ACE-536 Increases Hemoglobin and Reduces Transfusion Burden in Patients with Low or Intermediate-1 Risk Myelodysplastic Syndromes (MDS): Preliminary Results from a Phase 2 Study

Abstract Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis, such as myelodysplastic syndromes (MDS). Patients with MDS often have elevated levels of erythropoietin (EPO) and may be non-responsive or refractory to erythropoiesis-stimulating agents (ESAs). MDS patients have also been shown to have increased serum GDF11 levels (Suragani R et al., Nature Medicine 2014) and increased Smad 2/3 signaling in the bone marrow (Zhou L et al., Blood 2008). ACE-536 binds to ligands in the TGF-ß superfamily, including GDF11, inhibits Smad 2/3 signaling, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. RAP-536 (murine version of ACE-536) reduced Smad 2 signaling, increased hemoglobin (Hb) levels and decreased bone marrow erythroid hyperplasia in a mouse model of MDS (Suragani R et al., Nature Medicine 2014). In a healthy volunteer study, ACE-536 was well-tolerated and increased Hb levels (Attie K et al., Am J Hematol 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 on anemia in patients with Low or Int-1 risk MDS who have either high transfusion burden (HTB, defined as ≥4 units RBCs/8 weeks prior to baseline) or low transfusion burden (LTB, defined as <4 units RBCs/8 weeks prior to baseline). Study outcomes include erythroid response (either Hb increase in LTB patients or reduced transfusion burden in HTB patients), safety, tolerability, PK, and PD biomarkers. Methods.Inclusion criteria included Low or Int-1 risk MDS, age ≥ 18 yr, anemia (defined as either being HTB patient or having baseline Hb < 10.0 g/dL in LTB patient), EPO >500 U/L or nonresponsive/refractory to ESAs, no prior azacitidine or decitabine, and no current treatment with ESA, G-CSF, GM-CSF, or lenalidomide. In the dose escalation phase, ACE-536 was administered by subcutaneous (SC) injection once every 3 weeks in 7 sequential cohorts (n=3-6) at dose levels of 0.125, 0.25, 0.5, 0.75, 1.0, 1.33 and 1.75 mg/kg for up to 5 doses with a 3-month follow-up. An expansion cohort (n=30) is planned, and all patients completing this study may enroll in a 12-month extension study. Results. Preliminary data were available for 26 patients (7 LTB/19 HTB) as of 18 Jul 2014. Median age was 71 yr (range: 27-88 yr), 50% were female, 54% had prior EPO therapy and 15% had prior lenalidomide. 69% were WHO subtype RCMD, and the remaining patients were del(5q), RARS, or RAEB-1. Mean (SD) baseline Hgb for the LTB patients (n=7) was 9.1 (0.4) g/dL. Mean (SD) units RBC transfused in the 8 weeks prior to treatment was 0.9 (1.1) units for the LTB patients and 6.3 (2.4) units for the HTB patients. Two of the 7 LTB patients had an increase in mean Hb ≥1.5 g/dL over 8 weeks compared to baseline. Mean maximum Hb increase in the LTB patients was 0.8, 1.0, 2.2, and 2.7 g/dL in the 0.125 (n=1), 0.25 (n=1), 0.75 (n=3), and 1.75 (n=2) mg/kg dose groups, respectively. Six of the 7 LTB patients achieved RBC transfusion independence (RBC-TI) for ≥8 weeks during the study. Six of the 19 HTB patients had a ≥4 unit or ≥50% reduction in RBC units transfused over an 8-week interval during the treatment period compared to the 8 weeks prior to treatment; five of these 6 patients achieved RBC-TI ≥ 8 weeks during the study (range 71-152 days). Increases in neutrophil count following study drug administration were observed in some patients. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent adverse events regardless of causality were: diarrhea (n=4, grade 1/2), bone pain, fatigue, muscle spasms, myalgia, and nasopharyngitis (n=3 each, grade 1/2). Conclusions. Based on preliminary data in Low or Int-1 MDS patients, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels or decreased transfusion requirement, with a favorable safety profile. These data strongly support further evaluation of longer-term treatment with ACE-536 in patients with MDS. Disclosures Platzbecker: Celgene: Honoraria, Research Funding. Germing:Celgene: Honoraria, Research Funding. Goetze:Celgene Corp: Honoraria; Novartis Pharma: Honoraria. Radsak:Celgene: Research Funding. Hankin:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

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ACE-536 Increases Hemoglobin and Decreases Transfusion Burden and Serum Ferritin in Adults with Beta-Thalassemia: Preliminary Results from a Phase 2 Study

Blood ◽

10.1182/blood.v124.21.53.53 ◽

2014 ◽

Vol 124 (21) ◽

pp. 53-53 ◽

Cited By ~ 3

Author(s):

Antonio G. Piga ◽

Silverio Perrotta ◽

Angela Melpignano ◽

Caterina Borgna-Pignatti ◽

Ersi Voskaridou ◽

...

