Next Generation Sequencing Reveals Potentially Actionable Alterations in the Majority of Patients with Lymphoid Malignancies

Abstract Introduction: The rapid technological advances in next generation sequencing (NGS) have allowed oncologists to sequence tumorexomesin a clinically meaningful period of time. NGS allows for identification of alterations that may be potentially targetable by already available Food and Drug Administration (FDA) approved drugs, providing a biologic rational for consideration of therapies and/or experimental treatments (clinical trials) that would not have otherwise been contemplated. Here we report our experience using NGS in a cohort of 60 patients with various lymphoid malignancies. Methods: We retrospectively reviewed the medical charts of 60 patients with various lymphoid malignancies who had undergone NGS. Patients were seen at the UCSD Moores Cancer Center (La Jolla, CA) from October 2012 until March 2016. We collected tumor samples from tissue (Table 1) or peripheral blood from 60 patients that were submitted for testing to Foundation Medicine, a clinical laboratory improvement amendments (CLIA)-certified lab. Hybrid capture based NGS (405 gene panel) was performed (http://www.foundationone.com/). The methods used in this assay have been described in detail in a previous report (He, J. et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood. 2016. 127:3004-3014.). Results: Sixty patients including 35 men (58%) and 25 women (42%), were identified with lymphoid malignancies (Table 1). A total of 224 alterations were found by NGS in the entire cohort of 60 individuals. Types of alterations identified included substitutions, indels, copy number alterations (CNAs), and gene fusions. Figure 1 demonstrates the 15 most frequent alterations among the cohort: TP53 mutations (10 patients), IGH rearrangements (9 patients), loss of CDKN2A/B (8 patients), and BCL2 mutations (8 patients). The median number of alterations detected per patient was 3 (range, 0 to 14). Shown in Figure 2, 7 patients (12%) had no reportable alterations, 10 patients (17%) had 1 alteration, and 43 (71%) patients had 2 or more alterations. The maximum number of alterations identified was 14, which occurred in two patients (3%), one with chronic lymphocytic leukemia (CLL) and the other with diffuse large B-cell lymphoma (DLBCL). A total of 49 patients (82%) had potentially actionable alterations using FDA approved drugs and/or experimental therapies (clinical trials) while 11 patients (18%) had no theoretically actionable alterations. Only 3 patientshad an alteration for which an approved drug in the disease is available (on-label) while 45 patients (75%) had an alteration for which an approved drug is available in another disease (off-label). Twenty-three patients (38%), 12 patients (20%), and 10 patients (17%) had 1, 2 and³ 3 FDA targetable alterations, respectively. The median number of theoretical FDA actionable alterations was 1. Conclusions:Most patients with lymphoid malignancies will have alterations that are potentially pharmacologically identified by NGS; however, only a minority of patients will have alterations for which an approved drug in the disease is available (on-label). Patients with lymphoid malignancies who have exhausted standard therapy or who are unable to tolerate chemotherapy may be excellent candidates for matched targeted therapies, ideally administered in the context of a clinical trial. Figure 1 The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 1. The blue bars represent the number of patients with the designated number of total alterations. The red bars represent the number of patients with the designated number of potentially actionable alterations by an FDA approved drug (on or off label). Figure 2 Figure 2. Disclosures Goodman: Pfizer: Other: Fellowship funding. Costello:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kurzrock:Serono: Research Funding; Pfizer: Research Funding; Merck: Research Funding; Actuate Therapeutics: Research Funding; Sequenom: Research Funding; X Biotech: Research Funding; Genentech: Research Funding; Curematch: Equity Ownership; Novena: Equity Ownership.

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Updated Interim Results of the Safety and Efficacy of Different Lenalidomide Starting Dose Regimens in Patients with Relapsed or Refractory (rel/ref) Chronic Lymphocytic Leukemia (CLL) (CC-5013-CLL-009 Study)

Blood ◽

10.1182/blood.v120.21.3925.3925 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3925-3925 ◽

Cited By ~ 2

Author(s):

