Clinico-Molecular Features and Treatment Outcomes in Primary Myelofibrosis Phenotypes with Protracted Disease Dynamics

Abstract Background Primary myelofibrosis (PMF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Driven by constitutive activation of the JAK/STAT pathway, its prognosis is defined by cardinal clinical, cytogenetic and molecular features. While most patients require therapy for symptomatic splenomegaly, disease-related symptoms, or cytopenias, asymptomatic lower-risk patients may be appropriately monitored with active surveillance. The aim of this study was to explore disease characteristics and outcomes among pts who remained on prolonged active surveillance compared to those who received early treatment. Methods We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were stratified into two cohorts: those remaining on active surveillance for ≥ 36 months following diagnosis and those who received within 36 months of diagnosis. Results Between August 2000 and March 2021, we identified 626 patients with a diagnosis of MF. Among these, 48 (8%) did not receive treatment for at least 3 years. Table 1 summarizes the baseline characteristics comparing those pts who remained on active surveillance for ≥ 36 months (LTO-MF) to those who received treatment within 36 months of diagnosis (ET-MF). The LTO cohort presented at a younger age (median age 63 vs 68; p = 0.001), but otherwise demographic variables were balanced between the two cohorts. LTO patients were more likely to have primary MF (85.4% vs 60.9%, p=0.003). LTO patients were less likely to have leukocytosis (28.2% vs 49.9%, p=0.01), and constitutional symptoms (29.8% vs 44.6%, p=0.05), while having a higher reticulocyte percentage (81.4% vs 64.1%, p=0.02). LTO patients also had lower platelet counts (mean: 274k vs 359k, p=0.006), lower percentage of circulating blasts (0.4% vs 1.2%, p<0.001), and lower percentage of marrow myeloblasts (1.3% vs 1.9%, p<0.001) at baseline. Cohorts had comparable rates of anemia, thrombocytopenia, transfusion dependence, LDH levels and splenomegaly at baseline. Interestingly, the cohorts were well-balanced in terms of risk score based across all major prognostic scoring systems: IPSS (p=0.356), DIPSS (p=0.764), DIPSS+ (p=0.148), GIPSS (p=0.125), MIPSS70 (p=0.924) and MIPSS70+ (p=0.407). There was no association between GPSS karyotype risk and need to start treatment earlier (p=0.481) (Table 1). LTO patients were less likely to harbor JAK2 mutations (58.3% vs 72.4%, p=0.04). No significant differences were seen regarding CALR (p=0.144), MPL (p= 0.271), or triple-negative disease (p=0.521) (Table 2). The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). LTO patients had longer OS (mOS 170.3 mo vs 63.9 mo; (p<0.001). Rates of transformation to blast phase were comparable (6.2% vs 9.7%;p=0.441), but median time to blast phase transformation was longer for LTO MF: 66.3 mo vs 29 mo, p=0.011). Expectedly, time to first treatment longer for LTO patients (62.1 mo vs 0.9 mo; (p<0.001). No differences were noted between cohorts in terms of response to ruxolitinib, duration of response to ruxolitinib or response to lenalidomide/thalidomide (p = 0.91, 0.90, 0.83, respectively) Conclusion In this single-center study of patients seen at a tertiary referral center, the vast majority of MF patient required treatment within 36 months of diagnosis. Those monitored with active surveillance were younger, had less proliferative signs/symptoms, were less likely to have JAK2 mutations, and more favorable outcomes. Figure 1 Figure 1. Disclosures Tinsley-Vance: Fresenius Kabi: Consultancy; Novartis: Consultancy; Incyte: Consultancy, Speakers Bureau; Abbvie: Honoraria; Jazz: Consultancy, Speakers Bureau; Taiho: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Sallman: Magenta: Consultancy; Takeda: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Aprea: 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; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Jazz: Consultancy. Padron: Incyte: Research Funding; BMS: Research Funding; Taiho: Honoraria; Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria. Kuykendall: Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; BluePrint Medicines: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; PharmaEssentia: Honoraria; Abbvie: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria. Komrokji: AbbVie: Consultancy; Geron: Consultancy; Acceleron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees.

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Different Treatment Approaches to Blast Phase-Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-146945 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3641-3641

Author(s):

Franco Castillo Tokumori ◽

Najla Al Ali ◽

Onyee Chan ◽

David A. Sallman ◽

Seongseok Yun ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Initial Treatment ◽