Keyword(s):

Adverse Events ◽

Serum Ferritin ◽

Preliminary Data ◽

Late Stage ◽

Research Funding ◽

Beta Thalassemia ◽

Phase 2 ◽

Employment Equity ◽

Efficacy Data ◽

Equity Ownership

Abstract Introduction. ACE-536, a recombinant fusion protein containing modified activin receptor type IIB and IgG Fc, is being developed for the treatment of anemias due to ineffective erythropoiesis (IE), such as beta-thalassemia (β-thal). In β-thal, IE is due to intracellular α-globin aggregates causing premature death of late-stage erythroid precursors. Patients with β-thal often have elevated levels of EPO and are unresponsive to erythropoiesis-stimulating agents (ESAs). ACE-536 binds to ligands in the TGF-β superfamily, such as GDF11, and promotes late-stage erythroid differentiation via a mechanism distinct from ESAs. In a healthy volunteer study, ACE-536 was well-tolerated and increased hemoglobin (Hb) levels (Attie K et al., Am J Hematol 2014). Murine ACE-536 (RAP-536) increased Hb levels and decreased RBC inclusion bodies and hemolysis in a mouse model of β-thal (Suragani R et al., Blood 2014). Aims. This is an ongoing, phase 2, multicenter, open-label, dose-finding study to evaluate the effects of ACE-536 in adults with transfusion-dependent (TD, defined as ≥4 units RBCs/8 weeks prior to baseline) or non-transfusion dependent (NTD, defined as <4 units RBCs/8 weeks prior to baseline) β-thalassemia. Study outcomes include erythroid response (either Hb increase in NTD patients or reduced RBC transfusion burden in TD patients), safety, tolerability, PK, and pharmacodynamic biomarkers. Methods. Inclusion criteria included age ≥ 18 yr and anemia, defined as either being TD patient or having baseline Hb <10.0 g/dL in NTD patient. Transfusion burden in TD patients for any 12 weeks on treatment was compared with the 12 weeks prior to treatment. ACE-536 was administered by subcutaneous injection once every 3 weeks for up to 5 doses with a 2-month follow-up. Study design includes sequential cohorts (n=6 patients/cohort) at dose levels of 0.2, 0.4, 0.6, 0.8, 1.0, 1.25 and 1.5 mg/kg. An expansion cohort (n=30) is planned, and all patients completing this study may be eligible to enroll in a 12-month extension study. Results. Preliminary data were available for the 30 patients (23 NTD/7 TD) enrolled in the first 5 cohorts as of 18 Jul 2014. Median age was 34.5 yr (range: 20-57 yr), 16 (53%) were male and 83% had prior splenectomy. Mean (SD) baseline Hb for the NTD patients was 8.3 (0.9) g/dL. Efficacy data for the NTD patients in the 0.6 to 1.0 mg/kg cohorts demonstrated a maximum increase from baseline in Hb ≥ 1.5 g/dL in 7 of 11 (64%) patients. Efficacy data for the 7 TD patients treated in the 0.6 to 1.0 mg/kg cohorts demonstrated a >50% reduction in transfusion burden for all 7 patients. This was accompanied by a maximum decrease from baseline in serum ferritin levels ranging from 12-60%. Reductions in liver iron concentration by MRI were observed in both NTD and TD patients. Two patients with long-standing leg ulcers at baseline (one NTD, one TD) healed within approximately 3 months of ACE-536 treatment. ACE-536 was generally well tolerated. No related serious adverse events have been reported to date. The most frequent related adverse events included bone pain, headache and myalgia. No notable changes in platelets or WBC were observed. Conclusions. Based on preliminary data, ACE-536 administered SC every 3 weeks for up to 5 doses increased Hb levels in NTD patients and decreased transfusion requirement and serum ferritin levels in TD patients with β-thalassemia via a novel mechanism of action, and demonstrated a favorable safety profile. These data strongly support further evaluation of ACE-536 in patients with β-thalassemia. Disclosures Piga: Acceleron Pharma: Research Funding; Celgene: Honoraria; Novartis: Research Funding; ApoPharma: Research Funding. Voskaridou:Celgene Coporation: Membership on an entity's Board of Directors or advisory committees. Condon:Acceleron Pharma: Employment, Equity Ownership. Wilson:Acceleron Pharma: Employment, Equity Ownership. Sherman:Acceleron Pharma: Employment, Equity Ownership. Attie:Acceleron Pharma: Employment, Equity Ownership.

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Rapid and Robust Mobilization of CD34+ HSCs without G-CSF Following Administration of Mgta-145 Alone or in Combination with Plerixafor

Blood ◽

10.1182/blood-2019-127523 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1961-1961

Author(s):

John F. DiPersio ◽

Jonathan Hoggatt ◽

Steven Devine ◽

Lukasz Biernat ◽

Haley Howell ◽

...