Clemens Wendtner ◽

Michael Hallek ◽

Graeme Fraser ◽

Anne-Sophie Michallet ◽

Peter Hillmen ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Study Drug ◽

Median Number ◽

Advisory Committees ◽

Starting Dose ◽

Purine Analog ◽

Equity Ownership ◽

Grade 3 ◽

Dose Levels

Abstract Abstract 3925 Introduction: CLL patients (pts) who relapse following purine-analog or bendamustine-based treatments have a poor prognosis. These pts have limited therapeutic options and novel agents with alternative mechanisms of action are needed. Several phase 1 and 2 trials in rel/ref CLL showed promising activity with escalating dose regimens of lenalidomide (LEN). In other phase II studies improved clinical responses to lenalidomide appeared to correlate with dose levels > 5mg/day. This phase 2 trial investigates the safety of LEN initiated at 3 different starting doses followed by a step-wise dose escalation as tolerated in rel/ref CLL. Methods: In this ongoing trial, eligible pts with rel/ref CLL who have received ≥ 1 prior treatment regimen containing purine-analog or bendamustine are being enrolled. The objectives of this study are to evaluate primarily the safety and secondarily the efficacy of different LEN dose regimens. Pts are randomized 1:1:1 to receive a double-blinded starting dose of 5 mg, 10 mg, or 15 mg oral LEN on days 1–28 of each 28-day cycle. In all 3 treatment arms, the dose is escalated by 5 mg increments every 28 days to reach a maximum dose of 25 mg/d, depending on tolerability. In instances of poor tolerability, dose reductions also occur in 5 mg steps. Pts are stratified by relapsed versus refractory status to their last purine-analog or bendamustine-based treatment regimen and according to age (< 65 vs ≥ 65 years). Tumor lysis syndrome (TLS) prophylaxis comprises of oral hydration and allopurinol 300 mg/day and is initiated ≥ 3 days prior to starting study drug and for a minimum of the first 3 treatment cycles. A total of 105 pts are planned for enrollment to the study. Per protocol, unblinded interim analyses were conducted by the independent Data Monitoring Committee (DMC) after 18 subjects completed 1 cycle and continue at 13-week intervals. Results: To date, 95 pts are enrolled at a median age of 64 years (range 32–81). Enrolled pts are primarily male (67%) and Caucasian (92%). Cytogenetic data are available for 73 pts; 21% have del(17p), 55% have del(13q), 25% have del(11q), and of 72 patients evaluable for trisomy 12, 11 patients (15%) tested positive. IGVH is unmutated in 77% of 77 evaluable pts and 44% of 84 evaluable pts are ZAP70-positive. Based on the Binet and Rai staging systems 9 (10%), 25 (26%) and 24 (25%) of subjects are stage A, B and C, respectively; 7 (7%), 12 (13%) and 16 (17%) subjects are low, intermediate or high-risk disease, respectively. For 2 (2%) subjects the Binet/Rai staging is currently unknown. Overall, 19 pts (20%) received prior bendamustine-containing treatment and 71 pts (75%) received prior fludarabine-based treatment. The median number of prior therapies was 3 (range 1–10). Most common hematological grade ≥ 3 AEs include neutropenia (62%) and thrombocytopenia (34%). At baseline, 19% of pts presented with grade 1–2 neutropenia. The most common non-hematological ≥ grade 3 AEs include pneumonia (13%), tumor flare (13%), and fatigue (11%). TLS was reported in 3 pts (3%): grade 1, 3, and 4. In total, 8 grade 5 events were reported, 3 of which were suspected to be related to LEN: 2 cases of pneumonia and 1 death for unknown cause. At the time of the cut-off, 59 pts (62%) have discontinued treatment. Most common reasons for treatment discontinuation include disease progression (n = 20) and AEs (n = 20). To date, 47 pts (49%) have dose escalated above their starting dose levels of which 12 patients escalated to the highest dose level (25 mg daily). 18 subjects have had no dose level reduction or escalations and 1 patient is still in the first cycle of the study. Average duration of treatment is 6.5 cycles, and median number of cycles is 4. Efficacy evaluations are completed monthly after 3 months of study drug treatment. At time of the data reporting, 5 pts were on study drug but did not reach the first assessment at cycle. For the 90 pts evaluable for response, the investigator's assessment indicates 2 pts (2%) reached CR, 36 (40%) achieved PR, 33 (37%) patients had SD, and 19 (21%) pts progressed. Conclusion: The independent DMC, as of 14 June, 2012 (N=95), recommended that accrual into all three treatment arms should continue as planned, suggesting all three starting doses were well tolerated. To date, the ORR is 42% and 49% of pts were dose escalated at least once. In this rel/ref CLL population LEN appears active, and completion of accrual will clarify the appropriate dose at which to initiate therapy. Disclosures: Wendtner: Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: use of lenalidomie in relapsed/refractory CLL. Hallek:Celgene Corporation: Consultancy, Honoraria, Research Funding. Hillmen:Celgene Corporation: Honoraria. Gregory:Celgene Corporation: Honoraria, Research Funding. Stilgenbauer:Celgene Corporation: Honoraria, Research Funding, Speakers Bureau. Kipps:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Purse:Celgene Corporation: Employment, Equity Ownership. Zhang:Celgene Corporation: Employment, Equity Ownership. Mei:Celgene Corporation: Employment.

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A Phase 1 Study Of JNJ-40346527, a Colony Stimulating Factor-1 Receptor (CSF-1R) Inhibitor, In Patients With Relapsed Or Refractory Hodgkin Lymphoma

Blood ◽

10.1182/blood.v122.21.1812.1812 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1812-1812 ◽

Cited By ~ 4

Author(s):

Bastian von Tresckow ◽

Franck Morschhauser ◽

Vincent Ribrag ◽

Max S. Topp ◽

Caly Chien ◽

...

Keyword(s):

Board Of Directors ◽

Hodgkin Lymphoma ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Employment Equity ◽

Advisory Committees ◽

Overall Response ◽

Equity Ownership ◽

Systemic Therapies

Abstract Introduction JNJ-40346527 is a selective inhibitor of the colony stimulating factor-1 receptor (CSF-1R) tyrosine kinase. It impairs macrophage recruitment in animal models and reduces viability of Hodgkin lymphoma (HL) cell lines in vitro. Therefore, JNJ-40346527 has two potential targets in HL tumors: tumor associated macrophages and HL cancer cells. This study investigates JNJ-40346527 as a treatment for relapsed or refractory classical HL. Methods The patient population included men and women aged 18 years of age or older with a histopathologically confirmed initial diagnosis of classical HL and who have disease that has relapsed or is refractory after at least 1 appropriate therapy. Patients were assigned to sequential cohorts of oral daily dose of JNJ-40346527 (150, 300, 450, 600 mg QD, and 150 mg BID). Each treatment cycle consisted of 21 days. Dosing was continuous until progressive disease, toxicity or any other reason. Upon completion of 1 cycle (21 days of dosing, this may include any delays occurring during cycle 1) of each dose cohort, a review of all available study data was done by the study evaluation team (SET). The SET consists of the principal investigators (or their designees), the sponsor's medical monitors, and the sponsor's clinical pharmacologist. All (serious) adverse events, occurrence of dose limiting toxicities, pharmacokinetics and overall response rate were considered by the SET before deciding to go to the next dose level. Disease evaluations were done at baseline, end of cycle 2, end of cycle 6, and thereafter at the discretion of the investigator, and included CT/MRI and PET scan. Overall response was based upon both modalities. During the first cycle, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of blood samples was performed on days 1, 7, 14 and 21 and at various timepoints during the day. PD included total and phosphorylated CSF-1R after CSF-1 stimulation. The primary endpoint for dose escalation phase was to establish the recommended phase 2 dose. Secondary endpoints included safety, overall response rate, PK, and PD. Results In this ongoing phase 1 study, 21 patients ([150 mg: 3; 300 mg: 5; 450 mg: 3, 600 mg: 3] QD, and 150 mg: 7 BID) were enrolled, 10 men/11 women, median age 40 (range, 19–75) years, and median number of prior systemic therapies were 6 (range, 3–12); 12/21 pts underwent >5 prior systemic therapies and 18/21 pts received autologous stem cell transplant. In addition, 15/21 patients underwent radiotherapy and 3/21 patients had HL related surgery. No dose limiting toxicities were observed. Maximum tolerated dose has not been established yet. As of 01 June 2013, 6 patients are ongoing in the study. Best overall response seen is 1 patient with a complete response, ongoing in the study for 10 months, and 10 patients showing stable disease, varying from 1.5–8 months. A first disease evaluation is still pending for 2 patients. A total of 15 patients discontinued treatment, 13 patients due to progression of disease, 1 patient by investigator decision (increased PET activity), and 1 patient due to treatment-emergent adverse events (TEAEs, lung embolism noted at C1D1, which was a pre-existing event at study entry). Median number of cycles received was 3.5 (range, 1–15). Most common (≥20% of patients) possibly drug-related TEAEs (per investigator assessment) were nausea, headache and vomiting. Serious TEAEs were recorded for 4 patients, none of them related to treatment as per investigator assessment. Preliminary PK analysis showed that JNJ-40346527 exposure increased in a near dose-proportional manner over the dose range of 150–450 mg QD but plateaued out at 600 mg QD. Serum trough levels were within the projected pharmacologically active concentration range at a dose as low as 150 mg QD. Preliminary PD analysis confirmed target engagement and showed >80% inhibition of CSF-1R phosphorylation at 4 hours post dosing in peripheral blood mononuclear cells stimulated with CSF-1. Conclusion Preliminary results indicate that JNJ-40346527 was well-tolerated and may be effective for the treatment of Hodgkin lymphoma. Disclosures: von Tresckow: Novartis: honoraria for acting as a consultant: Consultancy; Takeda Pharma GmbH: reimbursement of congress, travel, and accommodation costs and honoraria for preparation of scientific educational events: Honoraria. Morschhauser: Janssen Research & Development : Honoraria. Ribrag: Bayer: Research Funding; takeda: Membership on an entity’s Board of Directors or advisory committees; Janssen Research & Development: Membership on an entity’s Board of Directors or advisory committees; Servier: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Chien: Janssen Research & Development: Employment, Equity Ownership. Seetharam: Janssen Research & Development: Employment, Equity Ownership. Aquino: Janssen Research & Development: Employment. Kotoulek: Janssen Research & Development: Employment. Khan: Janssen Research & Development: Employment, Equity Ownership. de Boer: Janssen Biologics B.V.: Employment, Equity Ownership. Engert: Millennium, Takeda: Consultancy, Honoraria, Research Funding.