Research Funding ◽

Clinical Characteristics ◽

Myeloproliferative Neoplasms ◽

Intensive Chemotherapy ◽

Blast Phase ◽

Advisory Committees

Abstract CONTEXT: Transformation to acute myeloid leukemia (AML) occurs in 5-20% of patients with myeloproliferative neoplasms (MPN). Overall survival in blast phase MPN (MPN-BP) is poor, usually in the range of 3 to 6 months, and is not significantly impacted by intensive chemotherapy. Current guidelines favor treatment with a hypomethylating agent (HMA), but survival remains poor, and allogeneic hematopoietic stem cell transplantation (AHSCT) holds the only potential for long term survival. OBJECTIVE: To describe the clinical characteristics and overall survival of MPN-BP according to different treatment approaches. DESIGN: Single-institution, retrospective analysis of 70 MPN patients that progressed to blast phase, who presented to our institution between 2001 and 2020. Transformation to AML defined as >20% myeloblasts in peripheral blood or bone marrow. We stratified the patients according to initial treatment strategy for AML. Baseline variables were compared between groups. Median overall survival (mOS) was measured from time of AML diagnosis to date of death. Kaplan-Meier plots were created to compare mOS. RESULTS: Among 70 MF patients that progressed to AML, initial treatment was: 19 best supportive care (BSC), 25 HMA (20 HMA only and 5 HMA + venetoclax), and 26 intensive chemotherapy (IC) [12 patients received standard "7+3" regimen with daunorubicin/idarubicin and cytarabine, 12 received high-dose cytarabine, cladribine +/- mitoxantrone (CLAG/CLAG-M), and 2 received CPX-351 (Vyxeos)]. Patients receiving IC were younger at time of leukemic transformation than those receiving BSC (median 63.9 years vs 72.9 years; p=0.029) or HMA (median 63.9 years vs. 69.0 years; p=0.026). Additionally, 70% of IC patients had an ECOG performance status of 0 or 1 compared to just 48% of patients receiving either BSC or HMA (p=0.088). Median OS for the entire cohort (n = 70) was 4.8 months. Compared to patients who received active treatment with HMA or IC, those treated with BSC had shorter survival (0.9 months vs 6.4 months; p=0.001). Median survival between patients treated with HMA and IC was not significantly different (4.5 months vs 9.6 months; p=0.13). Patients treated with IC were more likely to proceed to AHSCT (46% vs 5%; p < 0.001). Between HMA and IC groups, there was no difference in time from MPN-BP diagnosis to treatment (median 0.4 months vs 0.3 months; p=0.644) or total number of lines of treatment for MPN-BP. Focusing specifically on the role of AHSCT in patients treated with IC, we found that patients who received AHSCT had significantly longer mOS than those patients who did not (18.9 months vs 4.9 months; p=0.002), suggesting the beneficial role of intensive chemotherapy is critically tied to the ability to subsequently undergo AHSCT. Among patients who underwent AHSCT, 1-year and 2-year OS was 51% and 34%, respectively. In contrast, patients not receiving AHSCT had 1-year and 2-year OS of 14% and 2%, respectively. Independent of age, AHSCT (p=0.008) and receipt of therapy (p=0.017) significantly correlated with longer survival after AML diagnosis. Besides these factors, there were no significant differences in the clinical characteristics between the three groups. Acknowledging the limitations associated with small numbers, we did not note any difference in survival between patients who received HMA vs HMA + venetoclax (p=0.27). CONCLUSIONS: In MPN-BP, patients receiving treatment had superior outcomes to those that received BSC. Initial treatment with intensive chemotherapy was associated with non-significant improvement in survival; however, this appears to be critically linked to the receipt of AHSCT. In appropriate patients, intensive chemotherapy may be reasonable in an effort to provide an effective bridge to AHSCT. Still, this study reinforces the poor prognosis associated with MPN-BP and the desperate need for novel therapeutic approaches in this group of patients. Figure 1 Figure 1. Disclosures Sallman: AbbVie: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: 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, Speakers Bureau; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau. Sweet: Bristol Meyers Squibb: 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; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. Padron: BMS: Research Funding; Kura: Research Funding; Incyte: Research Funding; Blueprint: Honoraria; Taiho: Honoraria; Stemline: Honoraria. Lancet: Daiichi Sankyo: Consultancy; Celgene/BMS: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; AbbVie: Consultancy; Astellas: Consultancy; Agios: Consultancy; ElevateBio Management: Consultancy; Jazz: Consultancy. Komrokji: PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acceleron: Consultancy; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kuykendall: Novartis: Honoraria, Speakers Bureau; Prelude: Research Funding; Incyte: Consultancy; PharmaEssentia: Honoraria; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Evaluation of Tagraxofusp (SL-401) Alone and in Combination with Ruxolitinib for the Treatment of Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-129397 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2967-2967 ◽

Cited By ~ 1

Author(s):

Aishwarya Krishnan ◽

Maria Pagane ◽

Mikhail Roshal ◽

Erin McGovern ◽

Zoe Stone-Molloy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Single Agent ◽

Employment Equity ◽

Blast Phase ◽

Advisory Committees ◽

Provision Of Services ◽

Equity Ownership ◽

The Impact

Background: The introduction of the JAK1/2 inhibitor Ruxolitinib has resulted in significant benefits for patients with Myelofibrosis (MF) and Polycythemia Vera, including reduction of splenomegaly and improvement in symptom burden. However, Ruxolitinib has limited ability to alter the natural history and biology of disease in myeloproliferative neoplasms (MPNs). More importantly, patients often lose response to ruxolitinib or suffer disease progression despite therapy with ruxolitinib. These observations have prompted efforts to introduce novel therapeutic approaches and devise novel combinatorial treatment strategies to improve the outcomes of patients with MPNs. CD123 (interleukin-3 receptor-a; IL-3R-a) has been identified as a therapeutic target in several myeloid malignancies. CD123 is expressed in a variety of myeloid malignancies, including AML, myelodysplastic syndrome (MDS) and CMML. Further, Tagraxofusp (ELZONRIS®, SL-401), a targeted therapy directed to CD123 comprised of recombinant IL-3 fused to a truncated diphtheria toxin payload, was recently FDA approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN). In an ongoing Phase 1/2 trial, Tagraxofusp has demonstrated single agent clinical activity, with a predictable and manageable safety profile, in patients with relapsed/refractory MF. Thus, Tagraxofusp appears to have activity in MF. However, the utility of Tagraxofusp in more advanced forms of MPN (such as accelerated phase MPN), as well as the utility of combination Ruxolitinib and Tagraxofusp, have not been evaluated to date. To address these questions, we first evaluated CD123 expression using flow cytometry analysis of peripheral blood samples from patients with MF with progression to accelerated-phase (>10%) or blast-phase (>20%) disease. CD123 expression was generally noted to be higher than that observed in normal control samples, by mean florescence intensity (Figure 1A). We next sought to determine the effect of treatment with Tagraxofusp alone and in combination with Ruxolitinib in leukemia cell lines and primary patient samples. We performed cell viability assays using the JAK2V617F mutant cell line UKE1. We first determined the IC50 of Tagraxofusp in UKE1 cells (range 2.95-3.57nM). Using this data, we then tested the impact of the addition of Tagraxofusp to Ruxolitinib on UKE1 cell viability using a fixed concentration of Tagraxofusp (5nM). The IC50 of range of single agent Ruxolitinib was 44.42-70.93nM. However, the addition of Tagraxofusp to Ruxolitinib resulted in a decrease of the IC50 range to 11.72-21.6nM, indicating an effect of combination therapy (Figure 1B). We then determined the impact of Tagraxofusp both alone and in combination with Ruxolitinib using primary patient MPN peripheral blood mononuclear cells in methylcellulose. Patient characteristics are described in Table 1. In most samples, CD123 expression was confirmed. In all samples studied, Tagraxofusp was able to significantly reduce colony formation when compared to vehicle, at a dose range of 2.5nM to 20nM. Notably, this includes two samples (151, 455) from patients with accelerated-phase disease. As well, Tagraxofusp demonstrated activity across genotypes, including in cases with TP53 and ASXL1 mutations. A reduction in colony formation in samples treated with combination Ruxolitinib and Tagraxofusp beyond that observed with either agent alone was observed in several cases (Figure 1C). Conclusions: Current therapeutic options for patients with MF beyond Ruxolitinib are limited. This is particularly the case for patients with progression to accelerated and blast-phase MPN. Here, we demonstrate that CD123 expression is evident in many such cases. Further, therapeutic targeting of CD123 using Tagraxofusp either alone or in combination with Ruxolitinib has activity in primary patient samples, including those in accelerated-phase and with high molecular risk profiles. These data thus support further testing of Tagraxofusp in MPNs, and in advanced MPNs in particular. Disclosures Roshal: Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Chen:Stemline Therapeutics: Employment, Equity Ownership. Brooks:Stemline Therapeutics: Employment, Equity Ownership, Patents & Royalties. Levine:Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy; Prelude Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; Loxo: Membership on an entity's Board of Directors or advisory committees; Qiagen: Membership on an entity's Board of Directors or advisory committees; Lilly: Honoraria; Amgen: Honoraria; Roche: Consultancy, Research Funding. Rampal:Constellation, Incyte, and Stemline Therapeutics: Research Funding; Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy.