Keyword(s):

Single Dose ◽

Adverse Events ◽

Board Of Directors ◽

Preliminary Data ◽

Research Funding ◽

Fold Change ◽

Employment Equity ◽

Advisory Committees ◽

Cd34 Cells ◽

Equity Ownership

Background Granulocyte colony-stimulating factor (G-CSF) is the standard of care for mobilization of hematopoietic stem cells (HSCs). G-CSF requires 4-7 days of injections and often multiple aphereses to acquire sufficient CD34+ cells for transplant. The number of CD34+ HSCs mobilized can be variable and patients who fail to mobilize enough CD34+ cells are treated with the combination of G-CSF plus plerixafor. G-CSF use is associated with bone pain, nausea, headaches, fatigue, rare episodes of splenic rupture, and is contraindicated for patients with autoimmune and sickle cell disease. MGTA-145 (GroβT) is a CXCR2 agonist. MGTA-145, in combination with plerixafor, a CXCR4 inhibitor, has the potential to rapidly and reliably mobilize robust numbers of HSCs with a single dose and same-day apheresis for transplant that is free from G-CSF. MGTA-145 plus plerixafor work synergistically to rapidly mobilize HSCs in both mice and non-human primates (Hoggatt, Cell 2018; Goncalves, Blood 2018). Based on these data, Magenta initiated a Phase 1 dose-escalating study to evaluate the safety, PK and PD of MGTA-145 as a single agent and in combination with plerixafor. Methods This study consists of four parts. In Part A, healthy volunteers were dosed with MGTA-145 (0.0075 - 0.3 mg/kg) or placebo. In Part B, MGTA-145 dose levels from Part A were selected for use in combination with a clinically approved dose of plerixafor. In Part C, a single dose MGTA-145 plus plerixafor will be administered on day 1 and day 2. In Part D, MGTA-145 plus plerixafor will be administered followed by apheresis. Results MGTA-145 monotherapy was well tolerated in all subjects dosed (Table 1) with no significant adverse events. Some subjects experienced mild (Grade 1) transient lower back pain that dissipated within minutes. In the ongoing study, the combination of MGTA-145 with plerixafor was well tolerated, with some donors experiencing Grade 1 and 2 gastrointestinal adverse events commonly observed with plerixafor alone. Pharmacokinetic (PK) exposure and maximum plasma concentrations increased dose proportionally and were not affected by plerixafor (Fig 1A). Monotherapy of MGTA-145 resulted in an immediate increase in neutrophils (Fig 1B) and release of plasma MMP-9 (Fig 1C). Neutrophil mobilization plateaued within 1-hour post MGTA-145 at doses greater than 0.03 mg/kg. This plateau was followed by a rebound of neutrophil mobilization which correlated with re-expression of CXCR2 and presence of MGTA-145 at pharmacologically active levels. Markers of neutrophil activation were relatively unchanged (<2-fold vs baseline). A rapid and statistically significant increase in CD34+ cells occurred @ 0.03 and 0.075 mg/kg of MGTA-145 (p < 0.01) relative to placebo with peak mobilization (Fig 1D) 30 minutes post MGTA-145 (7-fold above baseline @ 0.03 mg/kg). To date, the combination of MGTA-145 plus plerixafor mobilized >20/µl CD34s in 92% (11/12) subjects compared to 50% (2/4) subjects receiving plerixafor alone. Preliminary data show that there was a significant increase in fold change relative to baseline in CD34+ cells (27x vs 13x) and phenotypic CD34+CD90+CD45RA- HSCs (38x vs 22x) mobilized by MGTA-145 with plerixafor. Mobilized CD34+ cells were detectable at 15 minutes with peak mobilization shifted 2 - 4 hours earlier for the combination vs plerixafor alone (4 - 6h vs 8 - 12h). Detailed results of single dose administration of MGTA-145 and plerixafor given on one day as well as also on two sequential days will be presented along with fully characterized graft analysis post apheresis from subjects given MGTA-145 and plerixafor. Conclusions MGTA-145 is safe and well tolerated, as a monotherapy and in combination with plerixafor and induced rapid and robust mobilization of significant numbers of HSCs with a single dose in all subjects to date. Kinetics of CD34+ cell mobilization for the combination was immediate (4x increase vs no change for plerixafor alone @ 15 min) suggesting the mechanism of action of MGTA-145 plus plerixafor is different from plerixafor alone. Preliminary data demonstrate that MGTA-145 when combined with plerixafor results in a significant increase in CD34+ fold change relative to plerixafor alone. Magenta Therapeutics intends to develop MGTA-145 as a first line mobilization product for blood cancers, autoimmune and genetic diseases and plans a Phase 2 study in multiple myeloma and non-Hodgkin lymphoma in 2020. Disclosures DiPersio: Magenta Therapeutics: Equity Ownership; NeoImmune Tech: Research Funding; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Consultancy; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Macrogenics: Research Funding, Speakers Bureau; Bioline Rx: Research Funding, Speakers Bureau; Celgene: Consultancy; Amphivena Therapeutics: Consultancy, Research Funding. Hoggatt:Magenta Therapeutics: Consultancy, Equity Ownership, Research Funding. Devine:Kiadis Pharma: Other: Protocol development (via institution); Bristol Myers: Other: Grant for monitoring support & travel support; Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta. Biernat:Medpace, Inc.: Employment. Howell:Magenta Therapeutics: Employment, Equity Ownership. Schmelmer:Magenta Therapeutics: Employment, Equity Ownership. Neale:Magenta Therapeutics: Employment, Equity Ownership. Boitano:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Cooke:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Goncalves:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Raffel:Magenta Therapeutics: Employment, Equity Ownership. Falahee:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Morrow:Magenta Therapeutics: Employment, Equity Ownership, Patents & Royalties. Davis:Magenta Therapeutics: Employment, Equity Ownership.