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Moffitt Cancer Center 2-Year Single-Institution Experience with Next-Generation Sequencing Minimal Residual Disease Detection: Clinical Utility, Application, and Correlation with Outcomes in Plasma Cell and Lymphoid Malignancies

Blood ◽

10.1182/blood-2019-129846 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4654-4654 ◽

Cited By ~ 1

Author(s):

Mohammad O Hussaini ◽

Jaya Srivastava ◽

Lik Wee Lee ◽

Taiga Nishihori ◽

Bijal Shah ◽

...

Keyword(s):

Board Of Directors ◽

Plasma Cell ◽

Research Funding ◽

Residual Disease ◽

Cancer Center ◽

Employment Equity ◽

Advisory Committees ◽

Lymphoid Malignancies ◽

Equity Ownership ◽

Generation Sequencing

Background: Measuring residual disease during the continuum of care is fundamental to oncology practice. In particular, minimal residual disease (MRD) assessments and trends over time can help inform clinical management, including change in treatment regimen or treatment discontinuation. In patients (pts) with plasma cell and lymphoid malignancies, next-generation sequencing (NGS)-MRD is a valuable tool for assessing MRD and depth of response to treatment. MRD status is strongly prognostic of time to relapse and overall survival in multiple myeloma (MM), acute lymphoblastic leukemia (ALL), mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL). In this report, we summarize our 2-year experience with clinical implementation of NGS-MRD (clonoSEQ®) testing across a spectrum of plasma cell and lymphoid disease. Methods: This retrospective analysis summarizes our experience using the NGS-MRD Assay (Adaptive Biotechnologies, Seattle, WA) in plasma cell and lymphoid malignancies. The assay uses multiplex polymerase chain reaction (PCR) and NGS to identify, characterize, and monitor unique disease-associated sequence rearrangements or clonotypes of immunoglobulin (Ig) IgH (V-J), IgH (D-J), IgK, and IgL receptor gene sequences, and translocated BCL1/IgH (J) and BCL2/IgH (J) sequences in DNA extracted from high disease burden diagnostic (ID) and post-treatment (MRD) samples. PCR amplification bias control ensures a quantitative read-out of the full B-cell receptor repertoire present in the ID sample and provides direct measure of tumor burden. Our study included pts with plasma cell and lymphoid malignancies, including MM, ALL, CLL, and MCL treated at the Moffitt Cancer Center between March 2017 and March 2019 who had provided at least an ID sample for NGS-MRD testing. Results: A total of 423 ID tests using DNA from bone marrow (BM; n=407) or peripheral blood (PB; n=16) and 384 MRD tracking tests (BM, n=321; PB, n=63) were performed in 297 pts (Table). The median turnaround time from shipment arrival to assay initiation was 2.1 hours and from activation to report date was 7.1 days. For MM, ALL, MCL, and CLL, the numbers of tests ordered, calibration rates (defined as proportion of ID samples with trackable sequence[s]), and mean number of trackable sequences are shown in the Table. More ID tests were ordered than number of pts (range: 108-178%) due to multiple tests performed for each patient. Sequences analyzed for MRD tests included IgH, IgK/IgL, and T-cell receptors β and γ. The proportion of pts with detectable MRD is shown by indication in the Table. In MM, autologous stem cell transplant (autoSCT)-eligible pts or those who achieved excellent initial responses but were transplant-ineligible, were primarily considered for NGS-MRD testing as part of standard of care. NGS-MRD testing was performed prior to autoSCT and post-SCT before initiation of maintenance therapy for prognostication. More than 90% of MM cases with successful NGS-MRD results had trackable clones. Negative NGS-MRD assured excellent disease control and supported the decision to discontinue therapy in some pts with significant toxicities. In pts with ALL, treatment response after induction and/or consolidation guided decision-making for allogeneic (allo) SCT at first remission. MRD burden prior to alloSCT could potentially guide the decisions and timing on performing SCT or conditioning regimen intensity. In pts with MCL, treatment response evaluated by NGS-MRD following 6 cycles of therapy was a decision point in a randomized trial of auto-transplant + rituximab vs rituximab alone (ClinicalTrials.gov: NCT03267433). MRD is also being used to guide the duration of rituximab maintenance therapy. Updated data analysis for all indications, including CLL, is underway and will be presented at the meeting. Conclusions: The NGS-MRD Assay is a highly sensitive diagnostic tool for the observation of deeper disease response to therapy in multiple specimen types and in various lymphoid and plasma cell malignancies. NGS-MRD may assist in therapeutic decision-making or prognostication. NGS-MRD is a sensitive and powerful prognostic tool available for the majority of pts, which will help our understanding of the role of MRD in clinical management of plasma cell and lymphoid malignancies. Table Disclosures Srivastava: Adaptive Biotechnologies: Employment, Equity Ownership. Lee:Adaptive Biotechnologies: Employment, Equity Ownership. Nishihori:Novartis: Research Funding; Karyopharm: Research Funding. Shah:AstraZeneca: Honoraria; Pharmacyclics: Honoraria; Adaptive Biotechnologies: Honoraria; Spectrum/Astrotech: Honoraria; Novartis: Honoraria; Celgene/Juno: Honoraria; Kite/Gilead: Honoraria; Incyte: Research Funding; Jazz Pharmaceuticals: Research Funding. Alsina:Janssen: Speakers Bureau; Amgen: Speakers Bureau; Bristol-Myers Squibb: Research Funding. Baz:Merck: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding. Pinilla Ibarz:Abbvie: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Sanofi: Speakers Bureau; Bayer: Speakers Bureau; TG Therapeutics: Consultancy; Teva: Consultancy; Janssen: Consultancy, Speakers Bureau. Shain:Adaptive Biotechnologies: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; AbbVie: Research Funding; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Novel Thrombogenic Biomarkers In Patients with Relapsed/Refractory Multiple Myeloma (MM) Treated with Lenalidomide (LEN) and Dexamethasone (Dex) Therapy