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Direct Oral Anticoagulant Use and Outcomes in Patients with High and Intermediate Risk BCR-ABL-Negative Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2019-129705 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1165-1165 ◽

Cited By ~ 1

Author(s):

Kelly L. Schoenbeck ◽

Giselle Salmasi ◽

Miguel Carlos Cerejo ◽

Patricia A. Cornett ◽

Lloyd E. Damon ◽

...

Keyword(s):

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Primary Myelofibrosis ◽

Intermediate Risk ◽

Advisory Committees ◽

Safety And Efficacy ◽

Hemorrhagic Event ◽

Common Diagnosis

Background: Patients with BCR-ABL-negative myeloproliferative neoplasms (MPNs) are prone to thrombohemorrhagic complications. Vitamin K antagonists (VKA) or low weight molecular heparin (LWMH) are considered standard treatments for venous or arterial thromboses in BCR-ABL-negative MPN patients. However, there is little information regarding the safety and efficacy of direct oral anticoagulants (DOACs) in this population. Our primary aim was to determine the prevalence and outcomes of DOAC use in BCR-ABL-negative MPN patients at our institution. Methods: We performed a single-center, retrospective cohort study of all active BCR-ABL-negative MPN patients in the UCSF Hematology Clinic between January 2017 and March 2019. Patients were identified by ICD-10 codes and chart abstraction. Problem and medication lists were reviewed for appropriate diagnoses and medications. Provider notes were reviewed for anticoagulation indication, treatment course, and hemorrhagic or thrombotic complications. Descriptive statistics were used to summarize the data. Results: Of 299 patients with BCR-ABL-negative MPNs, 42 were treated with anticoagulation during our abstraction period. Of the 42 patients, 22 (52%) were treated with DOACs, 17 (41%) with warfarin, and 3 (7%) with LWMH. Of the 22 patients on DOACs, the median age was 74 (range 39-94) with a female to male ratio of 1.2:1. Of those on DOACs, the most common diagnosis was essential thrombocythemia (ET) (n=9; 41%), followed by primary myelofibrosis (MF) and post-ET or post-PV myelofibrosis (n=7; 32%), polycythemia vera (PV) (n=5; 22%), and MPN-Unclassifiable (n=1; 5%). All ET and PV patients (except 1 ET) were high-risk by IPSET-thrombosis and clinical criteria, and all primary myelofibrosis and post-ET or post-PV myelofibrosis patients were intermediate-2 by DIPSS-plus. Most patients were JAK2 V617F positive (n=19; 86%), with the remainder positive for CALR type 2 (n=2; 9%) and type 1 (n=1; 5%). Almost all ET and PV patients were concurrently treated with hydroxyurea (12/14; 86%) and 1 out of 5 PV patients was also treated with phlebotomy. Roughly one-third of patients (n=8; 36%) remained on aspirin while on a DOAC. Of the 22 patients, 15 (68%) were prescribed DOACs for thrombosis treatment and prophylaxis. The primary indications were pulmonary embolus (PE) (n=5), deep venous thrombosis (DVT) (n=4), splanchnic thrombosis (SVT) (n=3), organ ischemia (n=2), and cerebral sinus thrombosis (CVT) (n=1). The remaining 7 patients were on DOACs for atrial fibrillation, although two had histories of prior thrombotic events (PE and stroke). Nine (41%) of the patients on DOACs had a history of more than one significant venous or arterial thrombotic event. Most were on long-term anticoagulation with a median DOAC prescription of 26 months (range 4 to 62). Nineteen patients (86%) remained on a DOAC at their last provider visit, with two having completed treatments for provoked PEs and one discontinued for thrombocytopenia. DOACs prescribed for thrombosis indications included apixaban (n=8), rivaroxaban (n=5), and dabigatran (n=2). Of the 22 patients on DOACs, none experienced significant thrombotic events and one patient had a hemorrhagic event shortly before establishing care at our institution; a post-PV MF patient on dabigatran for a splanchnic thrombosis had an upper gastrointestinal bleed and required reversal with idarucizumab. Of the patients on warfarin and LWMH, there were 4 significant thrombohemorrhagic events: 1 bleeding and 3 clotting. The bleeding event happened in a high risk ET patient on warfarin plus aspirin for a splanchnic vein thrombosis (INR 2.2). Three clotting events occurred in high risk ET and PV patients on warfarin. One was concurrently diagnosed with a DVT, PE, and arterial thrombus (INR 2.1), and the other two were diagnosed with portal vein thromboses (INRs of 1.8 and 2.2). None were taking hydroxyurea or aspirin at time of their recurrent thrombosis. Conclusions: DOACs were used more frequently than warfarin or LWMH in our high and intermediate risk BCR-ABL-negative MPN patients with no clotting events but one notable hemorrhagic event. Future research regarding the safety and efficacy of DOAC use in BCR-ABL-negative MPNs, including randomized controlled trials, should be considered. Disclosures Damon: Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Logan:Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; TeneoBio: Consultancy; Kadmon: Research Funding; Pharmacyclics: Research Funding; Abbvie: Consultancy; Astellas: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kiadis: Consultancy; Kite: Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Research Funding. Olin:MedImmune: Research Funding; Ignyta: Research Funding; Clovis: Research Funding; Mirati Therapeutics: Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Research Funding; Spectrum: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria; Novartis: Research Funding; Revolution Medicine: Consultancy; Daiichi Sankyo: Research Funding; Astellas: Research Funding. Smith:Revolution Medicines: Research Funding; Astellas Pharma: Research Funding; fujiFilm: Research Funding; Abbvie: Research Funding.