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

Blood ◽

10.1182/blood-2018-99-110388 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 690-690 ◽

Cited By ~ 12

Author(s):

Srdan Verstovsek ◽

Alessandro M. Vannucchi ◽

Alessandro Rambaldi ◽

Jason R. Gotlib ◽

Adam J. Mead ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Phosphate Binders ◽

Phase 2 ◽

Open Label ◽

Employment Equity ◽

Advisory Committees ◽

Lymphoid Neoplasms ◽

Equity Ownership

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

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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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Bone Marrow Hypocellularity Does Not Impair the Tolerability or Efficacy of Azacitidine (AZA) in Patients with Higher-Risk Myelodysplastic Syndromes Treated in the AZA-001 Study

Blood ◽

10.1182/blood.v120.21.3808.3808 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3808-3808

Author(s):

John F Seymour ◽

John M. Bennett ◽

Alan F List ◽

Ghulam J. Mufti ◽

Steven D. Gore ◽

...

Keyword(s):

Bone Marrow ◽

Supportive Care ◽

Myelodysplastic Syndromes ◽

Research Funding ◽

Prognostic Impact ◽

Effective Treatment Option ◽

Employment Equity ◽

Post Hoc Analysis ◽

Equity Ownership ◽

Post Hoc

Abstract Abstract 3808 Background: Approximately 10–15% of patients with myelodysplastic syndromes (MDS) have a hypocellular bone marrow (BM) at diagnosis. Some studies have suggested hypocellular MDS may have an adverse prognostic impact, but this is controversial. In the Phase 3 randomized AZA-001 study, AZA prolonged overall survival (OS) in patients with higher-risk MDS compared with conventional care regimens (CCR) (Lancet Oncol, 2009). However, the efficacy and tolerability of AZA in the subset of patients with hypocellular MDS has not been determined. Purpose: This post hoc analysis was conducted to determine whether the prolongation of OS observed with AZA compared with CCR in the AZA-001 study is influenced by baseline BM cellularity. We also sought to explore the tolerability of AZA treatment in patients with higher-risk MDS and hypocellular BM. Methods: Study design of AZA-001 is reported elsewhere (Lancet Oncol, 2009). Briefly, patients with higher-risk MDS (FAB: RAEB, RAEB-t, or CMML, and IPSS Int-2 or High risk disease) were randomized to AZA (75 mg/m2/d SC × 7d q 28d) or to CCR (supportive care, low-dose Ara-C [LDAC], or intensive chemotherapy [IC]). In the current analysis, patients were divided into 2 groups based on centrally reviewed baseline BM biopsy samples which confirmed the diagnosis of MDS (J. Bennett): a hypocellular (≤30%) group and a non-hypocellular (>30%) group. OS was assessed using Kaplan-Meier methods and treatments were compared by log-rank analysis. Results: Of 358 patients in AZA-001 (AZA n=179, CCR n=179), BM cellularity data were available for 299 patients (AZA n=154, CCR n=145). At baseline, 87% of patients (n=260) had non-hypocellular BM and 13% of patients (n=39) had hypocellular BM. Of patients with hypocellular BM in the CCR group (n=18), 7 patients (39%) received supportive care, 9 (50%) LDAC, and 2 (11%) IC. In general, baseline characteristics were similar between the hypocellular and non-hypocellular BM groups. Similarly, age, % BM blasts, cytogenetics, cytopenias, and transfusion dependence, were generally balanced across treatments within the 2 cellularity groups (Table). Median (range) duration of AZA treatment cycles in hypocellular patients was 35.5 (28–54) days and in non-hypocellular patients was 33.0 (15–75) days. Response (complete or partial response [CR+PR]) rates in hypocellular patients treated with AZA were 0% and with CCR were 5.6% (p=0.4615); and hematologic improvement (HI) rates were 52% and 41%, respectively (p=0.532). In non-hypocellular patients treated with AZA or CCR, rates of CR+PR were 7.5% and 0.8%, respectively (p=0.010); and HI rates were 48% and 28% (p=0.001), respectively. The improvement in OS in AZA-treated patients was more pronounced in the hypocellular group than the non-hypocellular group, whereas OS in CCR-treated patients was similar regardless of BM cellularity (Figure). Median OS was significantly prolonged with AZA vs. CCR in both the hypocellular and non-hypocellular groups. In patients with hypocellular BM, at 33 months median OS was not reached (NR; 95% CI: 19.2, NR) in the AZA arm vs. 16.9 months (95% CI: 11.1, 19.3) in the CCR arm (p=0.001). In patients with non-hypocellular BM, median OS in the AZA arm was 21.1 months (95% CI: 16.2, 34.7) vs. 15.3 months (95% CI: 9.3, 17.6) in the CCR arm (p=0.012). Safety and tolerability in the two BM cellularity groups were similar to that seen in the overall AZA-001 study (Lancet Oncol, 2009). Frequencies of grade 3–4 hematologic AEs in AZA-treated patients in the hypocellular and non-hypocellular groups were similar: anemia (9.5% vs 14.7%, respectively), febrile neutropenia (9.5% vs 11.6%), leukopenia (14.3% vs 13.2%), neutropenia (61.9% vs 60.5%), and thrombocytopenia (61.9% vs 58.1%). Conclusions: In this post hoc analysis, the prevalence of patients with hypocellular MDS was 13%, consistent with the reported prevalence in the general MDS population (Bennett, 2009). The survival advantage with AZA vs. CCR in both baseline BM cellularity groups observed in this analysis was consistent with the overall OS advantage with AZA shown in AZA-001. These findings suggest AZA is a safe and effective treatment option for patients with BM hypocellularity. Disclosures: Seymour: Celgene Corporation: Consultancy, Honoraria, Speakers Bureau, Travel support Other. Bennett:Celgene Corporation: Consultancy. List:Celgene Corporation: Consultancy. Mufti:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau. Gore:Celgene Corporation: Consultancy, Research Funding. Fenaux:Celgene: Honoraria, Research Funding. Hetzer:Celgene Corporation: Employment, Equity Ownership. Songer:Celgene Corporation: Employment, Equity Ownership. Skikne:Celgene: Employment, Equity Ownership. Beach:Celgene Corporation: Employment, Equity Ownership.