Blood ◽

10.1182/blood.v116.21.3187.3187 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3187-3187

Author(s):

Kate Burbury ◽

Peter C Gambell ◽

Amanda Choo ◽

Jennifer Curnow ◽

Kevin Lynch ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Median Number ◽

Autologous Stem Cell Transplant ◽

Cathepsin G ◽

Cell Transplant ◽

Advisory Committees ◽

Disease Heterogeneity ◽

R Ratio ◽

Number Of Patients

Abstract Abstract 3187 Thromboembolism (TE) is an important complication of cancer with substantial clinical implications. MM, treated with thalidomide (thal) and LEN, has TE rates up to 25%, particularly when used in combination with chemotherapy and corticosteroids. Given disease heterogeneity, bleeding and TE risks are different for all patients and individuals over time. With the emergence of novel antithrombotic agents, further understanding of the pathophysiology of both MM- and therapy-related hemostatic dysfunction and the identification of important biomarkers, may promote a risk-stratification process and allow a targeted therapeutic strategy. We prospectively and sequentially assessed novel thrombogenic biomarkers, with a plan to correlate with functional assays (thrombin generation and microparticles) in R-MM, before and after exposure to LEN/dex as part of a 150-patient phase-II clinical trial. Hemostatic assessments were performed at enrolment, 1-, 4-, 12-months and/or end of study. 27 patients at our institution, 15 males, median age 69 years (range 58–80) were included in the analysis: 16 had IgG monoclonal protein (13 kappa [k]), 9 IgA (6 k), 2 were k light chain only. The karyotype was diploid in 18, complex in 4 and 3 patients had t(4;14), t(11;14) or t(8;14) respectively. Median number of prior lines of therapy was 3 (range 1–7); 18 had prior thal and 15 had received a melphalan-based autologous stem cell transplant. Median (range) for Hb was 111g/L (80-137) and creatinine clearance 66.6mL/min (23-182). 6/27 had a prior TE: 1 arterial, 5 venous. All patients commenced antithrombotic therapy at enrolment: 20 received aspirin (100mg/day), 4 prophylactic and 2 therapeutic dose enoxaparin, 1 treatment dose warfarin. At enrolment (pre-LEN/dex) and after 4 weeks of therapy, the median (range) for the individual assays are outlined in table 1. Pre-LEN/dex: FVIIIc, vWFAg, Fib Mon, TAT, PF1+2 and TM were markedly elevated in the majority of patients. After 4 weeks of therapy, many biomarkers remained elevated, however, Fib Mon and PMN-E near normalised in all patients; FVIIIC and vWFAg was elevated in less patients; while Fib, PF1+2 and TAT increased. This early promising data demonstrate inflammatory, endothelial and hemostatic dysregulation in R-MM with an altered biomarker profile after exposure to LEN/dex. Further results of sequential analyses will be presented at the meeting. Study (cycle, day) C1D1 (pre–LEN/dex) n* C2D1 (4–weeks LEN/dex) n* Biomarker (units, NR) Median Range >ULN, <LLN Median Range >ULN <LLN APTT (s, 24–34) 34 24–48 13 0 33 26–52 8 0 PT (s, 11.8–14.6) 13.5 12–25.6 10 0 13.2 11.2–45.2 2 3 Fib (g/L, 2.0–4.0) 4 2.4–6.8 12 0 5.5 0.7–8.4 21 2 D-dimer (mg/L, 0.0–0.5) 0.5 0.1-1.5 9 NA 0.6 0.1–6.4 15 NA Plt (×109/L, 150–450) 214 43–372 0 7 225 30–385 0 6 FVIIIc (%, 50–150) 298 96–600 22 0 236.5 159–600 10 0 vWFAg (%, 50–160) 206 98–325 18 0 298 148–364 12 0 APC-R ratio (2–3.5) 2.3 1.7–3.4 0 3 3.2 1.7–3.6 1 1 AT (%, 80–120) 98 69–135 3 3 108 77–126 4 1 Fib Mon (μg/ml, 0.1– 6) 4.3 2.0–61.2 8 0 3.1 0–95 2 1 TAT (μg/L, <2.0–4.2) 1.1 0.4–37.6 9 14 8.1 2.7–54.7 19 0 PF1+2 (pmol/L, 69–229) 192.3 0.7–705.5 11 2 197.3 35.8–1266.5 8 5 anti-CG (U/ml, <15) 0.2 0-5.2 0 NA 0.1 0–0.6 0 NA TM (pg/mL, 2353–4541) 4739.1 2628–11656.3 15 0 4050.3 244–10613.2 8 2 PMN-E (ng/mL, 0–90) 44 22–276 6 NA 34.8 14–92 1 NA NR: Normal range; APTT: Activated partial thromboplastin time; PT: Prothrombin time; Fib: Fibrinogen; Plt: Platelet count; FVIIIc: Factor VIII-coagulant; vWFAg: von Willebrand factor Antigen; APC-R: Activated protein C resistance ratio; AT: Antithrombin; Fib Mon: Fibrin Monomers; TAT: Thrombin-antithrombin complex; PF1+2: Prothrombin fragments1+2; CG: Cathepsin G; TM: Thrombomodulin; PMN-E: PMN Elastase; NA: values <LLN or >ULN not clinically applicable. * Number of patients (n) within the cohort (n=27), in whom measured level was >upper limit of normal (>ULN) or <lower limit of normal (<LLN). Disclosures: Curnow: Celgene: Research Funding; Novartis: Consultancy. Lynch:Celgene Pty Ltd: Employment, Equity Ownership. Harrison:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Prince:Celegene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Westerman:Celgene: Research Funding.