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Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes

Blood ◽

10.1182/blood-2021-151978 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1494-1494

Author(s):

Luis E. E. Aguirre ◽

Akriti G Jain ◽

Somedeb Ball ◽

Najla Al Ali ◽

Sara Marie Tinsley-Vance ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Triple Negative ◽

Epigenetic Modification ◽

Myeloproliferative Neoplasms ◽

Prognostic Scores ◽

Response To Treatment ◽

Cancer Center ◽

Molecular Characteristics ◽

Advisory Committees

Abstract Background Myelofibrosis (MF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Approximately 90% of patients harbor a mutation affecting JAK2, MPL, or CALR which results in constitutive activation of the JAK/STAT pathway, resulting in proliferative and dysfunctional blood cell production, extramedullary hematopoiesis, and constitutional symptoms. Remaining patients are deemed to be "triple-negative" (TN), a designation associated with a poor prognosis. Methods We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were deemed to be TN if they had tested negative for mutations involving JAK2, MPL and CALR. TN patients were compared to non-TN patients who exhibited a mutation in at least one of these genes. Patients with incompletely driver mutation testing were excluded. Baseline demographic, clinical and molecular characteristics were assessed. Kaplan-Meier method was used to determine overall survival (OS) and leukemia-free survival (LFS). Results 626 patients with a diagnosis of MF were identified, among which 6% (n=38) were confirmed to harbor TN disease. See Table 1 for baseline characteristics of TN vs non-TN patients. Thrombocytopenia was more common in TN disease (28.9% vs 12.2%, p=0.003), as well as elevated EPO titers at baseline (88.9% vs 56.8%, p=0.007). Elevated LDH titers at baseline were less common with TN disease (78% vs 91%, p=0.009). Baseline Hb (p=.009), and % of marrow myeloblasts (p < .005) were lower in the TN cohort. Clinically, there were no differences regarding transfusion dependence, presence of constitutional symptoms or splenomegaly (Table 1). Regarding prognostic scores, patients with TN MF exhibited higher-risk disease per DIPSS+ (65.8% vs 58.1%, p=.034) and GIPSS (62.5% vs 47.1%, p=.001) compared to their non-TN counterparts. There were no significant differences in IPSS, DIPSS+, MIPSS70 or MIPSS70+ stratifications. The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). Patients with TN MF had shorter survival rates with a mOS of 37.4 months (95%CI 19.2-55.5) compared to 85.7 mo (95% CI 74.6-96.85) for non-TN disease (p=.009). The rate of transformation to AML was 10.5% for TN MF, 9.7% for JAK2, 7.3% for MPL and 5.2% for CALR MF (TN vs non-TN MF p=0.7). Median LFS was 65.2 mo for CALR, 34.1 mo for TN, 21.9 for JAK2 and 16.9 mo for MPL mutant MF (p = 0.498 for TN vs non-TN phenotypes). Nominally, TN patients had fewer responses (46.2% vs 63.4%) and shorter duration of response to ruxolitinib (8.0 mo vs 12.5 mo), though this did not meet significance (p = 0.21 and 0.5, respectively). There were no differences in response rate to lenalidomide/thalidomide, HMA, HMA/venetoclax (Table 1) Mutations involving SRSF2, SETBP1, IDH2, CBL, and GNAS were significantly enriched in TN disease (see table 2). U2AF1 mutations were more frequently seen in the non-TN cohort (11.2% vs 0%, p=0.032) (Table 2). Conclusion In our independent database of MF, we confirmed the unfavorable prognosis of TN-MF in terms of shorter OS and LFS. While lacking classic driver mutations, TN-MF frequently harbors mutations impacting splicing, epigenetic modification, and signaling that likely drive this aggressive clinical course, and may account for suboptimal responses to JAK inhibition. Figure 1 Figure 1. Disclosures Tinsley-Vance: Taiho: Consultancy; Jazz: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Sallman: Aprea: 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; Incyte: Speakers Bureau; Intellia: 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, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Astellas: Consultancy. Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding. Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Komrokji: AbbVie: Consultancy; Geron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

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Patient Characteristics and Outcomes in Adolescents and Young Adults (AYA) with Acute Myeloid Leukemia (AML): Princess Margaret Cancer Centre Experience

Blood ◽

10.1182/blood-2019-125449 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2609-2609

Author(s):

Muhned Alhumaid ◽

Georgina S Daher-Reyes ◽

Wilson Lam ◽

Arjun Law ◽

Tracy Murphy ◽

...

Keyword(s):

Board Of Directors ◽

Older Patients ◽

Myeloid Leukemia ◽

Research Funding ◽

Age Groups ◽

Treatment Strategies ◽

Patient Characteristics ◽

Cancer Center ◽

Advisory Committees ◽

Disease Behavior

Introduction: Clinical outcomes of acute myeloid leukemia (AML) in adolescents and young adults (AYA) are rarely reported as an isolated subgroup. Treatments vary little across age groups, and treatment intensity depends upon comorbid conditions and performance status. Optimal treatment strategies focused on disease behavior, biological factors, and the distinct needs of this subset of AML patients remain elusive. The purpose of this retrospective analysis is to determine the characteristics and outcomes of AYA AML patients treated at a specialized adult leukemia cancer center in comparison to older adults with AML (40-60 years). Methods: A retrospective analysis was performed on all patients treated at Princess Margaret Cancer Center from 2008-2018. Patients with acute promyelocytic leukemia were excluded. Clinical characteristics, treatment strategies, and survival outcomes were recorded for all patients. Overall survival (OS) and disease-free survival (DFS) rates were calculated using the Kaplan-Meier product-limit method and the impact of covariates were assessed using the Log-rank test. Finally, we compared the outcomes of AYA patients treated at our centre between 2015-2018 with older patients. Results: A total of 175 patients aged 18-39 were identified. Patient characteristics are shown in (Table 1). Cytogenetic were available in 163 patients. Based on MRC criteria, 27 (16%) were favorable risk, intermediate in 95 (54%), adverse in 39 (22%), and missing/failed in 14(8%). NPM1 status was available in 110 patients of whom 38 (35%) were positive. FLT3-ITD was available in 67 patients with 24 (36%) positive. Both mutations were present in 13 (54%) patients. There were no significant differences in terms of risk stratification based on cytogenetic and molecular markers based on age (18-29 vs.30-39) (P= 0.98). Most patients 172 (98%) received induction, 157 (91%) with 3+7, and 15 (9%) with FLAG-IDA. Complete remission (CR) was achieved in 133 (77%) after first induction [120 (76%) after 3+7 and 11 (73%) after FLAG-IDA]. Induction related mortality was low (2%). Of the 39 who did not achieve CR, thirty-four patients received re-induction (13 FLAG-IDA, 16 NOVE-HiDAC, 5 others) with CR in 21 (62%). Overall, 154 (89.5%) achieved CR1. Sixty-four (42%) proceeded to hematopoietic stem cell transplantation (HSCT) in CR1. 59 (38%) patients relapsed in CR1 with 8 (12%) relapsing post HSCT. Fifty-five (5 post HSCT) patients received reinduction with 30 (51%) (2 after HSCT) achieving CR2. Fifteen patients received HSCT in CR2. OS and DFS at 2 years were 62% (95% CI 0.53-0.69) and 50% (95% CI 0.41-0.57), respectively. Stratified by cytogenetic risk, OS was 81% for favorable risk, 61% for intermediate, and 50% for adverse risk (P=0.0001), respectively. DFS in these groups was 85%, 57%, and 46 % (P=0.0025), respectively. We further compared outcomes in the 18-29y and 30-39y age groups. The OS was 61.9% compared to 62.5% (P=0.91) and DFS of 52.1% compared to 47% (P=0.65) respectively. On univariate analysis for OS and DFS, cytogenetic risk stratification was the only significant variable (P=0.0004 and P=0.0042). We then compared the outcomes 67 sequential patients aged I8-39 treated from 2014-2018, with those of 176 sequential patients aged 40-60 treated during the same period (table 2). OS at 2 years was not statistically higher in the younger group compared to the older group (66.7% vs. 61.2%, P=0.372). While relapse rate was lower in older patients (15.5% vs. 22.6%, P=0.093), NRM was higher in older patients (29.7% vs. 18.8%,P=0.094). Conclusion: AYA pts. occupy a unique niche amongst AML as a whole. While treatment responses have improved in general, there may be potential for further gains in these patients. Increased tolerance for more intense treatment strategies as well as the incorporation of novel agents into standard treatment protocols may provide a means to optimize care in AYA patients. Finally, research is needed to elucidate biological mechanisms and predictors of disease behavior instead of arbitrary, age-stratified treatment schema. Disclosures McNamara: Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy. Schuh:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astellas: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Astex: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffman La Roche: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement. Gupta:Incyte: Honoraria, Research Funding; Celgene: 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, Research Funding; Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Mutations Highly Specific for Secondary AML Are Associated with Poor Outcomes in Patients with NPM1-Mutated ELN Favorable Risk AML