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Allogeneic Hematopoietic Stem Cell Transplantation Following Anti-CD19 BiTE® Blinatumomab in Adult Patients with Relapsed/Refractory B-Precursor Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood.v124.21.965.965 ◽

2014 ◽

Vol 124 (21) ◽

pp. 965-965 ◽

Cited By ~ 3

Author(s):

Anthony Stein ◽

Max S. Topp ◽

Nicola Goekbuget ◽

Ralf C. Bargou ◽

Hervé Dombret ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Research Funding ◽

Phase 2 ◽

Employment Equity ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Phase 2 Study ◽

Equity Ownership

Abstract Introduction: Improvements in the therapeutic options available for adult relapsed/refractory (r/r) B-precursor ALL are required. Blinatumomab is an investigational bispecific T-cell engager (BiTE®) antibody construct that redirects cytotoxic T cells to lyse CD19-positive B cells. Based on encouraging clinical data from a small phase 2 study (Topp MS et al. J Clin Oncol. 2014;32(15s): abstract 7005), we conducted a large confirmatory open-label, single-arm, multicenter phase 2 study of blinatumomab in patients with r/r B-precursor ALL. The aim of the present analysis from this phase 2 study was to characterize those patients who proceeded to allogeneic hematopoietic stem cell transplantation (HSCT) after achieving complete remission (CR)/complete remission with partial hematologic recovery (CRh*) with blinatumomab treatment. Methods: Eligible patients (≥18 years) had Philadelphia chromosome-negative r/r B-precursor ALL with one of the following negative prognostic factors: primary refractory, 1st relapse within 12 months of 1st remission, relapse within 12 months of HSCT, or ≥2nd salvage. Blinatumomab was given by continuous IV infusion (4 weeks on/2 weeks off) for up to 5 cycles. The primary endpoint was CR/CRh* within the first 2 cycles. Secondary endpoints included overall survival (OS), relapse-free survival (RFS), HSCT realization rate, 100-day mortality following HSCT, and adverse events. Results: 189 patients with a median age (range) of 39 (18‒79) years were enrolled and received blinatumomab for a median (range) of 2 (1‒5) cycles. At enrollment, 74 (39%) patients had received ≥2 prior salvage therapies, 64 (34%) had received prior HSCT, and 105 (56%) had ≥75% bone marrow blasts. 43% (81/189) of patients achieved CR/CRh* within 2 cycles, with similar rates of remission observed in both the HSCT-naïve (42%; 52/125) and prior HSCT (45%; 29/64) groups. In total, 32/81 responders (CR, n=28 and CRh*, n=4) underwent HSCT during blinatumomab-induced remission, yielding a transplantation realization rate for blinatumomab responders of 40% (Table 1). 52% (27/52) of the HSCT-naïve patients and 17% (5/29) of patients who had received prior HSCT proceeded to on-study HSCT during blinatumomab-induced remission. These 32 transplants occurred after a median of 2 (1-5) cycles of therapy, with 11 (34%) patients receiving myeloablative conditioning pre-HSCT, 12 (38%) reduced intensity conditioning, and 9 (28%) unknown regimens. Twenty-two (69%) patients used unrelated donors (stem cells derived from blood, n=11; bone marrow, n=6; cord blood, n=5), 7 (22%) used related donors including 6 siblings (blood, n=5; bone marrow, n=1) and 1 haploidentical mother (blood), with 3 (9%) donor types and stem cell sources unknown. Six patients achieving CR/CRh* after 2 cycles of blinatumomab underwent HSCT but were not included in the transplantation realization rate of 40% due to receiving subsequent antineoplastic therapy before HSCT conditioning (Table 1). Among the 43 patients who achieved CR/CRh* within 2 cycles of blinatumomab treatment but never reached HSCT, 20 (47%) had undergone prior HSCT, 7 (16%) were ≥65 years, and 2 (5%) were ≥65 years and had received prior HSCT (Table 1). Figure 1 Figure 1. At the time of the primary analysis (data cut-off in October 2013), with median follow-up of 9.8 months, median (95% CI) OS for the 189 blinatumomab-treated patients was 6.1 (4.2‒7.5) months. When censoring for HSCT, median OS was 5.1 (4.1‒7.1) months; although the medians are slightly different, the curves with and without HSCT censoring largely overlap. Median RFS was 5.9 months with and without censoring for HSCT. Nine patients died at any time after HSCT, with 5 deaths due to infection, 3 due to disease progression, and 1 due to graft-versus-host disease (GvHD). Three of these deaths (2 infections and 1 GvHD) were within 100 days of HSCT. The 100-day post-HSCT mortality rate was 11%. Summary: This large phase 2 study demonstrated antileukemia activity of single-agent blinatumomab in heavily pretreated or aggressive r/r ALL, irrespective of prior HSCT. The data suggest that blinatumomab enables patients to reach HSCT, with 11% 100-day mortality post-HSCT. Two-thirds of patients who did not reach HSCT after responding to blinatumomab were either ≥65 years old or had received prior HSCT. Longer follow-up is required to assess the role of HSCT in patients achieving CR/CRh* after treatment with blinatumomab. Disclosures Stein: Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Off Label Use: This presentation will discuss the off-label use of blinatumomab, as this agent is not approved for use by the FDA, EMA or any other regulatory authorities.. Topp:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Goekbuget:Amgen Inc.: Consultancy, Honoraria, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria. Dombret:Amgen Inc.: Honoraria, Research Funding. Larson:Amgen Inc.: Consultancy, Research Funding. Rambaldi:Amgen Inc.: Consultancy. Zugmaier:Amgen Reseach (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Jia:Amgen Inc.: Employment, Equity Ownership. Maniar:Amgen Inc.: Employment, Equity Ownership. Huber:Amgen Research (Munich) GmbH: Employment; Amgen Inc.: Equity Ownership. Nagorsen:Amgen Inc.: Employment, Equity Ownership, Related to blinatumomab Patents & Royalties. Kantarjian:Amgen Inc.: Research Funding; ARIAD: Research Funding; Pfizer: Research Funding.

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

Blood ◽

10.1182/blood-2018-99-114421 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1528-1528

Author(s):

Sebastian Stasik ◽

Jan Moritz Middeke ◽

Michael Kramer ◽

Christoph Rollig ◽

Alwin Krämer ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Employment Equity ◽

Advisory Committees ◽

Mutational Status ◽

Equity Ownership ◽

Acute Myeloid

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

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Randomized Phase II Study Evaluating the Efficacy and Safety of Romiplostim Treatment of Patients with Low or Intermediate Risk Myelodysplastic Syndrome (MDS) Receiving Lenalidomide.

Blood ◽

10.1182/blood.v114.22.1770.1770 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1770-1770 ◽

Cited By ~ 6

Author(s):

Roger M Lyons ◽

Richard A. Larson ◽

Michael A. Kosmo ◽

Sunil Gandhi ◽

Delong Liu ◽

...

Keyword(s):