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Relationship Between Patient-Reported Outcomes (PROs) and Health-Related Quality of Life (HRQoL) and Efficacy in Patients with Myelofibrosis in the Phase III Persist-1 Trial of Pacritinib Vs. Best Available Therapy (BAT)

Blood ◽

10.1182/blood.v126.23.1609.1609 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1609-1609

Author(s):

Ruben A. Mesa ◽

Claire N. Harrison ◽

Francisco Cervantes ◽

James P. Dean ◽

Lixia Wang ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Off Label Use ◽

Employment Equity ◽

Advisory Committees ◽

Off Label ◽

Eortc Qlq C30 ◽

Night Sweats ◽

Equity Ownership ◽

Eortc Qlq

Abstract Introduction: Myelofibrosis (MF) is a life-threatening hematologic malignancy characterized by splenomegaly and debilitating symptoms including fatigue, abdominal pain, night sweats, bone pain, pruritus, and unintentional weight loss. The myeloproliferative neoplasm symptom assessment form (MPN-SAF) is a PRO tool designed to measure MF-related symptom burden and was developed and validated at Mayo Clinic. It was modified (MPN-SAF total symptom score [TSS] and TSS 2.0) for use in the PERSIST-1 and PERSIST-2 phase 3 trials. For PERSIST-1, when examining the 6 common symptoms in both TSS versions (tiredness, night sweats, early satiety, itchiness, bone pain, and abdominal pain), pacritinib-treated patients (pts) had significant improvements in TSS overall and in individual symptoms vs BAT; Pt Global Impression of Change (PGIC) was also significantly improved for pts receiving pacritinib. Improvements in EORTC-QLQ-C30 scales were noted in the pacritinib arm (Mesa, EHA 2015). The proportion of pts achieving spleen volume reduction (SVR) ≥35% at Week 24 was significantly greater with pacritinib vs BAT (ITT: 19.1% vs 4.7%, p=0.0003; evaluable at baseline and Week 24: 25.0% vs 5.9%; p=0.0001). This analysis examines relationships between TSS improvement and changes in splenomegaly and HRQoL outcomes. Methods: Pts who received no prior JAK inhibitor therapy were randomized 2:1 to oral pacritinib 400 mg once daily or BAT. Pts were stratified by DIPSS risk (Int-1/Int-2 vs High) and platelet count (<50,000/μL vs 50,000/μL to <100,000/μL vs ≥100,000/μL). Pts must have had a baseline total TSS ≥13 using MPN-SAF TSS 2.0. Each symptom is rated on a scale from 0 (absent) to 10 (worst imaginable) using MPN-SAF TSS and TSS 2.0. Results for the 6 symptoms common to both TSS versions are reported. Additional PROs used for assessment of HRQoL included EORTC QLQ-C30 and EQ-5D-5L. In multivariate logistic regressions, odds of TSS reduction ≥50% at Week 24 were modeled as a function of Week 24 SVR ≥35%, spleen length reduction (SLR) ≥ 50%, PGIC, improvement in each EORTC scale, and improvement in EQ-5D-5L Overall Health State (OHS) and in each dimension individually while adjusting for treatment (pacritinib vs BAT). Correlations were examined in all pts and by baseline platelet counts (<50,000/μL, <100,000/μL, and ≥100,000/μL). Results: A total of 327 pts were enrolled (PAC: 220, BAT: 107). 62% of pts had primary MF, 32% had baseline platelets <100,000/μL, and 16% had baseline platelets <50,000/μL. TSS reduction ≥50% was found to be associated with SVR ≥35% and improvement in splenomegaly (SLR ≥50%). In the total pt population, there was a significant association between TSS reduction and SVR (odds ratio [OR]=2.60, p=0.016). In all pts, there was a significant association between TSS reduction and improvements in OHS as measured by EQ-5D-5L (OR=2.30, p=0.013). TSS reductions were also marginally associated with improvements in the QLQ-C30 Global Health Scale (GHS)/QoL Scale (OR=1.92, p=0.050) and, though not statistically significant, there was a trend of improvement in perceived overall health as measured by PGIC (OR=2.16, p=0.118). TSS reductions were further examined in pts grouped by baseline platelet count. Improvement in EQ-5D-5L OHS was marginally associated with TSS reductions in pts with platelets <50,000/μL (OR=6.03, p=0.057). For pts with platelets <100,000/μL, reductions in TSS were significantly associated with reductions in splenomegaly (SLR ≥50%; OR=9.53, p=0.004), and improvements in the QLQ-C30 GHS/QoL domain (OR=4.03, p=0.022) as well as the EQ-5D-5L OHS (OR=5.49, p=0.008). A significant association between TSS reductions and SVR ≥35% was observed in pts with platelets ≥100,000/μL (OR=3.99, p=0.005). In all pts, improvements in Fatigue as measured by QLQ-C30 were significantly associated with TSS reductions (OR=2.20, p=0.019) as well as in pts with baseline platelets <50,000/μL (OR=17.88, p=0.008) and <100,000/μL (OR=10.18, p<0.001). Conclusions: In the total pt population, TSS reduction was associated with improvements in spleen response and perceived overall health. This trend was also observed in pts with low baseline platelet counts. Additionally, TSS reduction was significantly associated with improvements in fatigue, a major contributor to poor HRQoL in pts with MF. This reinforces the clinical relevance of measuring TSS using a validated instrument as an endpoint in MF trials. Disclosures Mesa: NS Pharma: Research Funding; Pfizer: Research Funding; Gilead: Research Funding; Incyte Corporation: Research Funding; CTI Biopharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Genentech: Research Funding; Promedior: Research Funding. Off Label Use: This abstract discusses off-label use of pacritinib. Harrison:Shire: Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria; CTI Biopharma: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Cervantes:Novartis: Consultancy, Speakers Bureau; Sanofi-Aventis: Consultancy; CTI-Baxter: Consultancy, Speakers Bureau. Dean:CTI Biopharma: Employment, Equity Ownership. Wang:CTI Biopharma: Employment, Equity Ownership. Yang:Baxalta: Employment, Other: Stock. Vannucchi:Shire: Speakers Bureau; Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Baxalta: Membership on an entity's Board of Directors or advisory committees.

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Inhibition of C3 with APL-2 Results in Normalisation of Markers of Intravascular and Extravascular Hemolysis in Patients with Paroxysmal Nocturnal Hemoglobinuria (PNH)

Blood ◽

10.1182/blood-2018-99-110827 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2314-2314 ◽

Cited By ~ 7

Author(s):

Raymond SM Wong ◽

Humphrey W.H. Pullon ◽

Pascal Deschatelets ◽

Cedric G Francois ◽

Mohamed Hamdani ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Total Bilirubin ◽