Blood ◽

10.1182/blood-2021-150759 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 686-686

Author(s):

Onyee Chan ◽

Najla Al Ali ◽

Hammad Tashkandi ◽

Austin Ellis ◽

Somedeb Ball ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Univariate Analysis ◽

Prognostic Significance ◽

Cancer Center ◽

Cell Transplant ◽

Intermediate Risk ◽

Advisory Committees ◽

Secondary Aml ◽

The Impact

Abstract Background: NPM1 is commonly mutated in acute myeloid leukemia (AML) and represents a distinct entity under the WHO 2016 classification. It is one of the few mutations that can potentially support favorable risk by European LeukemiaNet (ELN) 2017 criteria. Mutations that are highly specific for secondary AML including SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, and STAG2 (sMut) (Lindsley et al.) have been shown to confer poor prognosis. The impact of these mutations on NPM1-mutated AML warrants further investigation. Objective: In this study, we explore the outcomes in patients with NPM1-mutated AML. Methods: This was a retrospective study of NPM1-mutated AML patients who were diagnosed and treated at the Moffitt Cancer Center from 2013 to March 2021. Inclusion was restricted to NPM1-mutated patients with mutation analysis (NGS) performed at diagnosis (n=159). Kaplan-Meier, univariate, and multivariate analyses were performed. Results: Among 159 patients (78M/81F, median age 63 years at diagnosis), 80.5% had de novo AML. By ELN 2017 criteria, 63.5% (101/159) had favorable risk, 27.7% (44/159) had intermediate risk, and 8.2% (13/159) had adverse risk disease. Almost 90% had intermediate risk cytogenetics at the time of diagnosis. Common co-mutations included DNMT3A (47.2%), FLT3-ITD (35.8%), TET2 (26.4%), IDH1 (17.6%), FLT3-TKD (15.1%), and IDH2 (13.8%). sMut comprised 19.5% (31/159) of patients and 20.8% (21/101) of those with ELN favorable risk. In patients with treatment response data, those with sMut never achieved CR/CRi in 35.7% (10/28) compared to 17.2% (22/128) of patients without sMut (p=0.038). The overall survival (OS) was 43.7 months with a median follow up of 35.5 months. Patients with sMut had worse OS compared to those without sMut (14.7 months vs 57.6 months, p=0.011). Among patients with favorable risk disease, OS was 11.6 months compared to not reached for those with sMut and without sMut, respectively (p<0.0001). Univariate analysis showed sMut and allogeneic hematopoietic cell transplant (HCT) significantly impacted OS (sMut: HR 3.48, 95% CI: 1.80-6.72, p<0.001; HCT: HR 0.17, 95% CI: 0.07-0.44, p<0.001). Multivariate regression using covariates including age, AML type, sMut, and HCT confirmed their prognostic significance on survival (sMut: HR 2.40, 95% CI: 1.17-4.93, p=0.017; HCT: HR 0.26, 95% CI: 0.08-0.56, p=0.002). Conclusions: Our findings suggest NPM1-mutated AML patients with sMut have significantly worse prognosis despite being classified primarily as favorable risk by ELN 2017 at diagnosis. This may have treatment implications altering the need for and/or timing of HCT. These findings should be assessed prospectively and validated in independent datasets. Figure 1 Figure 1. Disclosures Hussaini: Adaptive: Consultancy, Honoraria, Speakers Bureau; Stemline: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; Celegene: Consultancy; Decibio: Consultancy; Guidepoint: Consultancy; Bluprint Medicine: Consultancy. Talati: AbbVie: Honoraria; Pfizer: Honoraria; Astellas: Speakers Bureau; BMS: Honoraria; Jazz: Speakers Bureau. Kuykendall: Incyte: Consultancy; Novartis: Honoraria, Speakers Bureau; Protagonist: Consultancy, Research Funding; Celgene/BMS: Honoraria; Abbvie: Honoraria; Blueprint: Honoraria; Pharmaessentia: Honoraria. Padron: Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding; Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding. Sallman: Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Takeda: Consultancy; Kite: 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, Speakers Bureau; Incyte: Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Komrokji: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Geron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Acceleron: Consultancy; AbbVie: Consultancy; Jazz: Consultancy, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Agios: Consultancy; Astellas: Consultancy.