Bone Marrow ◽

Research Funding ◽

Intermediate Risk ◽

Employment Equity ◽

Treatment Groups ◽

Platelet Counts ◽

Equity Ownership ◽

Clinically Significant ◽

Dose Reductions ◽

Platelet Transfusions

Abstract Abstract 1770 Poster Board I-796 Introduction Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor. Low platelet counts in patients with myelodysplastic syndromes (MDS) may be due to the underlying disease or to treatment with disease-modifying agents, and platelet transfusions are often the only treatment for clinically significant thrombocytopenia (CST) or bleeding. This was a phase 2 multi-center, randomized, double-blind, placebo-controlled, dose-finding study that evaluated the effect of romiplostim on the incidence of clinically significant thrombocytopenic events (grade 3 or 4 thrombocytopenia and/or receipt of platelet transfusions) and the safety of romiplostim in patients with low or intermediate risk MDS receiving lenalidomide. Patients and Methods Patients who were ≥18 years old, had MDS by bone marrow exam and WHO criteria, had low or Intermediate-1 risk category MDS using the IPSS, and were planning to receive lenalidomide were eligible. Patients were randomized 1:1:1 into treatment groups receiving placebo, 500 μg romiplostim, or 750 μg romiplostim by weekly subcutaneous injections in combination with lenalidomide (one 10 mg capsule by mouth daily for each 28-day cycle). Treatments continued for a total of four cycles. Results The median age of the 39 randomized patients was 74 years (range, 39 to 90); 15 (39%) had platelet counts <50 × 109/L, and 7 (18%) had del(5q). We report trends due to baseline imbalances between treatment groups, likely due to the limited sample size. The overall incidence rates of CST appeared to be greater in the placebo group than either romiplostim group (Table). In contrast to the placebo patients, median platelet counts remained above 50 × 109/L in both the 500 μg and 750 μg romiplostim groups for the treatment period. The incidence of platelet transfusions appeared to be lower in the 500 μg romiplostim group, and the incidence of adverse events was comparable between all of the groups. No deaths were reported during the treatment period. Twelve patients (31%) discontinued the study. Disease progression to AML was reported in 1 patient in the romiplostim 500 μg group. The patient withdrew consent and discontinued the study. No bone marrow was available to confirm AML by protocol-defined criteria. Fewer lenalidomide dose reductions and delays due to thrombocytopenia were seen in both of the romiplostim treated groups. The proportion of patients who achieved an MDS treatment response was 8%, 36% and 15% for the placebo, 500 μg romiplostim, and 750 μg romiplostim groups, respectively. MDS response rates appeared higher in the romiplostim group, regardless of baseline del(5q) status. Baseline imbalance between groups due to the small sample size limited our interpretation of the data. Conclusions Romiplostim appeared to be well-tolerated in low and intermediate risk MDS patients receiving lenalidomide. This preliminary information suggests that romiplostim may reduce the rate of clinically significant thrombocytopenic events in these patients while increasing platelet counts and decreasing the incidence of lenalidomide dose reductions and delays due to thrombocytopenia Disclosures Lyons: GlaxoSmithKline: Consultancy, Speakers Bureau; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy; Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Use of romiplostim to treat Thrombocytopenia in MDS. Larson:Amgen Inc.: Equity Ownership, Research Funding. Liu:Amgen Inc.: Honoraria, Research Funding. Hu:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

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A Phase I/II Study of Lenalidomide in Combination with Rituximab in Relapsed/Refractory Mantle Cell Lymphoma.

Blood ◽

10.1182/blood.v114.22.2719.2719 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2719-2719 ◽