Intravascular Hemolysis ◽

Normal Range ◽

Employment Equity ◽

Advisory Committees ◽

Number Of Patients ◽

Transfusion Requirements ◽

Equity Ownership

Abstract Background: PNH is characterized by a degree of bone marrow failure and hemolysis resulting in debilitating hemolytic anemia and an increased risk of thrombosis. Uncontrolled complement activation leads to intravascular hemolysis mediated by the membrane attack complex and extravascular hemolysis mediated by accumulation of C3 fragments, such as C3b, at the cell surface. The only approved treatment for PNH is Soliris®, a C5 inhibitor which targets intravascular hemolysis however, a significant number of patients treated with Soliris® continue to experience ongoing anemia and its associated symptoms. Due to the key role of C3 in the complement cascade, upstream of C5, APL-2, a cyclic peptide inhibitor of C3, acts to prevent both intravascular and extravascular hemolysis. To our knowledge these data represent the first time that PNH patients have experienced significant increases in haemoglobin (Hb) combined with normalisation of lactate dehydrogenase (LDH), absolute reticulocyte count (ARC) and total bilirubin. Aims: This Phase Ib open-label, dose-escalation study being conducted in New Zealand, Thailand, Malaysia and Hong Kong was designed to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and efficacy of multiple doses of APL-2, administered by daily subcutaneous injection (SC), in patients with PNH. Methods: To be eligible for entry, PNH patients are required to have Hb levels < 105 g/L (normal range [NR] 119-180), LDH levels >2 times upper limit of normal (x ULN) at screening and have received ≥ 1 blood transfusion in the prior 12 months. The study will recruit 3 subjects into Cohort 1 and up to 20 subjects in Cohort 2 receiving 180 mg/d or 270 mg/d of APL-2, respectively. Efficacy is assessed by change from baseline in Hb, LDH, ARC, total bilirubin and transfusion requirements. Change from baseline in FACIT fatigue score is also reported. Results: As of 24 July 2018, Cohort 1 has been fully recruited and 17 subjects have been dosed in Cohort 2. Of the 17 subjects dosed in Cohort 2, 15 have been treated with APL-2 for >28 days and 9 have been treated for >84 days. Data is summarized for 14 (and 10) subjects in Cohort 2 who have received 270 mg/d of APL-2 for at least 28 (and 84) days; not included in the summary are 2 subjects who have not yet reached Day 28 and one subject who had underlying metastatic ovarian cancer with a chronic low gastrointestinal bleed, unknown at time of screening, resulting in artificially low Hb and high LDH levels determined to be unrelated to PNH. Baseline Hb was 84 g/L (range 55-110) which increased to 110 (74-135) and 116 (71-145) g/L at Days 29 and 85 respectively, representing a mean increase in Hb of 29 g/L and 33 g/L. At Day 29, Hb levels had increased in 100% of subjects with 57% achieving levels within the normal range. Hb increases were maintained in the 10 subjects with Day 85 data available. In the 12 months prior to APL-2 dosing, subjects received a total of 67 transfusions (average 4.8 per year per patient; range 0 to 15). Except for 2 subjects, each of whom received a single transfusion within the first two weeks of treatment i.e. before APL-2 had reached steady state concentration, no transfusions have been reported for any patient during the APL-2 treatment period. Mean baseline LDH of 2459 I/U (9.8x ULN) was reduced to 197 I/U (0.8x ULN) by Day 29. Mean baseline ARC and total bilirubin were reduced from 193 to 89 10^9/L (NR 30-100 10^9/L) and 39 umol/L to 10 umol/L (NR 3-15 umol/L), respectively. Of the 14 subjects, 13 (92%) had LDH and bilirubin within the normal range, and 11 (79%) had ARC in the normal range at Day 29. The Figure shows mean +/- SE for all available data for the 14 subjects through to Week 12. To date, APL-2 has been well-tolerated. No significant infections or thromboembolic events have been observed. One subject was withdrawn from the study due to progression of aplastic anemia related to underlying PNH. In clinical trials in PNH patients more than 5000 SC doses of APL-2 ≥ 270 mg/day have been administered, representing a cumulative systemic exposure of >700 patient weeks of APL-2 treatment. Summary/Conclusions: We demonstrate that systemic inhibition of C3 with APL-2, controls both intravascular and extravascular hemolysis in patients with PNH as shown by significant reductions in LDH, total bilirubin and ARC. Broad control of hemolysis leads to significant and sustained increases in Hb in the absence of transfusions. APL-2 was safe and well tolerated. Disclosures Wong: Alexion: Honoraria. Deschatelets:Apellis Pharmaceuticals: Employment, Equity Ownership. Francois:Apellis Pharmaceuticals: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Hamdani:Apellis Pharmaceuticals: Employment, Equity Ownership. Johnson:Apellis Pharmaceuticals: Consultancy, Equity Ownership. Tan:Apellis Pharmacueticals: Consultancy. Tse:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; MSD: Research Funding; Roche Pharma: 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; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie Inc: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Grossi:Apellis Pharmaceuticals: Employment, Equity Ownership.

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A Phase 1, Multicenter Study of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Patients with Proteasome Inhibitor Exposed and Lenalidomide-Refractory Myeloma (Trial MM-005)

Blood ◽

10.1182/blood.v126.23.3036.3036 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3036-3036 ◽

Cited By ~ 10

Author(s):

Paul G. Richardson ◽

Craig Hofmeister ◽

Noopur S. Raje ◽

David Siegel ◽

Sagar Lonial ◽

...

Keyword(s):

Board Of Directors ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Median Number ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership ◽