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RON Kinase Is a Novel Therapeutic Target for Philadelphia-Negative Myeloproliferative Neoplasms

Blood ◽

10.1182/blood-2021-148192 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 1462-1462

Author(s):

Lindsay Meg Gurska ◽

Rachel Okabe ◽

Meng Maxine Tong ◽

Daniel Choi ◽

Kristina Ames ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Marrow Transplant ◽

Jak Inhibitor ◽

Advisory Committees ◽

Hematopoietic Stem ◽

Stat Signaling ◽

Genetic Deletion

Abstract The Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineage compartments. Activation of JAK/STAT signaling is a major driver of all Ph-negative MPNs. During disease progression, MPN patients experience increased pro-inflammatory cytokine secretion, leading to remodeling of the bone marrow microenvironment and subsequent fibrosis. The JAK inhibitor ruxolitinib is an approved targeted therapy for MPN patients and has shown promise in its ability to reduce splenomegaly and the cytokine storm observed in patients. However, JAK inhibitors alone are not sufficient to reduce bone marrow fibrosis or to eliminate the JAK2-mutated clone. Furthermore, JAK inhibitor persistence, or reactivation of JAK/STAT signaling upon chronic JAK inhibitor treatment, has been observed in both MPN mouse models and MPN patients. Therefore, there is an urgent need for new treatment options in MPN. The tyrosine kinase RON, a member of the MET kinase family, has well-characterized roles in erythroblast proliferation and pro-inflammatory cytokine production. RON can be phosphorylated by JAK2 to stimulate erythroblast proliferation. However, the role of RON in MPN pathogenesis is unknown. We found that the ALK/MET/RON/ROS1 inhibitor crizotinib inhibited colony formation by MPN patient CD34+ cells, regardless of their disease subtype, mutation status, or JAK2 inhibitor treatment history (Figure 1A). To determine whether this is due to inhibition of the JAK/STAT signaling pathway, we performed phospho-flow cytometry of STAT3 and STAT5 in myelofibrosis patient erythroblasts treated with crizotinib ex vivo as well as Western blot analysis in the JAK2-mutated cell lines SET2 and HEL. We found that crizotinib inhibits the phosphorylation of JAK2, STAT3, and STAT5 (Figure 1B). Since crizotinib has not been reported to directly inhibit JAK2, we asked whether these effects of crizotinib in MPN cells could be explained by RON inhibition. Consistent with this hypothesis, we observed that shRNA knockdown of multiple RON isoforms also decreases the phosphorylation of JAK2, STAT5, and STAT3 in HEL cells (Figure 1C-D). To determine whether crizotinib can alter the MPN disease course in vivo, we tested crizotinib by oral gavage in the MPLW515L bone marrow transplant murine model of myelofibrosis at 100mg/kg daily for 2 weeks. We showed that crizotinib decreased the disease burden of MPL-W515L mice, as evidenced by decreased spleen and liver weights (Figure 1E). To determine the effects of RON genetic deletion on MPN pathogenesis, we tested whether genetic deletion of Stk (mouse gene for RON) impairs disease progression in the JAK2V617F bone marrow transplant MPN model by transplanting Stk-/- c-Kit+ bone marrow cells transduced with the JAK2V617F-GFP retrovirus into lethally irradiated recipients. We observed a significant delay in disease onset in Stk-/- transplant recipients compared to WT controls (Figure 1F). However, we found that Stk-/- mice have normal numbers of hematopoietic stem and progenitor cells, and normal bone marrow myeloid colony forming capacity, suggesting that RON is a safe therapeutic target. To determine whether RON plays a role in the JAK inhibitor persistence phenotype, we generated persistent cells by treating SET2 cells with increasing doses of ruxolitinib over 8 weeks, and confirmed persistent proliferation and JAK/STAT activation. Interestingly, we found that RON phosphorylation is enhanced in JAK inhibitor persistent cells, and that dual inhibition of RON and JAK2 overcomes JAK inhibitor persistence in SET2 cells (Figure 1G-H), suggesting that RON may potentiate the JAK2 persistence phenotype in response to ruxolitinib. Importantly, we showed by immunoprecipitation that phospho-RON and phospho-JAK2 physically interact in JAK inhibitor persistent SET2 cells, and that this interaction is disrupted by crizotinib (Figure 1I). In summary, our data demonstrate that RON kinase is a novel mediator of JAK/STAT signaling in MPNs, and that it plays a particularly important role in JAK inhibitor persistence. Our work suggests that therapeutic strategies to inhibit RON, such as crizotinib, should be investigated in MPN patients. Figure 1 Figure 1. Disclosures Halmos: Guardant Health: Membership on an entity's Board of Directors or advisory committees; Apollomics: Membership on an entity's Board of Directors or advisory committees; TPT: Membership on an entity's Board of Directors or advisory committees; Eli-Lilly: Research Funding; Advaxis: Research Funding; Blueprint: Research Funding; Elevation: Research Funding; Mirati: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Boehringer-Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding. Gritsman: iOnctura: Research Funding.

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The Impact of Myeloproliferative Neoplasms (MPNs) on Patients' Quality of Life and Productivity: Results from the International MPN Landmark Survey

Blood ◽

10.1182/blood.v128.22.4267.4267 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4267-4267

Author(s):

Claire N. Harrison ◽

Steffen Koschmieder ◽

Lynda Foltz ◽

Paola Guglielmelli ◽

Tina Flindt ◽

...

Keyword(s):

