.: Employment, Equity Ownership. Ganz:Intrinsic LifeScience: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Silarus Pharma: Consultancy, Equity Ownership; Keryx Pharma: Consultancy, Research Funding; Akebia: Consultancy, Research Funding; Vifor: Consultancy; Gilead: Consultancy; Ablynx: Consultancy; La Jolla Pharma: Consultancy, Patents & Royalties: Patent licensed to La Jolla Pharma by UCLA. Baker Brachmann:Gilead Sciences, Inc.: Employment, Equity Ownership.

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Progression-Free Survival Analysis of Denosumab Vs Zoledronic Acid in Intent to Transplant Multiple Myeloma Patients Based on Treatment Regimen and Baseline Characteristics

Blood ◽

10.1182/blood-2019-127290 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 606-606 ◽

Cited By ~ 7

Author(s):

Evangelos Terpos ◽

Ramón García-Sanz ◽

Kazuyuki Shimizu ◽

Wolfgang Willenbacher ◽

Anthony Glennane ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Board Of Directors ◽

Research Funding ◽

Performance Status ◽

Employment Equity ◽

Advisory Committees ◽

Treatment Regimens ◽

Equity Ownership ◽

Baseline Characteristics

Introduction: Denosumab is a monoclonal antibody targeting Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) that has been shown to reduce skeletal related events associated with bone lesions in patients with multiple myeloma and solid tumors. Results from the full primary analysis of 1718 patients with newly diagnosed multiple myeloma in an international double blind, randomized, controlled phase 3 (20090482) study that assessed the efficacy of denosumab (Dmab) vs zoledronic acid (ZA) for preventing SREs met its primary end point of non-inferiority regarding time to first SRE. The analysis of the PFS exploratory endpoint showed a clinically meaningful 10.7 months median PFS benefit (HR, 0.82; 95% CI, 0.68-0.99; descriptive P= 0.036) of Dmab vs ZA. This benefit was most pronounced in patients who were stratified into the "intent to undergo Autologous Stem Cell Transplant (ASCT)" group at randomization. Thus, we present an in-depth analysis of relevant baseline characteristics, treatment regimens and PFS outcome in patients with intent to undergo transplant receiving Dmab and ZA. Methods: Adult patients with newly diagnosed multiple myeloma (NDMM) and stratified as "intent to undergo ASCT" at randomization were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. In this subgroup, the PFS outcome was examined. Baseline characteristics and treatment regimens were compared between treatment arms. Results: 54.1% of the 1718 enrolled patients were stratified into "intent to undergo ASCT" as part of their front-line therapy, and 61.8% of "intent to undergo ASCT" did receive an ASCT. In the "intent to undergo ASCT" group, 19.6% patients had disease progression in the Dmab arm compared to 28.0% in the ZA arm (HR 0.65 (0.49-0.85)) (Figure 1). No imbalance in terms of triplet therapy use between the two study arms (TABLE 1). 55.1% in Dmab vs 52.6% in ZA arm received Triplet Therapies which included Bortezomib, Cyclophosphamide, Dexamethasone (VCD), Bortezomib, Thalidomide, Dexamethasone (VTD), Cyclophosphamide, Thalidomide, Dexamethasone (CTD), or Bortezomib, Lenalidomide, Dexamethasone (VRD). The percentage of triplet therapies used in the "intent to undergo ASCT"patients was higher than in patients with no intent to undergo ASCT. Percentage of patients with ECOG performance status 2 was 19.4% in the Dmab group vs 18.6% in the ZA group. 26.2% of patients in the Dmab arm and 25% in the ZA arm had Multiple Myeloma ISS stage III upon diagnosis. Among intent to transplant patients there was no imbalance in terms of age, performance status, ISS stage, risk status, weight, bone marrow plasma cell % between the ZA and the Dmab arm Conclusion: Results from this post-hoc subgroup analysis suggest a more profound PFS benefit in the "intent to undergo ASCT" patient subgroup. Multiple myeloma treatment received in the intent to undergo transplant subjects was similar between the denosumab and zoledronic acid arms. No significant imbalance in demographics or baseline disease characteristics was observed between the two treatment arms. Disclosures Terpos: Janssen: Honoraria, Other: Travel expenses, Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria, Other: Travel expenses, Research Funding; Medison: Honoraria; Genesis: Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria. Shimizu:Medical Biological Laboratory: Consultancy; Takeda: Speakers Bureau; Daiichi: Consultancy; Amgen: Consultancy; Fujimoto: Consultancy. Willenbacher:Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; oncotyrol: Employment, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees. Glennane:amgen: Employment, Equity Ownership. Dai:Amgen: Employment, Equity Ownership. Pasteiner:Amgen: Employment, Equity Ownership. Raje:Amgen Inc.: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene Corporation: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Merck: Consultancy.

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