Cited By ~ 2

Author(s):

Luhua Wang ◽

Luis Fayad ◽

Fredrick B. Hagemeister ◽

Sattva Neelapu ◽

Felipe Samaniego ◽

...

Keyword(s):

Mantle Cell Lymphoma ◽

Research Funding ◽

Cell Lymphoma ◽

Phase 1 ◽

Progression Free Survival ◽

Phase 2 ◽

Employment Equity ◽

Mantle Cell ◽

Equity Ownership ◽

Grade 3

Abstract Abstract 2719 Poster Board II-695 Background: Rituximab directly targets CD20 positive lymphoma cells while lenalidomide targets the microenvironment. This combination was proven effective in vitro and in vivo in mantle cell lymphoma (Wu et al, Clin Cancer Res 2008; Zhang et al, Am J Hematol 2009). Clinically, lenalidomide (Habermann et al, Br J Haematol 2009) and rituximab have single-agent activity in mantle cell lymphoma (MCL) and may be an effective combination. The goal of our study was to determine the maximum tolerated dose (MTD) in phase 1 and evaluate the efficacy and safety of lenalidomide plus rituximab in patients with relapsed/refractory MCL in phase 2. Methods: Patients with relapsed/refractory MCL received lenalidomide on days 1–21 of every 28-day cycle, and rituximab (375 mg/m2) weekly during cycle 1. Dose escalation was used to determine the MTD with lenalidomide (10 mg, 15 mg, 20 mg, and 25 mg). Dose-limiting toxicity (DLT) was defined as grade 3 or 4 non-hematologic, or grade 4 hematologic adverse events in cycle 1. Phase 2 has reached targeted enrolment with 45 patients treated at MTD. Kaplan-Meier method was used to estimate progression free survival rate and response duration. Median time to event in months with 95% confidence interval was calculated. Of 45 patients treated at the MTD, the median age was 66 (46–85), 91% were males. All patients had received prior rituximab and were enrolled regardless of prior rituximab sensitivity or resistance. Results: The median follow-up time for the censored observations was 11.4 months. Two DLTs occurred at 25 mg in phase 1 (hypercalcemia, non-neutropenic fever); therefore, the MTD was 20 mg. The grade 3–4 non-hematologic events included elevated AST, elevated ALT, fatigue, myalgia, tremors, ataxia, cough, deep vein thrombosis, dyspnea, edema (facial), infection, neuropathy sensory, rash, and respiratory failure. Grade 3–4 hematologic adverse events included neutropenia (37 events), neutropenic fever (4 events), and thrombocytopenia (16 events). There were no responses in patients treated at 10 mg or 15 mg. Thirty six patients (36) were evaluable for response. Nine (9) patients are too early in their treatment and are not yet eligible for response evaluation. Among the 36 evaluable patients, 11 (31%) patients achieved CR, 8 (22%) patients achieved PR, 3 (8%) patients had minor response, 6 (17%) patients had stable disease and 8 (22%) patients had progressive mantle cell lymphoma. The overall response rate (CR + PR) was 53%. Seventy eight (78%) patients achieved stable disease or better and benefited from oral Lenalidomide plus 4 doses of rituximab. The median time to response was 2 months (2–8), and the median duration of response for the 19 patients with CR or PR was 18 months (95% CI: 10.6, NA) (range1–30 months). The median progression free survival for all patients on phase 2 was 14 months (95% CI: 9.8, NA) (ranging from 1–32 months). Conclusion: Oral lenalidomide plus rituximab resulted in durable responses in relapsed/refractory MCL with a favourable toxicity profile. Disclosures: Wang: Celgene: Honoraria, Research Funding. Hagemeister:Celgene Corporation: Consultancy. Samaniego:Celgene Corporation: Research Funding. Yi:Celgene Corporation: Research Funding. Shah:Celgene Corporation: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Elan: Consultancy; Millennium: Research Funding, Speakers Bureau. Bell:Celgene Corporation: Employment, Equity Ownership. Knight:Celgene Corporation: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Zeldis:Celgene: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