Board Of Directors ◽

Interim Analysis ◽

Research Funding ◽

Myeloproliferative Neoplasms ◽

Well Being ◽

Ability To Work ◽

Advisory Committees ◽

The Past ◽

Night Sweats ◽

The Impact

Abstract Background Myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPNs) whose associated disease burden includes a range of debilitating symptoms, thrombosis, hemorrhage, and shortened survival. To enhance patient care, it is important to understand the impact of MPNs in patients' lives; however, little is known regarding how these conditions affect patients' quality of life (QOL), activities of daily living, productivity, and emotional well-being. The US LANDMARK survey (Mesa et al. BMC Cancer 2016) captured data for US patients. Here, we present an interim analysis of results of another MPN LANDMARK survey conducted in the rest of the world. Methodology MPN LANDMARK survey is a cross-sectional survey of MPN patients across 6 countries (Australia, Canada, Germany, Japan, Italy, and UK). Patients completed an online questionnaire to measure MPN related symptoms experienced over the past 12 months and the impact of their condition on their QOL and ability to work. Additional questions related to employment productivity and activity impairment (including absenteeism and loss of productivity over the past 7 days). Patients included in this interim analysis had completed the survey by July 18, 2016, with enrollment continuing in all countries. Results Patients: Overall, 437 patients had completed the survey (98 MF, 121 PV, 218 ET). For MF and PV, the male to female gender split was relatively even (54% male for each), whereas an expected greater proportion of ET patients was female (70%). Patients with MF were significantly older than PV and ET patients (mean ages, 62, 59, and 55 years, respectively) and more had been diagnosed within 2 years of experiencing their symptoms (83% MF, 67% PV, 71% ET). MPN Symptoms (Table): Most patients (94%) experienced MPN-related symptoms in the past 12 months. The most commonly reported symptom among all subtypes was fatigue (69% MF, 62% PV, 73% ET), incidence of other common symptoms varied depending on disease subtype (MF: shortness of breath [38%], bruising [36%], night sweats [35%], early satiety [33%]; PV: night sweats [36%], trouble concentrating [36%], trouble sleeping [34%], dizziness [34%]; ET: trouble sleeping [37%], dizziness [37%], bruising [35%], night sweats [35%]). When asked which symptom patients would most like to have resolved, most patients preferred to have feeling of fatigue/tiredness improved across all disease subtypes (31% MF, 30% PV, 33% ET). Patients experienced an average of 6.4 symptoms at diagnosis but this progressed to an average of 7.6 symptoms since diagnosis after a median time of 6 years. QOL: A majority of patients indicated that they experienced a reduction in QOL due to MPN symptoms (87% MF, 71% PV, 73% ET) with 33% and 26% of MF and ET patients expressing that their condition has caused emotional hardship, and one-third of patients with PV reporting that they have felt worried or anxious about their disease (39%). MPN Impact on Activity/Employment: Patients reported a high impact on their ability to work, 12% reported voluntarily leaving their job, 10% had taken early retirement, 10% had moved onto disability living allowance, 8% moved to a lower paid job, and 2% experienced involuntary loss of work (Table). Of the patients who were in full-time or part-time employment at the time of the survey (MF [n=17]), PV [n=41], ET [n=98]), approximately, 40% had been absent from work within the past 7 days; this was the highest in MF patients (41% MF, 38% PV, 33% ET). On an average, over the past 7 days, MF patients had missed 3.1 hours from work, PV patients 2.3 hours and ET patients 2 hours. Across all subgroups, a substantial proportion of patients reported impairment in work (mean: 34% MF, 33% PV, 31% ET) and overall activity (mean: 46% MF, 42% PV, 39% ET). Conclusions This interim analysis from the MPN LANDMARK survey indicates that MPN patients experience a high burden of disease, including a high prevalence of symptoms, an increase in the number of symptoms from diagnosis and reduction of their emotional well-being, QOL, and ability to work. These results are consistent with those from the previous US LANDMARK survey with the addition of novel data on how MPNs impact work. When treating MPN patients, care should be taken in trying to manage a patient's disease burden, so as to minimize the impact on a patient's daily life. Further results from additional survey responses will be presented at the congress. Disclosures Harrison: Baxaltra: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Incyte Corporation: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau. Koschmieder:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Foltz:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Koehler:Novartis Inc. (Germany): Consultancy, Other: Training. Komatsu:Shire: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Boothroyd:Novartis: Employment, Equity Ownership. Spierer:Novartis: Employment. Ronco:Novartis: Employment. Taylor-Stokes:Adelphi Real World: Employment. Waller:Adelphi Real World: Employment. Mesa:Celgene: Research Funding; Galena: Consultancy; Novartis: Consultancy; CTI: Research Funding; Ariad: Consultancy; Incyte: Research Funding; Gilead: Research Funding; Promedior: Research Funding.

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Does Trial Participation Improve Outcomes for Higher-Risk Myelodysplastic Syndromes (MDS) Patients Treated at Specialty Centers?

Blood ◽

10.1182/blood-2018-99-117174 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3096-3096

Author(s):

Sudipto Mukherjee ◽

David P. Steensma ◽

Rami S. Komrokji ◽

Amy E. DeZern ◽

Gail J. Roboz ◽

...

Keyword(s):

Clinical Trials ◽

Board Of Directors ◽

Research Funding ◽

Standard Of Care ◽

Wald Test ◽

Genetic Alterations ◽

Cancer Center ◽

Trial Participation ◽

Advisory Committees ◽

Risk Categories

Abstract Background: For some rare cancers, better outcomes have been reported for patient (pts) treated at high volume or specialty centers compared to pts who did not receive such care. Greater availability of interventional clinical trials may be one of the drivers of better outcomes in specialty centers. However, not all pts referred to specialty centers are eligible or willing to participate in trials, and it is not known how outcomes compare for pts treated at specialty centers on clinical trials versus standard of care. In this study, we compared the outcomes of higher-risk MDS pts treated in and out of clinical trials at MDS specialty centers. Methods: Pts treated at MDS Clinical Research Consortium institutions (Moffitt Cancer Center, Cleveland Clinic, MD Anderson Cancer Center, Cornell University, Dana-Farber Cancer Institute, and Johns Hopkins) from 2006-2016 were included. Pts were diagnosed with MDS according to 2008 WHO criteria and identified as having "higher-risk" disease based on the revised IPSS (IPSS-R) criteria that included Intermediate, High and Very high risk categories. All pts treated outside clinical trials received hypomethylating agents (HMAs), either azacitidine (AZA) or decitabine (DAC). Trial and non-trial pts were matched 1:1 based on age, sex, number of treatment regimens prior to HMA (for non-trial pts) or experimental regimen (for trial pts) and IPSS-R categories. All non-trial pts included in the analysis received at least 4 cycles of AZA or DAC at the same institution. Transplant rates and overall survival (OS) were evaluated for association with trial participation. OS was estimated by the Kaplan-Meier method and compared using Cox proportional hazard regression with two-sided Wald test with adjustment for matching variables. The relative odds of transplant following initial treatment were estimated using logistic regression and compared with two-sided Wald test. Results: Of 774 pts in the MDS CRC database for whom complete data were available, 323 were treated in clinical trials and 451 were treated with AZA or DAC. The trial and non-trial MDS cohorts were well matched with regards to median age (68.5 vs 68.2 yrs; P=0.65), females (28.4% vs 29.9%, P=0.75), numbers of regimens (3 vs 3, P=0.77) and IPSS-R risk categories (P=0.86). Estimated median OS of pts treated in and out of clinical trials was 44.5 and 50.6 months (P=0.67), respectively. Compared to standard of care, trial participation was not associated with any survival advantage [Hazard ratio (HR), 95% CI, 0.94 (0.72-1.24), P=0.67] (Figure 1). Clinical trial participation did not significantly increase the odds of proceeding to transplant [Odds Ratio (OR) (95% CI), 1.5 (0.68, 1.61), P = 0.83)]. As shown in Table 1, in multivariate analyses, among all factors, increasing number of regimens received was significantly associated with better survival, possibly reflecting a bias towards healthier pts who survived longer to receive multiple regimens. Conclusions: In a matched-pair analysis, we found comparable survival outcomes between trial and non-trial higher-risk MDS pts treated at specialty centers. Our matched analysis failed to identify any statistical evidence to suggest that an average patient benefited from trial participation within the MDS CRC sites. Additional research is necessary to interrogate these comparisons for specific patient subpopulations by genetic alterations, co-morbidities and regimen sequence, for which trial participation may have been beneficial. Based on the population-average findings, however, we expect any improvement in survival to be modest. Disclosures Komrokji: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Roboz:Orsenix: Consultancy; Celltrion: Consultancy; Janssen Pharmaceuticals: Consultancy; Astex Pharmaceuticals: Consultancy; Eisai: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; AbbVie: Consultancy; AbbVie: Consultancy; Eisai: Consultancy; Celltrion: Consultancy; Roche/Genentech: Consultancy; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Roche/Genentech: Consultancy; Daiichi Sankyo: Consultancy; Argenx: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Cellectis: Research Funding; Celgene Corporation: Consultancy; Orsenix: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Bayer: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy; Sandoz: Consultancy; Argenx: Consultancy; Otsuka: Consultancy; Aphivena Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Cellectis: Research Funding. Nazha:MEI: Consultancy. Maciejewski:Apellis Pharmaceuticals: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ra Pharmaceuticals, Inc: Consultancy; Apellis Pharmaceuticals: Consultancy; Ra Pharmaceuticals, Inc: Consultancy; Alexion Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees.