Immunomodulatory Drug ◽

Grade 3

Abstract Background: The combination of an immunomodulatory drug with the proteasome inhibitor (PI), bortezomib (BORT), and low-dose dexamethasone (LoDEX) has demonstrated preclinical synergy and considerable clinical activity in relapsed and refractory multiple myeloma (RRMM; Mitsiades et al Blood, 2002; Richardson et al Blood, 2014). Treatment (Tx) with the immunomodulatory drug pomalidomide (POM) + LoDEX has been shown to delay disease progression and extend survival in patients (pts) with myeloma previously treated with lenalidomide (LEN) and BORT (Richardson et al Blood, 2014; San Miguel et al Lancet Oncol, 2013). This approach was tested using POM + BORT + LoDEX (PVd) in MM-005; preliminary results showed that PVd was effective and well tolerated in LEN-refractory and BORT-exposed pts. Subcutaneous (SC) BORT was shown to be non-inferior to intravenous (IV) BORT and had an improved safety profile in RRMM (Moreau et al Lancet Oncol, 2011). In addition to a cohort of PVd with IV BORT, MM-005 included a cohort of PVd with SC BORT. Methods: In this phase 1 dose-escalation trial, pts must have received 1-4 lines of prior Tx, with ≥ 2 consecutive cycles of LEN plus a PI. Pts had to be PI exposed and refractory to LEN but not to BORT. A 3 + 3 design with 21-day cycles was used to determine the maximum tolerated dose (MTD). Cycles 1-8 of dose-escalation cohorts received POM (1-4 mg/day on days 1-14), IV or SC BORT (1-1.3 mg/m2 on days 1, 4, 8, and 11), and LoDEX (20 mg/day, or 10 mg/day for pts aged > 75 years, on days 1, 2, 4, 5, 8, 9, 11, and 12) until progressive disease (PD) or unacceptable adverse event (AE). After cycle 8, BORT was administered on days 1 and 8, and LoDEX was administered on days 1, 2, 8, and 9. The primary endpoint was MTD, and secondary endpoints included safety, overall response rate (ORR; ≥ partial response [PR]), duration of response (DOR), and time to response. Results: Of the 34 pts enrolled from March 2012 to August 2014, the median age was 58.5 years (range, 36-76 years) and 59% were male. The median number of prior antimyeloma Tx lines (PAMTL) was 2 (range, 1-4), the proportion of pts with ≥ 2 PAMTL was 56%, and the Eastern Cooperative Oncology Group performance status was ≤ 1 for all pts. All pts were refractory to LEN, and all were exposed to prior PI (33 pts [97%] received prior BORT and 2 pts [6%] received prior ixazomib). All pts discontinued Tx, most commonly due to PD (n = 23), but none due to Tx-related AEs. No dose-limiting toxicities were reported in the dose-escalation cohorts or at the maximum planned dose (MPD) of POM 4 mg, BORT 1.3 mg/m2, and LoDEX 20 mg (10 mg for pts aged > 75 years). The median number of Tx cycles received was 9 (range, 2-36) for all pts and was 11 (range, 2-19) vs 8 (range, 3-15) in the MPD with IV BORT (n = 10) vs SC BORT (n = 12) cohorts. The ORR for all pts was 65% (n = 22), with 2 complete responses (CRs), 1 stringent CR, 10 very good PRs (VGPRs), and 9 PRs; all pts achieved at least stable disease. The median DOR for the 22 responders was 7.4 months. Commonly reported grade 3/4 AEs were more frequent at the MPD level with IV BORT vs SC BORT (90% vs 75%), including neutropenia (60% vs 17%), thrombocytopenia (40% vs 8%), and pneumonia (30% vs 8%). There were no reports of grade 3/4 peripheral neuropathy (PN) or deep vein thrombosis (DVT) in any of the cohorts. Conclusions: PVd was effective, with an ORR of 65% in pts with LEN-refractory and PI-exposed myeloma. PVd was well tolerated, with no grade 3/4 PN or DVT and no Tx discontinuation due to Tx-related AE; toxicities were well managed. Moreover, AEs were generally less frequent with SC vs IV BORT. Thus, the favorable tolerability and efficacy of PVd, which could be a highly attractive therapeutic option in pts with RRMM, is under further evaluation in the large ongoing phase 3 trial MM-007. Disclosures Richardson: Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz Pharmaceuticals: 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; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide in combination with bortezomib. Raje:BMS: Consultancy; Takeda: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy; Onyx: Consultancy; Eli Lilly: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Acetylon: Research Funding. Siegel:Celgene Corporation: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Novartis: Speakers Bureau; Merck: Speakers Bureau. Lonial:Janssen: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Millennium: Consultancy, Research Funding. Laubach:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; Celgene Corporation: Research Funding. Vesole:Celgene Corporation: Speakers Bureau; Idera Pharmaceuticals: Research Funding. Nooka:Spectrum Pharmaceuticals: Consultancy; Onyx: Consultancy. Zaki:Celgene Corporation: Employment, Equity Ownership. Herring:Celgene Corporation: Employment. Li:Celgene Corporation: Employment, Equity Ownership. Shah:Celgene Corporation: Employment, Equity Ownership. Chen:Celgene Corporation: Employment, Equity Ownership. Anderson:Oncocorp: Equity Ownership; Celgene Corporation: Consultancy; acetylon pharmaceuticals: Equity Ownership; Gilead: Consultancy; BMS: Consultancy; Millennium: Consultancy.

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Rationale for Therapy Discontinuation in Patients with Lower-Risk Transfusion-Dependent Myelodysplastic Syndromes (MDS)

Blood ◽

10.1182/blood.v128.22.3541.3541 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3541-3541

Author(s):

Aaron T. Gerds ◽

Shaloo Gupta ◽

Gary Binder ◽

Mikkael A. Sekeres ◽

Aziz Nazha ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Lower Risk ◽

Research Funding ◽

Treatment Discontinuation ◽

Employment Equity ◽

Advisory Committees ◽

Number Of Patients ◽

Equity Ownership

Abstract Introduction: Approximately 50% of patients with MDS are anemic at initial diagnosis, with many becoming transfusion dependent (TD), necessitating the introduction of therapy with a goal of achieving transfusion independence (TI). In addition to transfusions, treatments to improve hemoglobin levels have historically been limited to erythropoiesis-stimulating agents (ESAs), whereas patients with more advanced disease may require treatment with a hypomethylating agent (HMA) (azacitidine [AZA] or decitabine [DAC]) or lenalidomide (LEN). As there is no predetermined treatment course, these therapies are continued until unacceptable toxicity, lack/loss of response, or disease progression. We examined treatment patterns, clinical outcome(s) of patients with MDS, and the physician's report of reason for treatment discontinuation (previously shown to vary from patients' perspectives) in patients who became TD at or after MDS diagnosis (Gerds et al. Blood 2014;124:abstract 2642). Methods:Data were derived from disease-specific physician surveys and patient charts, which provided information on demographic, treatment, and outcome data on lower-risk TD MDS patients. Patient inclusion criteria were: age ≥ 18 years, diagnosis of Low/Intermediate-risk MDS (International Prognostic Scoring System defined) 2-6 years prior to study entry, and becoming TD at least once during the minimum follow-up of 24 months. TD was defined as having received ≥ 2 transfusions within 8 weeks during the follow-up period. Patients who progressed to higher-risk disease or acute myeloid leukemia prior to becoming TD, had an additional malignancy, or were in an MDS clinical trial were excluded. Demographics, disease history, treatment history, TI, and reasons for treatment discontinuation were collected and reported descriptively. Results: A total of 239 physicians provided information on 1,221 lower-risk TD MDS patients. The median age of patients was 65 years (range 27-95 years), 56.3% were male, and median time since diagnosis was 3.2 years (range 2-6 years). Along with packed red blood cell transfusions, 354 patients (29%) were prescribed LEN [of whom 12.7% had del(5q)], 348 patients (28.5%) were prescribed ESAs, and 32 patients (2.6%) were prescribed HMAs. During the follow-up period, 31.3% of ESA patients discontinued therapy (at a median of 12 months; range 3-47 months), 32% of HMA patients discontinued therapy (at a median of 10 months; range 3-52 months), and 26% of LEN patients discontinued therapy (at a median of 13 months; range 2-30 months). In the LEN-treated group, only 9.8% of patients who discontinued therapy had del(5q). The main reason cited for treatment discontinuation across therapy groups reported by physicians was "patients completing the scheduled course of treatment" (28.2%), which occurred in 32.6%, 20.2%, and 22.6% of the LEN, ESA, and HMA groups, respectively. Other reported reasons for discontinuation included "insufficient initial response" (20.0%), "patients no longer responding to therapy" (19.0%), "disease progression" (18.0%), "death" (13.3%), and "worsening hemoglobin levels" (12.8%). Across therapy groups, "patient preference to stop therapy" was reported less frequently (9.7%), occurring in 7.6%, 8.3%, and 12.9% of the LEN, ESA, and HMA groups, respectively. Conclusions:Over 30% of TD lower-risk MDS patients receiving LEN, ESAs, AZA, or DAC discontinued therapy. Per physician reports, the most frequent reason for discontinuation of therapy was completion of scheduled treatment course, which is in stark contrast to recommendations in consensus guidelines, as MDS is a chronic disease in which treatment should be continued ad infinitum. The significant number of patients who stop therapy for alternative reasons suggests opportunities for further investigation. Education on the expected duration of therapy is essential to help support physicians and inform patients about optimal treatment decisions in the care of all MDS patients. Disclosures Gupta: Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. Binder:Celgene Corporation: Employment, Equity Ownership. Carraway:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Amgen: Membership on an entity's Board of Directors or advisory committees. Hawthorne:Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. King-Concialdi:Kantar Health: Employment; Celgene Corporation: Consultancy, Research Funding. McGuire:Celgene Corporation: 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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Treatment Patterns and Outcomes in Elderly Patients with Newly Diagnosed Multiple Myeloma: Results from the Connect® MM Registry