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Use of a New Rotary Powered Device for Bone Marrow Aspiration and Biopsy Yields Excellent Specimens Quickly and Efficiently.

Blood ◽

10.1182/blood.v114.22.4544.4544 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4544-4544

Author(s):

Ronan T. Swords ◽

Kevin R. Kelly ◽

Devalingam Mahalingam ◽

Stephen C. Cohen ◽

Larry J. Miller ◽

...

Keyword(s):

Bone Marrow ◽

Bone Marrow Biopsy ◽

Clinical Evaluation ◽

Research Funding ◽

Bone Marrow Aspiration ◽

Swine Model ◽

Employment Equity ◽

Equity Ownership ◽

Specimen Quality ◽

The Mean

Abstract Abstract 4544 Background The importance of bone marrow aspiration and biopsy in the evaluation of hematopoietic and non-hematopoietic disorders is well established. Recently, a new FDA-cleared battery powered bone marrow biopsy system was developed to allow operators access to the bone marrow space quickly and efficiently. Aims The first aim of this study was to evaluate the quality of core specimens using the new powered device compared to specimens obtained using the traditional manual technique in a swine model. The second aim was to evaluate the safety and efficacy of the device in patients presenting for outpatient hematology clinic visits. Materials and Methods For the pre-clinical evaluation of the device, three anesthetized pigs were used for the study. The powered device (OnControl, Vidacare Corporation, San Antonio, TX, USA) was comprised of a battery powered driver and needle set. The manual device used was a T-Handle Jamshidi bone marrow biopsy needle (Cardinal Health, Dublin, OH, USA). Core biopsy samples obtained were assessed for length and sample quality and then submitted for analysis to a pathologist blinded to the device used. The clinical evaluation of the device was conducted in accordance with practice guidelines and directions for use. Data collection included insertion success, time from insertion to removal, specimen quality, operator satisfaction with control/function of the device and overall operator satisfaction based on a scoring system (0-5; 0=totally unacceptable, 5=outstanding). Results Twenty six samples were collected from the swine model (19 samples using the powered device and 9 using the manual technique). No cellular artifact or thermal damage was reported in any of the samples obtained. The mean lengths for samples obtained using the powered and manual techniques were respectively 19.4mm±1.6mm and 18.6mm±5.3mm. For the clinical evaluation of the device, 16 patients were recruited from 2 centers. Mean insertion time was 11.25±3.39 seconds and mean time from needle contact with skin to needle removal was 38.5±13.94 seconds. No complications were reported. Five operators rated the overall use of the device as outstanding in 75% of cases. Conclusions In this study, the manual and powered samples were equivalent in specimen quality. The powered device however, captured longer biopsies when compared to the manual technique. In the patients evaluated, the device was easy to use as well as being safe and effective. The mean procedural time was significantly faster than previously reported with a manual technique. A randomized study of the powered device compared to the manual technique is underway. Disclosures: Swords: Vidacare Corporation: Research Funding. Kelly:Vidacare Corporation: Research Funding. Mahalingam:Vidacare Corporation: Research Funding. Cohen:Vidacare Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding. Miller:Vidacare Corporation: Employment, Equity Ownership. Philbeck:Vidacare Corporation: Employment, Equity Ownership. Brenner:Vidacare Corporation: Consultancy, Research Funding. Giles:Vidacare Corporation: Research Funding.

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