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Expression and in Vitro Binding of Protease Activated Receptor1 (PAR1) with Novel Anti-PAR1 Molecules: Data on Fresh Myeloma Marrow Plasma Cells and Human Myeloma Cell Lines

Blood ◽

10.1182/blood.v126.23.4440.4440 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4440-4440

Author(s):

Meral Beksac ◽

Pinar Ataca ◽

Berna Atesagaoglu ◽

Klara Dalva ◽

Andry Nur Hidayat ◽

...

Keyword(s):

Board Of Directors ◽

Cell Lines ◽

Research Funding ◽

Plasma Cells ◽

Myeloma Cell ◽

Lower Percentage ◽

Advisory Committees ◽

In Silico Docking ◽

Human Myeloma Cell

Abstract Introduction and Aim: Myeloma plasma cells are dependent on stromal support which is mediated through cell adhesion. Heparanase activity has been shown to be associated with aggressive behavior or Bortezomib resistance and can lead to increased levels of proteases as well as shedding of heparan sulfate proteoglycan syndecan-1(CD138) from myeloma cells. We have recently published in vivo anti-myeloma effects of low molecular weight heparin (Beksac et al Acta Haematol 2015). Protease activated Receptor (PAR1) is a thrombin receptor. PAR1 gene and antigen expression on myeloma patient samples and cell lines (HMCL) has been recently reported by University of Arkansas (UAMS) group (Tian et al ASH 2011). They were able to find HMCLs H929, U266, JJN3 to express PAR1. Also expression was found to be highest among patients with 5q amplification where the PAR1 gene is located. Patients and Methods: We analyzed PAR1 expression (WEDE15 PE, Beckman Coulter) by flow cytometry, on CD38+CD138+/-CD27+/- cells obtained from fresh patient bone marrow samples obtained either at diagnosis (n: 84)(NDMM) or relapse (n: 54)(RRMM) and were compared with marrow samples taken from patients without MM (n: 43). Our group in Ankara University had previously synthesized and published novel benzamide and phenyl acetamide derivatives. We performed an in silico docking analysis on these molecules, and eleven (TD10,TD12,TD12A,TD12B,TD13,TD14,TD14B,XT2,XT2B,XT5,XT11) were found to bind to PAR1. These molecules were screened using 72 hour MTT assay on primary and refractory cell lines (U266BR ,U266, JJN3BR, JJN3, H929R, OPM2, OPM2R, KMS28PE). Results: PAR1 expression was highest on platelets followed by myeloma plasma cells (0-81.9%) and did not correlate with ISS. PAR1 expression (Threshold: >2.5 % or >5%) could be detected in NDMM (35 % or 14%) and RRMM (31% or 19%) of patients (Table1). PAR1+CD38+138+ cells were more frequent among patients with lower percentage of plasma cells in RRMM group (2,98 ± 4,5 vs 1,93 ± 3,96, P=0.028) but not NDMM. PAR1 was similarly highly expressed on HCML. Two of the novel PAR1 binding molecules (XT5 and XT2B) were found to have the lowest IC50. The IC50 were similar for all HMCLs, primary and refractory, with XT5. With XT2B the IC50 was less (U266) or higher (JJN3) or similar (OPM2) for refractory compared to the primary HMCL. PAR1 expression and anti-myeloma IC50 values of cell lines are summarized in Table 2. Conclusion: PAR1 expression is detectable at very low or very high percentages on CD138+plasma cells. Expression is higher on cells with CD27 expression (patient samples) or lacking CD27 (HMCL). Inverse correlation between PAR1 expression and plasma cell percentage among myeloma patients is detected among RRMM but not on NDMM samples. This finding may point to expression of PAR1 on quiescent plasma progenitors as suggested by Tian et al previously. The intensity or frequency of PAR1 expression on HMCL did not influence the anti-myeloma effects of these novel molecules. PAR1 binding molecules, in particular XT5, are promising as they are effective even on Bortezomib refractory HCML. However their mechanism of action and the role of PAR1 require further investigations. This study has been supported by a research grant from Turkish Academy of Sciences. Table 1. Frequency of PAR1 expression (> 2.5 %) on total plasma cells (CD38+138+) and on quiescent plasma cells (CD38+138+27+) Control (n=43) NDMM (n=84) RRMM (n=54) P CD38+138+ (%) 0,56± 0,66 4,48 ± 7,67 5,44 ± 12,13 0,007 PAR1+ among CD38+138 (%) 6,18 ± 13,14 4,14 ± 11,00 3,42 ± 8,81 0,394 PAR1+ among CD38+138+27+(%) 5,44 ± 12,13 3,42 ± 8,81 3,58 ± 8,57 0,207 Table 1. Comparison of Flow Cytometric PAR1 expression and IC50 (in uM after 72 hours)of the two novel molecules on three Human Myeloma Cell Lines. H929 RPMI8221 U266 IC50 XT2B 33.9 >100 34.3 IC50 XT5 8.12 5.45 9.77 CD38+138+ (total%) 85 % 75 % 80 % PAR1% and (MFI) within CD38+138+ 83 %(13,6) 90 % (2,1) 85 % (2,1) Disclosures Beksac: Celgene: Consultancy, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: Elotuzumab is an investigational agent being studied for the treatment of multiple myeloma.. Usmani:Millennium: Honoraria, Speakers Bureau; Sanofi: Honoraria, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Array BioPharma: Honoraria, Research Funding; Pharmacyclics: Research Funding; Janssen Oncology: Honoraria, Research Funding. Tian:University of Arkansas for Medical Sciecnes: Employment.

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