Blood ◽

10.1182/blood-2019-126205 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3129-3129

Author(s):

Hans C. Lee ◽

Sikander Ailawadhi ◽

Cristina Gasparetto ◽

Sundar Jagannath ◽

Robert M. Rifkin ◽

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Keyword(s):

Board Of Directors ◽

Research Funding ◽

Causes Of Death ◽

Age Groups ◽

Treatment Patterns ◽

Age Group ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Equity Ownership

Background: Multiple myeloma (MM) is common among the elderly, with 35% of patients (pts) diagnosed being aged ≥75 years (y). With increasing overall life expectancy, the incidence and prevalence of newly diagnosed and previously treated MM patients ≥80 y is expected to increase over time. Because elderly pts are often excluded from clinical trials, data focused on their treatment patterns and clinical outcomes are lacking. The Connect® MM Registry (NCT01081028) is a large, US, multicenter, prospective observational cohort study of pts with newly diagnosed MM (NDMM) designed to examine real-world diagnostic patterns, treatment patterns, clinical outcomes, and health-related quality of life patient-reported outcomes. This analysis reviews treatment patterns and outcomes in elderly pts from the Connect MM Registry. Methods: Pts enrolled in the Connect MM registry at 250 community, academic, and government sites were included in this analysis. Eligible pts were adults aged ≥18 y with symptomatic MM diagnosed ≤2 months before enrollment, as defined by International Myeloma Working Group criteria; no exclusion criteria were applied. For this analysis, pts were categorized into 4 age groups: <65, 65 to 74, 75 to 84, and ≥85 y. Pts were followed from time of enrollment to the earliest of disease progression (or death), loss to follow-up, or data cutoff date of February 7, 2019. Descriptive statistics were used for baseline characteristics and treatment regimens. Survival outcomes were analyzed using Cox regression. Time to progression (TTP) analysis excluded causes of death not related to MM. Results: Of 3011 pts enrolled (median age 67 y), 132 (4%) were aged ≥85 y, and 615 (20%) were aged 75-84 y at baseline. More pts aged ≥85 y had poor prognostic factors such as ISS stage III disease and reduced hemoglobin (<10 g/dL or >2 g/dL <LLN) compared with other age groups, although no notable differences between creatinine and calcium levels were observed across age groups (Table). A lower proportion of elderly pts (75-84 and ≥85 y) received triplet regimens as frontline therapy. More elderly pts received a single novel agent, whereas use of 2 novel agents was more common in younger pts (Table). The most common frontline regimens among elderly pts were bortezomib (V) + dexamethasone (D), followed by lenalidomide (R) + D, whereas those among younger pts included RVD, followed by VD and CyBorD (Table). No pt aged ≥85 y, and 4% of pts aged 75-84 y received high-dose chemotherapy and autologous stem cell transplant (vs 61% in the <65 y and 37% in the 65-74 y age group). The most common maintenance therapy was RD in pts ≥85 y (although the use was low) and R alone in other age groups (Table). In the ≥85 y group, 27%, 10%, and 4% of pts entered 2L, 3L, and 4L treatments respectively, vs 43%, 23%, and 13% in the <65 y group. Progression-free survival was significantly shorter in the ≥85 y age group vs the 75-84 y age group (P=0.003), 65-74 y age group (P<0.001), and <65 y age group (P<0.001; Fig.1). TTP was significantly shorter in the ≥85 y group vs the <65 y group (P=0.020); however, TTP was similar among the 65-74 y, 75-84 y, and ≥85 y cohorts (Fig. 2). Overall survival was significantly shorter in the ≥85 y group vs the 75-84 y, 65-74 y, and <65 y groups (all P<0.001; Fig. 3). The mortality rate was lowest (46%) during first-line treatment (1L) in pts aged ≥85 y (mainly attributed to MM progression) and increased in 2L and 3L (47% and 54%, respectively); a similar trend was observed in the younger age groups. The main cause of death was MM progression (29% in the ≥85 y vs 16% in the <65 y group). Other notable causes of death in the ≥85 y group included cardiac failure (5% vs 2% in <65 y group) and pneumonia (5% vs 1% in <65 y group). Conclusions: In this analysis, elderly pts received similar types of frontline and maintenance regimens as younger pts, although proportions varied with decreased use of triplet regimens with age. Considering similarities in TTP across the 65-74 y, 75-84 y, and ≥85 y cohorts, these real-world data support active treatment and aggressive supportive care of elderly symptomatic pts, including with novel agents. Additionally, further clinical studies specific to elderly patients with MM should be explored. Disclosures Lee: Amgen: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Ailawadhi:Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Cellectar: Research Funding. Gasparetto:Celgene: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; Janssen: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed ; BMS: Consultancy, Honoraria, Other: Travel, accommodations, or other expenses paid or reimbursed . Jagannath:AbbVie: Consultancy; Merck & Co.: Consultancy; Bristol-Myers Squibb: Consultancy; Karyopharm Therapeutics: Consultancy; Celgene Corporation: Consultancy; Janssen Pharmaceuticals: Consultancy. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy. Narang:Celgene: Speakers Bureau. Terebelo:Celgene: Honoraria; Jannsen: Speakers Bureau; Newland Medical Asociates: Employment. Toomey:Celgene: Consultancy. Hardin:Celgene: Membership on an entity's Board of Directors or advisory committees. Wagner:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; American Cancer Society: Other: Section editor, Cancer journal. Omel:Celgene, Takeda, Janssen: Other: Patient Advisory Committees. Srinivasan:Celgene: Employment, Equity Ownership. Liu:TechData: Consultancy. Dhalla:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:BMS: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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